African Journal of Rheumatologyaflar.net/wp-content/uploads/2018/01/AJR_1_2013_Jan.pdfthe epidemiology of pyomyositis and osteomyelitis. Osteoarthritis is a universal problem. Juvenile

EDITORIALRheumatology in sub-Saharan Africa: Present and future challenges

McGill P

REVIEW ARTICLE Pulmonary manifestations of rheumatoid arthritis: a reviewBiomdo IC, Oyoo GO

RESEARCH ARTICLES Viscosupplementation in the treatment of osteoarthritis of the knee: Outcome and literature reviewAdelowo OO, Ima-Edomwonyi EU, Oduenyi I

Cardiovascular risk factors in patients with rheumatoid arthritis at Kenyatta National Hospital, Nairobi, KenyaKirui F, Oyoo GO, Ogola EN, Amayo EO

Characteristics of systemic sclerosis patients in Nairobi, Kenya : a retrospective studyIlovi CS, Oyoo GO

Platelet counts in patients with rheumatoid arthritis at the Kenyatta National Hospital, Nairobi, KenyaMbuthia BM, Oyoo GO, Kitonyi GWIncidence of non-steroidal anti-inflamma-tory drugs induced gastric discomfort in patients with knee osteoarthritisOguntona SA

CASE REPORTSInfliximab induced remission in a case of severe Crohns enteropathic arthropathy with pyoderma gangrenosumGhetia TA, Ghetia HA, Kenawy SAAssociation of sarcoidosis and myasthenia gravis: Case reportKaouther BA, Khaoula BA, Sami T, Zakraoui L, Khedher A An atypical case of systemic lupus erythe-matosus presenting as fleeting hemorrhagic pleural effusion with normal complement levelOchieng PO, Abrudescu A

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CONTENTS

Volume 1: January, 2013

Published by The African League of Associations for Rheumatology (AFLAR).

AfricanJournal ofRheumatology

Afr J Rheumatol 2013; 1(1)

EDITORIAL BOARD

RHEUMATOLOGY JOURNAL EDITORIAL BOARD

EDITOR-IN-CHIEF Prof. Asgar ali Kalla (South Africa)

ASSOCIATE EDITORSDr. Omondi Oyoo (Kenya)Prof. Femi Adelowo (Nigeria)

EDITORIAL MANAGERMr. David Ng’ethe (Kenya)

EDITORIAL BOARDDr. Marie Doualla (Cameroon) Dr. Panganani Njobvu (Zambia)Prof. Najia Hajjaj-Hassouni (Morocco)Prof. Ladjouza Rezig Aicha (Algeria)Prof. Tamer A Gheita (Egypt)

EDITORIAL ADVISORSProf. Robert J. Moots (UK)Prof. Tonyn Woolf (UK)Prof. Rohini Handa (India)Prof. Paul Davis (Canada)Prof. Paul MCGill Glascow (Scotland)Dr. Adgwale O. Adebajo (UK)

Afr J Rheumatol 2013; 1(1): 1-21 Afr J Rheumatol 2013; 1(1): 8-121

Rheumatology in sub-Saharan Africa: Present and future challenges

Non-communicable diseases (NCDs) are predicted to become leading causes of morbidity and mortality in developing countries including sub-Saharan Africa1-3. This region has a particularly high double burden of both communicable and NCDs and the least resources to submit an effective challenge. It is bad enough that WHO estimates suggest that age-specific death rates from non-communicable diseases are not only higher in sub-Saharan Africa(sSA) than in high-income countries and overall match the death rates for infectious diseases but this statistic takes no account of the morbidity imposed by these largely chronic disorders. Fostering political will to address this approaching pandemic is essential and the collection of quality data is the tool needed to open the door of opportunity to allow the resource stream to flow where most needed. Competition for sometimes meagre resources will be fierce. If musculoskeletal conditions (MSC) are not to be left to drown in the wake of a surge to cardiovascular disease diabetic and cancer etc. a start must be made now to build on existing data and gather data where none exists. While there is in general a lack of good quality epidemiological data on chronic NCD burden in sub-Saharan Africa the dearth of robust data on MSC/rheumatological conditions is of particular concern. What meagre data there is however points towards MSC at community level matching the morbidity associated with for example cardio-respiratory conditions. In a recent study from Burkino –Faso, 16.2% and 24% respectively of the study population suffered joint pain and backache compared with 17% angina and 11% asthma 3. Evidence from secondary care sources shows rheumatoid arthritis and systemic lupus erythematosus to be increasing in frequency in the indigenous populations of East, Central and Southern Africa. Gout is now more prevalent than ever throughout the subcontinent. HIV has spawned a variety of previously rare spondyloarthropathies (reactive arthritis, psoriatic arthritis, enthesopathy) and changed the epidemiology of pyomyositis and osteomyelitis. Osteoarthritis is a universal problem. Juvenile chronic arthritis is not rare and rheumatic fever is common. Acute and chronic locomotor problems associated with diverse entities such as leprosy, brucellosis, meningococcus, alpha viruses, parasites, fluorosis, rickets and haemoglobinopathies enhance diagnostic diversity and therapeutic and educational requirements5. The challenge posed by this burden of rheumatic disorders in sSA is enormous. The near absence of a rheumatology presence in most countries of the sSA region is a major disadvantage and progress has been erratic to say the least. However where a rheumatology presence is established work towards an improved health system can begin. It is crucial to acquire the data required to formulate policies, practices and funding6-7. The difficulty is getting started and while there is no standard

recipe, crucial to the whole enterprise is the presence of an individual(s) who will, come what may, create the scenario to allow the discipline of musculoskeletal medicine to flourish. A case in point is Kenya. In February 2000 at the invitation of the Kenya Association of Physicians, a medical /nursing team from South Africa and Scotland conducted a series of postgraduate medical and nursing lectures and seminars at the Kenyatta National Hospital and various other hospitals in Nairobi. At that time no formal rheumatology service existed in Kenya and our presence reflected a perceived need and a desire among physicians to see a basic service and teaching capacity established. A major objective of this exercise was to stimulate interest in the speciality and highlight the benefits of a specialist rheumatology workforce in the detection and management of musculoskeletal disorders. The first stage, of necessity, required a trained and experienced individual to take the helm and develop a service to match the then high standard of the other medical services in Kenya. Dr. Omondi Oyoo who organised this inaugural course progressed to establish a fledgling rheumatology service and for the past decade he has been remorseless in his endeavours to develop and expand this service nationally for the benefit of Kenyan citizens. He brought the AFLAR congress to Nairobi in 2008 and is using his voice as the current President of AFLAR to direct the attention of the rheumatology world to the problems in the developing world and in particular Africa. His ambition is to establish in Nairobi a centre of rheumatological excellence and so over the past decade a steady stream of rheumatologists from the UK, Canada and the USA have been persuaded to give of their time and expertise to help fulfil this dream. A cadre of young Kenyan physicians are now increasingly attracted to the discipline and if current progress continues there is surely cause for optimism. Other activities vigorously pursued include increasing public awareness by education and research and extending professional training through CME, incorporate rheumatology in the medical school curriculum and develop an outreach programme to take to regional and district hospitals. In March 2012 a team led by Professor Anthony Woolf (UK), took a group of eight regional consultant physicians through a comprehensive musculoskeletal training programme specifically designed to enable them to teach basic musculoskeletal skills and awareness issues to health workers in their respective health district. In July 2012 a Copcord (Community Oriented Programme for the Control of Rheumatic Diseases) ILAR study commenced in Nairobi and its environs supervised by Dr. Etau Ekwom. This is the first Copcord study conducted in sub Saharan Africa.

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Elsewhere, outwith South Africa, evidence of sustained progress has yet to materialise. However this year saw the launching of the Rheumatic Diseases Association of Zambia at a ceremony in Lusaka preceded by a two day CME course attended by a large assembly of doctors nurses and physiotherapists both local and regional. ILAR funding has enabled the paediatric and adult rheumatology services at the University Hospital Lusaka to commence the acquisition of data essential to designing appropriate future service requirements and direct resource acquisition. The next planned activity is to extend CME activity to the regional centres along the lines of the above “ Train The Trainer” programme. So more than a decade down the road where are we? Well the publication of this fi rst edition of African Journal of Rheumatology says it all, a long way forward but a long road to go._________________

Paul MCgill, Department of Rheumatology, Stabhill Hospital, Glasgow G21 3UW, Scotland. Email: [email protected]

References

1. Lins NE, Jones CM, Nilson JR. New frontiers for the sustainable prevention and control of non-communicaable diseases (NCDs): a view from sub-Saharan Africa. Global Health Promot. 2010;17(2suppl): 27-30.

2. Maher D, Sekajugo J, Harries AD, Grosskurth H. Research needs for an improved primary care response to chronic non-communicable diseases in Africa. Trop Med Int Health. 2010; 15 : 176-181.

3. Miszkurka M. Haddad S. Langlois EV. Freeman EE. Kouanda S. Zunzunegui MV.

4. Heavy burden of non-communicable diseases at early age and gender disparities in an adult population of Burkina Faso: World Health Survey. BMC Public Health. 2012; 12: 24.

5. Mcgill P, Adebajo A, Njobvu PD, Brooks P. Tropical Rheumatology: Challenge of the future. Brit J Rheum. 1997: 36; 307-309.

6. Adebajo A., Gabriel SE. Addressing musculoskeletal health inequity in Africa. Arthritis care & research. 2010; 62(4):439-41.

7. Adebajo A., McGill P., Tikly M. Tropical rheumatology--a global issue. Rheumatology. 2009; 48(6):599-601.

McGill P, Department of Rheumatology, Stobhill Hospital, Balornock Rd, Glasgow G21 3UW, Scotland. Email: [email protected]

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Adebajo A., McGill P., Tikly M. Tropical rheumatology

McGill P,


Pulmonary manifestations of rheumatoid arthritis: a review

Biomdo IC and Oyoo GO.

Department of Clinical Medicine and Therapeutics, School of Medicine, University of Nairobi, P O Box 19676-00202, Nairobi, Kenya

Corresponding author: Dr. I. C. Biomdo. Email: [email protected]

REVIEW ARTICLE

Abstract

Background: Pulmonary involvement is a frequent and among the most severe extra-articular manifestations of rheumatoid arthritis. Rheumatoid arthritis can aff ect the lung parenchyma, airways and pleura. Pulmonary complications are directly responsible for 10-20% of all mortality in RA patients.Objective: To highlight the common and important manifestations of rheumatoid lung disease and discuss the recent studies on each.Data source: Articles on rheumatoid lung disease, reviews done in the American Thoracic Society and European Respiratory Society, Medscape and Upto date Version 19.3.Data extraction: This was done over a period of 6 months from November 2011 to April 2012.Conclusion: A thorough history and examination for pulmonary symptoms and signs should be performed in all RA patients. When abnormalities are found, further investigations are likely to be required to defi ne the process. Lung function tests can be used as the baseline tests to detect those who will need more expensive and/or invasive investigations such as HRCT, bronchoscopy with bronchoalveolar lavage, and transbronchial or surgical lung biopsy, when indicated.

Key words: Rheumatoid arthritis, Lung diseases, Interstitial, Bronchiolitis

Introduction

Rheumatoid arthritis (RA) is the most commonly encountered connective tissue disease. It is a chronic infl ammatory and systemic disease which mostly affects the synovial joints with a prevalence ranging from 0.5% to 2%1. It is a progressive autoimmune process characterized by

symmetrical erosive synovitis. Although the central pathology of RA develops within the synovium of diarthrodial joints, many nonarticular organs become involved, particularly in patients with severe joint disease. The female to male ratio of RA is 2.5:1 most frequently seen in the 25-55 year age group. The prevalence of widely disseminated lesions in other regions of the body has been highlighted with clinical observation and studies, thus pointing out the systemic nature of the disease. The strongest predictors of premature mortality appear to be the presence of RA-related complications and associated co morbidities, specifi cally, cardiovascular disease and pulmonary disease2. In recent cohort studies, nearly 40% of patients with RA suffered from some type of extra-articular manifestations 2-4. Pulmonary involvement is a frequent and among the most severe extra-articular manifestation of RA5. It is a leading cause of excess death in patients with RA6 and might be the second cause of death in this patient population7. RA pulmonary complications are directly responsible for 10 to 20% of all mortality 8-10. When compared with control populations, patients with RA and with a respiratory disease have an estimated standardized

mortality ratio that ranges from 2.5 to 5.06,9. The majority of lung disease occurs within the fi rst 5 years after the initial diagnosis, and may be a presenting manifestation in 9 to 20% of patients. The onset of respiratory manifestation may even precede the onset of symptoms of arthritis. Lung disease directly associated with the underlying RA is more common, even though pulmonary infection and drug toxicity are frequent complications of RA. The lung is involved in rheumatoid disease because of the abundant vasculature and connective tissue which is involved in collagen vascular diseases. RA can affect the lung parenchyma, airways,

Dr IC. Biomdo. Email:[email protected]

, Oyoo GO


and the pleura, with variable amounts of pathological inflammation and fibrosis. The prevalence of a particular complication varies based on: The characteristics of the population studied, the definition of lung disease used and the sensitivity of the clinical investigations employed. However, all studies concur in that a high prevalence of abnormality can be found. Furthermore, while the prevalence of other serious extra-articular manifestations is declining, RA-associated lung disease is increasing10

both pulmonary infection and drug-induced lung disease included11,12.

Pleuropulmonary manifestations of rheumatoid arthritis can be considered under seven categories:1. Pleural disease2. Parenchymal involvement

• Interstitial lung disease• Rheumatoid nodules• Caplans syndrome (rheumatoid pneumoconiosis)

3. Pulmonary airway involvement• Cricoarytenoid arthritis• Bronchiolitis• Bronchiectasis

4. Infections 5. Drug induced disease6. Thoracic cage abnormality7. Vascular involvement

(1) Pleural disease: Pleural involvement is a common, subclinical entity in RA patients. The annual incidence of rheumatoid pleural effusion in the RA population is 0.34 % in women and 1.54 % in men13. The estimated prevalence is approximately 5%. Many pleural effusions are found incidentally on chest radiography. Sequelae of pleurisy (pleural thickening and/or effusion) were found in 24% of men and 16% of women in 309 chest radiographs of RA patients 14,15. Rheumatoid pleuritis can be transient, chronic, or relapsing. It is most common in patients with long-standing RA, middle-aged men with high rheumatic factor titers and rheumatoid nodules. A genetic predisposition to rheumatoid pleurisy has also been reported, with a high prevalence of HLA-B8 and Dw3 associated with rheumatoid pleural effusion16. Patients with large pleural effusion may complain of dyspnea, fever, and pleuritic chest pain. The reported frequency of pleuritic chest pain in RA patients varied from 30 to 50%12. Dyspnea out of proportion to the amount of pleural effusion reflects severe underlying lung pathology that can be found in about one-third of RA patients with pleural disease12. Unresolved rheumatoid effusion may result in marked pleural thickening, trapped lung with progressive restriction of lung volume, necessitating pleural decortication and even lung resection, or occasionally may be complicated by bacterial empyema17,18.Thoracocentesis reveals pleural fluid which is exudative, nonodorous, and usually straw coloured. Glucose levels

are typically low although in acute or recent rheumatoid pleurisy, glucose levels may be normal. PH levels are generally less than 7.3 and reflect ongoing inflammation in the pleural cavity. High LDH levels (above 700IU/L) are considered an indicator of the degree of pleural inflammation and may be useful in monitoring the effects of therapeutic intervention.

2. Parenchymal involvement

2.1 Interstitial lung disease: Interstitial lung disease (ILD) is a frequent manifestation of rheumatoid lung disease and a significant cause of morbidity and mortality in the RA patient population, often asymptomatic 6,19. Estimates of the prevalence of interstitial lung disease (ILD) in RA range between 19% and 44% 19, 20. The reported prevalence of ILD in patients with RA is highly variable and depends on the methods of detection e.g. high-resolution CT [HRCT] scan, chest radiograph, or pulmonary function testing and the population selected for study i.e. symptomatic or asymptomatic, autopsy series. Through chest radiography, the diagnosis of rheumatoid lung disease is made in 1% - 5% of RA patients10. In most cases it may be normal albeit presence of disease. The estimated prevalence of RA-ILD using HRCT is 20–44%20 and is a highly sensitive modality to use although expensive investigation in resource limited centres. It has been shown that 40% of patients may have restrictive abnormalities when pulmonary function tests (PFTS) - Spirometry and reduction in CO diffusion capacity (DLCO) when used as diagnostic measures20. Asymptomatic ILD often precedes the articular manifestations of RA by months or years. ILD typically becomes symptomatic late in its course when fibrosis is present. Presentation is more common at 50 to 60 years of age, in men, and in association with seropositive and erosive joint disease 21.Pathogenesis: Clinical, genetic, and environmental factors have been used to predict the development of lung disease in RA. In contrast to most connective tissue diseases, RA-ILD is three times more common in males than in females, in individuals with late-onset disease, high titre rheumatoid factor and in smokers 22, 23. High-titre rheumatoid factor (RF) has been associated with the presence of RA-ILD 24 and decreased diffusion capacity for carbon monoxide (DLCO)25,26. One hypothesis for the development of lung fibrosis in RA is that a cellular inflammatory process is required for and initiates a secondary fibro proliferative process, and that the fibro proliferative process may become progressive and independent of its initiating cause. A similar paradigm has been hypothesized in patients

with hypersensitivity pneumonitis. In these patients, reversible granulomatous inflammation is generally seen. However, once the fibro proliferative process begins, the clinical course and gene expression profile become similar to those of idiopathic interstitial fibrosis (IPF), the prototypical fibrosing lung disease, and the disease becomes unresponsive to immunosuppression27,28.

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Pathology: A wide variety of histopathology features have been observed in RA, not only various types of interstitial pneumonia, but also airway diseases with frequent overlap between different patterns of interstitial pneumonia in the same patient, making the pathological diagnosis more complicated29, 30. These disorders affect not only the interstitium (space between endothelial and epithelial basement membranes) but also the adjacent airspaces, the peripheral airways, and the vessels. Currently available data show that among RA-ILD patients, there is a higher proportion of a patient with usual interstitial pneumonia (UIP) pattern compared to patients with other connective tissue diseases. Lee et al.31 found UIP to be the most common histopathology pattern in RA-ILD patients (56%). This was followed by non-specific interstitial pneumonia (NSIP)-(33%) and organizing pneumonia (11%). Flaherty et al32 demonstrated that patients with collagen vascular disease-associated UIP pattern had fewer fibroblastic foci and better survival compared to patients with the idiopathic type, which may be related to better prognosis of UIP associated with collagen vascular diseases. RA patients with NSIP tend to be women and nonsmokers. Lymphocytic interstitial pneumonia (LIP) usually occurs when RA is complicated by Sjögren’s syndrome31.

Diagnosis: The diagnosis of RA-ILD is generally based on the combination of clinical presentation, pulmonary function testing, HRCT, and in some cases, lung biopsy34. A careful exposure history (including occupational, environmental and pharmaceutical) should be conducted to evaluate potential alternative causes. Pulmonary function tests frequently demonstrate reduced lung volumes and Diffusion Capacity of Carbon monoxide (DLCO) even in the absence of symptoms20. Reduced DLCO was suggested to be the most sensitive marker for interstitial pneumonia on HRCT34. Progressive dyspnea as measured by a standardized questionnaire is a strong predictor of shortened survival35. The declining size of the lung as measured by plain chest radiographic study36 as well as the extent of disease seen on HRCT37

are powerful predictors of disease. Serial changes in pulmonary physiology with declines in forced vital capacity 38 - 40 can be used both in detection, prediction and follow up tool of disease progression. These changes over time are stronger prognostic markers than baseline measures41.

Treatment: In general, more aggressive treatment is justified in patients with evidence of inflammation on HRCT, lymphocytes on bronchoalveolar lavage, or a non-UIP pattern on biopsy. Glucocorticoid therapy is the treatment of choice with variable subjective and objective improvement in the treatment of RA-ILD26,33, 42. Other drugs reported to be beneficial include cyclophosphamide, azathioprine, hydroxychloroquine, D-penicillamine, and cyclosporine44,

45. Effective treatment of the joint disease should not be used as a surrogate for beneficial or even adequate

treatment of the ILD. Just as clinically important diffuse lung disease can precede the development of active joint disease in RA, progressive ILD can occur despite

the absence of synovitis33. This strongly argues for continued regular pulmonary follow-up of known lung disease in patients with even excellent control of their joint disease as well as early pulmonary referral when respiratory symptoms develop or progress in patients with RA, regardless of the activity of their joint disease. Despite the absence of effective treatments for advanced respiratory disease it is possible that therapeutic intervention at an early stage may be beneficial. It has been suggested that early diagnosis and treatment with antifibrotic agents may alter the prognosis of pulmonary fibrosis 33.

2.2 Rheumatoid nodules

Rheumatoid nodulosis is considered a benign variant of rheumatoid arthritis and is the only pulmonary manifestation specific for the disease. They are more common in men than in women and are usually asymptomatic unless cavitated. They usually present more of a diagnostic than a therapeutic challenge because malignancy has to be ruled out through biopsy. Rheumatoid lung nodules are detected on chest radiograph in about 0.2% of unselected patients with RA12 and more frequently on HRCT (4%)45. In chest radiographs they are usually multiple or solitary, well circumscribed masses ranging from a few millimeters to 7cm in diameter. They are located in sub pleural areas or in association with interlobular septa. Histologically, the pulmonary nodules are similar to nodules at other sites, with central necrosis, palisading epithelioid cells, a mononuclear cell infiltrate, and associated vasculitis. The clinical course of pulmonary nodules is variable. The nodules may precede the clinical manifestation of RA or be concurrent. They may increase in size, resolve spontaneously, or appear at new sites as older nodules resolve46. Complications may include pleural effusion, pneumothorax, hemoptysis and infection.

2.3 Rheumatoid pneumoconiosis (Caplan’s syndrome)

Caplan in 1953, defined rheumatoid pneumoconiosis as characterized by rounded, peripheral pulmonary radiological images, 0.5–5.0cm in diameter, with or without small opacities, consistent with pneumoconiosis or massive pulmonary fibrosis, found in patients with RA who were exposed to mineral, coal, or silica dust. The prevalence of this entity among patients with pneumoconiosis is low. Caplan found a prevalence of 0.4% and, more recently, Honma and Vallyathan showed that the incidence was 0.75% in Japan and 1.5% in the USA 47. Although the syndrome was originally described in coal miners, several cases have since been diagnosed in individuals exposed to free silica or asbestos.

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Histologically, the findings are similar to those with simple rheumatoid nodules, except that the nodules in Caplan’s syndrome are surrounded by pigmented cells. There is no effective treatment for Caplan’s syndrome, but the prognosis is good.

3.0 Pulmonary airway involvement

Rheumatoid arthritis is known to cause both upper and lower airway disease. Cricoarytenoid arthritis and bronchiectasis are the major manifestations of large airways involvement. Major manifestations of small airway disease encompass bronchiolitis; follicular bronchiolitis, constrictive bronchiolitis/obliterative bronchiolitis, fibrosing alveolitis and panbrochiolitis.

3.1 Cricoarytenoid arthritis The cricoarytenoid joints are small diarthrodial joints that rotate with the vocal cords as they abduct and adduct to vary the pitch and tone of the voice. Though not disabling, the cricoarytenoid joints may become inflamed and immobilized with the vocal cords adducted to midline, causing inspiratory stridor and upper airway obstruction. Upper airway involvement is more common in women and in patients with long-standing RA. Jurik and Pedersen48 found arthritis of the cricoarytenoid joints in 55% of 150 patients with RA. The incidence was higher in females (65%) than in males (20%). When HRCT and fiber optic laryngoscopy were used, cricoarytenoid abnormalities were seen in up to 75% of the patients although symptoms were reported in only about half this number 49.

3.2 Bronchiolitis

Bronchiolitis is a generic term that encompasses a group of diseases with diverse etiologies. In general, it indicates the presence of inflammation in the small airways, which by definition measure less than 2mm in diameter. These include bronchiolar diseases such as follicular bronchiolitis and constrictive bronchiolitis (also called bronchiolitis obliterans). These diseases are usually seen in patients with positive rheumatoid factor and active joint disease. The symptoms are characterized by dyspnea and nonproductive cough. Although chest radiograph is generally normal, computed tomography may show areas of air trapping, small nodular opacities in centrilobular distribution (follicular bronchiolitis and bronchiolitis obliterans), patchy areas of low attenuation (bronchiolitis obliterans), and peribronchial thickening (follicular bronchiolitis and bronchiolitis obliterans). Pulmonary function tests reveals airflow obstruction with normal DLco.

Follicular bronchiolitis: In RA, follicular bronchiolitis represents lymphoid hyperplasia in response to an extrinsic immune stimulus or altered systemic immune response, situated in the walls of the bronchioles and,

to some extent, in larger bronchi. Although in the past lymphocytic bronchiolitis was thought to be rare and there are only few series and case reports in the literature, Tansey et al50 and Rangel-Moreno et al51 showed that in biopsies from patients with RA, most patients had follicular bronchiolitis as the main pattern of pulmonary disease, or as a finding occurring with another form of RA-associated pulmonary disease .

Constrictive bronchiolitis or obliterative bronchiolitis: Constrictive bronchiolitis (CB) or obliterative bronchiolitis (OB) is a rare, usually fatal, condition characterized by progressive concentric narrowing of membranous bronchioles 52. Although Geddes et al.53 first reported CB with RA in 1977 only a few years later, it became clear that the disease was related to RA. Patients typically present with the rapid onset of dyspnea and dry cough. The rapidity of onset and severity of symptoms are out of keeping with most other forms of lung disease and should lead to suspicion of the diagnosis. The prognosis and response to therapy are poor. Although no therapy has proven consistently effective, a trial of high dose glucocorticoids (e.g., prednisolone 1–1.5mg/kg per day) is warranted. The reported prevalence of obstructive dysfunction in small airways in RA patients, estimated on the basis of decreases in FEF 25-75 values, varies among studies, ranging from 8% to 65%. This variation may be explained by the different criteria used in different studies to assess small-airway disease as well as by variation in the patient populations examined. Shunsuke et al54 in Japan obtained evidence suggesting that obstructive dysfunction of small airways is common among 155 RA patients, even among those without a diagnosis of interstitial pneumonia or bronchiolitis pattern on HRCT. Prevalence of obstructive small-airway disease in RA patients without the IP or bronchiolitis HRCT pattern was 30.3%. In Africa, a study done by Amir et al 55on Egyptian patients with rheumatoid arthritis (non smokers) revealed that out of the 36 patients studied 23 (64%) demonstrated abnormalities in PFTs and 47% in HRCT. Mixed restrictive and obstructive pattern was the commonest and reported in nearly 31%. ILD was the commonest pulmonary affection detected by HRCT at 39%.

Pathogenesis: The reason for the high incidence of small-airway obstruction in RA patients remains unclear. One of the most attractive explanations is that the obstructive changes are due to frequent and recurrent infections in the small airways53. Colonization of the small airways by pathogenic microorganisms has been reported in patients with clinically stable bronchiectasis55,56 the evidence indicates that RA patients may have an increased susceptibility to airway infections or a reduced ability to eradicate these infections. Chronic colonization, secondary persistent inflamma-tion, and progressive lung injury may contribute to the frequent development of airway obstruction during the disease course. As an alternative explanation, several stud-

Afr J Rheumatol 2013; 1(1): 8-1221

ies have proposed that bronchi/bronchioles are one of the main targets of autoimmunity in RA patients. Bronchiolar inflammation may secondarily induce mucosal edema, which eventually leads to development of small-airway obstruction 57 58. Such pulmonary lesions may create a favorable environment for persistent infections. It is uncertain whether microbial colonization may precede bronchiolar obstructive changes or not. Regardless of which came first, a vicious spiral of infections and obstructive changes in the small airways can develop in the lungs of RA patients.

Diagnosis: The diagnosis of RA-associated pulmonary disease should be supported by clinical features (signs, symptoms and laboratory tests), abnormal pulmonary function tests, and either a compatible computed tomography or a lung biopsy59. Pulmonary function testing (PFT) has proved valuable in detection of RA-associated lung disease. High resolution computed tomography (HRCT) has been widely used and is highly sensitive for detecting the presence of interstitial lung disease (ILD), with variable incidence of reported abnormalities may reach up to 80% of the patients in some studies34.

The precise characterization of obstructive changes in small airways that is enabled by both PFT and HRCT appears to be helpful in evaluating not only their long-term significance as pulmonary complications of RA but also their implication in RA pathogenesis.

3.3 Brochiectasis

An association between bronchiectasis and RA has been noted and bronchiectasis may result from recurrent infections, retraction in interstitial lung diseases-traction bronchiectasis, or the progression of lymphocytic/constrictive bronchiolitis60.Walker et al 12 has shown that patients with RA are more prone to respiratory tract infections than patients with osteoarthrosis, and bronchiectasis is also more common The prevalence of bronchiectasis in HRCT among RA patients is 16.6– 58% 61 62.

4.0 Infections

Patients with RA have been shown to have an increased risk of infections compared with the general population, even after adjustment for age, sex, smoking status, leukopenia, corticosteroid use, and diabetes mellitus 63 64. Several treatment modalities for RA may induce infections, including corticosteroids, disease-modifying agents (DMARDS),TNF antagonist, and new biotherapies. Opportunistic infections may also appear. Pneumonia is a major cause of mortality in patients with RA and is probably the most common respiratory cause of death9. The relative risk for pneumonia and lower respiratory tract infections is 1.68 and 1.88 respectively 64. Wolfe et al. reported an incidence density of pneumonia of 17 per 1000 patient-years. They found

a dose-related relationship between prednisone use and pneumonia risk in RA patients, and no increase in risk for anti-TNF therapy or methotrexate use. Treatment of RA and other autoimmune disorders with anti-TNF agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis 65 66. The rate of TB in patients with RA treated with anti-TNF therapy is three to four times higher in patients receiving infliximab and adalimumab than in those receiving etanercept 65. Geddes et al 53 attributed the high prevalence of obstructive airway disease in RA patients may be due to frequent respiratory tract infections.

5.0 Drug-induced lung disease

Several of the medications used to treat RA can be associated with lung injury. The incidence of pulmonary toxicity in patients treated with methotrexate for RA is 1–5% 66. There appears to be no relationship between the occurrence of pulmonary toxicity and cumulative dosage. Toxicity is rare with doses less than 20 mg per week, although more recent studies have reported that methotrexate pneumonitis occurs with a dose of 5 mg per week67.

Methotrexate: MTX lung injury is most often a subacute process, in which symptoms are present for several weeks before diagnosis. Approximately 50% of cases are diagnosed within 32 weeks of initiation of MTX treatment 68. Predominant clinical features of MTX lung injury include shortness of breath, cough, and fever 68.

Hypoxemia and a restrictive pattern on pulmonary function testing are observed. Chest X-rays and CT demonstrate diffuse infiltrates. In 70% of cases, HRCT demonstrates diffuse homogeneous ground-glass opacity (GGO) with sharp demarcation by interlobular septa-type A GGO 69. Methotrexate should be temporarily stopped in any patient with RA on MTX therapy who complains on nonproductive cough and dyspnea, without evidence of upper respiratory infection. In patients with new evidence for interstitial lung disease, it should be stopped permanently. Earlier recognition and drug withdrawal may avoid the serious and sometimes fatal outcomes that have been observed 70. Patients generally respond to withdrawal of methotrexate and the prognosis is usually good. Uncontrolled studies suggest that glucocorticoids can hasten recovery and may be important for severely ill patients.

Leflunomide: Interstitial pneumonia as an adverse reaction of leflunomide is rare. The incidence of such cases is reported to be 0.02% in Western countries71. In Japan in 2003, 16 cases (0.48%) of ILD, including five fatal cases (0.15%), were associated with leflunomide therapy among 3360 registered patients72. Leflunomide has been reported to induce interstitial lung disease and cases of new or accelerated pulmonary nodule formation, which stabilized after cessation of the drug 8.






3.2 Bronchiolitis






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3.3 Brochiectasis


4.0 Infections








59

60,61

Walker and Wright12 has shown that patients with RA are more

62,63

63 Wolfe et al 64.

Afr J Rheumatol 2013; 1(1): 8-12 20





3.2 Bronchiolitis






Afr J Rheumatol 2013; 1(1): 8-1221




3.3 Brochiectasis


4.0 Infections









6.0 Thoracic cage abnormality

Abnormalities of thoracic cage mobility can be present in RA and is associated with pleurisy, myopathy, and thoracic rigidity. Restrictive patterns with reduced lung volumes with a low or normal DLCO and a high DLCO/VA have been reported 9.

7.0 Vascular involvement

Vascular inflammation is considered the primary event in the formation of rheumatoid nodules. During nodule formation, small-vessel vasculitis leads to fibrinoid necrosis that forms the core of the lesion, surrounded by fibroblastic proliferation. However, primary vasculitic involvement of the lung is uncommon and must be distinguished from interstitial lung disease that is not vasculitic in nature.

Conclusion

A thorough history and examination for pulmonary symptoms and signs should be performed in all RA patients. When abnormalities are found, further investigations are likely to be required to define the process. Lung function tests can be used as the baseline tests to detect those who will need more expensive and/or invasive investigations such as HRCT, bronchoscopy with bronchoalveolar lavage, and transbronchial or surgical lung biopsy, when indicated.

References

1. Gabriel SE, Crowson CS, Kremers HM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003; 48:54–58.

2. Turesson C, Jacobsson L, Crowson CS. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003; 62:722–727.

3. Carmona L, Gonzalez-Alvaro I, Balsa A, Angel Belmonte M, Tena X, Sanmarti R. Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity. Ann Rheum Dis. 2003;62:897–900.

4. Cimmino MA, Salvarani C, Macchioni P, Montecucco C, Fossaluzza V, Mascia MT, et al. Extra-articular manifestations in 587 Italian patients with rheumatoid arthritis. Rheumatol Int. 2000;19:213–217.

5. Liote´ H. Pulmonary manifestation of rheumatoid arthritis. Rev Mal Respir. 2008; 25(8):973–988.

6. Young A, Koduri G, Batley M, Kulinskaya E, Gough A, Norton S, Dixey J, Early Rheumatoid Arthritis Study (ERAS) group. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford). 2007; 46:350–357.

7. Cortet B, Perez T, Roux N, Flipo RM, Duquesnoy B, Delcambre B, Re´my-Jardin M. Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis. 1997; 56(10):596–600.

8. Minaur N.J., Jacoby R.K., Cosh J.A., Taylor G., Rasker J.J. Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity, and mortality J Rheumatol Suppl. 2004 ; 69:3-8.

9. Sihvonen S., Korpela M., Laippala P., Mustonen J., Pasternack A. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol. 2004; 33: 221-227.

10. Bartels C.M., Bell C.L., Shinki K., Rosenthal A., Bridges A.J. Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years. Rheumatology (Oxford). 2010; 49 (9): 1670-1675.

11. Frank, S.I., J.G. Weg, L.E Harkleroas, and R.F Fitch. Pulmonary dysfunction in rheumatoid arthritis. Chest. 1973; 63: 27-34.

12. Walker W.C., Wright V. Pulmonary lesions and rheumatoid arthritis. Medicine (Baltimore). 1968: 501-502.

13. Highland K.B., Heffner J.E. Pleural effusion in interstitial lung disease Curr Opin Pulm Med. 2004;10: 390-396.

14. Juric AG, Davidsen D, Graudal H. Prevalence of pulmonary involvement in rheumatoid arthritis and its relationship to some characteristics of the patients. A radiological and clinical study. Scand J Rheumatol. 1982; 11:217-224.

15. Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis Am Rev Respir Dis. 1985; 131: 770-777.

16. Hakala M., Tiilikainen A., Hameenkorpi R., Ilonen J., Jalava S., Ruuska P., et al. Rheumatoid arthritis with pleural effusion includes a subgroup with autoimmune features and HLA-B8, Dw3 association. Scand J Rheumatol. 1986; 15: 290-296.

17. Yarbrough J.W., Sealy W.C., Miller J.A. Thoracic surgical problems associated with rheumatoid arthritis. J Thorac Cardiovasc Surg. 1975; 69: 347-354.

18. Carroll GJ, Thomas R, Phatours CC, et al. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J Rheumatol . 1994; 21:51–54.

19. Tanoue LT. Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med. 1998; 19:667.

20. Mohd Noor, MS, Mohd Shahrir MS, Shahid R, Abdul Manap AM, Shahizon A, Azhar SS. Clinical and high resolution computed tomography characteristics of patients with rheumatoid arthritis lung disease. Int J Rheum Dis. 2009; 12(2): 136–144.

21. Castagnaro A, Chetta A, Marangio E, Zompatori M, Olivieri D. The lung in immune-mediated disorder: rheumatoid arthritis. Curr Drug Targets Inflamm Allergy. 2004;3(4):449-554.

Afr J Rheumatol 2013; 1(1): 8-1223

22. Freemer MM, King JrTE Jr. Connective tissue disease. In: King Jr TE, Schwarz MI, editors. Interstitial lung disease. 4th ed. Hamilton, ON, Canada: Decker; 2003. p. 536

23. Manfredsdottir VF, Vikingsdottir T, Jonsson T, Geirsson AJ, Kjartansson O. et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford) 2006 ; 45 : 734-737.

24. Masdottir B, Jonsson T, Manfredsdottir V, Vikingsson A, Brekkan A, Valdimarsson H. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis Rheumatology (Oxford). 2000; 39: 1202-1205.

25. Sakaida H. IgG rheumatoid factor in rheumatoid arthritis with interstitial lung disease Ryumachi. 1995; 35: 671-677[Japanese]

26. Luukkainen R, Saltyshev M, Pakkasela R, Nordqvist E, Huhtala H, Hakala M. Relationship of rheumatoid factor to lung diffusion capacity in smoking and non-smoking patients with rheumatoid arthritis Scand J Rheumatol. 1995; 24: 119-120.

27. Selman M, Pardo A, Barrera L, Estrada A, Watson SR. et al. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2006;173:188–198.

28. Vourlekis JS, Schwarz MI, Cherniack RM, Curran-Everett D, Cool CD. et al. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med. 2004;116:662–668.


30. Tansey D, Wells AU, Colby TV, Ip S, Nikolakoupolou A, du Bois RM., et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis Histopathology. 2004; 44 (6): 585-596.

31. Lee HK, Kim DS, Yoo B, Seo JB, Rho JY, Colby TV. et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005 ; 127 : 2019-2027.

32. Flaherty KR, Colby TV, Travis WD, Toews GB, Mumford J. et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003; 167: 1410-1415.

33. Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM. et al. Interstitial lung disease guideline: The British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008; 63 (Suppl. 5): v1-v58.

34. Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax. 2001; 56 : 622-627.

35. Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168: 538–542.

36. Kawabata H, Nagai S, Hayashi M, Nakamura H, Nagao T, Shigematsu M, Kitaichi M, Izumi T. Significance of lung shrinkage on CXR as a prognostic factor in patients with idiopathic pulmonary fibrosis. Respirology. 2003;8:351–358.

37. Lynch DA, David Godwin J, Safrin S, Starko KM, Hormel P. et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172:488–493.

38. Martinez F, Safrin S, Weycker D, Starko KM, Bradford WZ. et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–967.

39. Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH. et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia.

40. Martinez F, Safrin S, Weycker D, Starko KM, Bradford WZ, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–967.

41. Latsi PI, Du Bois RM, Nicholson AG, Colby TV, Bisirtzoglou D. et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med. 2003;5:5.

42. Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI. Fishman’s pulmonary diseases and disorders. 4th ed. Columbus, OH: The McGraw–Hill Companies 2008

43. Nanki N., Fujita J., Yamaji Y., Maeda H., Kurose T., Kaji M., et al. Nonspecific interstitial pneumonia/fibrosis completely recovered by adding cyclophosphamide to corticosteroids.

44. Chang H.K., Park W., Ryu D.S. Successful treatment of progressive rheumatoid interstitial lung disease with cyclosporine: a case report. J Korean Med Sci. 2002 ; 17(2) : 270-273.

45. Anaya JM, Diethelm L, Ortiz LA, et al. Pulmonary involvement in rheumatoid arthritis. Semin Arthritis Rheum. 1995; 24:242–254.

46. Honma K, Vallyathan V. Rheumatoid pneumoconiosis. A comparative study of autopsy cases between Japan and North America. Ann Occup Hyg. 2002; 46 (Suppl. 1) : 265-267.

47. Freemer MM, King JrTE Jr. Connective tissue disease. In: King Jr TE, Schwarz MI, editors. Interstitial lung disease. 4th ed. Hamilton, ON, Canada: Decker; 2003. p. 536.

48. Jurik AG, Pedersen U. Rheumatoid arthritis of the crico-arytenoid and crico-thyroid joints: a radiological and clinical study. Clin Radiol. 1984; 35(3) : 233-236.

1968; 3

2004;

3


6.0 Thoracic cage abnormality

Abnormalities of thoracic cage mobility can be present in RA and is associated with pleurisy, myopathy, and thoracic rigidity. Restrictive patterns with reduced lung volumes with a low or normal DLCO and a high DLCO/VA have been reported 9.

7.0 Vascular involvement

Vascular inflammation is considered the primary event in the formation of rheumatoid nodules. During nodule formation, small-vessel vasculitis leads to fibrinoid necrosis that forms the core of the lesion, surrounded by fibroblastic proliferation. However, primary vasculitic involvement of the lung is uncommon and must be distinguished from interstitial lung disease that is not vasculitic in nature.

Conclusion

A thorough history and examination for pulmonary symptoms and signs should be performed in all RA patients. When abnormalities are found, further investigations are likely to be required to define the process. Lung function tests can be used as the baseline tests to detect those who will need more expensive and/or invasive investigations such as HRCT, bronchoscopy with bronchoalveolar lavage, and transbronchial or surgical lung biopsy, when indicated.

References

1. Gabriel SE, Crowson CS, Kremers HM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003; 48:54–58.

2. Turesson C, Jacobsson L, Crowson CS. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003; 62:722–727.

3. Carmona L, Gonzalez-Alvaro I, Balsa A, Angel Belmonte M, Tena X, Sanmarti R. Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity. Ann Rheum Dis. 2003;62:897–900.

4. Cimmino MA, Salvarani C, Macchioni P, Montecucco C, Fossaluzza V, Mascia MT, et al. Extra-articular manifestations in 587 Italian patients with rheumatoid arthritis. Rheumatol Int. 2000;19:213–217.

5. Liote´ H. Pulmonary manifestation of rheumatoid arthritis. Rev Mal Respir. 2008; 25(8):973–988.

6. Young A, Koduri G, Batley M, Kulinskaya E, Gough A, Norton S, Dixey J, Early Rheumatoid Arthritis Study (ERAS) group. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford). 2007; 46:350–357.

7. Cortet B, Perez T, Roux N, Flipo RM, Duquesnoy B, Delcambre B, Re´my-Jardin M. Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis. 1997; 56(10):596–600.

8. Minaur N.J., Jacoby R.K., Cosh J.A., Taylor G., Rasker J.J. Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity, and mortality J Rheumatol Suppl. 2004 ; 69:3-8.

9. Sihvonen S., Korpela M., Laippala P., Mustonen J., Pasternack A. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol. 2004; 33: 221-227.

10. Bartels C.M., Bell C.L., Shinki K., Rosenthal A., Bridges A.J. Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years. Rheumatology (Oxford). 2010; 49 (9): 1670-1675.

11. Frank, S.I., J.G. Weg, L.E Harkleroas, and R.F Fitch. Pulmonary dysfunction in rheumatoid arthritis. Chest. 1973; 63: 27-34.

12. Walker W.C., Wright V. Pulmonary lesions and rheumatoid arthritis. Medicine (Baltimore). 1968: 501-502.

13. Highland K.B., Heffner J.E. Pleural effusion in interstitial lung disease Curr Opin Pulm Med. 2004;10: 390-396.

14. Juric AG, Davidsen D, Graudal H. Prevalence of pulmonary involvement in rheumatoid arthritis and its relationship to some characteristics of the patients. A radiological and clinical study. Scand J Rheumatol. 1982; 11:217-224.


16. Hakala M., Tiilikainen A., Hameenkorpi R., Ilonen J., Jalava S., Ruuska P., et al. Rheumatoid arthritis with pleural effusion includes a subgroup with autoimmune features and HLA-B8, Dw3 association. Scand J Rheumatol. 1986; 15: 290-296.

17. Yarbrough J.W., Sealy W.C., Miller J.A. Thoracic surgical problems associated with rheumatoid arthritis. J Thorac Cardiovasc Surg. 1975; 69: 347-354.

18. Carroll GJ, Thomas R, Phatours CC, et al. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J Rheumatol . 1994; 21:51–54.

19. Tanoue LT. Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med. 1998; 19:667.

20. Mohd Noor, MS, Mohd Shahrir MS, Shahid R, Abdul Manap AM, Shahizon A, Azhar SS. Clinical and high resolution computed tomography characteristics of patients with rheumatoid arthritis lung disease. Int J Rheum Dis. 2009; 12(2): 136–144.

21. Castagnaro A, Chetta A, Marangio E, Zompatori M, Olivieri D. The lung in immune-mediated disorder: rheumatoid arthritis. Curr Drug Targets Inflamm Allergy. 2004;3(4):449-554.

Afr J Rheumatol 2013; 1(1): 8-1223

22. Freemer MM, King JrTE Jr. Connective tissue disease. In: King Jr TE, Schwarz MI, editors. Interstitial lung disease. 4th ed. Hamilton, ON, Canada: Decker; 2003. p. 536

23. Manfredsdottir VF, Vikingsdottir T, Jonsson T, Geirsson AJ, Kjartansson O. et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford) 2006 ; 45 : 734-737.

24. Masdottir B, Jonsson T, Manfredsdottir V, Vikingsson A, Brekkan A, Valdimarsson H. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis Rheumatology (Oxford). 2000; 39: 1202-1205.

25. Sakaida H. IgG rheumatoid factor in rheumatoid arthritis with interstitial lung disease Ryumachi. 1995; 35: 671-677[Japanese]

26. Luukkainen R, Saltyshev M, Pakkasela R, Nordqvist E, Huhtala H, Hakala M. Relationship of rheumatoid factor to lung diffusion capacity in smoking and non-smoking patients with rheumatoid arthritis Scand J Rheumatol. 1995; 24: 119-120.

27. Selman M, Pardo A, Barrera L, Estrada A, Watson SR. et al. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2006;173:188–198.

28. Vourlekis JS, Schwarz MI, Cherniack RM, Curran-Everett D, Cool CD. et al. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med. 2004;116:662–668.


30. Tansey D, Wells AU, Colby TV, Ip S, Nikolakoupolou A, du Bois RM., et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis Histopathology. 2004; 44 (6): 585-596.

31. Lee HK, Kim DS, Yoo B, Seo JB, Rho JY, Colby TV. et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005 ; 127 : 2019-2027.

32. Flaherty KR, Colby TV, Travis WD, Toews GB, Mumford J. et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003; 167: 1410-1415.

33. Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM. et al. Interstitial lung disease guideline: The British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008; 63 (Suppl. 5): v1-v58.

34. Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax. 2001; 56 : 622-627.

35. Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168: 538–542.

36. Kawabata H, Nagai S, Hayashi M, Nakamura H, Nagao T, Shigematsu M, Kitaichi M, Izumi T. Significance of lung shrinkage on CXR as a prognostic factor in patients with idiopathic pulmonary fibrosis. Respirology. 2003;8:351–358.

37. Lynch DA, David Godwin J, Safrin S, Starko KM, Hormel P. et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172:488–493.

38. Martinez F, Safrin S, Weycker D, Starko KM, Bradford WZ. et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–967.

39. Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH. et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia.

40. Martinez F, Safrin S, Weycker D, Starko KM, Bradford WZ, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–967.

41. Latsi PI, Du Bois RM, Nicholson AG, Colby TV, Bisirtzoglou D. et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med. 2003;5:5.

42. Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI. Fishman’s pulmonary diseases and disorders. 4th ed. Columbus, OH: The McGraw–Hill Companies 2008

43. Nanki N., Fujita J., Yamaji Y., Maeda H., Kurose T., Kaji M., et al. Nonspecific interstitial pneumonia/fibrosis completely recovered by adding cyclophosphamide to corticosteroids.

44. Chang H.K., Park W., Ryu D.S. Successful treatment of progressive rheumatoid interstitial lung disease with cyclosporine: a case report. J Korean Med Sci. 2002 ; 17(2) : 270-273.

45. Anaya JM, Diethelm L, Ortiz LA, et al. Pulmonary involvement in rheumatoid arthritis. Semin Arthritis Rheum. 1995; 24:242–254.

46. Honma K, Vallyathan V. Rheumatoid pneumoconiosis. A comparative study of autopsy cases between Japan and North America. Ann Occup Hyg. 2002; 46 (Suppl. 1) : 265-267.



35. Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168: 538-542.

36. Kawabata H, Nagai S, Hayashi M, Nakamura H, Nagao T, Shigematsu M, Kitaichi M, Izumi T. Significance oflung shrinkage on CXR as a prognostic factor in patients with idiopathic pulmonary fibrosis. Respirology.2003;8:351-358.

37. Lynch DA, David Godwin J, Safrin S, Starko KM, Hormel P. et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis.Am J Respir Crit Care Med.. 2005;172:488-493.

38. Martinez F, Safrin S, Weycker D, Starko KM, Bradford WZ. et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963-967.

39. Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH. et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit care med 2003; 28:28

40. Martinez F, Safrin S, Weycker D, Starko KM, Bradford WZ, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963-967.

41. Latsi PI, Du Bois RM, Nicholson AG, Colby TV, Bisirtzoglou D. et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am JRespir Crit Care Med. 2003;5:5.

42. Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI. Fishman's pulmonary diseases and disorders. 4th ed. Columbus, OH: The McGraw- Hill Companies 2008

43. Nanki N., Fujita J., Yamaji Y., Maeda H., Kurose T., Kaji M., et al. Nonspecific interstitial pneumonia/fibrosis completely recovered by adding cyclophosphamide to corticosteroids. Inter Med 2002; 41 (10) 867-870

44. Chang H.K., Park W., Ryu D.S. Successful treatment of progressive rheumatoid interstitial lung disease with cyclosporine: a case report. J Korean Med Sci. 2002 ;17(2) : 270-273.

45. Anaya JM, Diethelm L, Ortiz LA, et al. Pulmonary involvement in rheumatoid arthritis. Semin Arthritis Rheum. 1995; 24:242-254.

46. Honma K, VallyathanV. Rheumatoidpneumoconiosis. A comparative study of autopsy cases between Japan and North America. Ann Occup Hyg. 2002; 46 (Suppl. 1) : 265-267.



Am J Respir Crit Care Med. 2003; 28:28

J Respir

Inter Med. 2002; 41 (10): 867-870.

Nanki N, Fujita J, Yamaji Y, Maeda H, Kurose T, Kaji M.


Viscosupplementation in the treatment of osteoarthritis of the knee: Outcome and literature reviewAdelowo OO1, Ima-Edomwonyi EU2, Oduenyi I1,3

Afr J Rheumatol 2013; 1(1): Afr J Rheumatol 2013; 1(1): Afr J Rheumatol 2013; 1(1): Afr J Rheumatol 2013; 1(1): Afr J Rheumatol 2013; 1(1): Afr J Rheumatol 2013; 1(1): Afr J Rheumatol 2013; 1(1): 8-12

1Rheumatology Unit, Department of Medicine, Olabisi Onabanjo University Teaching Hospital, Sagamu2Department of Medicine, Lagos University Teaching Hospital, Idi-Araba3Arthrimed Specialist Clinic, Ikeja, Lagos

Corresponding author: Prof. O O Adelowo, P.O. Box 7231, Ikeja, Lagos, NigeriaEmail:[email protected]

RESEARCH ARTICLE

Abstract

Background: Viscosupplementation is a recognised mode of management of osteoarthritis (OA) of the knee, especially in patients who have failed treatment with NSAIDs.Objectives: To review the literature on viscosupplementation as well as assess its e� cacy in Nigerians with OA of the knee.Methods: Patients presenting to a private practice rheumatology clinic with symptomatic and radiographic proven OA of the knee were included, having failed two or more NSAIDs. Intra articular cross linked hyaluronan (synvisc) was given in three consecutive weekly doses. Assessment were by both patients numerical pain score and physicians global pain assessment at six and twelve weeks.Results: There was improvement in both assessments. There were few minor and transient adverse e� ects.Conclusion: Viscosupplementation is both e� cacious and safe in Nigerians with OA knee, as shown elsewhere.

Introduction

Osteoarthritis (OA) is the commonest type of arthritis, especially among the elderly1. It is responsible for considerable clinical and economic burden in the affected. OA is also associated with reduction in quality of life due to pain, as well as decreased mobility and eventual disability. The pathogenetic mechanism of OA is due to the associated progressive loss of the articular cartilage and chondrocytes within the synovial joints. These processes manifest as joint pains and eventual loss of function. An additional pathogenetic factor is the associated reduction in the concentration and molecular weight of the lubricating hyaluronic acid (hyaluronate, hyaluronan) in the synovial fl uid. Such reduction leads to loss of its lubricating

and shock absorbing properties. The reduction in the molecular weight of hyaluronic acid (HA) in arthritic joints has been attributed to its dilution from joint infl ammatory effusions as well as presence of abnormal synoviocytes and molecular fragmentations2-4. Hyaluronan, as the compound sodium hyaluronate, is a highly viscous polysaccharide normally found in extracellular matrix and is a major constituent of synovial fl uid and cartilage4. It belongs to the family of glycosaminoglycan and is composed of 1000’s of repeating disaccharides units (N - acetyl glucosamine and glucuronic acid) to form a long polysaccharide chain of varying length with a high molecular weight of 5 -7 x 106 da. When this molecule is fully hydrated, it occupies a large spheroidal shape4. After synthesis in the joint by the chondrocytes and synoviocytes, HA is released into the synovial ligament and cartilage. Synovial fl uid elastoviscosity is essential for normal joint function. HA has both viscous and elastic properties, depending on the joint loading and conditions. For instance in the presence of slow and low loading, HA exhibits high viscosity with reduced elasticity. On the contrary, with increased high and fast loading, it becomes more elastic, hence acting as a shock absorber5,6. Apart from this viscoelasticity property, other pharmacologic properties have been identifi ed. These include inhibition of infl ammatory mediators, inhibition of phagocytic cell function, stimulation of cartilage matrix synthesis, and decreased degradation of cartilage7-10. On the basis of the foregoing, extrinsic HA is being increasingly used in the management of pain and stiffness for patients presenting with moderate to severe OA of the knee. This is particularly so in patients not responding or unsuitable for Non-Steroidal Anti-Infl ammatory Drugs (NSAIDs). It has been recommended for the control of knee pain by both the

OO

and radiographically proven

Assessment were by both patients’ verbal numeric pain rating scale and physician’s

3


American College of Rheumatology (ACR) as well as the European League Against Rheumatism (EULAR). The recommendations are especially in patients with osteoarthritis of the knee and hip who have failed to respond adequately to other therapies11-14. Although intra-articular HA has been mostly used in OA of the knee, clinical efficacy have also been reported in OA of the hip and shoulder joints. Randomised controlled trials and open trials have shown significant decrease in pain at rest, on movement as well as functional index15-

20. Osteoarthritis of the knee and other joints have been reported among Nigerians21. However there has been no documented report on the use of HA in the management of OA of the knee. The objectives of this study are to assess the efficacy of HA in Nigerian patients presenting with OA of the knee and who have failed two or more NSAIDs; as well as to review the literature.

Materials and Methods

Subjects presenting with moderate to severe knee pain to a private practice rheumatology clinic, located in Lagos, Arthrimed Specialist Clinic, were recruited into the study. These patients were seen between the period January 2009 and July 2011. The patients fulfilled the American College of Rheumatology (ACR) criteria for diagnosis of osteoarthritis of the knee. Such patients were included if they had failed to respond to at least two previous NSAIDs or narcotic analgesics such as codeine based compound and tramadol. Radiographs of both knees were requested and those fulfilling radiographic criteria for OA of the knees were included. Subjects fulfilling criteria for other diagnostic types of arthritis were excluded, even if they showed radiographic features of OA. Standard procedure of arthrocentesis was carried out. Standard cleansing of the site of arthrocentesis was done with savlon and methylated spirit. The skin was infiltrated with lignocaine (2%) at the lateral aspect of the knee, and occasionally the medial aspect. Intra-articular hyaluronan (Synvisc Hylan GF - 20 Genzyme Corporation) was administered in weekly consecutive doses (Days 1, 8, 15). Effusions were aspirated at each visit (when present) before injecting hyaluronan. Patients were seen every two weeks for at least three months and beyond. Assessments were by a) patient’s numerical pain rating on a 10 point scale with zero being ‘no pain’ and 10 being ‘pain as bad as it can be’. b) Physician’s assessment of pain as ‘mild’ - no pain at rest but on severe physical exertion; ‘moderate’ - pain on moderate physical exertion as walking up the staircase; ‘severe’ - pain at rest and disturbing patient’s sleep. Patients were allowed rescue medications such as NSAIDs or Co-Codamol.

Results

A total of fifty patients with radiographic OA of the knees were included in the study having fulfilled the ACR criteria for OA of the knees. The demographic characteristics are as shown in Table 1. Most of the subjects were female and the mean age was 62.8 years. Both knees were involved in 41 patients (82%) while the left knee and right knee involvement were in 5 (10%) and 4 (8%) respectively. The duration of symptoms varied between 8 to 300 months with a mean of 72.9 months. Pain intensity in all patients before viscosupplementation was 8-10 by Patients Numerical Pain score and ‘Moderate’ to ‘Severe’ by the physician’s global pain rating. The patient’s numerical pain rating at six weeks and twelve weeks are as in Tables 2 and 3. Eleven patients were not assessed at 12 weeks as they had defaulted. More than 80% had little or no pain at both times. Physician’s global assessment of pain at onset of trial and subsequently are as shown in Tables 4, 5 & 6.

Table1: Demographic characteristics of 50 OA patients treated with viscosupplementation

Demography Frequency (%)Sex Female MaleFemale:MaleAge (years) Range Mean MedianDuration of symptoms (months) Range Mean

41 (82)9 (18)4.6:1

37 - 8662.866

8 - 30072.9

Table 2: Patients numerical pain score at six weeks after viscosupplementationPain Score Frequency (%)0-34-78-10

42 (84)6 (12)2 (4)

Table 3: Patients numerical pain score in 36 patients at 12 weeks after viscosupplementationPain Score Frequency (%)0-34-78-10

32 (82,1)4 (10.3)3 (7.6)

Afr J Rheumatol 2013; 1(1): 8-12 32

Table 4: Physician’s assessment before viscosupplementation

Physician’s Pain Assessment No. (%)

NoneMildModerateSevere

004 846 92

Table 5: Physician Global pain assessment at 6 weeksPhysician Pain Assessment No. (%)

None Mild Moderate Severe

38 768 163 61 2

Table 6: Physician’s Pain Assessment of at 12 weeks Physician Pain Assessment No. (%)

None MildModerateSevere

29 61.69 23.03 7.73 7.7

Table 7: Adverse effectsAdverse effects No. of

Patients (%)

Post injection enthesopathyJoint effusionLocalised reaction - pruritusFeverHeadache

7 146 12 5 10 3 6 1 2

Discussion

Our study of fifty patients with radiographic OA of the knees has confirmed the usual female preponderance and the occurrence in the middle aged to elderly (Table 1). The patients numerical pain rating was in the range of 8-10 at the onset of the study but at 6 weeks, 84% had virtually no pain (0-3) with another 12% having moderate pain of 4-7, though 4% still had severe pain. The number with virtually no pain (82.1%) remain high at 12 weeks though three of the patients still rated their pain as severe (Tables 2, 3). The number assessed at 12 weeks (39 patients) was however lower consequent to default. There was also improvement in Physician’s global assessment of pain between the baseline of severe pain and at both 6 and 12 weeks with 92% and 84.6% respectively having ‘none’ to ‘mild’ pain (Tables 4-6). It was difficult to follow these patients up beyond this period as the number defaulting

thereafter was high. One can only assume that these patients did not come for further follow up because they were better. Adverse effects were seen in 12 cases, all of them mild. Joint effusions were the commonest, seen in six patients (Table 6) while localized transient pruritus, usually with the first injection was seen in five cases. Fever and headache were also seen. The three subjects who reported fever, one associated with the headache, could most likely have had malaria fever considering that this is endemic in Nigeria. Eleven cases presented with medial knee tendon enthesopathy usually after completion of the course of injections. Such patients, however, improved with intralesional steroid injection or local application of diclofenac. This adverse event (medial knee tendon enthesopathy) has rarely been reported in other studies. It is possible that it was present with the knee arthralgia before viscosupplementation and only came to the fore with the improvement of the knee joint pain. Previous studies have demonstrated the efficacy and safety of intra-articular hyaluronate in the treatment of OA of the knee15-18. There are numerous hyaluronate preparations with different molecular weights available in medical practice. Such preparations are available either as three dose or five dose packs. These preparations include Synvisc (hylan G-F 20 Genzyme); Hyalgan (sodium hyaluronate, Sanofi - Aventis); Supartz (sodium hyaluronate, Smith and Nephew); Euflexxa (sodium hyaluronate Ferring Pharmaceuticals); Orthovisc (high molecular weight hyaluronan Depuyi Mitek). The mode of action of hyaluronate does not seem to depend on the resident time of the compound in the synovial cavity of the knee. Exogenous hyaluronate actually begins to leave the joint within two hours of injection, though Synvisc remains up to 3 days following injection22. On the other hand, Supartz, Euflexxa and Orthovisc remain in the joint less than 24 hours after injection23-25. It has been suggested that the major effect of these agents depends on their ability, among others, to stimulate production of good synovial fluid by synovial cells and not on their resident time in the joints. There have been conflicting reports on the role the molecular weight of hyaluronate plays in its properties of elastoviscosity in the joints. Balazcs and Denlinger5 have suggested that increase in the molecular weight of exogenous hyaluronan increases its elastoviscosity. Other studies have however indicated otherwise 26. Studies comparing the clinical efficacies of various preparations have reached different conclusions. For instance, Wobig and colleagues27 have shown the efficacy of cross-linked hyaluronate (MW 800Kda). Another retrospective study comparing Synvisc (a cross-linked hyaluronate preparation) with hyaluronan (MW 615 Kda) reported statistical improvement in both preparations but also concluded that the former was superior to the latter in many parameters 28. Major constraints in the use of these agents are their cost and availability. A dose of three injections costs about US$700. There are, however, some generics available on the Nigerian market. While they are about five times cheaper than the branded names like Synvisc, there is a dearth of studies on their efficacy and safety and most of

score

score

Afr J Rheumatol 2013; 1(1): 10-14 12Afr J Rheumatol 2013; 1(1): 8-1231

American College of Rheumatology (ACR) as well as the European League Against Rheumatism (EULAR). The recommendations are especially in patients with osteoarthritis of the knee and hip who have failed to respond adequately to other therapies11-14. Although intra-articular HA has been mostly used in OA of the knee, clinical efficacy have also been reported in OA of the hip and shoulder joints. Randomised controlled trials and open trials have shown significant decrease in pain at rest, on movement as well as functional index15-

20. Osteoarthritis of the knee and other joints have been reported among Nigerians21. However there has been no documented report on the use of HA in the management of OA of the knee. The objectives of this study are to assess the efficacy of HA in Nigerian patients presenting with OA of the knee and who have failed two or more NSAIDs; as well as to review the literature.


Subjects presenting with moderate to severe knee pain to a private practice rheumatology clinic, located in Lagos, Arthrimed Specialist Clinic, were recruited into the study. These patients were seen between the period January 2009 and July 2011. The patients fulfilled the American College of Rheumatology (ACR) criteria for diagnosis of osteoarthritis of the knee. Such patients were included if they had failed to respond to at least two previous NSAIDs or narcotic analgesics such as codeine based compound and tramadol. Radiographs of both knees were requested and those fulfilling radiographic criteria for OA of the knees were included. Subjects fulfilling criteria for other diagnostic types of arthritis were excluded, even if they showed radiographic features of OA. Standard procedure of arthrocentesis was carried out. Standard cleansing of the site of arthrocentesis was done with savlon and methylated spirit. The skin was infiltrated with lignocaine (2%) at the lateral aspect of the knee, and occasionally the medial aspect. Intra-articular hyaluronan (Synvisc Hylan GF - 20 Genzyme Corporation) was administered in weekly consecutive doses (Days 1, 8, 15). Effusions were aspirated at each visit (when present) before injecting hyaluronan. Patients were seen every two weeks for at least three months and beyond. Assessments were by a) patient’s numerical pain rating on a 10 point scale with zero being ‘no pain’ and 10 being ‘pain as bad as it can be’. b) Physician’s assessment of pain as ‘mild’ - no pain at rest but on severe physical exertion; ‘moderate’ - pain on moderate physical exertion as walking up the staircase; ‘severe’ - pain at rest and disturbing patient’s sleep. Patients were allowed rescue medications such as NSAIDs or Co-Codamol.

Results

A total of fifty patients with radiographic OA of the knees were included in the study having fulfilled the ACR criteria for OA of the knees. The demographic characteristics are as shown in Table 1. Most of the subjects were female and the mean age was 62.8 years. Both knees were involved in 41 patients (82%) while the left knee and right knee involvement were in 5 (10%) and 4 (8%) respectively. The duration of symptoms varied between 8 to 300 months with a mean of 72.9 months. Pain intensity in all patients before viscosupplementation was 8-10 by Patients Numerical Pain score and ‘Moderate’ to ‘Severe’ by the physician’s global pain rating. The patient’s numerical pain rating at six weeks and twelve weeks are as in Tables 2 and 3. Eleven patients were not assessed at 12 weeks as they had defaulted. More than 80% had little or no pain at both times. Physician’s global assessment of pain at onset of trial and subsequently are as shown in Tables 4, 5 & 6.

Table1: Demographic characteristics of 50 OA patients treated with viscosupplementation

Demography Frequency (%)Sex Female MaleFemale:MaleAge (years) Range Mean MedianDuration of symptoms (months) Range Mean

41 (82)9 (18)4.6:1

37 - 8662.866

8 - 30072.9

Table 2: Patients numerical pain score at six weeks after viscosupplementationPain Score Frequency (%)0-34-78-10

42 (84)6 (12)2 (4)

Table 3: Patients numerical pain score in 36 patients at 12 weeks after viscosupplementationPain Score Frequency (%)0-34-78-10

32 (82,1)4 (10.3)3 (7.6)

Afr J Rheumatol 2013; 1(1): 8-12 32

Table 4: Physician’s assessment before viscosupplementation

Physician’s Pain Assessment No. (%)

NoneMildModerateSevere

004 846 92

Table 5: Physician Global pain assessment at 6 weeksPhysician Pain Assessment No. (%)

None Mild Moderate Severe

38 768 163 61 2

Table 6: Physician’s Pain Assessment of at 12 weeks Physician Pain Assessment No. (%)

None MildModerateSevere

29 61.69 23.03 7.73 7.7

Table 7: Adverse effectsAdverse effects No. of

Patients (%)

Post injection enthesopathyJoint effusionLocalised reaction - pruritusFeverHeadache

7 146 12 5 10 3 6 1 2

Discussion

Our study of fifty patients with radiographic OA of the knees has confirmed the usual female preponderance and the occurrence in the middle aged to elderly (Table 1). The patients numerical pain rating was in the range of 8-10 at the onset of the study but at 6 weeks, 84% had virtually no pain (0-3) with another 12% having moderate pain of 4-7, though 4% still had severe pain. The number with virtually no pain (82.1%) remain high at 12 weeks though three of the patients still rated their pain as severe (Tables 2, 3). The number assessed at 12 weeks (39 patients) was however lower consequent to default. There was also improvement in Physician’s global assessment of pain between the baseline of severe pain and at both 6 and 12 weeks with 92% and 84.6% respectively having ‘none’ to ‘mild’ pain (Tables 4-6). It was difficult to follow these patients up beyond this period as the number defaulting

thereafter was high. One can only assume that these patients did not come for further follow up because they were better. Adverse effects were seen in 12 cases, all of them mild. Joint effusions were the commonest, seen in six patients (Table 6) while localized transient pruritus, usually with the first injection was seen in five cases. Fever and headache were also seen. The three subjects who reported fever, one associated with the headache, could most likely have had malaria fever considering that this is endemic in Nigeria. Eleven cases presented with medial knee tendon enthesopathy usually after completion of the course of injections. Such patients, however, improved with intralesional steroid injection or local application of diclofenac. This adverse event (medial knee tendon enthesopathy) has rarely been reported in other studies. It is possible that it was present with the knee arthralgia before viscosupplementation and only came to the fore with the improvement of the knee joint pain. Previous studies have demonstrated the efficacy and safety of intra-articular hyaluronate in the treatment of OA of the knee15-18. There are numerous hyaluronate preparations with different molecular weights available in medical practice. Such preparations are available either as three dose or five dose packs. These preparations include Synvisc (hylan G-F 20 Genzyme); Hyalgan (sodium hyaluronate, Sanofi - Aventis); Supartz (sodium hyaluronate, Smith and Nephew); Euflexxa (sodium hyaluronate Ferring Pharmaceuticals); Orthovisc (high molecular weight hyaluronan Depuyi Mitek). The mode of action of hyaluronate does not seem to depend on the resident time of the compound in the synovial cavity of the knee. Exogenous hyaluronate actually begins to leave the joint within two hours of injection, though Synvisc remains up to 3 days following injection22. On the other hand, Supartz, Euflexxa and Orthovisc remain in the joint less than 24 hours after injection23-25. It has been suggested that the major effect of these agents depends on their ability, among others, to stimulate production of good synovial fluid by synovial cells and not on their resident time in the joints. There have been conflicting reports on the role the molecular weight of hyaluronate plays in its properties of elastoviscosity in the joints. Balazcs and Denlinger5 have suggested that increase in the molecular weight of exogenous hyaluronan increases its elastoviscosity. Other studies have however indicated otherwise 26. Studies comparing the clinical efficacies of various preparations have reached different conclusions. For instance, Wobig and colleagues27 have shown the efficacy of cross-linked hyaluronate (MW 800Kda). Another retrospective study comparing Synvisc (a cross-linked hyaluronate preparation) with hyaluronan (MW 615 Kda) reported statistical improvement in both preparations but also concluded that the former was superior to the latter in many parameters 28. Major constraints in the use of these agents are their cost and availability. A dose of three injections costs about US$700. There are, however, some generics available on the Nigerian market. While they are about five times cheaper than the branded names like Synvisc, there is a dearth of studies on their efficacy and safety and most of

pain assessment

Physician’s

pain assessment

No (%)

Table 6: Physician’s pain assessment at 12 weeks Pain assessment No. (%)

Effects No. (%)


them depend on the data from the branded compounds.Our study has shown, that as reported in other studies, hyaluronan, Synvisc GF- 20 is an efficacious and safe agent in the treatment of knee OA especially in patients not responding to NSAIDs.

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50. Tansey D, Wells AU, Colby TV, Ip S, Nikolakoupolou A, du Bois RM. et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology. 2004; 44(6): 585-596.

51. Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest. 2006; 116 (12): 3183-3194.

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55. Amir et al. Respiratory symptoms in rheumatoid arthritis: relation to pulmonary abnormalities detected by high-resolution CT and pulmonary functional testing. 2011;

56. Angrill J, Agusti C, De Celis R, Filella X, Rano A, Elena M, et al. Bronchial infl ammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med. 2001;164:1628–1632.

57. Nicotra MB, Rivera M, Dale AM, Shepherd R, Carter R. Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort. Chest. 1995;108:955–961.

58. Hassan WU, Keaney NP, Holland CD, Kelly CA. Bronchial reactivity and airfl ow obstruction in rheumatoid arthritis. Ann Rheum Dis. 1994; 53:511–514.

59. Pappas DA, Giles JT, Connors G, Lechtzin N, Bathon JM, Danoff SK . Respiratory symptoms and disease characteristics as predictors of pulmonary function abnormalities in patients with rheumatoid arthritis: an observational cohort study. Arthritis Res Ther. 2010; 12(3):R104.

60. Kochbati S, Boussema F, Ben Miled M, Shili S, Chérif M, Ben Amor G, et al. Bronchiectasis in rheumatoid arthritis. High resolution computed pulmonary tomography. Tunis Med. 2003 ; 81(10): 768-773.

61. Metafratzi ZM, Georgiadis AN, Ioannidou CV, Alamanos Y, Vassiliou MP. et al. Pulmonary involvement in patients with early rheumatoid arthritis. Scand J Rheumatol. 2007; 36(5): 338-344.

62. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002; 46: 2287-2293.

63. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, Chan KA. The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol. 2008; 35 (3): 387-393[Epub 2008 Feb 1].

64. Simon TA, Askling J, Lacaille D, Franklin J, Wolfe F, Covucci A, et al. Infections requiring hospitalization in the abatacept clinical development program: an epidemiological assessment. Arthritis Res Ther. 2010; 12(2): R67[Epub 2010 Apr 14].

65. Gomez-Reino JJ, Carmona L, Rodriguez Valverde V, Martin Mola E, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to signifi cant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003; 48: 2122-2127.

66. Harris J, Keane J. How tumour necrosis factor blockers interfere with tuberculosis immunity. Clin Exp Immunol. 2010; 161(1): 1-9.

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49. Brazeau-Lamontagne L, Charlin B, Levesque RY, Lussier A. Cricoarytenoiditis. CT assessment in rheumatoid arthritis. Radiol. 1986; 158 : 463-466.

50. Tansey D, Wells AU, Colby TV, Ip S, Nikolakoupolou A, du Bois RM. et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology. 2004; 44(6): 585-596.

51. Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD. Inducible bronchus- associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest.2006; 116 (12): 3183-3194.

52. Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN. Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of theliterature. Ann Diagn Pathol. 1998; 2 (5): 321-334.

53. Geddes DM, Corrin B, Brewerton DA., Davies RJ, Turner-Warwick M. Progressive airway obliteration in adults and its association with rheumatoid disease. Q J Med. 1977; 46: 427-444.

54. Shunsuke Mori,Yukinori Koga Minecharu sugimoto.Small airway obstruction in patients with rheumatoid arthritis. Mod Rheumatol. 2011; 21:164-17356.

55. Amir A Youssef, Shereen A. Respiratory symptoms in rheumatoid arthritis: relation to pulmonary abnormalities detected by high-resolution CT and pulmonary functional testing. 2011;

56. Angrill J, Agusti C, De Celis R, Filella X, Rano A, Elena M, et al. Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med.2001;164:1628-1632.

57. Nicotra MB, Rivera M, Dale AM, Shepherd R, Carter R. Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort. Chest. 1995;108:955-961.

58. Hassan WU, Keaney NP, Holland CD, Kelly CA. Bronchial reactivity and airflow obstruction in rheumatoid arthritis. Ann Rheum Dis. 1994; 53:511514.

59. Pappas DA, Giles JT, Connors G, Lechtzin N, Bathon JM, Danoff SK . Respiratory symptoms and disease characteristics as predictors of pulmonary function abnormalities in patients with rheumatoid arthritis: an observational cohort study. Arthritis Res Ther. 2010;12(3):R104.

60. Kochbati S, Boussema F, Ben Miled M, Shili S, Cherif M, Ben Amor G, et al. Bronchiectasis in rheumatoid arthritis. High resolution computed pulmonary tomography. Tunis Med. 2003 ; 81(10): 768-773.

61. Metafratzi ZM, Georgiadis AN, Ioannidou CV, Alamanos Y, Vassiliou MP. et al. Pulmonary involvement in patients with early rheumatoid arthritis.Scand J Rheumatol. 2007; 36(5): 338-344.

62. Doran MF, Crowson CS, Pond GR O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a

population-based study. Arthritis Rheum. 2002; 46: 2287-2293.

63. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, Chan KA. The risk of hospitalized infection in patients with rheumatoid arthritis.J Rheumatol. 2008; 35 (3): 387-393[Epub 2008 Feb 1].

64. Wolfe F, Caplan L, Michand K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone disease modifying antirheumatic drugs, and anti-tumour necrosis factor therapy. Arthiritis Rheum. 2006; 54: 628-634

65. Simon TA, Askling J, Lacaille D, Franklin J, Wolfe F, Covucci A, et al. Infections requiring hospitalization in the abatacept clinical development program: an epidemiological assessment. Arthritis Res Ther. 2010;12(2): R67[Epub 2010 Apr 14].

66. Gomez-Reino JJ, Carmona L, Rodriguez Valverde V, Martin Mola E, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum.2003; 48: 2122-2127.

67. Harris J, Keane J. How tumour necrosis factor blockers interfere with tuberculosis immunity. Clin Exp Immunol. 2010; 161(1): 1-9.

68. Carroll GJ, Thomas R, Phatours CC, et al. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J Rheumatol. 1994; 21:51-54.

69. Dowson JK, Graham DR, Desmond J. et al. Investigation ofthe chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests. Rheumatology.2002; 41:262-267.

70. Kremer JM, Alarcon GS, Weinblatt ME, Kaymakcian MV, Macaluso M. et al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum. 1997; 40: 1829-1837.

71. Kamata Y, Nara H, Kamimura T, et al. Rheumatoid arthritis complicated with acute interstitial pneumonia induced by leflunomide as an adverse reaction. Inter Med 2004; 43:12011204

72. Sawada T., Inokuma S., Sato T., Otsuka T., Saeki Y. et al. Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford). 2009;48: 1069-1072.

2012 32(37): 1985 - 1995.


Cardiovascular risk factors in patients with rheumatoid arthritis at Kenyatta National HospitalKirui F, Oyoo GO, Ogola EN, , Amayo EO

Department of Clinical Medicine and Therapeutics, School of Medicine, University of Nairobi, P. O. Box 19676 – 00202, Nairobi, Kenya

Corresponding author: Dr GO Oyoo. Email: [email protected] / [email protected]

RESEARCH ARTICLE

Abstract

Background: Rheumatoid arthritis is associated with excessive cardiovascular morbidity and mortality. This is predom-inantly due to accelerated coronary artery and cerebrovascular athero-sclerosis. Traditional cardiovascular risk factors as well as extra articular disease have been associated with occurrence of myocardial infarction. Objective: To identify cardiovascular risk factors in patients with rheumatoid arthritis at Kenyatta National Hospital and compare with healthy controls. Design: This was a comparative cross sectional survey.Setting: Kenyatta National Hospital medical outpatient clinic. The study population were patients with rheumatoid arthritis and the controls were individuals without RA age and sex matched sta� of KNH. All those who consented were enrolled and a clinical evaluation was done as per the study protocol.Results: One hundred patients with RA were screened out of which 80 were enrolled. The prevalence of hypertension among RA patients was 41.3%, diabetes 6.3%, dyslipidemia 71.3%, smoking 5%, obesity 22.5%, abnormal WHR 33.8%, family history of sudden death 5%, no family history of stroke or heart attack was reported. In the control group one hundred and � ve were screened and twenty � ve were excluded. The prevalence of hypertension was 22.5%, diabetes 5%, dyslipidemia 73.8%, smoking 2.5%, obesity 32.5%, abnormal WHR 33.8% family history of sudden death 10%, stroke 1.3% no history of heart attack was reported. Eighty percent of patients with RA were on at least one DMARD, 57.5% were on steroids and 37.5% were on NSAIDS.Conclusion: There was a high prevalence of hypertension among RA patients (41.3%) than in the controls

(22.5%) and this was statistically signi� cant (OR 2.42 (95 CI 1.22-4.81) P = 0.017). Hypertension was also signi� cantly associated with the use of DMARDS OR 2.189 (95% CI 1.111-4.312) P= 0.022 and steroids OR 2.06(95% CI 1.008-4.207) P= 0.022. No signi� cant di� erence between patients with RA and controls in other risk factors including diabetes, dyslipidemia, smoking, obesity, abnormal waist hip ratio and family history of cardiovascular events was found.Recommendations: Clinicians should keenly look out for hypertension in patients with RA for early identi� cation and if necessary aggressive management of hypertension. Screening of cardiovascular risk factors in patients with RA should be done routinely and a larger study with normal controls from the general population should be undertaken in order to measure this cardiovascular risk factors and cardiovascular disease in this population.

Key words: Cardiovascular, rheumatoid

arthritis, KNH.

_____________

Introduction

Rheumatoid arthritis is a chronic systemic autoimmune infl ammatory disorder. It is characterized by deforming symmetrical polyarthritis of varying extent and severity, associated with synovitis of joint and tendon sheaths. It is also associated with articular cartilage loss, erosion of juxta-articular bone and, in most patients, the presence of IgM rheumatoid factor in blood. In some patients systemic and extra-articular features may be observed during the course of the disease and, rarely prior to onset of joint disease. These include anemia, splenomegaly, weight loss, vasculitis, serositis, mononeuritis multiplex, interstitial infl ammation in the lungs and exocrine salivary and lacrimal

Amayo EO

Kenyatta National Hospital.

R


glands as well as nodules in subcutaneous, pulmonary and scleral tissue1 .

Rheumatoid arthritis (RA) is associated with excessive cardiovascular morbidity and mortality. This is predominantly due to accelerated coronary artery and cerebrovascular atherosclerosis. Traditional cardiovascular risk factors as well as extra articular disease have been associated with occurrence of myocardial infarction (MI) . A study done by Han and colleagues2, showed that individuals with rheumatoid arthritis are 30% to 60% more likely to suffer a cardiovascular event compared to the general population, especially myocardial infarction. The incidence and prevalence of stroke generally has been reported to be similar in rheumatoid arthritis as in the general population or in patients with osteoarthritis . One study found a higher prevalence of stroke in patients with rheumatoid arthritis than in controls3. The main objective of this study was to identify cardiovascular risk factors in patients with rheumatoid arthritis at Kenyatta National Hospital, Nairobi, Kenya. It also sought to determine the prevalence of hypertension, diabetes, dyslipidemia and smoking. We also wanted to determine anthropometric measures in patients with RA, mainly Basal Metabolic Index (BMI), Waist Hip Ratio(WHR), family history of cardiovascular events such as sudden death, MI or stroke. We also sought to compare the cardiovascular risk factors in patients with rheumatoid arthritis with the controls. The other objectives in this study were to document cardiovascular events (stroke, MI, HF) in patients with RA and to document the use of DMARDS ( disease modifying anti rheumatic drugs), steroids, NSAIDS, biologic DMARDS, anti-hypertensives, anti-diabetics, statins, and aspirin in patients with RA. Materials and Methods

This was a descriptive comparative cross sectional survey done at the Medical Out Patient Clinics (MOPC) at Kenyatta National Hospital. Patients included in the study were above 18 years, confirmed to have rheumatoid arthritis as per ACR criteria and gave an informed consent. The controls were healthy individuals above 18 matched for age and sex. They were also confirmed not to have rheumatoid arthritis as per the ACR criteria. Patients below 18 years and those who declined to give consent were excluded. Sample size was calculated based on the current data available with a prevalence of 30%4 for hypertension at 95% confidence interval and a 5% margin of error. The minimum sample size needed was 80 with rheumatoid arthritis and 80 controls (Figure 1).

A total of 205 patients with rheumatoid arthritis and healthy controls were screened for recruitment into the study. Patients with or suspected to have RA were 100 and of these four individuals did not consent, 88 fulfilled ACR criteria and were recruited, 8 were lost to follow up and 80 were enrolled. One hundred and five healthy individuals without RA were screened for enrollment, 15 refused consent, 90 were recruited and 10 were lost to follow up. A total of 160 cases and controls were enrolled, 22 (13.75%) were males and 138 (86.25%) were female (Table 1).

Results

The mean age for patients with RA was 44.7 years, the median age 48 years and [range 18-75 years]. For the healthy individuals without RA, the mean age was 44.6 years, the median was 43 years and [range 22- 75 years] (Table 1). There were two peaks of disease in the patients with RA with the peaks at age ranges 20-29 and 50-59 years (Figure 2).

Figure 1: Flow chart showing patient flow in the study

CONSENT 205

EXCLUDE FROM THE STUDY

FULLFILING ACR CRITERIA (88)

HISTORY/ CLINICAL EXAM BP/BMI/QNAIRE (CV) SCREENING

NO

YES

Y

NO

NEXT APPOINTMENT

FASTED

YES LIPID/PROFILE/

FASTING RBS

FASTING LIPID PROFILE/FASTING RBS

EXCLUDE FROM THE STUDY (4)

NO

CONSENT

CONTROLS

YES

NO

OO

Exclude


Table 1: Demographic characteristics of patients with rheumatoid arthritis and healthy controls

Variables/ categories Case Control Total P valueNo. (%) No. (%) No. (%)

Sex Male 11 13.8 11 13.8 22 13.8 1.000 Female 69 86.2 69 86.2 138 86.2

Marital status Married 56 70 47 58.8 103 64.4

0.264 Single 19 23.8 24 30 43 26.9 Widowed 3 3.8 8 10 11 6.9 Divorced 2 2.5 1 1.3 3 1.9

Level of education None 4 5 2 2.5 6 3.8

<0.001 Primary 28 35 10 12.5 38 23.8 Secondary 15 18.7 9 11.3 24 15 College 20 25 47 58.7 67 41.9 Tertiary 13 16.3 12 15 25 15.6

Employment Unemployed 24 30 20 25 44 27.5

0.012 Employed 29 36.3 48 60 77 48.1 Self employed 19 23.7 8 10 27 16.9 Retired 8 10 4 5 12 7.5

Age Mean ±SD 44.7±15.3(18-75) 45.0± 13(22-75) 44.8 + 14.2 (18 – 75) 0.894 Median 48 43 45

There was significant association between level of education and rheumatoid arthritis (P= 0.001). Majority with education less than college level had higher disease burden compared to those who had college education and above. There was a significant association between type of employment and disease status. Majority of those who had rheumatoid arthritis were self employed, and unemployed (P = 0.012) (Table 1).

Figure 2: Age distribution of patients with rheumatoid arthritis

Age distribution in years, RA cases

10 - 19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70 and above

Thirty three patients (41.3%) with RA had hypertension compared to 18 (22.5%) healthy controls. This difference was statistically significant, (OR 2.42 (95 CI 1.22-4.81) P = 0.017) Five (6.3%) patients with rheumatoid arthritis had diabetes while controls were 4(5%) controls. This was not statistically significant (OR 1.28 (95 CI 0.33-4.90) P =1.0). Fifty seven patients with RA (71.3%) had dyslipidemia, while 59(73.8%) of the healthy controls had dyslipidemia, however this was not statistically significant. (OR 0.88 (95 CI 0.44-1.77) P =0.723). Four (5%) patients with rheumatoid arthritis smoked and 2 (2.5%) healthy controls smoked cigarette. There was no statistical significance (OR 0.49 (95 CI 0.09-2.74) P =0 .687 Eighteen (22.5%) patients with rheumatoid arthritis were obese while 26 (32.5%) of the controls were obese. This was however not statistically significant. O.R 0.603 (95 CI 0.299-1.218) P =0.157. Twenty seven (33.7%) of patients with RA had a high waist hip ratio, a similar number was observed in the controls and this was not statistically significant. OR 1 (95 CI 0.519-1.926) P =1.0.


There was no family history of myocardial infarction among the patients with rheumatoid arthritis and the healthy controls, one person from the controls reported a family history of stroke. Four patients with RA reported a family history of sudden death while 8 people in the healthy control group did report it; however, when compared, this was not statistically significant. OR 0.47

95%CI (0.137-1.641) P = 0.369. Only one patient with RA reported past history of heart failure; none of the patients or healthy controls reported a previous history of myocardial infarction or stroke. Drug therapy as used by all the patients is summarized in Table 2.

Table 2: Drug therapy in patients with RA and controls

Characteristic Cases No. (%)

Controls No. (%)

Drugs

Steroids 46 57.5 0 0

Statins 1 1.3 2 2.5

Nitrates 0 0 0 0

Aspirin 1 1.3 3 3.8

DMARDS 64 80 0 0

Biological DMARDS 0 0 0 0

NSAIDS 30 37.5 6 7.5

Proportion of hypertensive patients on medication

8 24.2 1 5.5

Proportion of diabetics on treatment

3 60 2 50

Data AnalysisTable 3: Bivariate analysis on correlates of cardiovascular risk factors in patients with rheumatoid arthritis and healthy controls

Factors Category Disease outcome P. value OR CI OR

Case No. (%)

ControlNo. (%)

Hypertension 33 41.3 18 22.5 0.017 2.42 1.22 - 4.81

Diabetes 5 6.3 4 5 1 1.27 0.33 - 4.90

Smoking 4 5 2 2.5 0.681 0.49 0.09 - 2.74

Abnormal WHR 27 33.8 27 33.8 1 1 0.52 -1.93

Sudden death 4 5 8 10 0.369 0.474 0.14 - 1.64

Dyslipidemia

BMI

57 71.3

18 22.5

59 73.8

26 32.5

0.723

0.157

0.882

0.603

0.440 -1.767

0.299 - 1.218

By controlling for disease outcome 19 (44.2%) patients with RA and obesity were hypertensive, however there was no statistically significance between hypertension and obesity. Likewise in the control group there was no association between hypertension and obesity. OR 1.96 (95 C I 0.67 -5.76) P = 0.259. The controls who were obese were almost two times more at risk to have hypertension than those not obese. One patient with RA and diabetes (20%) was hypertensive, while two

controls who were diabetic had hypertension. The odds of being hypertensive among diabetics compared to non diabetic was three times more, however this was not statistically significant OR 3.75(95% C.I 0.490-28.727) P= 0.217. Twelve (40%) individuals with RA who used NSAIDS regularly were hypertensive while one control had hypertension; however this was not statistically significant (Table 4).

There was no family history of myocardial infarction among the patients with rheumatoid arthritis and the healthy controls, one person from the controls reported a family history of stroke. Four patients with RA reported a family history of sudden death while 8 people in the healthy control group did report it; however, when

compared, this was not statistically significant. OR 0.47 95%CI (0.137-1.641) P = 0.369. Only one patient with RA reported past history of heart failure; none of the patients or healthy controls reported a previous history of myocardial infarction or stroke. Drug therapy as used by all the patients is summarized in Table 2.



Table 4: Bivariate analysis –Controlling for disease status

Disease outcome CaseNo. (%)

ControlNo. (%)

Case 95% CI P value Control 95% CI

P value

Hypertension/Obesity 8 24.2 8 44.4 1.2 (0.41-3.42) 0.791 1.96 (0.67 - 5.76) 0.259

Hypertension/Diabetes 1 20 2 50 0.34(0.04-3.15) 0.399 3.75 (0.49-28.7) 0.217

Hypertension/NSAIDS 12 40 1 16.7 0.92 (0.37-2.3) 1 0.67(0.73-6.14) 1

Among the patients with rheumatoid arthritis 64 (80%) were on DMARDS, 49 (61.3%) were on one DMARD, 14 (17.5%) were on two DMARDS and only one patient with rheumatoid arthritis was on treatment with three DMARDS. (Figure 3).

Figure 3: Use of DMARDS among individuals with rheumatoid arthritis

1 DMARD 61%

2 DMARD 18%

3 DMARD 1%

NO DMARD 20%

Table 5: Hypertension in relation to drug therapy in patients with RA and controls

Variables/ category

Hypertension No Hypertension O. R 95% O.RP valueNo. (%) No. (%) Lower Upper

Use of DMARDS 27 42.2 37 57.8 2.189 1.111 4.312 0.022No use of DMARDS 24 25.0 72 75.0

Use of steroids 20 43.5 26 56.52.06 1.008 4.207 0.045No use of

steroids 31 27.2 83 72.8

Use of NSAID 13 36.1 23 63.91.279 0.586 2.79 0.536No use of

NSAID 38 30.6 86 69.4

None of the patients seen at the clinic were using biological agents for the treatment of rheumatoid arthritis (Table 2). Twenty seven patients who used DMARDS were hypertensive as compared to 24 who did not. Those who used DMARDS were significantly more likely to have hypertension. OR 2.189(95% CI 1.111-4.312) P= 0.022. Likewise those patients with RA who used steroids were

more likely to be hypertensive than the controls and this was statistically significant OR 2.06(95% CI 1.008-4.207) P= 0.022 (Table 5). Forty six (57.5%) individuals with RA were on treatment with steroids. Only one patient with rheumatoid arthritis was on treatment with statins while two controls were using statins. Only one patient with RA who was using antiplatelet agent while three controls were on antiplatelet agents. None of the cases or controls was on treatment with nitrates. Eight (24.2%) individuals who had RA and hypertension were on treatment for hypertension while three (60%) individuals were on treatment for diabetes. Thirty (37.5%) individuals with RA were taking NSAIDS

regularly as compared to six individuals in the control group. Among the individuals with RA taking NSAIDS regularly 12(40%) were hypertensive. More than half the patients with rheumatoid arthritis 46(57.5%) were using glucocorticoids (Table 2). Eleven patients with RA had no risk factor measured in this study, 20 patients had 1 risk factor, 27 two risk factors, 18 three risk factors and 4 with four risk factors.

Afr J Rheumatol 2012; 1(1): 8-12 48

There was no family history of myocardial infarction among the patients with rheumatoid arthritis and the healthy controls, one person from the controls reported a family history of stroke. Four patients with RA reported a family history of sudden death while 8 people in the healthy control group did report it; however, when compared, this was not statistically significant. OR 0.47

95%CI (0.137-1.641) P = 0.369. Only one patient with RA reported past history of heart failure; none of the patients or healthy controls reported a previous history of myocardial infarction or stroke. Drug therapy as used by all the patients is summarized in Table 2.


Characteristic Cases No. (%)

Controls No. (%)

Drugs

Steroids 46 57.5 0 0

Statins 1 1.3 2 2.5

Nitrates 0 0 0 0

Aspirin 1 1.3 3 3.8

DMARDS 64 80 0 0

Biological DMARDS 0 0 0 0

NSAIDS 30 37.5 6 7.5

Proportion of hypertensive patients on medication

8 24.2 1 5.5

Proportion of diabetics on treatment

3 60 2 50

Data AnalysisTable 3: Bivariate analysis on correlates of cardiovascular risk factors in patients with rheumatoid arthritis and healthy controls

Factors Category Disease outcome P. value OR CI OR

Case No. (%)

ControlNo. (%)

Hypertension 33 41.3 18 22.5 0.017 2.42 1.22 - 4.81

Diabetes 5 6.3 4 5 1 1.27 0.33 - 4.90

Smoking 4 5 2 2.5 0.681 0.49 0.09 - 2.74

Abnormal WHR 27 33.8 27 33.8 1 1 0.52 -1.93

Sudden death 4 5 8 10 0.369 0.474 0.14 - 1.64

Dyslipidemia

BMI

57 71.3

18 22.5

59 73.8

26 32.5

0.723

0.157

0.882

0.603

0.440 -1.767

0.299 - 1.218

By controlling for disease outcome 19 (44.2%) patients with RA and obesity were hypertensive, however there was no statistically significance between hypertension and obesity. Likewise in the control group there was no association between hypertension and obesity. OR 1.96 (95 C I 0.67 -5.76) P = 0.259. The controls who were obese were almost two times more at risk to have hypertension than those not obese. One patient with RA and diabetes (20%) was hypertensive, while two

controls who were diabetic had hypertension. The odds of being hypertensive among diabetics compared to non diabetic was three times more, however this was not statistically significant OR 3.75(95% C.I 0.490-28.727) P= 0.217. Twelve (40%) individuals with RA who used NSAIDS regularly were hypertensive while one control had hypertension; however this was not statistically significant (Table 4).

Disease outcome Case Control Case 95% CI P value Control 95% P value No. (%) No. (%) CI


In the control arm 7 did not have any risk factor, 31 had 1 risk factor, 27 two risk factors, 10 three risk factors, 4 had four risk factors and 1 with fi ve risk factors. When the cases and controls were compared there was no statistical signifi cance in terms of number of risk factors.

Figure 4: Distribution of risk factors by cases and controls

Discussion

From our results we found women were the most affected by the disease accounting for 69(86.2 %) of the individuals with RA, as opposed to eleven (13.8%) males. A local study done by Owino et a l5 found 86.7% females with a male to female ratio of 1:6.5. This observation was in agreement to what we observed in our study. The mean age of patients with RA in this study was 44.7 ± 15.3 years and this was almost similar to that observed by owino et al5 but older than that observed by Bagg et al 6. In the study done by panoulas and colleagues7 the mean age for patients with RA was 61 ± 12.02 years. This was an older population than what we saw in our study and could explain our higher prevalence of rheumatoid arthritis among women, since the disease has been shown to be more common in younger women compared to younger males; but the difference diminishes as the age increases. In this study the prevalence of hypertension among the patients with rheumatoid arthritis was 41.3%, and this was higher than the 22.5% observed in the healthy controls and was statistically signifi cant. Owino et al5 found the prevalence of hypertension among patients with rheumatoid arthritis to be around 14%. This was much lower than what we observed in our study. The mean age of his patients was 41.3 years indicating a younger population than in ours. This may partly explain the lower prevalence although other factors might have contributed to the difference observed. Owino and his colleagues5 relied on patient’s records and there was no physical measurement by the clinician or study assistant of blood pressure and this may partly explain the low prevalence he got from his study. A study done by panoulas et al 7 in the UK found a

higher prevalence of 70% with a mean age of 62 years. This population was older than our study population and it has been shown that hypertension is more common in older age group8 of individuals. The prevalence of hypertension might have been also high in Panoulas study population and this with the high mean age might explain the difference with our study. Use of medium dose steroids for long term (more than six months) in patients with RA has been associated with a high prevalence hypertension9 . In this study 46 (57.5%) patients with RA were on steroids out of which 20(43.5%) had hypertension. Those who used steroids were twice at risk of being hypertensive than those who did not use and this was statistically signifi cant. We did not document the daily steroid use in our study and therefore would not have a daily steroid dose to correlate with other studies fi ndings. The use of steroids in patients with RA could explain the higher prevalence of hypertension in this patient group compared to the controls. The study done by Owino and colleagues5 had 66.7% of patients with RA on steroids; which was much higher than in our study but this cannot explain the difference in the prevalence of hypertension, probably other factors could explain this observation. Antonio et al 4 found 33% of patients with RA had hypertension. This was a multicentre study and involved different geographical and demographic groups globally but mostly in Europe and North America. This prevalence of hypertension was lower than what we observed in our study. Their mean age was 57 years. These fi ndings were not in agreement with what has been observed in other studies, our study included. Only 24.2 % of the individuals with rheumatoid arthritis and hypertension were on treatment for hypertension in our study, and this shows a signifi cant proportion of individuals are not diagnosed with hypertension and therefore could not benefi t from early treatment. Panoulas and colleagues7 observed that 39.4% of the individuals with RA were undiagnosed for hypertension and therefore could not get treatment in his study. This is despite the fact that patients with RA in that country (UK) were regular attendees of the rheumatology clinics where vital signs were recorded regularly. In our study the prevalence of diabetes was 6.5% among patients with rheumatoid arthritis and 5% in the controls. In a study done by Owino5 3.5% of individuals were diabetic and hypertensive. Other studies like the one done by Antonio and his colleagues4 observed a prevalence of diabetes of 8%. This was a multicentre study and had varied demographic characteristics although 90% of the patients were Caucasians and they had a higher mean age than in our study. Another study done by Del Rincon et al10, found a prevalence of 8.3% of diabetes among patients with RA and 6.3% in his controls, however, this was not statistically signifi cant. This fi nding was observed in patients and controls below 55 years of age. He did observe a higher prevalence in those who were above 55 years. The patients in his study were older than in our study and this could explain the higher prevalence


he observed in his study or probably the prevalence of diabetes was higher in his study population. Steroids have been shown to predispose patients to diabetes 11 and we may associate to the higher prevalence of diabetes in patients with RA in our study since over half (57.5%) of them were on steroids. Fifty seven (71.3%) of our patients with RA had dyslipidemia and almost a similar number was observed in the control group. We have no local data on dyslipidemia among patients with RA. This was higher than what was observed by Antonio and his colleagues4 (14%). The low prevalence observed by Antonio and colleagues could have been due to the difference in the cut off levels for lipid profiles or their definition of dyslipidemia. Crowson et al12 observed a higher prevalence of dyslipidemia in his study (59.4%). This was a study done in the US looking at risk of developing heart failure attributable to traditional cardiovascular risk factors in patients with RA. A small proportion of our patients with Rheumatoid arthritis smoked, likewise this trend was observed in the healthy controls. This low prevalence might have been influenced by the cultural trends in our society since majority of the study population were women. Older women in the Kenyan society tend to be conservative and therefore few of them smoke, although of late the trend of smoking has been seen to be rising among young women in Kenya. Our findings were in sharp contrast to what was seen in the quest RA study where the prevalence of ever smoking was at 43%. These could be explained by the population studied in Quest RA study which was more of a western society where a significant proportion of women smoke cigarettes. Panoulas et al observed a prevalence of 18.5% of smoking in his study and these was still higher than what we saw in our study. Obesity particularly central obesity is associated with an increased risk of cardiovascular risk 13. In our study the prevalence of obesity among patients with rheumatoid arthritis was 22.5% compared to 32.5% in the controls. Antonio and his colleagues4 in the quest RA study found a lower prevalence of 18% . Patients with RA tend to present with weight loss when the disease is active and while on treatment and this might explain the difference we got from our study when we compared our cases and the controls. Other studies in the general population have shown that overweight and obese are important mediators of hypertension in the context of ex smokers with insulin resistance (Yokoyama 2004)1, and associate with current or future hypertension and relevant end organ damage in non RA population. The number of individuals with RA using DMARDS was 64(80%) in our study. Owino et a l5 observed that 46.7% of patients with RA were on treatment with at least one DMARD these was lower than what we observed in our study. We think that there could have been some improvement in knowledge of the healthcare workers in the use of DMARDS in patients with RA and therefore more people are being put on DMARDS now than before, or may be DMARDS are now more affordable.

A study done by Panoulas et al 7 found out that 87.5% of patients with RA were using DMARDS. This was higher than what we found in our study although the trend was almost similar with over two thirds of our patients with RA using DMARDS. In our study in patients with RA; 61.3% were on one DMARD, 17.5% on two DMARDS and one 1.3% on three DMARDS as compared to the ones in a study done by Panoulas et al7 where 56.8% of patients with RA were on only one DMARD. This was lower than what we observed in our study, the reason being that more patients were on more than one DMARD (30.8%) in that study. These might reflect on our local practice because in other parts of the world rheumatologist are increasingly prescribing combination therapy 14 because single DMARD therapy often fails to control clinical symptoms or prevent disease progression. The use of NSAIDS especially Cox 2 inhibitors 15 have been associated with hypertension , unlike in our study where there was no significant association of hypertension and use of NSAIDS. None of the patients in our study were using biological agents such as Rituximab, which has been shown to be quite effective in treating RA. This is most likely due to its prohibitive cost and also most of the patients coming to Kenyatta Hospital have a lower socio economic status. The family history of documented cardiovascular events was lower than that observed by Crowson et al12 in the US. There could have been recall bias among our patients on current disease or their social desirability might have influenced their response. Recording and maintaining updated records of this information in our local set up might have posed a significant challenge and this might explain the low prevalence we got from our study. Most of the controls in our study were individuals working at the hospital. They included the nursing staff, clinical officers and supportive staff, a large proportion of them had dyslipidemia (73.8%) and this was more than in the cases. Although this was not statistically significant it still shows that this population was at risk. The healthy individuals who were used as controls were also more obese (32.5%) than the patients with RA indicating that they were at more risk, although this was also not statistically significant. They also documented more family history of sudden death than in the cases with RA. From our findings it seems the control group which was presumed healthy had actually more risk factors than thought and these might have influenced our results especially looking at the lipid profile where we expected to have more dyslipidemia in patients with RA than in the controls as seen in a study done by Situnayake and kitas. Most of the patients and controls had clustering of risk factors and when the two groups were compared there was no significance in the number of risk factors. It seems the increased risk of cardiovascular events in RA is independent of traditional cardiovascular risk factors. This suggests other additional mechanisms are

Afr J Rheumatol 2013; 1(1): 15-22 22 Afr J Rheumatol 2013; 1(1): 8-1225

Characteristics of systemic sclerosis patients in Nairobi, Kenya : a retrospective studyIlovi S and Oyoo GO

Department of Clinical Medicine and Therapeutics, School of Medicine, University of Nairobi, P.O. Box 19676-00202 Nairobi, Kenya

Corresponding author: Dr. S. Ilovi, P.O. Box 79625-00200, Nairobi, Kenya. Email: [email protected]

RESEARCH ARTICLE

Abstract

Objectives: Systemic sclerosis is a rare rheumatologic disorder that has not been well characterized in African populations. No previous studies have been carried out in Kenya, or in the East African region. Design: A retrospective descriptive study. Methods: Records of patients at the Kenyatta National Hospital and Nairobi Arthritis Clinic with a diagnosis of systemic sclerosis based on the American College of Rheumatology criteria were recruited into the study. The study covered a ten year period between 2001 and 2011. Results: A total of 50 patients were identi� ed, with a predilection of the disease to the female gender (M:F 1:4). The mean age of presentation was 41.7 years with a range of 4 years to 70 years. Majority of the patients (82%) presented with di� use cutaneous systemic sclerosis. Overlap syndromes were documented in eight of the patients. Skin manifestation was the commonest presentation (100%), followed by Raynaud’s phenomenon (64%), pulmonary disease (56%) and esophageal disease (54%). Antinuclear antibodies were present in 67% of the patients tested. Of the patients tested for anti- SCL-70 autoantibodies, only 28% were positive. Most of the patients (80%) were on immunosuppresants whereas 54% were on proton pump inhibitors/prokinetics. Conclusion: Patients in Nairobi with systemic sclerosis have similar characteristics as cases described elsewhere in Africa.

Key words: Systemic sclerosis, Sclero-derma, Kenyatta National Hospital, Nai-robi Arthritis Clinic

Introduction

Systemic sclerosis is an autoimmune disease of unknown etiology which is characterized by vasculopathy, thickening of the skin, internal organ involvement especially gastrointestinal system, lungs, kidney and heart as well as development of autoantibodies1-3. The etiology of the disease is not well understood, but possible triggers have been described. These include viruses such as cytomegalovirus and retroviruses, environmental triggers such as silica and industrial fumes, gadolinium contrast agent and some cytotoxic medications used in cancer treatment 4. There are four main subtypes of the disease depending on the extent of fi brosis and internal organ involvement. In limited cutaneous systemic sclerosis, scleroderma is limited to the skin distal to the elbow and has minimal internal organ manifestation. The diffuse cutaneous form is widespread; skin thickening can involve the whole body including the face. It is associated with more internal organ disease. Localized scleroderma, also called morphea, is limited to the skin with no internal organ disease. Systemic sclerosis sine scleroderma has purely internal organ fi brosis with no features of scleroderma. Very few studies have been carried out on the African continent on systemic sclerosis, and none in Kenya or the East African region. The estimated prevalence of the disease ranges from 50 to 300 cases per 1 million persons5. Females are more predisposed to developing the disease as compared to males, with a male: female ratio of between 1:3 and 1:142. Studies carried out in North America have shown increased cases of systemic sclerosis in African Americans compared to Caucasians 6,7. The hallmark of systemic sclerosis is thickening of the skin (scleroderma). Internal organ fi brosis occurs mainly in the lungs, gastrointestinal system, kidneys, muscle, joints and the heart. Vasculopathy

Ilovi CS and Oyoo GO

Dr. CS Ilovi, P.O. Box 1967600202, Nairobi Kenya.Email: [email protected], [email protected]

Nairobi Arthritis clinic

Afr J Rheumatol 2012; 1(1): 8-12 52

responsible for cardiovascular disease in RA and further research needs to be done.

Conclusions

This study has shown that;(i)There is a high prevalence of hypertension in patients with RA as compared to the controls. (ii)Hypertension was also associated with the

use of DMARDS and steroids.(iii) A large proportion of patients with RA and

healthy controls had dyslipidemia.(iv) There was no significant difference between patients and controls in terms of other risk factors i.e. diabetes mellitus, dyslipidemia, smoking, BMI, WHR, and family history of cardiovascular events.(v) There was clustering of risk factors among patients and the healthy controls although this was not significant. From this it seems the increased risk of cardiovascular events in RA is independent of traditional cardiovascular risk factors. This suggests other additional mechanisms are responsible for cardiovascular disease in RA.

References

1. Warrell DA, Cox TM, Firth JD et al. Oxford Textbook of medicine.4th edition. New York. Oxford University Press Inc. 2003.

2. Han C, Robinson DW, Hackert MV, Clark P, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis and ankylosing spondylitis. J Rheumatol. 2006; 33:2167-2172.

3. Turesson C, Jarenros A, Jacobsson L: Increased incidence of cardiovascular disease in patients with rheumatoid arthritis: results from a community based study. Ann Rheum Dis. 2004; 63:952-955.

4. Antonio N, Tuulikki S, Miguel AD, Jaime CA, Kim HP, Luukkanen KR. et al. Cardiovascular disease in patients with rheumatoid arthritis: results from QUEST-RA study.Arthritis Res Ther2008 BMC 10: R30 (doi :10. 1186 /a r 2383).

5. Owino BO, Oyoo GO, Otieno CF . Rheumatoid arthritis at Kenyatta National Hospital. a clinical and quality of life evaluation. MMED dissertation 2007.

6. Bagg LR, Hansen DP, Lewis C. et al. RA in Kenya I. Clinical observations. Ann Rheum Dis 1979; 38:23-25.

7. Panoulas VF, Douglas KM, Millions HJ et al. Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology. 2007; 46:1477-1482.

8. Solomon D, Karison E, Rimm E, Cannuscio C, Mandi M. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303-1307.

9. Panoulas VF, Doughlas KMJ, Stavropoulas KA, Metsios GS, Nightingale P, Kita MD, Elisaf MS, Kitas GD. Long term exposure to medium dose glucocorticoids therapy associated with hypertension. in patients with rheumatoid arthritis. Rheumatology 2008; 47:72-75.

10. Del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001; 44:2737–2745.

11. O’Dell JR. Therapeutic strategies for RA. N Engl J Med. 2004; 350: 2591-2602.

12. Crowson SC, Paulo J Nicola, Hilal MK, Ofallon WM et al. How much of increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease. Arthritis Rheum. 2005; 32:3039-3044.

13. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi- Sunyer FX et al. Obesity and cardiovascular disease: Pathophysiology, evaluation, and effect of Council on Nutrition, Physical Activity and Metabolism: Statement on Obesity and Heart Disease From the Obesity Committee of the Weight Loss: An update of the 1997 American Heart Association Scientific. Circulation. 2006; 113: 898-918.

14. O’Dell JR, Haire CE, Erikson N et al. Treatment of RA with methothrexate alone, sulfasalazine and hydroxychloroquine, or combination of all three medications. N Engl J Med. 1996; 334:1287-1291.

15. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005; 165:490–496.

16. Situnayake RD, Kitas G. Dyslipidaemia and rheumatoid arthritis. Ann Rheum Dis. 1997; 56:341–342.


Characteristics of systemic sclerosis patients in Nairobi, Kenya : a retrospective studyIlovi S and Oyoo GO

Department of Clinical Medicine and Therapeutics, School of Medicine, University of Nairobi, P.O. Box 19676-00202 Nairobi, Kenya

Corresponding author: Dr. S. Ilovi, P.O. Box 79625-00200, Nairobi, Kenya. Email: [email protected]

RESEARCH ARTICLE

Abstract

Objectives: Systemic sclerosis is a rare rheumatologic disorder that has not been well characterized in African populations. No previous studies have been carried out in Kenya, or in the East African region. Design: A retrospective descriptive study. Methods: Records of patients at the Kenyatta National Hospital and Nairobi Arthritis Clinic with a diagnosis of systemic sclerosis based on the American College of Rheumatology criteria were recruited into the study. The study covered a ten year period between 2001 and 2011. Results: A total of 50 patients were identi� ed, with a predilection of the disease to the female gender (M:F 1:4). The mean age of presentation was 41.7 years with a range of 4 years to 70 years. Majority of the patients (82%) presented with di� use cutaneous systemic sclerosis. Overlap syndromes were documented in eight of the patients. Skin manifestation was the commonest presentation (100%), followed by Raynaud’s phenomenon (64%), pulmonary disease (56%) and esophageal disease (54%). Antinuclear antibodies were present in 67% of the patients tested. Of the patients tested for anti- SCL-70 autoantibodies, only 28% were positive. Most of the patients (80%) were on immunosuppresants whereas 54% were on proton pump inhibitors/prokinetics. Conclusion: Patients in Nairobi with systemic sclerosis have similar characteristics as cases described elsewhere in Africa.

Key words: Systemic sclerosis, Sclero-derma, Kenyatta National Hospital, Nai-robi Arthritis Clinic

Introduction

Systemic sclerosis is an autoimmune disease of unknown etiology which is characterized by vasculopathy, thickening of the skin, internal organ involvement especially gastrointestinal system, lungs, kidney and heart as well as development of autoantibodies1-3. The etiology of the disease is not well understood, but possible triggers have been described. These include viruses such as cytomegalovirus and retroviruses, environmental triggers such as silica and industrial fumes, gadolinium contrast agent and some cytotoxic medications used in cancer treatment 4. There are four main subtypes of the disease depending on the extent of fi brosis and internal organ involvement. In limited cutaneous systemic sclerosis, scleroderma is limited to the skin distal to the elbow and has minimal internal organ manifestation. The diffuse cutaneous form is widespread; skin thickening can involve the whole body including the face. It is associated with more internal organ disease. Localized scleroderma, also called morphea, is limited to the skin with no internal organ disease. Systemic sclerosis sine scleroderma has purely internal organ fi brosis with no features of scleroderma. Very few studies have been carried out on the African continent on systemic sclerosis, and none in Kenya or the East African region. The estimated prevalence of the disease ranges from 50 to 300 cases per 1 million persons5. Females are more predisposed to developing the disease as compared to males, with a male: female ratio of between 1:3 and 1:142. Studies carried out in North America have shown increased cases of systemic sclerosis in African Americans compared to Caucasians 6,7. The hallmark of systemic sclerosis is thickening of the skin (scleroderma). Internal organ fi brosis occurs mainly in the lungs, gastrointestinal system, kidneys, muscle, joints and the heart. Vasculopathy

Ilovi CS and Oyoo GO

Dr. CS Ilovi, P.O. Box 1967600202, Nairobi Kenya.Email: [email protected], [email protected]

Nairobi Arthritis clinic

, Oyoo GO


presents as pulmonary arterial hypertension, Raynaud’s phenomenon, digital ulcers, acro-osteolysis and renal disease. Other clinical presentations include calcinosis cutis and arthritis. It is these clinical presentations that result in the high morbidity and mortality of the disease. A study carried out in 30 countries (24 European, 6 non- European), involving 3656 patients was undertaken between 2004 and 2006. The male to female ratio was 1:6. Diffuse cutaneous systemic sclerosis was present in 36.9% while limited cutaneous disease was present in 63.1%. Patients with localized scleroderma were excluded from this study. Autoantibodies against SCL-70, which is highly specific for the disease, were positive in 36.4% of the patients8. A South African study carried out in Johannesburg in a black population, involving 63 patients found the mean age of onset at 36.1 years, with a male: female ratio of 1:4.6. Of the 63 patients, 13 had been exposed to silica from gold mines, a possible trigger factor of the disease in susceptible individuals. Raynaud’s phenomenon was the most common symptom, occurring in 90% of the patients, with 98% of the patients having antinuclear autoantibodies9. Another study, also carried out in South Africa, found antinuclear autoantibodies in 96% of the 160 patients10. Studies done elsewhere have also implicated silica in the pathogenesis of systemic sclerosis11-15. A study undertaken in Nigeria and involving 14 patients showed a predilection of the female gender, with a male: female ratio of 1:6. Diffuse cutaneous was the commonest variant in 57.1% of the study patients. Raynaud’s phenomenon was present in only 14.3% of the patients. Antinuclear antibodies were positive in 64.3% of the patients16. A study that reviewed the cause of death in systemic sclerosis from 1972 to 2002 in an American centre found that from 1972 to 1976 the commonest cause of death was scleroderma renal crisis. The trend declined and at the end of the study period (1997-2001), pulmonary disease, either pulmonary fibrosis or pulmonary arterial hypertension, was the commonest cause of death. This was attributed to better management of scleroderma renal crisis by use of dialysis services and drugs such as angiotensin converting enzyme inhibitors17. A study evaluating the radiological hand involvement in systemic sclerosis in 120 patients found that arthritis, distal phalange resorption, flexion contractures and extra articular calcification were the commonest radiological findings 18. A study which evaluated cardiac involvement by using cardiac MRI in 52 systemic sclerosis patients found an abnormality in 75% of them. These included pericardial effusion, altered ejection fractions of the right or left ventricle and ventricular kinetic abnormalities19. Systemic sclerosis is a poorly understood and rarely studied disease in the African population. Few studies have been carried out in Africa, with majority done in South Africa 9-14,15 and

the rest in Nigeria16,20,21. Kenyatta National Hospital is a tertiary referral and teaching hospital situated in Nairobi, Kenya; and is one of two in the country. It is the only public hospital with a rheumatology clinic, which has been in operation for one year, having been started in February 2010. Prior to the inauguration of this clinic, patients were seen in the general medical outpatient clinics. The rheumatology clinic is run under the auspices of qualified rheumatologists who review patients attending the clinic together with the registrars/residents from internal medicine attached to the unit. Nairobi arthritis clinic, a private rheumatology clinic based in Nairobi caters for a large number of patients with rheumatologic disorders including systemic sclerosis. These two rheumatology centers serve as the catchment area for the whole country due to the paucity of rheumatologists in Kenya.

Patients and methods Patient’s records covering a 10 year period between January 2001 and August 2011 were reviewed and those fulfilling the American College of Rheumatology criteria for systemic sclerosis were recruited into the study. Clinical presentation, age, gender, organ involvement, laboratory and radiological investigations, treatment modalities were documented.

Results

A total of 55 patients were identified. Five patients were excluded from the final analysis as they had localised scleroderma/morphea. The mean age at diagnosis was 41.7 years with a range of 4 to 70 years. Only one patient was aged less than 18 years. Female patients were 44 while 11 were male (M:F 1:4) (Table 1).

Table 1: Demographics _____________________________________Female 44 (80%) Male 11 (20%) Mean age 41.7 years Age range 4 years- 70 years _____________________________________

Majority of the patients (41) presented with diffuse cutaneous systemic sclerosis. Nine patients had limited cutaneous disease and no patient with systemic sclerosis sine scleroderma was identified. Fourteen of the patients had an overlap of scleroderma with another connective tissue disease (Tables 2, 3).

Table 2: Clinical variants __________________________________Diffuse cutaneous 41 (82%) SSc sine scleroderma 0 Limited cutaneous 9 (18%)__________________________________

Afr J Rheumatol 2013; 1(1): 8-1227

Table 3: Overlap syndromes ____________________________________________Syndrome No.____________________________________________

SLE/ Diffuse cutaneous 5 SLE/ Localised cutaneous 2 Rheumatoid arthritis/ Diffuse cutaneous 2 Sjogrens / Diffuse cutaneous 2 Dermatomyositis/ Diffuse cutaneous 3 ____________________________________________

The commonest clinical presentation was skin manifestation which was present in all the patients. Raynaud’s phenomenon was present in 32 of the patients. In the rest of the patients, the information in the patient records did not indicate that symptoms of Raynaud’s were not present or it was that they were not asked for. Therefore the actual incidence of Raynaud’s phenomenon may have been higher. Esophageal involvement; either from symptoms or confirmed by barium studies was present in 27 of the patients. Pulmonary involvement was present in 20 of the patients, with the 18 having pulmonary fibrosis both radiologically and on pulmonary function test and 10 having pulmonary arterial hypertension on echocardiogram (Table 4). One patient with diffuse cutaneous systemic sclerosis and rheumatoid arthritis presented with rapidly progressive glomerulonephritis which was managed successfully with intravenous cyclophosphamide. The other patient with scleroderma renal disease presented with protenuria and was managed with ACE inhibitors. Three deaths were documented, with all three patients having died from severe pulmonary disease and the attendant cor pulomonale.

Table 4: Clinical features _______________________________________ Feature No. (%)Skin involvement 50 100 Raynaud’s phenomenon 32 64 Pulmonary involvement 28 56

Pulmonary fibrosis 18 36 Pulmonary arterial hypertension 10 20

Esophageal involvement 27 54 Myopathy 16 32 Cardiac 11 22 Calcinosis 5 10 Acro-osteolysis 3 6 Scleroderma renal crisis 2 4 Arthritis/ arthalgia 8 16 Alopecia 4 8 Sicca symptoms 2 4 Vasculitis 1 2 Telengectasia 1 2________________________________________

Various autoantibodies were carried out in the patients. Antinuclear antibody (ANA) test was carried out in 40 of the patients and was positive in 27 of the patients. Antibody to SCl-70 was carried out in 23 patients and was positive in six patients only (Table 5).

Table 5: Autoantibody profile __________________________________________Antibody No. (%)..Antinuclear 27/40 67.5 Anti- SCL- 70 6/23 28.6 Anti- ds-DNA 4/16 25 Anti- CCP 0/8 Rheumatoid factor 7/27 25.9 Anti- SM 2/28 7.1 Anti- SSA 3/29 10.3 Anti- SSB 2/29 6.9 Anti- JO1 2/27 7.4 Anti- RNP 4/28 14.3__________________________________________

Table 6: Treatment modalities _________________________________________Modality No. (%)Acetylsalicylic acid/ antiplatelet agent 18 36 PPI/H2 blocker 27 54 Calcium channel blocker 31 62 Prokinetic agent 6 12 Sildenafil 2 4 Immunosuppressants 40 80 Methrotrexate 20/40 50 Cyclophosphamide 9/40 22.5 Mycophenolate mofetil 5/40 12.5 Azathioprine 5/40 12.5Hydroxychloroquine 4/40 10 Prednisone 20/40 50__________________________________________

Treatment modalities in the patients varied according to the presenting symptoms and extent of organ involvement. Twenty seven of the patients were on a proton pump inhibitor (PPI)/ H2 receptor blocker, 31 were on a calcium channel blocker, 18 were of acetylsalicylic acid and 40 were on immunosuppressant therapy, either in combination or as a single agent (Table 6).

Discussion Systemic sclerosis/ scleroderma is a rare condition with an estimated prevalence of 50 to 300 cases per 1 million persons and an incidence ranging from 2.3 to 22.8 cases per 1 million persons per year2,5 with an increased incidence reported amongst blacks 6,7. The mean age of at diagnosis was 41.7 years; compared to 40.3 years in the Nigerian series16 and 36.1 years in the South African study9 .The male to female ratio was 1:4 which is comparable to South African data (M:F 1:4.6)9 and Nigerian study M:F 1:616. The youngest patient in our study was a four year old male who presented with localized scleroderma with negative autoantibody profile, while the oldest were three patients aged 70 years. Diffuse cutaneous was the commonest clinical variant, occurring in 74%, with no cases being described with systemic sclerosis sine scleroderma. A Nigeria study16 had 57% of their patients presenting as diffuse cutaneous while a South African study9 had 65% of the patients presenting as diffuse cutaneous. Patients with systemic sclerosis sine


presents as pulmonary arterial hypertension, Raynaud’s phenomenon, digital ulcers, acro-osteolysis and renal disease. Other clinical presentations include calcinosis cutis and arthritis. It is these clinical presentations that result in the high morbidity and mortality of the disease. A study carried out in 30 countries (24 European, 6 non- European), involving 3656 patients was undertaken between 2004 and 2006. The male to female ratio was 1:6. Diffuse cutaneous systemic sclerosis was present in 36.9% while limited cutaneous disease was present in 63.1%. Patients with localized scleroderma were excluded from this study. Autoantibodies against SCL-70, which is highly specific for the disease, were positive in 36.4% of the patients8. A South African study carried out in Johannesburg in a black population, involving 63 patients found the mean age of onset at 36.1 years, with a male: female ratio of 1:4.6. Of the 63 patients, 13 had been exposed to silica from gold mines, a possible trigger factor of the disease in susceptible individuals. Raynaud’s phenomenon was the most common symptom, occurring in 90% of the patients, with 98% of the patients having antinuclear autoantibodies9. Another study, also carried out in South Africa, found antinuclear autoantibodies in 96% of the 160 patients10. Studies done elsewhere have also implicated silica in the pathogenesis of systemic sclerosis11-15. A study undertaken in Nigeria and involving 14 patients showed a predilection of the female gender, with a male: female ratio of 1:6. Diffuse cutaneous was the commonest variant in 57.1% of the study patients. Raynaud’s phenomenon was present in only 14.3% of the patients. Antinuclear antibodies were positive in 64.3% of the patients16. A study that reviewed the cause of death in systemic sclerosis from 1972 to 2002 in an American centre found that from 1972 to 1976 the commonest cause of death was scleroderma renal crisis. The trend declined and at the end of the study period (1997-2001), pulmonary disease, either pulmonary fibrosis or pulmonary arterial hypertension, was the commonest cause of death. This was attributed to better management of scleroderma renal crisis by use of dialysis services and drugs such as angiotensin converting enzyme inhibitors17. A study evaluating the radiological hand involvement in systemic sclerosis in 120 patients found that arthritis, distal phalange resorption, flexion contractures and extra articular calcification were the commonest radiological findings 18. A study which evaluated cardiac involvement by using cardiac MRI in 52 systemic sclerosis patients found an abnormality in 75% of them. These included pericardial effusion, altered ejection fractions of the right or left ventricle and ventricular kinetic abnormalities19. Systemic sclerosis is a poorly understood and rarely studied disease in the African population. Few studies have been carried out in Africa, with majority done in South Africa 9-14,15 and

the rest in Nigeria16,20,21. Kenyatta National Hospital is a tertiary referral and teaching hospital situated in Nairobi, Kenya; and is one of two in the country. It is the only public hospital with a rheumatology clinic, which has been in operation for one year, having been started in February 2010. Prior to the inauguration of this clinic, patients were seen in the general medical outpatient clinics. The rheumatology clinic is run under the auspices of qualified rheumatologists who review patients attending the clinic together with the registrars/residents from internal medicine attached to the unit. Nairobi arthritis clinic, a private rheumatology clinic based in Nairobi caters for a large number of patients with rheumatologic disorders including systemic sclerosis. These two rheumatology centers serve as the catchment area for the whole country due to the paucity of rheumatologists in Kenya.

Patients and methods Patient’s records covering a 10 year period between January 2001 and August 2011 were reviewed and those fulfilling the American College of Rheumatology criteria for systemic sclerosis were recruited into the study. Clinical presentation, age, gender, organ involvement, laboratory and radiological investigations, treatment modalities were documented.

Results

A total of 55 patients were identified. Five patients were excluded from the final analysis as they had localised scleroderma/morphea. The mean age at diagnosis was 41.7 years with a range of 4 to 70 years. Only one patient was aged less than 18 years. Female patients were 44 while 11 were male (M:F 1:4) (Table 1).

Table 1: Demographics _____________________________________Female 44 (80%) Male 11 (20%) Mean age 41.7 years Age range 4 years- 70 years _____________________________________

Majority of the patients (41) presented with diffuse cutaneous systemic sclerosis. Nine patients had limited cutaneous disease and no patient with systemic sclerosis sine scleroderma was identified. Fourteen of the patients had an overlap of scleroderma with another connective tissue disease (Tables 2, 3).

Table 2: Clinical variants __________________________________Diffuse cutaneous 41 (82%) SSc sine scleroderma 0 Limited cutaneous 9 (18%)__________________________________

Afr J Rheumatol 2013; 1(1): 8-1227

Table 3: Overlap syndromes ____________________________________________Syndrome No.____________________________________________

SLE/ Diffuse cutaneous 5 SLE/ Localised cutaneous 2 Rheumatoid arthritis/ Diffuse cutaneous 2 Sjogrens / Diffuse cutaneous 2 Dermatomyositis/ Diffuse cutaneous 3 ____________________________________________

The commonest clinical presentation was skin manifestation which was present in all the patients. Raynaud’s phenomenon was present in 32 of the patients. In the rest of the patients, the information in the patient records did not indicate that symptoms of Raynaud’s were not present or it was that they were not asked for. Therefore the actual incidence of Raynaud’s phenomenon may have been higher. Esophageal involvement; either from symptoms or confirmed by barium studies was present in 27 of the patients. Pulmonary involvement was present in 20 of the patients, with the 18 having pulmonary fibrosis both radiologically and on pulmonary function test and 10 having pulmonary arterial hypertension on echocardiogram (Table 4). One patient with diffuse cutaneous systemic sclerosis and rheumatoid arthritis presented with rapidly progressive glomerulonephritis which was managed successfully with intravenous cyclophosphamide. The other patient with scleroderma renal disease presented with protenuria and was managed with ACE inhibitors. Three deaths were documented, with all three patients having died from severe pulmonary disease and the attendant cor pulomonale.

Table 4: Clinical features _______________________________________ Feature No. (%)Skin involvement 50 100 Raynaud’s phenomenon 32 64 Pulmonary involvement 28 56

Pulmonary fibrosis 18 36 Pulmonary arterial hypertension 10 20

Esophageal involvement 27 54 Myopathy 16 32 Cardiac 11 22 Calcinosis 5 10 Acro-osteolysis 3 6 Scleroderma renal crisis 2 4 Arthritis/ arthalgia 8 16 Alopecia 4 8 Sicca symptoms 2 4 Vasculitis 1 2 Telengectasia 1 2________________________________________

Various autoantibodies were carried out in the patients. Antinuclear antibody (ANA) test was carried out in 40 of the patients and was positive in 27 of the patients. Antibody to SCl-70 was carried out in 23 patients and was positive in six patients only (Table 5).

Table 5: Autoantibody profile __________________________________________Antibody No. (%)..Antinuclear 27/40 67.5 Anti- SCL- 70 6/23 28.6 Anti- ds-DNA 4/16 25 Anti- CCP 0/8 Rheumatoid factor 7/27 25.9 Anti- SM 2/28 7.1 Anti- SSA 3/29 10.3 Anti- SSB 2/29 6.9 Anti- JO1 2/27 7.4 Anti- RNP 4/28 14.3__________________________________________

Table 6: Treatment modalities _________________________________________Modality No. (%)Acetylsalicylic acid/ antiplatelet agent 18 36 PPI/H2 blocker 27 54 Calcium channel blocker 31 62 Prokinetic agent 6 12 Sildenafil 2 4 Immunosuppressants 40 80 Methrotrexate 20/40 50 Cyclophosphamide 9/40 22.5 Mycophenolate mofetil 5/40 12.5 Azathioprine 5/40 12.5Hydroxychloroquine 4/40 10 Prednisone 20/40 50__________________________________________

Treatment modalities in the patients varied according to the presenting symptoms and extent of organ involvement. Twenty seven of the patients were on a proton pump inhibitor (PPI)/ H2 receptor blocker, 31 were on a calcium channel blocker, 18 were of acetylsalicylic acid and 40 were on immunosuppressant therapy, either in combination or as a single agent (Table 6).

Discussion Systemic sclerosis/ scleroderma is a rare condition with an estimated prevalence of 50 to 300 cases per 1 million persons and an incidence ranging from 2.3 to 22.8 cases per 1 million persons per year2,5 with an increased incidence reported amongst blacks 6,7. The mean age of at diagnosis was 41.7 years; compared to 40.3 years in the Nigerian series16 and 36.1 years in the South African study9 .The male to female ratio was 1:4 which is comparable to South African data (M:F 1:4.6)9 and Nigerian study M:F 1:616. The youngest patient in our study was a four year old male who presented with localized scleroderma with negative autoantibody profile, while the oldest were three patients aged 70 years. Diffuse cutaneous was the commonest clinical variant, occurring in 74%, with no cases being described with systemic sclerosis sine scleroderma. A Nigeria study16 had 57% of their patients presenting as diffuse cutaneous while a South African study9 had 65% of the patients presenting as diffuse cutaneous. Patients with systemic sclerosis sine

Feature

Antibody

Modality

No. (%)

No. (%)

No. (%)


scleroderma may have presented to other specialties such as gastroenterologists or chest physicians depending on the predominant organ involved. This may account for the absence of this variant at our rheumatology clinic. Similarly, patients with localized forms of scleroderma may have presented to the dermatology clinic and thus lead to underreporting in our series. Skin involvement was the commonest manifestation (100%), followed by with Raynauds phenomenon at 58% and esophageal disease was present in 49% of the patients. The relatively lower incidence of Raynaud’s compared to other largely western studies8 may be due to hotter climate and darker skin pigmentation leading to underreporting in our population. Nigerian study documented Raynaud’s in only two patients (14%). The South African study, which was carried out in blacks, reported occurrence of raynaud’s in 90% of their patients9. The lower incidence of Raynauds may also be attributed to the retrospective nature of the study. Antinuclear antibody was done in 21 patients and was positive in 67%. Anti- SCL-70 autoantibody, which is specific for scleroderma was, present in only 4 out of the 14 patients tested (28%). All the patients with antibodies to SCL-70 had the diffuse cutaneous variant. Anti- SCL-70 antibodies are more common in the diffuse cutaneous variant and are associated with severer forms of the disease. Two of these patients had severe lung restrictive patterns on pulmonary function tests, two had esophageal dysmotility whereas one had peripheral gangrene. One of the mortalities reported in our case series had anti- SCL-70 antibodies. Two patients presented with diffuse cutaneous systemic sclerosis after having been diagnosed to have breast cancer and subsequently underwent mastectomy followed by radiation and chemotherapy consisting of cyclophosphamide, methrotrexate and 5-florouracil. One patient developed the disease three years after the diagnosis of breast cancer. In this patient the autoantibodies done were all negative. The other patient developed diffuse cutanoeus disease 10 years after the diagnosis of cancer. In this patient rheumatoid factor as well as SCL-70 antibodies were positive. Cytotoxic medications have been implicated in the pathogenesis of this disease4. Treatment modalities varied depending on the clinical presentation. Fourty nine percent of the patients were on either prokinetic or PPI/H2 blocker. Immunosuppressants were administered to 72% of the patients , mainly due to internal organ involvement especially pulmonary involvement. The three deaths reported were as a results of pulmonary involvement (both fibrosis and pulmonary arterial hypertension) and cor pulmonale. The two cases of scleroderma renal crisis were documented in our series were managed successfully with immunosuppressants and angiotensin converting enzyme inhibitors. This is in keeping with data that shows the commonest cause of death currently is as a result of pulmonary involvement17. Limitations of the study included loss of follow up of majority of the patients. More than half of the patients

had not presented to the clinic in over one year. Some of these patients may have succumbed to their disease in peripheral health facilities. This is a recurrent problem in most of the outpatient clinics due to a variety of reasons such as lack of financial resources and residing far from the hospital. There was a limitation of the investigations carried out due to financial constraints. Being a retrospective study, some data may have been missing from the patients’ records. It is hoped that this study will provide vital information for a rare disease, which has not been studied much in the African population and that it will serve as a reference for future studies.

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14. Sluis-Cremer GK, Hessel PA, Nizdo EH, Churchill AR, Zeiss EA. Silica, silicosis, and progressive systemic sclerosis. Br J Ind Med. 1985 42(12):838-43.

15. Cowie RL. Silica-dust-exposed mine workers with scleroderma (systemic sclerosis). Chest 1987;92(2):260-262 .

16. Oguntona. Scleroderma (systemic sclerosis) among Nigerians. Clinical Rheumatology 2009; 1121-1125.

17. Steen, Medsgers . Changes in causes of death in systemic sclerosis, 1972 -2002. Ann Rheum Dis. 2007; 66: 940-944 .

18. Avouac J, Guerini H, Wipff J et al. Radiological hand involvement in systemic sclerosis. Ann Rheum Dis. 2006; 65:1088–1092. doi: 10.1136/ard.2005.044602

19. Hachulla A-L, Launay D, Gaxotte V et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis. 2009; 68:1878–1884.

20. Jacyk WK. Progressive systemic sclerosis; a case report from Nigeria and review of African cases. J Trop Med Hyg. 1979; 82 (2):42–44.

21. Ladipo GO. Progressive systemic sclerosis (scleroderma): first case report in a Nigerian. Dermatologica. 1979; 153(3):196–201.

Forty

Gabrielli A, Avvedimento E, Krieg T. Sceroderma mecha-


scleroderma may have presented to other specialties such as gastroenterologists or chest physicians depending on the predominant organ involved. This may account for the absence of this variant at our rheumatology clinic. Similarly, patients with localized forms of scleroderma may have presented to the dermatology clinic and thus lead to underreporting in our series. Skin involvement was the commonest manifestation (100%), followed by with Raynauds phenomenon at 58% and esophageal disease was present in 49% of the patients. The relatively lower incidence of Raynaud’s compared to other largely western studies8 may be due to hotter climate and darker skin pigmentation leading to underreporting in our population. Nigerian study documented Raynaud’s in only two patients (14%). The South African study, which was carried out in blacks, reported occurrence of raynaud’s in 90% of their patients9. The lower incidence of Raynauds may also be attributed to the retrospective nature of the study. Antinuclear antibody was done in 21 patients and was positive in 67%. Anti- SCL-70 autoantibody, which is specific for scleroderma was, present in only 4 out of the 14 patients tested (28%). All the patients with antibodies to SCL-70 had the diffuse cutaneous variant. Anti- SCL-70 antibodies are more common in the diffuse cutaneous variant and are associated with severer forms of the disease. Two of these patients had severe lung restrictive patterns on pulmonary function tests, two had esophageal dysmotility whereas one had peripheral gangrene. One of the mortalities reported in our case series had anti- SCL-70 antibodies. Two patients presented with diffuse cutaneous systemic sclerosis after having been diagnosed to have breast cancer and subsequently underwent mastectomy followed by radiation and chemotherapy consisting of cyclophosphamide, methrotrexate and 5-florouracil. One patient developed the disease three years after the diagnosis of breast cancer. In this patient the autoantibodies done were all negative. The other patient developed diffuse cutanoeus disease 10 years after the diagnosis of cancer. In this patient rheumatoid factor as well as SCL-70 antibodies were positive. Cytotoxic medications have been implicated in the pathogenesis of this disease4. Treatment modalities varied depending on the clinical presentation. Fourty nine percent of the patients were on either prokinetic or PPI/H2 blocker. Immunosuppressants were administered to 72% of the patients , mainly due to internal organ involvement especially pulmonary involvement. The three deaths reported were as a results of pulmonary involvement (both fibrosis and pulmonary arterial hypertension) and cor pulmonale. The two cases of scleroderma renal crisis were documented in our series were managed successfully with immunosuppressants and angiotensin converting enzyme inhibitors. This is in keeping with data that shows the commonest cause of death currently is as a result of pulmonary involvement17. Limitations of the study included loss of follow up of majority of the patients. More than half of the patients

had not presented to the clinic in over one year. Some of these patients may have succumbed to their disease in peripheral health facilities. This is a recurrent problem in most of the outpatient clinics due to a variety of reasons such as lack of financial resources and residing far from the hospital. There was a limitation of the investigations carried out due to financial constraints. Being a retrospective study, some data may have been missing from the patients’ records. It is hoped that this study will provide vital information for a rare disease, which has not been studied much in the African population and that it will serve as a reference for future studies.

References

1. John Vagra: Systemic sclerosis (scleroderma) and related disorders, Harrison’s Principles of Internal Medicine 17th edition. 2096- 2106.

2. Gabrielli, Avvedimento, Krieg. Scleroderma mecha-nism of disease. N Engl J Med. 2009; 360:1989-2003.

3. Jimenez D. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med. 2004;140: 37-50.

4. Nietert PJ, Silver RM. Systemic sclerosis: environmental and occupational risk factors. Curr Opin Rheumatol. 2000;12: 520-526.

5. Chifflot H, Fautzi B, Sordet C. et al. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008; 37:223-235.

6. Mayes MD, Lacey JV, Beebe-Dimmer J. et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003; 48: 2246-2255.

7. Reveille JD. Ethnicity and race in systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations. Curr Rheumatol Rep. 2003;5:160-167.

8. Walker U, Tyndall A, Czirja´k L et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis. 2007;66:754–763.

9. Tager, Tikly: Clinical and laboratory manifestation of systemic sclerosis (scleroderma) in black South Africans. Rheumatology. 1999; 38:397-400.

10. Pudifin DJ, Dinnematin H, Duursma J. Anti nuclear antibodies in systemic sclerosis: clinical and ethnic associations. S Afr Med J. 1991; 80(9):438–440.

11. Anandan S, Othman M, Cheong I. et al. Scleroderma secondary to silica exposure- a case report. Singapore Med J. 1995; 36: 559-561.

12. Cowie RL, Dansey RD. Features of systemic sclerosis (scleroderma) in South African goldminers. South Afr Med J. 1990; 77: 400-402.

13. Erasmus LD. Scleroderma in goldminers on the Witwatersrand with particular reference to pulmonary manifestations. S Afr J Lab Clin Med . 1957; 3: 209-231.

Afr J Rheumatol 2013; 1(1): 8-1229

14. Sluis-Cremer GK, Hessel PA, Nizdo EH, Churchill AR, Zeiss EA. Silica, silicosis, and progressive systemic sclerosis. Br J Ind Med. 1985 42(12):838-43.

15. Cowie RL. Silica-dust-exposed mine workers with scleroderma (systemic sclerosis). Chest 1987;92(2):260-262 .

16. Oguntona. Scleroderma (systemic sclerosis) among Nigerians. Clinical Rheumatology 2009; 1121-1125.

17. Steen, Medsgers . Changes in causes of death in systemic sclerosis, 1972 -2002. Ann Rheum Dis. 2007; 66: 940-944 .

18. Avouac J, Guerini H, Wipff J et al. Radiological hand involvement in systemic sclerosis. Ann Rheum Dis. 2006; 65:1088–1092. doi: 10.1136/ard.2005.044602

19. Hachulla A-L, Launay D, Gaxotte V et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis. 2009; 68:1878–1884.

20. Jacyk WK. Progressive systemic sclerosis; a case report from Nigeria and review of African cases. J Trop Med Hyg. 1979; 82 (2):42–44.

21. Ladipo GO. Progressive systemic sclerosis (scleroderma): first case report in a Nigerian. Dermatologica. 1979; 153(3):196–201.

Adelowo OO, Oguntona S. Scleroderma (systematic sclerosis)among Nige r i ans .C l in Rheumato l 2009;28 . (9 ) : 1121-1125

J.


Platelet counts in patients with rheumatoid arthritis at the Kenyatta National Hospital- Nairobi, Kenya

Mbuthia BM1, Oyoo GO1, Kitonyi GW2


1Department of Clinical Medicine and Therapeutics 2Department of Haematology and blood Transfusion School of Medicine, University of Nairobi, P O Box 19676, 00202 Nairobi. Kenya

Corresponding author: Dr. G. W. Kitonyi. Email: [email protected]

RESEARCH ARTICLE

Abstract

Background: Rheumatoid arthritis (RA) is a disease associated with signi� cant morbidity and mortality. Thrombocytosis is one of the haematological manifesta-tions of rheumatoid arthritis that occurs in active disease. Platelet counts may vary depending on disease activity and the variation has been shown to correlate with clinical and laboratory indices of disease activity in RA. Occa-sionally patients with RA may have drug induced thrombocytopenia.Objectives: To determine the relationship between platelet counts and clinical disease activity in patients with RA at Kenyatta National Hospital (KNH). Design: A cross-sectional descriptive study. Setting: Rheumatoid arthritis patients attending the KNH Rheumatology Outpatient Clinic (ROPC). Methods: Patients presenting to the clinic were screened and those meeting the inclusion criteria recruited into the study. Consecutive sampling technique was done. A targeted history was obtained, following which a physical exam was done on the recruited patients. The patients’ platelet counts were measured using Abbot Cell Dyn 1300. The patents’ erythrocyte sedimentation rate (ESR)) was measured with the Wintrobe’s method. The patients’ clinical disease activity using the DAS 28 score was recorded.Results: One hundred and four patients were recruited over the 6 months period between November 2010 and April 2011. Females were 90(86.5%) and 14(13.5%) were males giving a male to female ratio of 1:6.4. The mean age of the patients was 48 years. Regarding medication use, 75% of the patients were on disease modifying anti-rheumatic drugs (DMARDs), 72.1% on non-steroidal analgesics (NSAIDs) and 46.2% on steroids. The mean platelet count was 313.2 ±SD94 x 109/L

with a range of 152 -611 x 109/L. Only 15 (14.4%) had thrombocytosis (>400x 109/L). No case of thrombocytopenia was recorded. Ninety two had active disease (88.5%) while 10(11.5%) were in remission. Among those with active disease,10(9.6%) had mild disease, 51(49%) moderate disease and 31(29.6%) high disease activity. The DAS28 score was not signi� cantly di� erent between those who had thrombocytosis and those who had normal platelet counts (p=0.413). However, HB, MCV and MCH were signi� cantly lower in those with thrombocytosis at P values of 0.02, 0.002, 0.03 respectively. No correlation was found between platelet counts and clinical disease activity (DAS28).Conclusion: While thrombocytosis was found in 14.4% of patients with RA, this study demonstrated that no relationship exists between platelet counts and dis-ease activity in patients with rheumatoid arthritis seen at KNH.

Introduction

Rheumatoid arthritis is a chronic systemic infl ammatory disorder characterised by deforming symmetrical polyarthritis often leading to joint destruction, deformity and loss of function. Extra-articular features and systemic symptoms can commonly occur and may antedate the onset of joint symp-toms1 . Chronic pain, disability and excess mortality are common sequelae. High standardised mortality rates have been observed in the RA population compared with the general population2,3. Thrombo-cytosis is among one of the haematologi-cal manifestations of rheumatoid arthritis (RA). Various studies have demonstrated thrombocytosis in RA with prevalence ranges from 16% to 51% in different studies4,5. Several possible mechanisms are thought to cause the increased platelet count. These include, decreased platelet survival, increased erythropoeitin levels, infl ammatory cytokines, increased

2 Department of Human Pathology, unit of Hematology and Blood TransfusionSchool of Medicine University of Nairobi, P O Box 1967600202, Nairobi, Kenya

Dr G W Kitonyi.

Unit

,

Haematology

Dr. BM [email protected]

4-7.

Afr J Rheumatol 2013; 1(1): 28-3229 Afr J Rheumatol 2013; 1(1): 8-1229 Afr J Rheumatol 2013; 1(1): 8-1235

thrombopoietin levels and analgesic-induced occult gastrointestinal bleeding 6-14. Thrombocytosis has been shown to have consistent correlation with disease activity in different studies. Thrombocytosis is associated with more active disease and extra-articular manifestations are more common 4,5. Elevated platelet counts are also associated with more joint damage15. Platelet counts have also been shown to positively correlate with acute phase reactants such as ESR, CRP in RA 4,16,17. This study was undertaken to describe the platelet counts in patients with RA and determine any relationship to clinical disease activity.


The was a cross-sectional descriptive study carried out at the Kenyatta National Referral and Teaching Hospital from November 2010 to April 2011. The study population were patients with RA on follow up at the KNH ROPC. The inclusion criteria were patients aged 18 years and above with rheumatoid arthritis attending the ROPC and those who gave informed consent. Patients excluded included those with acute febrile illnesses, bleeding disorders, haematological conditions, patients known to have malignancies and RA with mixed connective tissue disease. The main outcome variables were clinical disease activity and platelet count. Clinical disease activity as per DAS28 scores was classified as follows: Remission≤ 2.6, Mild 2.6-3.2, Moderate >3.2-5.1 and High ≥ 5.1. Platelet count was graded as follows: Thrombocytopenia <150 × 109/l , Normal platelet 150– 400 × 109/l , Mild Thrombocytosis 400-600 × 109/l , Moderate thrombocytosis 650-800 × 10109/l , Marked thrombocytosis >800 × 109/l . In the ROPC, all patients on follow up for RA were screened for recruitment into the study. The files of patients who met the inclusion criteria were selected and consecutively sampled for study. Of the eligible patients, informed consent was obtained from them to participate in the study. Once consent was given, history was taken, physical examination performed and blood collected from them for laboratory investigation as outlined below. The principal investigator obtained socio- demographic data which included age, gender, marital status, place of residence, and occupation from both the patients and/or the patients’ records. Disease history obtained included duration of illness, when first diagnosed, whether on any treatment, response to treatment and any current concurrent illness. Physical examination was carried out to check for features of active RA. All joints were examined for swelling and tenderness. The number of joints swollen and/ tender was recorded on the DAS28 score sheet. The patient was asked to assess his/her general well being using the Visual Analog Scale (VAS) and this too recorded in the DAS28 score sheet.

Three millilitres of venous blood was drawn aseptically from the forearm and collected in an EDTA bottle for a full blood count and ESR estimation in consenting patients. The blood was analyzed using Abbot Cell Dyn 1300 in the Department of Pathology, Haematology unit University of Nairobi. The ESR was also carried out by the Wintrobe’s method. The ESR level was then recorded in the DAS score sheet. The total DAS score was then calculated using the DAS28 calculator . All data was collected on the study proforma and entered into a computer data base MS Access. Statistical analysis was done using Statistical Package for Social Scientists (SPSS) version 17.0 software. Continuous variables such as age, DAS 28 scores platelet counts and ESR are summarized into means, median, and ranges. Comparison of means was done using Student’s t test for normally distributed data and Mann Whitney U test for non-normal data. Platelet count was correlated to DAS28 score using the spearman Rho coefficients. Bivariate analysis was done using the Man Whitney test, Pearson’s chi-square or Fisher exact test. Multivariate analysis done by linear regression was used to determine the relationship between platelet count and DAS28 adjusting for various factors. Comparisons were considered statistically significant at a P value ≤ 0.05. Ninety five percent confidence limits were used as a measure of certainty. Results are presented in form of charts, graphs and tables. The study was carried out upon approval by the local ethics board.Results

In a period of 6 months, among the patients attending ROPC, 104 patients with RA were identified. These were screened and recruited into the study. Most of the patients were aged between 40 to 59 years at 53.9% with a mean age of 48 years ± 14 and a median age of 49 years (18-79 years) and a male to female ratio of 1: 6.4. Most of the patients had been diagnosed with RA over the last 1 to 5 years at 43.3% while in 25 (24%) the diagnosis had been made over the last one year. Majority of the patients were on DMARDs at 78 (75%) while on 48 (46.2%) were on steroids. The most commonly used DMARD was methotrexate in 72(69.2%) of the patients while only one patient was on leflunomide The platelet counts in the study population varied between 152 to 611 x109/L with a mean of 313.2 ±SD 94.0 and a median of 294.5 x109/L. Eighty nine (85.6%) had normal platelet counts while 15 (14.4%) [95% CI: 8.9-22.4] had thrombocytosis. No case of moderate (more than 650 x109/L) or severe thrombocytosis (>800 x109/L) was recorded. Among those with thrombocytosis 12(80%) were female and 3(20%) were male. Platelet counts of the study population are shown in Table 1.

Afr J Rheumatol 2013; 1(1): 8-12 36

Table 1: Platelet counts in study population

Platelet counts No. (%)

Median 294 x109/L

Mean 313.2±94 x109/L

Range 152-611 x109/LNormal platelet counts(150- 400 x 109/L

89 (85.6%)

Thrombocytosis (mild)Above 400 x 109/L

15 (14.4%)

Comparison of various parameters between those with thrombocytosis and those with normal platelet counts was done. Comparison between those with normal versus

elevated platelet counts showed that the median DAS28 score was slightly lower in those with normal platelet scores at 4.2 versus 4.6 in those with thrombocytosis but insignifi cant (p 0.413). Differences in the median age and erythrocyte sedimentation rate (ESR) levels were also insignifi cant and P values of 0.715 and 0.185 respectively. Signifi cant differences in the median of the haemoglobin levels, RBC indices and WBC counts were found between the two groups. Lower HB, MCV and MCH were associated with elevated platelet counts while higher WBC was associated with thrombocytosis (Table 2). The signifi cant values were then subjected to a multivariate analysis by linear regression as shown in Table 5. While haemoglobin lost signifi cance MCV remained signifi cant demonstrating that the MCV is independently associated with platelet levels as is WBCs.

Table 2: Comparison of various parameters in those with normal Vs high platelet counts

Laboratory parameters

Platelet count (>400x109/L) Platelets count (150- 400x 109/L)P valueNo. Median (Range) No. Median (Range)

DAS28 Score 15 4.6 (2.2-7.1) 89 4.2 (1.7-8.4) 0.413Age (years) 15 46.0 (25.0 - 76.0) 89 50.0 (18.0 - 79.0) 0.715ESR(mm/hr) 15 40.0 (6.0-60.0) 89 35.0 (2.0-63.0) 0.185HB(g/dl) 15 11.5 (4.4-13.9) 89 12.8 (7.4-16.3) 0.020MCV(fl ) 15 72.0 (56.0-87.0) 89 83.0 (55.0-101.0) 0.002MCH(pg) 15 22.8 (15.6-28.9) 89 26.8 (16.0-34.0) 0.001WBC x109/L 15 7.6 (4.8-13.6) 89 6.1 (3.0-12.2) 0.030

Regarding the clinical disease activity, the mean DAS28 score was 4.5 ± 1.5 with a median of 4.3 and a range of 1.7-8.4. Majority of the patients had moderate disease activity at 52 (49 %) while only 12 (11.5) % had their disease in remission. Thirty (29.8%) had high disease activity and 10 (9.6%) mild disease as shown in Figure 1.Figure 1: Distribution of clinical disease activity.

Figure 1: Distribution of clinical disease activityFigure 1: Distribution of clinical disease activity

In terms of platelet counts for the various levels of disease activity,the median platelet count for those in remission was 285x 109/L, mild disease 310x109/L, 285x109/L for moderate disease and 311x109/L for those with high disease activity. This is best illustrated in Figure 3.

This

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Afr J Rheumatol 2013; 1(1): 8-12 36



Median 294 x109/L

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Afr J Rheumatol 2013; 1(1): 8-1235






Afr J Rheumatol 2013; 1(1): 8-12 36



Median 294 x109/L

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Figure 2: Boxplot of various DAS scores and respective platelet counts

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Correlation between platelet counts and DAS28 scores revealed a correlation coefficient of r=0.084 which is statistically insignificant at p=0.394 as shown in the scatter plot below (Figure 3).

Figure 3: Correlation between plaletet counts and DAS28 scores

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Platelet = 289.64 + 5.27 * das28R-Square = 0.01

r r = 0.084, p=0.394

Discussion

The mean platelet count in the study population was 313.2 ±94 x10⁹/L , a median of 294 x10⁹/L and a range of 152-611x 10⁹/L. These figures are much higher than platelet counts in normal healthy adults. In 1981 Mukibi

et al19 found a mean platelet count of 200 x10⁹/L in healthy Kenyan adults. A more recent study by Rajab et al20 on haematological parameters in healthy Kenyan blood donors found a mean platelet count of 241.2 ±86.6 x10⁹/L and median of 235.1 x10⁹/L. Bain21 found even lower platelet counts of a mean of 183 x10⁹/L in black females and 207 x10⁹/L in black males in a study comparing ethnic and gender differences in healthy adults though in a different set up. It can therefore be inferred from these previous studies that patients with RA have higher platelet counts. Our results are comparable to a Turkish study by Yacizi et al 22who found mean platelets of 307±99 x10⁹/L in patients with active RA compared to a mean of 258 ±58 x10⁹/L in healthy controls . It is worth noting that despite the significant use of DMARDs, no case of thrombocytopenia was recorded. The prevalence of thrombocytopenia in various studies ranges from 0.8 to 3.1% in patients using DMARDs23,24. Buhroo et al24 in a study in India found only 2 out of 245 patients (0.8 %) had thrombocytopenia. This is close to our study that recorded no case of thrombocytopenia The consistent concurrent use of folate use in our patients may account for this finding as folate has been shown to reduce the adverse effects of methotrexate24. Thrombocytosis was found in only 15(14.4%) of the study population. Studies elsewhere have recorded higher prevalences of thrombocytosis. Hutchingsons

et al 5 and Selroos4 found prevalences of 51% and 33% respectively. Notably these studies were done in the 70s and 80s when use of DMARDs was not widespread. A higher prevalence of thrombocytosis in Caucasians could also be attributable to the fact that Caucasians have been shown to have higher levels of platelets compared to Africans in several studies19,20. Therefore a relatively lower baseline platelet count to start with will result to fewer cases of thrombocytosis when using the same cut-off as the Western studies despite a similar increase in platelet counts. A case control study in future may bring out these differences. A more recent Saudi Arabia study found a prevalence of 16%25.This is comparable to the findings of this study. No similar study has been done in Africa to which the findings can be compared. Majority of the patients had active disease at 88.5% (DAS28 scores >2.6). The majority of these had moderate disease activity (49%) while 29.7% had high disease activity and only 9.6 with mild disease activity..This is probably because a significant number of the patients (24%) were diagnosed during the study period and had previously not been on treatment and therefore had high disease activity. Another possible explanation is that more aggressive treatment maybe needed for these patients such as anti-TNF antagonist or use of biological of which none of the patients was on. The study did not assess compliance to treatment which could also affect the levels of disease activity seen in the study population. While comparing different parameters in those with thrombocytosis versus normal PCs, no significant difference was found in the median DAS28 scores between the groups i.e 4.6 versus 4.2 (p=0.413). This precludes any meaningful relationship between platelet counts and disease activity in this study. The Hb, MCV

Afr J Rheumatol 2013; 1(1): 8-12 38

and MCH were however noted to be signifi cantly lower in the group with thrombocytosis at p of 0.20,0.002 and 0.001 respectively. This is similar to what other studies have reported. Hutchingsons et al5 found higher platelet counts in those with lower Hb mean of 12.47(+0.10) in platelets <450 x109/L and 11.27 +0.77 in >450 x109/L. The lower Hb was noted to be mainly microcytic hypochromic. This was confi rmed by the multivariate analysis that confi med MCV to be an independent contributor to platelet counts. The microcytic anaemia is usually due to either iron defi ciency anaemia(IDA) or less commonly anaemia of chronic disease (ACD). IDA is usually associated with a reactive thrombocytosis. ACD may also be associated with a reactive thrombocytosis secondary to chronic infl ammation9. This can explain the association between thrombocytosis and low MCV. Further studies are needed to defi ne the exact cause(s) of the low MCV/MCH in our study population. Correlation between disease activity and platelet count revealed no signifi cant correlation at p=0.394. These fi ndings are in contrast to earlier studies by Hutchingsons et al5 and Farr et al9 who both found a positive correlation. However they used different measures of disease activity with Hutchingsons et al5 including a presence of extraarticular manifestations, morning stiffnes and grip strength which are not assessed in the DAS 28 score. Farr et al9 used the total articular index i.e summation of pain on movement, stiffness, swelling, heat and tenderness of each joint. Notably, the other studies had recorded higher levels of thrombocytosis to start with. Our fi ndings are more comparable to Yacizi’s et al22 who used the DAS score in assessment of disease activity. The study demonstrated a fall in mean platelet counts after a period of treatment but the platelet counts did not correlate with disease activity however. In conclusion, patients with RA have relatively increased platelet counts compared to the general population in our black patients. While thrombocytosis was found in 14.4% of the patients with RA, no relationship was found between platelet counts and disease activity in patients with RA in this study.

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prognosis, and causes of death in rheumatoid arthritis. Arthritis Rheum. 1986; 29:706–714.

2. Sokka T, Mottonen T, Hannonen P. Mortality in early ‘sawtooth’ treated RA patients during the fi rst 8-14 years. Scand J Rheumatol. 1999; 28:282-287.

3. Gabriel SE, Crowson CS, O’Fallon WM. Mortality in RA: Have we made an impact in four decades? J Rheumatol. 1999; 26:2529-2533.

4. Selroos O. Thrombocytosis in rheumatoid arthritis. Scand J Rheumat. 1972; 1(3) 136-140.

5. Hutchingsons RM, Davis P, Jayson M. Thrombocy-tosis in rheumatoid arthritis. Ann Rheum Dis. 1976; 35:138-142.

6. Dixon JS, Martin MF, Wright VA. Comparison of platelet count and acute phase proteins in measurement of disease activity in RA. Rheumatology. 1983; 22(4):233-238.

7. Aisha AG, Suzan MA. Extra-articular manifestations of rheumatoid arthritis: A hospital-based study. Ann Saudi Med. 2009: 29 (3) 189-193.

8. Garg SK, Amorosi EL, Karpatkin S. Use of megathrombocyte as an index of megakarocyte number. New Eng J Med. 1971; 284:11.

9. Farr M, Scott T, Constable TJ, et al .Thrombocytosis of active RA. Ann Rheum Dis. 1983; 42:545-549.

10. Farr M, Wainwright A, Salmon, M., et al. Platelets in the synovial fl uid of patients with rheumatoid arthritis. Rheumatol Int. 1984; 4(1):13-17.

11. Beguin Y. Erythropoeitin and platelet production. Hematologica. 1999; 84(6):541-547.

12. Ertenil I, Kiras Z, Ozturk MA. et al. Pathological thrombopoeisis of RA. Rheumatol Int. 2003; 23(2):49-60.

13. Haznedaroğlu IC, Ertenil I, Ozcebe OI. et al. Meg-akaryocyte-related interleukins in reactive thrombo-cytosis versus autonomous thrombocythemia. Acta Haematol. 1996; 95(2):107-111.

14. Hollen CW, Henthorn J, Koziol JA. et al. Serum IL-6 levels in patients with thrombocytosis. Leukemia Lymphoma.1998; 8(3):235-241.

15. Ceresa IF, Patrizia N, Chiara A. et al. Thrombopeitin is not uniquely responsible for thrombocytosis in infl ammatory disorders. Platelets 2000; 18(8):579-582.

16. Kiraz S, Ertenli I, Ozturk MA. et al. Bloodstream thrombopoeitin in rheumatoid arthritis with thrombocytosis. Clinical Rheumatol. 2002; 21(6):453-456.

17. Milovanovic M, Nilsson E. Järemo P. Relationships between platelets and infl ammatory markers in rheumatoid arthritis Clinica Chimica Acta. 2004; 343: 237-240.

18. Aiping LZ. Correlations among cartilage erosions, IgA levels, red bloodcell and platelet counts in 436 RA patients with path analysis. Bioinformat Biomed Engineering 2009; 6:1-3.

19. Mukibi JM, Okelo GA, Kanja C. Platelet in normal Kenyan adults. East Afr Med J. 1981; 58:136-139.

20. Rajab JA, Muchina WP, Orinda DA et al. Blood donor haematology parameters in two regions of Kenya. East Afr Med J. 2005; 82: 123-127.

21. Bain JB. Ethnic and sex differences in the total and differential white cell count and platelet count. J Clin Path. 1996; 49:664-666.

22. Yacizi S, Yacizi M., Erer B. The platelet indices in patients with rheumatoid arthritis. Platelets. 2010; 21(2):122-125.

23. Franck H, Rau R. Herborn G. Thrombocytopenia in patients with RA on long term treatment with low dose methotrexate. Clin Rheumatol. 1997; 16(4): 429-430.

24. Buhroo AM, Baba AN. Adverse effects of low dose methotrexate in patients with rheumatoid arthritis. Indian J Physical Med Rehab.2006; 17(2): 21-25.

25. Hornung N, Ellingsen T, Stengaard-Pedersen K. et al. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement. J Rheumatol. 2004;31(12):2374.

x109 /L

x109 /L

x109 /L

et al19 found a mean platelet count of 200 xl09/L in healthy Kenyan adults. A more recent study by Rajab et al20 on haematological parameters in healthy Kenyan blood donors found a mean platelet count of 241.2 ±86.6 x109/L and median of 235.1 x109/L. Bain21 found even lower platelet counts of a mean of l83 xl09/L in black females and 207 x109/L in black males in a study comparing ethnic and gender differences in healthy adults though in a different set up. It can therefore be inferred from these previous studies that patients with RA have higher platelet counts. Our results are comparable to a Turkish study by Yacizi et al 22who found mean platelets of 307±99 x109/L in patients with active RA compared to a mean of 258 ±58 x109/L in healthy controls .

It is worth noting that despite the significant use of DMARDs, no case of thrombocytopenia was recorded. The prevalence of thrombocytopenia in various studies ranges from 0.8 to 3.1% in patients using DMARDs23,24. Buhroo et al24 in a study in India found only 2 out of 245 patients (0.8 %) had thrombocytopenia. This is close to our study that recorded no case of thrombocytopenia The consistent concurrent use of folate use in our patients may account for this finding as folate has been shown to reduce the adverse effects of methotrexate25.

Thrombocytosis was found in only 15(14.4%) of the study population. Studies elsewhere have recorded higher prevalences of thrombocytosis. Hutchingsons et al 5 and Selroos4 found prevalences of 51% and 33% respectively. Notably these studies were done in the 70s and 80s when use of DMARDs was not widespread. A higher prevalence of thrombocytosis in Caucasians could also be attributable to the fact that Caucasians have been shown to have higher levels of platelets compared to Africans in several studies20,21. Therefore a relatively lower baseline platelet count to start with will result to fewer cases of thrombocytosis when using the same cut off as the Western studies despite a similar increase in platelet counts. A case control study in future may bring out these differences. A more recent Saudi Arabia study found a prevalence of 16%6.This is comparable to the findings of this study. No similar study has been done in Africa to which the findings can be compared.

Most of the patients had active disease at 88.5% (DAS28 scores >2.6). The majority of these had moderate disease activity (49%) while 29.7% had high disease activity and only 9.6% had mild disease activity. This is probably because a significant number of the patients (24%) were diagnosed during the study period and had previously not been on treatment and therefore had high disease activity. Another possible explanation is that more aggressive treatment maybe needed for these patients such as anti-TNF antagonist or use of biological agents of which none of the patients was on. The study did not assess compliance to treatment which could also affect the levels of disease activity seen in the study population.

While comparing different parameters in those with thrombocytosis versus normal PCs, no significant difference was found in the median DAS28 scores between the groups i.e 4.6 versus 4.2 (p=0.413). This precludes any meaningful relationship between platelet counts and disease activity in this study. The Hb, MCV

27


Figure 2: Boxplot of various DAS scores and respective platelet counts

<2.6 2.6 - 3.2 3.3 - 5.1 >5.1DAS28 Score

0

100

200

300

400

500

600

700

Plat

elet

cou

nt

Correlation between platelet counts and DAS28 scores revealed a correlation coefficient of r=0.084 which is statistically insignificant at p=0.394 as shown in the scatter plot below (Figure 3).

Figure 3: Correlation between plaletet counts and DAS28 scores

2.0 4.0 6.0 8.0DAS28 Score

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100

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300

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600

700

Plat

elet

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Platelet = 289.64 + 5.27 * das28R-Square = 0.01

r r = 0.084, p=0.394

Discussion

The mean platelet count in the study population was 313.2 ±94 x10⁹/L , a median of 294 x10⁹/L and a range of 152-611x 10⁹/L. These figures are much higher than platelet counts in normal healthy adults. In 1981 Mukibi

et al19 found a mean platelet count of 200 x10⁹/L in healthy Kenyan adults. A more recent study by Rajab et al20 on haematological parameters in healthy Kenyan blood donors found a mean platelet count of 241.2 ±86.6 x10⁹/L and median of 235.1 x10⁹/L. Bain21 found even lower platelet counts of a mean of 183 x10⁹/L in black females and 207 x10⁹/L in black males in a study comparing ethnic and gender differences in healthy adults though in a different set up. It can therefore be inferred from these previous studies that patients with RA have higher platelet counts. Our results are comparable to a Turkish study by Yacizi et al 22who found mean platelets of 307±99 x10⁹/L in patients with active RA compared to a mean of 258 ±58 x10⁹/L in healthy controls . It is worth noting that despite the significant use of DMARDs, no case of thrombocytopenia was recorded. The prevalence of thrombocytopenia in various studies ranges from 0.8 to 3.1% in patients using DMARDs23,24. Buhroo et al24 in a study in India found only 2 out of 245 patients (0.8 %) had thrombocytopenia. This is close to our study that recorded no case of thrombocytopenia The consistent concurrent use of folate use in our patients may account for this finding as folate has been shown to reduce the adverse effects of methotrexate24. Thrombocytosis was found in only 15(14.4%) of the study population. Studies elsewhere have recorded higher prevalences of thrombocytosis. Hutchingsons

et al 5 and Selroos4 found prevalences of 51% and 33% respectively. Notably these studies were done in the 70s and 80s when use of DMARDs was not widespread. A higher prevalence of thrombocytosis in Caucasians could also be attributable to the fact that Caucasians have been shown to have higher levels of platelets compared to Africans in several studies19,20. Therefore a relatively lower baseline platelet count to start with will result to fewer cases of thrombocytosis when using the same cut-off as the Western studies despite a similar increase in platelet counts. A case control study in future may bring out these differences. A more recent Saudi Arabia study found a prevalence of 16%25.This is comparable to the findings of this study. No similar study has been done in Africa to which the findings can be compared. Majority of the patients had active disease at 88.5% (DAS28 scores >2.6). The majority of these had moderate disease activity (49%) while 29.7% had high disease activity and only 9.6 with mild disease activity..This is probably because a significant number of the patients (24%) were diagnosed during the study period and had previously not been on treatment and therefore had high disease activity. Another possible explanation is that more aggressive treatment maybe needed for these patients such as anti-TNF antagonist or use of biological of which none of the patients was on. The study did not assess compliance to treatment which could also affect the levels of disease activity seen in the study population. While comparing different parameters in those with thrombocytosis versus normal PCs, no significant difference was found in the median DAS28 scores between the groups i.e 4.6 versus 4.2 (p=0.413). This precludes any meaningful relationship between platelet counts and disease activity in this study. The Hb, MCV

Afr J Rheumatol 2013; 1(1): 8-12 38

and MCH were however noted to be signifi cantly lower in the group with thrombocytosis at p of 0.20,0.002 and 0.001 respectively. This is similar to what other studies have reported. Hutchingsons et al5 found higher platelet counts in those with lower Hb mean of 12.47(+0.10) in platelets <450 x109/L and 11.27 +0.77 in >450 x109/L. The lower Hb was noted to be mainly microcytic hypochromic. This was confi rmed by the multivariate analysis that confi med MCV to be an independent contributor to platelet counts. The microcytic anaemia is usually due to either iron defi ciency anaemia(IDA) or less commonly anaemia of chronic disease (ACD). IDA is usually associated with a reactive thrombocytosis. ACD may also be associated with a reactive thrombocytosis secondary to chronic infl ammation9. This can explain the association between thrombocytosis and low MCV. Further studies are needed to defi ne the exact cause(s) of the low MCV/MCH in our study population. Correlation between disease activity and platelet count revealed no signifi cant correlation at p=0.394. These fi ndings are in contrast to earlier studies by Hutchingsons et al5 and Farr et al9 who both found a positive correlation. However they used different measures of disease activity with Hutchingsons et al5 including a presence of extraarticular manifestations, morning stiffnes and grip strength which are not assessed in the DAS 28 score. Farr et al9 used the total articular index i.e summation of pain on movement, stiffness, swelling, heat and tenderness of each joint. Notably, the other studies had recorded higher levels of thrombocytosis to start with. Our fi ndings are more comparable to Yacizi’s et al22 who used the DAS score in assessment of disease activity. The study demonstrated a fall in mean platelet counts after a period of treatment but the platelet counts did not correlate with disease activity however. In conclusion, patients with RA have relatively increased platelet counts compared to the general population in our black patients. While thrombocytosis was found in 14.4% of the patients with RA, no relationship was found between platelet counts and disease activity in patients with RA in this study.

References1. Mitchell DM, Spitz PW, Young DY et al. Survival,

prognosis, and causes of death in rheumatoid arthritis. Arthritis Rheum. 1986; 29:706–714.

2. Sokka T, Mottonen T, Hannonen P. Mortality in early ‘sawtooth’ treated RA patients during the fi rst 8-14 years. Scand J Rheumatol. 1999; 28:282-287.

3. Gabriel SE, Crowson CS, O’Fallon WM. Mortality in RA: Have we made an impact in four decades? J Rheumatol. 1999; 26:2529-2533.

4. Selroos O. Thrombocytosis in rheumatoid arthritis. Scand J Rheumat. 1972; 1(3) 136-140.

5. Hutchingsons RM, Davis P, Jayson M. Thrombocy-tosis in rheumatoid arthritis. Ann Rheum Dis. 1976; 35:138-142.

6. Dixon JS, Martin MF, Wright VA. Comparison of platelet count and acute phase proteins in measurement of disease activity in RA. Rheumatology. 1983; 22(4):233-238.

7. Aisha AG, Suzan MA. Extra-articular manifestations of rheumatoid arthritis: A hospital-based study. Ann Saudi Med. 2009: 29 (3) 189-193.

8. Garg SK, Amorosi EL, Karpatkin S. Use of megathrombocyte as an index of megakarocyte number. New Eng J Med. 1971; 284:11.

9. Farr M, Scott T, Constable TJ, et al .Thrombocytosis of active RA. Ann Rheum Dis. 1983; 42:545-549.

10. Farr M, Wainwright A, Salmon, M., et al. Platelets in the synovial fl uid of patients with rheumatoid arthritis. Rheumatol Int. 1984; 4(1):13-17.

11. Beguin Y. Erythropoeitin and platelet production. Hematologica. 1999; 84(6):541-547.

12. Ertenil I, Kiras Z, Ozturk MA. et al. Pathological thrombopoeisis of RA. Rheumatol Int. 2003; 23(2):49-60.

13. Haznedaroğlu IC, Ertenil I, Ozcebe OI. et al. Meg-akaryocyte-related interleukins in reactive thrombo-cytosis versus autonomous thrombocythemia. Acta Haematol. 1996; 95(2):107-111.

14. Hollen CW, Henthorn J, Koziol JA. et al. Serum IL-6 levels in patients with thrombocytosis. Leukemia Lymphoma.1998; 8(3):235-241.

15. Ceresa IF, Patrizia N, Chiara A. et al. Thrombopeitin is not uniquely responsible for thrombocytosis in infl ammatory disorders. Platelets 2000; 18(8):579-582.

16. Kiraz S, Ertenli I, Ozturk MA. et al. Bloodstream thrombopoeitin in rheumatoid arthritis with thrombocytosis. Clinical Rheumatol. 2002; 21(6):453-456.

17. Milovanovic M, Nilsson E. Järemo P. Relationships between platelets and infl ammatory markers in rheumatoid arthritis Clinica Chimica Acta. 2004; 343: 237-240.

18. Aiping LZ. Correlations among cartilage erosions, IgA levels, red bloodcell and platelet counts in 436 RA patients with path analysis. Bioinformat Biomed Engineering 2009; 6:1-3.

19. Mukibi JM, Okelo GA, Kanja C. Platelet in normal Kenyan adults. East Afr Med J. 1981; 58:136-139.

20. Rajab JA, Muchina WP, Orinda DA et al. Blood donor haematology parameters in two regions of Kenya. East Afr Med J. 2005; 82: 123-127.

21. Bain JB. Ethnic and sex differences in the total and differential white cell count and platelet count. J Clin Path. 1996; 49:664-666.

22. Yacizi S, Yacizi M., Erer B. The platelet indices in patients with rheumatoid arthritis. Platelets. 2010; 21(2):122-125.

23. Franck H, Rau R. Herborn G. Thrombocytopenia in patients with RA on long term treatment with low dose methotrexate. Clin Rheumatol. 1997; 16(4): 429-430.

24. Buhroo AM, Baba AN. Adverse effects of low dose methotrexate in patients with rheumatoid arthritis. Indian J Physical Med Rehab.2006; 17(2): 21-25.

25. Hornung N, Ellingsen T, Stengaard-Pedersen K. et al. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement. J Rheumatol. 2004;31(12):2374.

(0 .10)0 .77

50.1011.27+ 0.77

11.

;

.

.

.

.


Incidence of non-steroidal anti-infl ammatory drugs induced gastric discomfort in patients with knee osteoarthritisOguntona SA

Rheumatology Unit, Department of Medicine, Olabisi Onabanjo University, Consultant Physician, Olabisi Onabanjo University Teaching Hospital, Sagamu, P.O.Box 231 Sagamu, Ogun State, Nigeria.

E- mail: [email protected], [email protected]

RESEARCH ARTICLE

Abstract

Background: Osteoarthritis is an age related degenerative disease seen predominantly in the elderly. Non-steroidal anti-in� ammatory drug (NSAID) is a major therapeutic component in the management of osteoarthritis. Selective NSAID was developed to reduce the incidence of gastric irritation and erosion caused by the regular NSAIDS. Methods: All elderly patients with clinical and radiographic features of osteoarthritis were included in the study. Some patients were placed on regular NSAIDS while others were placed on selective NSAIDS, being randomly selected. The trial was carried out in a private clinic over three years. Proton pump inhibitor was added as soon as patients complain of abdominal discomfort.Results: Osteoarthritis was made up of 30.9 % of the total rheumatology cases seen over the three years period. Both patients on non-selective and selective NSAIDS presented with gastric discomfort. Symptoms were more noticeable in patients on non-selective NSAIDS. Females were more a� ected. Only two patients (2.1%) presented with symptomless gastro-intestinal bleeding. Proton pump inhibitor was helpful in majority of patients.Conclusion: Gastric discomfort is very common in elderly patients on NSAIDS. Selective NSAIDS is not an exception though better than non-selective NSAIDS. Contributory factors may be co-intake of low dose aspirin and few others on corticosteroid and anticoagulant. Key words: NSAIDS, Gastric discomfort, Osteoarthritis, Elderly.

Introduction

Peptic ulcer disease is a heterogeneous group of disorder involving the gastrointestinal tract and results from an imbalance between the aggressive forces

of acid and pepsin and the defensive mechanism of the gastric mucosa1-3. There has been a decline in the prevalence of uncomplicated peptic ulcer disease since the discovery of Helicobacter pylori, however, among the elderly people has been found a rise in admission for ulcer haemorrhage and perforation. The rise has been attributed to the increased use of NSAIDS and low dose aspirin4. Symptoms usually do not correlate with the severity of mucosa damage. Elderly patients however need to understand the prudent use of NSAIDS to prevent serious complications5,6. NSAIDS are commonly prescribed for a variety of musculoskeletal conditions such as rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis7. NSAIDS cause damage to the gastric mucosa through inhibition of gastric prostaglandin synthesis. The inhibition leads to the reduction in the level of protection of the gastric mucosa by the prostaglandin (PGE2, PGI2) and also leads to alteration in mucus and bicarbonate production as well as blood fl ow into the gastric mucosa, all of which are prostaglandin dependent functions8. When NSAID is taken orally, it dissociates in the gastric lumen and concentrates in the gastric mucosa. Once within the gastric mucosa cell, acidic NSAID inhibit prostaglandin production and prostaglandin dependent cell protection function9. NSAID gain access to the gastric mucosa via three routes. Direct contact of the ingested drug with the gastric mucosa, indirect route via secretion in the bile and backward refl ux into the stomach, and systemic route via circulation in the blood10.


Elderly patients aged 50 years and above that presented with clinical and radiological features of knee osteoarthritis were included in the study. Exclusion criteria include- known ulcer patients, past history of ulcer disease or gastrointestinal

Keywords: NSAIDS, Gastric discomfortOsteorthritis, Elderly.Key words: ,

Introduction

Afr J Rheumatol 2013; 1(1): 33-36 34

bleeding, and patients on concomitant anticoagulant or steroid. All rheumatology cases seen over 3 years were noted and all cases of primary osteoarthritis of the knee were extracted and the percentage of knee osteoarthritis in the total rheumatology cases determined. Patients were randomly selected, some were placed on regular NSAIDS (diclofenac, ibuprofen), and others on selective NSAID (e.g. Celebrex). Patients that developed symptoms of gastric irritation were given proton pump inhibitor (omeprazole).

Results

Osteoarthritis represented 30.9% of the total cases seen over 3 years. Gastrointestinal disturbances were noted in both groups (regular and selective NSAIDS). The disturbances were more noticeable in patients on regular NSAIDS. Total of 84 patients presented with gastrointestinal disturbances (80.8%), 24 males (28.6%) and 60 females (71.4%). Proton pump inhibitor was helpful in majority of symptomatic patients. Two patients (1.9%) however presented with symptomless gastrointestinal bleeding while eight patients (7.7%) were lost to follow-up.

Discussion

There are so many people on NSAIDS both prescribed and over-the-counter consumption11. There is an increased prevalence of NSAIDS induced gastrointestinal injury because of widespread use of the drug12. The readily availability of NSAIDS as over-the- counter medications adds to the incidence of gastrointestinal injury because people tend to consume more than the recommended doses13. Some of the studied patients combined two or more NSAIDS. The pathogenesis of NSAID- induced gastrointestinal mucosa injury is complex14,15. The direct-injury hypothesis suggests that both NSAID-mediated direct acidity damage and the suppression of prostaglandin synthesis are necessary to induce gastric damage14. The first insult to the gastro-duodenum mucosa is as a result of the acidic property of the NSAIDS, and the later mucosa damage is as a result of active hepatic metabolites of NSAIDS and the NSAID-related decrease in the gastric mucosa prostaglandins14,15. When the hepatic metabolites in the bile are secreted into the duodenum, they cause mucosa damage to the stomach by duodenogastric reflux and to the small intestine by antegrade passage through the gastrointestinal tract15. Prostaglandins maintain an intact gastric mucosa barrier by increasing secretion of mucus and bicarbonate maintaining mucosal blood flow, and decreasing acid-

secretion16. Suppression of prostaglandin synthesis can occur systemically with both oral and parenteral NSAID therapy16. The antiplatelet activity of some NSAIDS in low doses may cause bleeding from pre-existing ulcers17. There are two isoforms of the enzymes cyclooxygenase (cox) and NSAIDS inhibit both isoforms18. The isoform cox1 produces protective prostaglandins in the stomach and the isoform cox2 is inducible at sites of inflammation19,20. Researchers have developed a new type of NSAIDS that specifically inhibits cox2 while sparing cox119. Selective inhibitors should theoretically provide analgesics and anti-inflammatory effects of older NSAIDS with a reduced risk of gastro-intestinal injury. It was however found out that the selective cox2 are not completely devoid of gastric mucosa injury20. When NSAIDS irritate the gastric mucosa, they weakens the resistance to acid, causing gastritis, ulcers, bleeding, or perforation21. The damage ranges from superficial injury to single or multiple ulcers, some of which may bleed. The clinical manifestations seen in our patients include dyspepsia, nausea and vomiting. Only very few presented with diarrhea. Two patients however presented with symptomless gastro-intestinal bleeding. The clinical features however do not correlate with the severity of the mucosa damage22. The NSAIDS differ with regard to their risk of inducing upper gastro-intestinal bleeding and or perforation23,24. Elderly patients are especially at risk for NSAID-induced gastro-duodenal mucosa injury because of their multiple medical conditions and polypharmacy. Risk factors include concomitant corticosteroid or anticoagulant therapy25. Patients with a history of peptic ulcer disease and gastritis are also at risk26. The prevalence of endoscopically confirmed gastro-intestinal ulcers in NSAIDS users is quoted to be between 15 and 30%. Between 12 to 30% of NSAID induced ulcers are gastric ulcer, whereas 2 to 19% are duodenal ulcers. NSAID-induced ulcers are symptomatic only in 1% of patients after 3 to 6 months and in 2 to 4% of patients after one year27. This study has shown that 8 out of 10 elderly patients on prolonged NSAIDS eventually develop some degree of gastro-intestinal discomfort, and that the symptoms are more noticeable in elderly women. It is therefore advisable that drugs causing gastro-intestinal toxicity as a consequence of a systemic effect should be co-prescribed with suitable prophylactic agents such as proton pump inhibitors and misoprostol in elderly patients28,29. The importance of gastro-protection is vital in preventing patient morbidity and mortality especially in patients with a number of risk factors which include patients over the age of sixty years, smokers, patients with a history of peptic ulcer disease, or concomitant use of anti-coagulants, bisphosphonates, or corticosteroids.


bleeding, and patients on concomitant anticoagulant or steroid. All rheumatology cases seen over 3 years were noted and all cases of primary osteoarthritis of the knee were extracted and the percentage of knee osteoarthritis in the total rheumatology cases determined. Patients were randomly selected, some were placed on regular NSAIDS (diclofenac, ibuprofen), and others on selective NSAID (e.g. Celebrex). Patients that developed symptoms of gastric irritation were given proton pump inhibitor (omeprazole).

Results

Osteoarthritis represented 30.9% of the total cases seen over 3 years. Gastrointestinal disturbances were noted in both groups (regular and selective NSAIDS). The disturbances were more noticeable in patients on regular NSAIDS. Total of 84 patients presented with gastrointestinal disturbances (80.8%), 24 males (28.6%) and 60 females (71.4%). Proton pump inhibitor was helpful in majority of symptomatic patients. Two patients (1.9%) however presented with symptomless gastrointestinal bleeding while eight patients (7.7%) were lost to follow-up.

DiscussionThere are so many people on NSAIDS both prescribed and over-the-counter consumption11. There is an increased prevalence of NSAIDS induced gastrointestinal injury because of widespread use of the drug12. The readily availability of NSAIDS as over-the- counter medications adds to the incidence of gastrointestinal injury because people tend to consume more than the recommended doses13. Some of the studied patients combined two or more NSAIDS. The pathogenesis of NSAID- induced gastrointestinal mucosa injury is complex 14,15. The direct-injury hypothesis suggests that both NSAID-mediated direct acidity damage and the suppression of prostaglandin synthesis are necessary to induce gastric damage14. The first insult to the gastro-duodenum mucosa is as a result of the acidic property of the NSAIDS, and the later mucosa damage is as a result of active hepatic metabolites of NSAIDS and the NSAID-related decrease in the gastric mucosa prostaglandins14,15. When the hepatic metabolites in the bile are secreted into the duodenum, they cause mucosa damage to the stomach by duodenogastric reflux and to the small intestine by antegrade passage through the gastrointestinal tract15.Prostaglandins maintain an intact gastric mucosa barrier by increasing secretion of mucus and bicarbonate maintaining mucosal blood flow, and decreasing acid-secretion16. Suppression of prostaglandin synthesis can

occur systemically with both oral and parenteral NSAID therapy16. The antiplatelet activity of some NSAIDS in low doses may cause bleeding from pre-existing ulcers17. There are two isoforms of the enzymes cyclo-oxygenase (cox) and NSAIDS inhibit both isoforms18. The isoform cox1 produces protective prostaglandins in the stomach and the isoform cox2 is inducible at sites of inflammation19,20.Researchers have developed a new type of NSAIDS that specifically inhibits cox2 while sparing cox119. Selective inhibitors should theoretically provide analgesics and anti-inflammatory effects of older NSAIDS with a reduced risk of gastro-intestinal injury. It was however found out that the selective cox2 are not completely devoid of gastric mucosa injury20. When NSAIDS irritate the gastric mucosa, they weakens the resistance to acid, causing gastritis, ulcers, bleeding, or perforation21. The damage ranges from superficial injury to single or multiple ulcers, some of which may bleed. The clinical manifestations seen in our patients include dyspepsia, nausea and vomiting. Only very few presented with diarrhea. Two patients however presented with symptomless gastro-intestinal bleeding. The clinical features however do not correlate with the severity of the mucosa damage22. The NSAIDS differ with regard to their risk of inducing upper gastro-intestinal bleeding and or perforation23,24. Elderly patients are especially at risk for NSAID-induced gastro-duodenal mucosa injury because of their multiple medical conditions and polypharmacy. Risk factors include concomitant corticosteroid or anticoagulant therapy25. Patients with a history of peptic ulcer disease and gastritis are also at risk26. The prevalence of endoscopically confirmed gastro-intestinal ulcers in NSAIDS users is quoted to be between 15 and 30%. Between 12 to 30% of NSAID induced ulcers are gastric ulcer, whereas 2 to 19% are duodenal ulcers. NSAID-induced ulcers are symptomatic only in 1% of patients after 3 to 6 months and in 2 to 4% of patients after one year27. This study has shown that 8 out of 10 elderly patients on prolonged NSAIDS eventually develop some degree of gastro-intestinal discomfort, and that the symptoms are more noticeable in elderly women.It is therefore advisable that drugs causing gastro-intestinal toxicity as a consequence of a systemic effect should be co-prescribed with suitable prophylactic agents such as proton pump inhibitors and misoprostol in elderly patients28,29. The importance of gastro-protection is vital in preventing patient morbidity and mortality especially in patients with a number of risk factors which include patients over the age of sixty years, smokers, patients with a history of peptic ulcer disease, or concomitant use of anti-coagulants, bisphosphonates, or corticosteroids.

Afr J Rheumatol 2013; 1(1): 8-1215

Table 1: Spectrum of rheumatology cases seen over 3 years (July 2009- June 2012)

Serial No. Condition Number Male (%) Female (%)

1 Osteoarthritis 104 32 30.8 72 69.22 Rheumatoid

arthritis12 4 33.3 8 66.7

3 Cervical spondylosis

36 23 63.9 13 36.1

4 Lumbar spondylosis

25 21 56 14 44

5 Low back pain 48 37 77.1 11 22.9

6 Gout 28 22 78.6 6 21.47 SLE 6 1 16.7 5 83.38 Shoulder pain

syndrome12 4 33.3 8 66.7

9 Hypermobility syndrome

8 0 0 8 100

10 Fibromyagia 6 0 0 6 100

11 Polymyalgia rheumatica

2 0 0 2 100

12 Bursitis 4 3 75 1 25

13 Trigger finger 16 6 37.5 10 62.5

14 Sjorgren’s syndrome

1 0 0 1 100

15 Reiter’s syndrome

1 1 100 0 0

16 Septic arthritis 2 0 0 2 100

17 Lateral epicondylitis

2 2 100 0 0

18 Medial epicondylitis

2 2 100 0 0

19 Scleroderma 2 0 0 2 100

20 Psoriatic arthropathy

1 1 100 0 0

21 Plantar fasciitis 7 2 28.6 5 71.4

22 Carpal tunnel syndrome

3 1 33.3 2 66.7

23 Archilis tendinitis

8 1 12.5 7 87.5

Total 336 160 176

Afr J Rheumatol 2013; 1(1): 33-36 36

References

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2. Ramakrishnan K, Salinas RC. Pepticulcer disease. Am Fam Physician. 2007; 76 (7):1005-1012.

3. Chan FKL, Leung WK. Peptic-ulcer disease. Lancet 2002; 360:933-941.

4. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs:HELP NSAIDs study. Lancet. 1998; 352:1016-1021.

5. Zullo A, Hassan C, Campo SM, Morini S. Bleeding peptic ulcer in the elderly: risk factors and prevention strategies. Drugs Aging. 2007; 24 (10):815-828.

6. Byrd DC. NSAID-inducedgastropathy: preventionand treatment strategies. Pharm Times. 1999; 65:44-50.

7. Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study. Arch Intern Med. 1996; 156:1530-1536.

8. Singh G. Recent considerations in nonsteroidal anti- inflammatory drug gastropathy. Am J Med. 1998; 105:31S-38S.

9. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999; 340:1889-1899.

10. Perini R, Fiorucci S, Wallace JL. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cylooxygenase-inhibiting nitric oxide donors. Can J Gastroenterol. 2004; 18(4):229-236.

11. Graumlich JF. Preventing gastrointestinal complica-tions of NSAIDs. Risk factors recent advances and latest strategies. Postgrad Med. 2001; 109: 117-120.

12. Gore RM,Levine MS,Ghahremani GG. Drug- induced disorders of the stomach and duodenum. Abdom Imaging. 1999; 24:9-16.

13. Ofman JJ, MacLean CH, Straus WL et al. A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. J Rheumatol. 2002; 29: 804-812.

14. Schoen RT, Vender RJ. Mechanisms of nonsteroidal anti-inflammatory drug- inducedgastric damage. Am J Med. 1989; 86: 449-458.

15. Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol. 1996; 25 (Suppl 102): 9-21.

16. Vane JR, Botting RM. Overview: the mechanism of actionof anti-inflammatory drugs. In: Vane JR, Botting R, eds. Clinical significance and potential of selective Cox-2 inhibitors. London: William Harvey Press, 1998: 1-18.

17. McCarthy DM.Nonsteroidanti-inflammatory drugs - the clinical dilemmas. Scand J Gastroenterol. 1992; 192(suppl): 9-16.

18. Simon LS. The evolution of arthritis anti inflammatory care; where are we today? J Rheumatol. 1999; 26 (suppl 56): 11-17.

19. Mohammed S, Croom DW II. Gastropathy due to celecoxib, a cyclooxygenase-2 inhibitor. NEngl JMed. 1999; 340: 2005-2006.

20. Harmful effects of medicines on the adult digestive system. U.S. Department of Health and Human Services. NIH Publication No. 97-3421, September 1992.

21. Bjorkman DJ. Nonsteroidal anti-inflammatory drug- inducedgastrointestinal injury. Am J Med. 1996; 101: (Suppl 1A): 25S-32S.

22. Henry D, Lim LL-Y, Rodriguez LA. et al. Variability inrisk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Brit Med J. 1996; 312:1563-1566.

23. Rodriguez LA. Variability in risk of gastrointestinal complications with different nonsteroidal anti-inflammatory drugs. Am J Med. 1998; 104: 30S-34S.

24. Lee A, Morris J. Drug-induced gastrointestinal disorders. The Pharmaceut J. 1997; 258:742-747.

25. Udd M, Miettinen P, Palmu A, Heikkinen M, Janatuinen E, Pasanen P. et al. Analysis of the risk factors and their combinations in acute gastroduodenal ulcer bleeding: a case-control study. Scand J Gastroenterol. 2007; 42(12):1395-1403.

26. Palmer KR, Penman ID, Paterson-Brown S. Alimentary tract and pancreatic disease. In: Haslett C, Chilvers ER, Boon NA, Colledge NR, editors. Davidson’s Principles and Practice of Medicine,19thed. Edinburgh: Churchill Livingstone; 2002.

27. FordAC, Marwaha A,Lim A, Moayyedi P. What is the prevalenceof clinically significant endoscopic findings in subjects with dyspepsia? Systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2010; 8(10): 830-837.

28. Laine L. The role ofproton pump inhibitors in NSAID- associated gastropathy and upper gastrointestinal symptoms. Rev Gastroenterol Disord. 2003; 3 (Suppl. 4): S30-S39.

29. Graham DY, Agrawal NM, Campbell DR et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo- controlled study of misoprostol vs lansoprazole. Arch Intern Med. 2002; 162: 169-175.


Infl iximab induced remission in a case of severe Crohns enteropathic arthropathy with pyoderma gangrenosum: Case report Tamer AG1, Heba AG2, Sanaa AK3


1Rheumatology Department, Faculty of Medicine, Cairo University2Pharmacology Department, Atomic Energy Authorization, Cairo, Egypt3Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University

Corresponding author: Prof. AG Tamer, Rheumatology Department,Faculty of Medicine, Cairo University. Email: [email protected]

CASE REPORT

Abstract

Background: The indications for anti-TNFα therapy for in� ammatory bowel diseases (IBD) have increased to include demonstrable mucosal healing, improvement in quality of life, and treatment of extraintestinal manifestations including arthritis, sacroiliitis and pyoderma gangrenosum (PG). Case report: A male smoker, 27 years old, with enteropathic arthropathy on top of Crohns disease (CD) had a disease duration of 2.25 years. He had severe Crohns disease activity index (CDAI = 473) and a poor health status as assessed by the IBD questionnaire (IBDQ) of 39. He had oligoarthritis and bilateral sacroiliitis. There was limited chest expansion and lumbar spine mobility. The patient had PG on the dorsum of the right foot and mild bilateral uveitis. He was receiving sulphasalazine 2000 mg/day and low dose corticosteroids 10 mg/day and was then given cyclosporine for a month and the steroid dose elevated (60 mg/day) but with partial improvement. Cyclosporine was stopped and the patient remarkably improved after receiving, in addition to the corticosteroids, IV induction regimen of in� iximab 5mg/kg at 0,2 and 6 weeks. A remission occurred (CDAI 98.5) with fading of arthritis, notable decrease in the size and severity of the PG lesion and a signi� cant disappearance of the back sti� ness with an increase in the chest expansion and lumbar spine mobility. The IBDQ signi� cantly improved to be 159. Conclusion: Anti-TNFα such as in� iximab could be considered as a promising option for treatment of severe CD patients and for those with PG.

Keywords: Crohns disease, In� iximab, Pyoderma gangrenosum

Introduction

Infl ammatory bowel diseases (IBD) are intestinal infl ammatory conditions of unknown etiology, characterized by remissions and exacerbations, with Crohn’s disease (CD) as one of the main phenotypes1. The pathogenesis of CD is not totally understood, but bowel damage is induced by uncontrolled immune activation and inappropriate response to luminal antigens resulting in an imbalance between pro and anti-infl ammatory cytokines which maintains chronic tissue damage2. Arthritis is the most common extraintestinal manifestation of IBD having an impact on morbidity and quality of life, yet the mechanisms surrounding its development remain unclear 3,4. Major advances have been achieved over the last decade both in the clinical and scientifi c understanding of the spondyloarthritides (SpA). The proven high effi cacy of TNF blocker treatment has meant a breakthrough for SpA patients, who until recently had only quite limited treatment options5.

Case report

A male smoker, 27 years old, with enteropathic arthropathy on top of Crohns disease (CD) fulfi lled the European spondyloarthropathies study group (ESSG) spondyloarthropathy classifi cation criteria6. The disease duration was 2.25 years. The Crohns Disease Activity Index (CDAI) was assessed7 as well as the Infl ammatory Bowel Disease Questionnaire (IBDQ)8. Thorough rheumatologic examination was performed for any joint or axial involvement. Plain X-ray of the affected and sacroiliac joints was performed. The New York scoring method for the sacroiliac joints (SIJ) was followed9. The study was approved by local ethics committee and a written consent was obtained according to the Declaration of Helsinki.

Ghetia TA1, Ghetia HA2, Kenawy SA3

TA Ghetia

approved by the


The patient had severe CD (CDAI = 473) and IBDQ of 39. He had oligoarthritis involving the left knee and ankle. There was severe tenderness of the ankle and moderate in the knee with moderate effusion in both. There was associated bilateral clinical sacroiliitis with moderate tenderness. The plain X-ray of the SIJ showed grade II-III while the X-ray of the knee and ankle were free. The patient had enthesitis of the tendoachillis of the left side and chostochondritis. There was back stiffness for 40 minutes and limited lumbar spine mobility as measured by the Schöber test (which increased from 15 cm to 16.7 cm). The chest expansion was limited (2 cm). The patient had an associated skin lesion diagnosed as pyoderma gangrenosum (PG) on the dorsum of the right foot (8.5 x 6 cm). The histopathology revealed infi lterate of infl ammatory cells with predominance of lymphocytes and polymorphonuclear leukocytes and few histiocytes. The patient had mild bilateral uveitis.

Figure 1: A male patient with enteropathic arthritis with underlying Crohns disease. (a) dorsum of the foot showing Pyoderma gangrenosum. (b) Plain X-ray showing bilateral sacroiliitis.

free. The patient had enthesitis of the tendoachillis of the left side and chostochondritis. There was back stiffness for 40 minutes and limited lumbar spine mobility as measured by the Schöber test (which increased from 15 cm to 16.7 cm). The chest expansion was limited (2 cm). The patient had an associated skin lesion diagnosed as pyoderma gangrenosum (PG) on the dorsum of the right foot (8.5 x 6 cm). The histopathology revealed infi lterate of infl ammatory cells with predominance of lymphocytes and polymorphonuclear leukocytes and few histiocytes. The patient had mild bilateral uveitis.


The laboratory investigations of the patient were unremarkable; rheumatoid factor was negative, hemoglobin level (9.8 g/dl), white blood cell (WBC) count (4.85 x103/mm3), platelets (152.97 x103/mm3), and erythrocyte sedimentation rate (ESR) (46.12 mm /1st hr). The HLA-B27 was negative. The patient received azathioprine 100 mg/day for 5 months after the disease onset with different doses and variable periods of oral steroids and sulphasalazine. On presentation, the patient was receiving sulphasalazine 2000 mg/day and low dose corticosteroids 10 mg/day.

The patient was given cyclosporine for a month and the steroid dose elevated (60 mg/day) but with partial improvement. The cyclosporine was stopped and the patient remarkably improved after receiving, in addition to the corticosteroids (60mg/day), IV induction regimen of infl iximab 5mg/kg at 0,2 and 6 weeks. A remission occurred (CDAI 98.5) with fading of arthritis, notable decrease in the size and severity of the PG lesion and a signifi cant disappearance of the back stiffness with an

increase in the lumbar spine mobility (from 15 cm to 18.6 cm). The chest expansion increased to be 3.5 cm. The uveitis resolved in one eye and remained mild in the other. The IBDQ signifi cantly improved to be 159. The patient was then maintained on infl iximab 5mg/kg every 8 weeks and 20 mg prednisolone. Figure 1 shows the skin lesion and sacroiliitis in this patient at his initial presentation.

Discussion

In the present case with an IBD (Crohns disease), arthritis and sacroiliitis was present. It has been reported in other studies that seronegative spondyloarthropathy (SpA) symptoms are present in up to 50% of IBD patients10 with articular involvement being the most common extraintestinal manifestation occurring in 16% to 33% of the cases3. The present case also had an associated rare skin lesion, pyoderma gangrenosum (PG) which improved more after the administration of infl iximab. The advent of biological therapies for IBD began in 1998 with the approval of infl iximab for the treatment of refractory (to conventional agents) Crohn’s disease. Since then, the indications for anti-TNFα therapy for IBD have increased to include demonstrable mucosal healing, improvement in quality of life, reduction in surgeries and hospitalizations, and the treatment of extraintestinal manifestations including arthritis, sacroiliitis and PG11. Pyoderma gangrenosum is an uncommon and challenging infl ammatory, neutrophilic ulcerative dermatosis, highly associated with co morbidities, but poorly characterized from a therapeutic perspective12,13. In this case, HLA typing was negative. This is supported by the fi ndings that the association with HLA-B27 is less strong in IBD-associated SpA than in ankylosing spondylitis (AS). The adaptive immune response in IBD is thought to be strictly differentiated through Th1 in CD. Recent fi ndings, suggested that novel effector pathways could drive tissue damage, the most important pathway now emerging is the IL-23/IL-17 axis. A common infl ammatory pathogenic pathway has been suggested in gut and joint infl ammation in IBD. Treatment of SpA associated with IBD has gained important progress with the introduction of anti-TNF-α therapy14. This patient remarkably improved regarding the peripheral and axial arthritis with a notable decrease in the PG size after a combination of high dose corticosteroids and infl iximab therapy. In another study, PG was 34% associated with IBD and 19% with seronegative arthritis. Similarly, it was most commonly located on the lower leg; contrarily, was found to be more frequent in females and unfortunately had a high mortality rate (16%)15. Pyoderma gangrenosum is associated with a variety of systemic diseases including IBD as CD and arthritis. The pathogenesis of PG remains unknown. Some patients with PG have abnormalities in cell and humoral immunity, with an increase in interleukin expression, particularly

Afr J Rheumatol 2013; 1(1): 8-12 10

TNF-α 11. It has been reported that treatment of IBD is not always sufficient for control of arthritis and treatment with biologic agents is promising4. Over recent years, the management of IBD has dramatically changed. In particular, advances in understanding the pathogenesis and the natural course of the disease have substantially changed the therapeutic algorithms with the introduction of new biological drugs. Among these the anti-TNF-α monoclonal antibodies infliximab is currently approved for the management of CD, in particular for patients with moderately and severely active luminal disease who are nonresponders to conventional therapy2. These newly developed treatment modalities are proving to be valuable additions to the current therapeutic armamentarium and add to our knowledge so that IBD patients could be treated with the right drug at the right time. In conclusion, anti-TNFα such as infliximab could be considered as a promising option for treatment of severe CD patients and for those with PG. To confirm our results we propose that more cases of CD and/or PG are studied and for longer periods of follow up.

Conflicts of interest: none.

References

1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007; 369:1627–1640.

2. Guidi L, Pugliese D, Armuzzi A. Update on the management of inflammatory bowel disease: specific role of adalimumab. Clin Exp Gastroenterol. 2011; 4:163-172.

3. Brakenhoff LK, van der Heijde DM, Hommes DW, Huizinga TW, Fidder HH. The joint-gut axis in inflammatory bowel diseases. J Crohns Colitis. 2010; 4(3):257-268.

4. Arvikar SL, Fisher MC. Inflammatory bowel disease associated arthropathy. Curr Rev Musculoskelet Med. 2011; 4(3):123-131.

5. Sieper J. Developments in the scientific and clinical understanding of the spondyloarthritides. Arthritis Res Ther. 2009; 11(1):208.

6. Dougados M, van der Linden S, Juhlin R. et al. The European Spondylarthropathy Study Group prelimi-nary criteria for the classification of spondyloarthrop-athy. Arthritis Rheum. 1991; 34:1218–1227.

7. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology. 1976; 70: 439–444.

8. Guyatt G, Mitchell A, Irvine EJ. et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology. 1989; 96: 804–810.

9. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984; 27:361–368.

10. Zochling J, Smith EU. Seronegative spondyloarthritis. Best Pract Res Clin Rheumatol. 2010; 24(6):747-756.

11. Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011; 106(4):685-698.

12. Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities, and therapy in 103 patients. Br J Dermatol. 2011 Aug 9. doi: 10.1111/j.1365-2133.2011.10565.x. [Epub ahead of print]

13. Santos M, Talhari C, Rabelo RF, Schettini AP, Chirano CA, Talhari S. Pyoderma gangrenosum: a clinical manifestation of difficult diagnosis. An Bras Dermatol. 2011; 86(1): 153-156.

14. Faustini F, Zoli A, Ferraccioli GF. Immunologic and genetic links between spondylarthropathies and inflammatory bowel diseases. Eur Rev Med Pharmacol Sci. 2009; 13 (Suppl 1):1-9.

15. Asarch A, Barak O, Loo DS, Gottlieb AB. Th17 cells: a new therapeutic target in inflammatory dermatoses. J Dermatolog Treat. 2008; 19(6):318-326.

Afr J Rheumatol 2013; 1(1): 37-3939Afr J Rheumatol 2013; 1(1): 8-129

The patient had severe CD (CDAI = 473) and IBDQ of 39. He had oligoarthritis involving the left knee and ankle. There was severe tenderness of the ankle and moderate in the knee with moderate effusion in both. There was associated bilateral clinical sacroiliitis with moderate tenderness. The plain X-ray of the SIJ showed grade II-III while the X-ray of the knee and ankle were free. The patient had enthesitis of the tendoachillis of the left side and chostochondritis. There was back stiffness for 40 minutes and limited lumbar spine mobility as measured by the Schöber test (which increased from 15 cm to 16.7 cm). The chest expansion was limited (2 cm). The patient had an associated skin lesion diagnosed as pyoderma gangrenosum (PG) on the dorsum of the right foot (8.5 x 6 cm). The histopathology revealed infi lterate of infl ammatory cells with predominance of lymphocytes and polymorphonuclear leukocytes and few histiocytes. The patient had mild bilateral uveitis.

Figure 1: A male patient with enteropathic arthritis with underlying Crohns disease. (a) dorsum of the foot showing Pyoderma gangrenosum. (b) Plain X-ray showing bilateral sacroiliitis.



The laboratory investigations of the patient were unremarkable; rheumatoid factor was negative, hemoglobin level (9.8 g/dl), white blood cell (WBC) count (4.85 x103/mm3), platelets (152.97 x103/mm3), and erythrocyte sedimentation rate (ESR) (46.12 mm /1st hr). The HLA-B27 was negative. The patient received azathioprine 100 mg/day for 5 months after the disease onset with different doses and variable periods of oral steroids and sulphasalazine. On presentation, the patient was receiving sulphasalazine 2000 mg/day and low dose corticosteroids 10 mg/day.

The patient was given cyclosporine for a month and the steroid dose elevated (60 mg/day) but with partial improvement. The cyclosporine was stopped and the patient remarkably improved after receiving, in addition to the corticosteroids (60mg/day), IV induction regimen of infl iximab 5mg/kg at 0,2 and 6 weeks. A remission occurred (CDAI 98.5) with fading of arthritis, notable decrease in the size and severity of the PG lesion and a signifi cant disappearance of the back stiffness with an

increase in the lumbar spine mobility (from 15 cm to 18.6 cm). The chest expansion increased to be 3.5 cm. The uveitis resolved in one eye and remained mild in the other. The IBDQ signifi cantly improved to be 159. The patient was then maintained on infl iximab 5mg/kg every 8 weeks and 20 mg prednisolone. Figure 1 shows the skin lesion and sacroiliitis in this patient at his initial presentation.

Discussion

In the present case with an IBD (Crohns disease), arthritis and sacroiliitis was present. It has been reported in other studies that seronegative spondyloarthropathy (SpA) symptoms are present in up to 50% of IBD patients10 with articular involvement being the most common extraintestinal manifestation occurring in 16% to 33% of the cases3. The present case also had an associated rare skin lesion, pyoderma gangrenosum (PG) which improved more after the administration of infl iximab. The advent of biological therapies for IBD began in 1998 with the approval of infl iximab for the treatment of refractory (to conventional agents) Crohn’s disease. Since then, the indications for anti-TNFα therapy for IBD have increased to include demonstrable mucosal healing, improvement in quality of life, reduction in surgeries and hospitalizations, and the treatment of extraintestinal manifestations including arthritis, sacroiliitis and PG11. Pyoderma gangrenosum is an uncommon and challenging infl ammatory, neutrophilic ulcerative dermatosis, highly associated with co morbidities, but poorly characterized from a therapeutic perspective12,13. In this case, HLA typing was negative. This is supported by the fi ndings that the association with HLA-B27 is less strong in IBD-associated SpA than in ankylosing spondylitis (AS). The adaptive immune response in IBD is thought to be strictly differentiated through Th1 in CD. Recent fi ndings, suggested that novel effector pathways could drive tissue damage, the most important pathway now emerging is the IL-23/IL-17 axis. A common infl ammatory pathogenic pathway has been suggested in gut and joint infl ammation in IBD. Treatment of SpA associated with IBD has gained important progress with the introduction of anti-TNF-α therapy14. This patient remarkably improved regarding the peripheral and axial arthritis with a notable decrease in the PG size after a combination of high dose corticosteroids and infl iximab therapy. In another study, PG was 34% associated with IBD and 19% with seronegative arthritis. Similarly, it was most commonly located on the lower leg; contrarily, was found to be more frequent in females and unfortunately had a high mortality rate (16%)15. Pyoderma gangrenosum is associated with a variety of systemic diseases including IBD as CD and arthritis. The pathogenesis of PG remains unknown. Some patients with PG have abnormalities in cell and humoral immunity, with an increase in interleukin expression, particularly

Afr J Rheumatol 2013; 1(1): 8-12 10

TNF-α 11. It has been reported that treatment of IBD is not always sufficient for control of arthritis and treatment with biologic agents is promising4. Over recent years, the management of IBD has dramatically changed. In particular, advances in understanding the pathogenesis and the natural course of the disease have substantially changed the therapeutic algorithms with the introduction of new biological drugs. Among these the anti-TNF-α monoclonal antibodies infliximab is currently approved for the management of CD, in particular for patients with moderately and severely active luminal disease who are nonresponders to conventional therapy2. These newly developed treatment modalities are proving to be valuable additions to the current therapeutic armamentarium and add to our knowledge so that IBD patients could be treated with the right drug at the right time. In conclusion, anti-TNFα such as infliximab could be considered as a promising option for treatment of severe CD patients and for those with PG. To confirm our results we propose that more cases of CD and/or PG are studied and for longer periods of follow up.


References

1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007; 369:1627–1640.

2. Guidi L, Pugliese D, Armuzzi A. Update on the management of inflammatory bowel disease: specific role of adalimumab. Clin Exp Gastroenterol. 2011; 4:163-172.

3. Brakenhoff LK, van der Heijde DM, Hommes DW, Huizinga TW, Fidder HH. The joint-gut axis in inflammatory bowel diseases. J Crohns Colitis. 2010; 4(3):257-268.

4. Arvikar SL, Fisher MC. Inflammatory bowel disease associated arthropathy. Curr Rev Musculoskelet Med. 2011; 4(3):123-131.

5. Sieper J. Developments in the scientific and clinical understanding of the spondyloarthritides. Arthritis Res Ther. 2009; 11(1):208.

6. Dougados M, van der Linden S, Juhlin R. et al. The European Spondylarthropathy Study Group prelimi-nary criteria for the classification of spondyloarthrop-athy. Arthritis Rheum. 1991; 34:1218–1227.

7. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology. 1976; 70: 439–444.

8. Guyatt G, Mitchell A, Irvine EJ. et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology. 1989; 96: 804–810.

9. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984; 27:361–368.

10. Zochling J, Smith EU. Seronegative spondyloarthritis. Best Pract Res Clin Rheumatol. 2010; 24(6):747-756.

11. Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011; 106(4):685-698.

12. Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities, and therapy in 103 patients. Br J Dermatol. 2011 Aug 9. doi: 10.1111/j.1365-2133.2011.10565.x. [Epub ahead of print]

13. Santos M, Talhari C, Rabelo RF, Schettini AP, Chirano CA, Talhari S. Pyoderma gangrenosum: a clinical manifestation of difficult diagnosis. An Bras Dermatol. 2011; 86(1): 153-156.


15. Asarch A, Barak O, Loo DS, Gottlieb AB. Th17 cells: a new therapeutic target in inflammatory dermatoses. J Dermatolog Treat. 2008; 19(6):318-326.

TNF-a 11. It has been reported that treatment of IBD is not always sufficient for control of arthritis and treatment with biologic agents is promising4.

Over recent years, the management of IBD hasdramatically changed. In particular, advances inunderstanding the pathogenesis and the natural course of the disease have substantially changed the therapeuticalgorithms with the introduction of new biological drugs.Among these the anti-TNF-a monoclonal antibodiesinfliximab is currently approved for the management of CD, in particular for patients with moderately and severely active luminal disease who are nonresponders toconventional therapy2. These newly developed treatment modalities are proving to be valuable additions to the current therapeutic armamentarium and add to ourknowledge so that IBD patients could be treated with theright drug at the right time.

In conclusion, anti-TNFa such as infliximab could beconsidered as a promising option for treatment of severeCD patients and for those with PG. To confirm our resultswe propose that more cases of CD and/or PG are studiedand for longer periods of follow up.


References

1. Baumgart DC, Carding SR. Inflammatory boweldisease: cause and immunobiology. Lancet. 2007;369:1627-1640.

2. Guidi L, Pugliese D, Armuzzi A. Update on themanagement of inflammatory bowel disease: specificrole of adalimumab. Clin Exp Gastroenterol. 2011;4:163-172.

3. Brakenhoff LK, van der Heijde DM, Hommes DW, Huizinga TW, Fidder HH. The joint-gut axis ininflammatory bowel diseases. J Crohns Colitis. 2010;4(3):257-268.

4. Arvikar SL, Fisher MC. Inflammatory bowel diseaseassociated arthropathy. Curr Rev Musculoskelet Med.2011; 4(3):123-131.

5. Sieper J. Developments in the scientific and clinicalunderstanding of the spondyloarthritides. Arthritis Res Ther. 2009; 11(1):208.

6. Dougados M, van der Linden S, Juhlin R. et al. TheEuropean Spondylarthropathy Study Group prelimi-nary criteria for the classification of spondyloarthrop-athy. Arthritis Rheum. 1991; 34:1218-1227.

7. Best WR, Becktel JM, Singleton JW, Kern F Jr.Development of a Crohn's disease activity index.National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444.

8. Guyatt G, Mitchell A, Irvine EJ. et al. A new measureof health status for clinical trials in inflammatory bowel disease. Gastroenterology. 1989; 96: 804-810.

9. van der Linden S, Valkenburg HA, Cats A. Evaluationof diagnostic criteria for ankylosing spondylitis. Aproposal for modification of the New York criteria.Arthritis Rheum. 1984; 27:361-368.

10. Zochling J, Smith EU. Seronegative spondylarthritis.BestPract Res Clin Rheumatol. 2010; 24(6):747-756.

11. Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am JGastroenterol. 2011; 106(4):685-698.

12. Binus AM, Qureshi AA, Li VW, Winterfield LS.Pyoderma gangrenosum: a retrospective review ofpatient characteristics, comorbidities, and therapy in103 patients. Br J Dermatol. 2011; Dec; 165 (6): 1244-1250

13. Santos M, Talhari C, Rabelo RF, Schettini AP, Chirano CA, Talhari S. Pyoderma gangrenosum: a clinical manifestation of difficult diagnosis. An Bras Dermatol.2011; 86(1): 153-156.


15. Asarch A, Barak O, Loo DS, Gottlieb AB. Th17 cells: anew therapeutic target in inflammatory dermatoses.JDermatolog Treat. 2008; 19(6):318-326.J Dermatol

.165 (6):


Association of sarcoidosis and myasthenia gravis

Kaouther BA2, Khaoula BA1, Sami T1, Zakraoui L2, Khedher A1

1Internal Medicine Department-Charles Nicolle Hospital-Tunis-University of Tunis El Manar- Tunisia2Rheumatology Department – Mongi Slim Hospital – 2034-La Marsa – University of Tunis El Manar- Tunisia

Corresponding author: Dr. BA Kaouther. E-mail address: [email protected]

CASE REPORT

Abstract

Whereas the coexistence of di�erent autoimmune or rheumatologic diseases with myasthenia gravis (MG) is well documented, its combination with sarcoidosis is extremely rare. Presented here is an interesting case with coexisting MG and sarcoidosis.

Case report

A 42-year-old female patient su� ered from a facial palsy. Clinical examination was normal, as well as brain MRI. A chest CT scan con� rmed multiple mediastinal adenopathy with interstitial syndrome. Spirometry showed a restrictive lung disease. The bronchoalveolar lavage showed a lymphocytic alveolitis at 48%. The patient’s calcium level was normal. Further tests showed increased serum angiotensin converting enzyme (ACE) levels. The tuberculin test was negative. Mediastinoscopy was performed and a lymph node biopsy showed multiple typical noncaseating granulomas. The diagnosis of systemic sarcoidosis with pulmonary and neurological involve-ment was established. The patient was treated with 1mg/kg/day corticosteroids leading to clinical improvement of her facial palsy. Then, steroid treatment was declined. Two years later, she su� ered from recurrence of facial palsy with epi-sodes of dysphonia, ptosis and swallowing di�culties. Neurological examination revealed weakness in all her extremi-ties, both proximal and distal. Ampli� ca-tion of symptom intensity after exercise was also reported and documented on examination. The tensilon test, as well as the repetitive nerve stimulation test, was positive. Acetylcholine receptor (AChR) binding antibodies were elevated consistent with MG. Based on all the above-mentioned � ndings, the patient was diagnosed with having coexistent MG and sarcoidosis. A new CT of the thorax revealed no signs of thymic hyperplasia or thymoma. Oral administra-tion of pyridostigmine was started. Since no full symptom remission was achieved,

prednisone was added leading to fur-ther clinical improvement. During her hospital stay, she developed respiratory distress and hypoxemia for which the patient was intubated. Intravenous immunoglobulins were performed, providing rapid but transitory improve-ment. Plasmapheresis was slightly more e� cient.

DiscussionThe coexistence of sarcoidosis and MG is very rare. Based on a literature review, only 12 cases were reported 1-10. In some cases, MG come � rst, while in others, sarcoidosis was already diagnosed when myasthenic features began. The originality of our case is the occurrence of sarcoidosis and the MG at the same time. neurosarcoidosis is a complication in around 5% of patients with sarcoidosis 11. Its most frequent manifestation is cranial neuropathy. The facial nerve is most commonly a� ected, often bilaterally (around 25% in all reports). In our patient’s case, systemic disease was also present, a� ecting the chest. This clinical data had clearly supported the diagnosis of neurosarcoidosis. At this moment, other cranial nerve examinations were normal. According to the literature, the AChR binding antibodies were elevated in all cases except one, where antibodies to muscle-specific tyrosine kinase were found10. Whether a common immunogenetic basis between MG and sarcoidosis exists or not, remains unclear. Indeed, on the one hand MG is antibody-mediated. On the other hand, sarcoidosis is characterized by the accumulation of activated T-cells in the a�ected tissues with subsequent granuloma formation. However, the finding of granulomas in cases of MG has recently been reported12,13.

Conclusion

It is noteworthy to report this case because of the multiple interesting features observed as well as the rarity of occurrence.

Confl ict of interest: none

[email protected]

: Case report


References

1. Andonopoulos AP, Papathanasopoulos PG, Karatza C, Angelopoulos J, Papapetropoulos T. Sarcoidosis in a patient with myasthenia gravis. Case report and review of the literature. Clin Rheumatol. 1991;10:323–325.

2. Takanami I, Imamura T, Kodaira S. Myasthenia gravis complicated by sarcoidosis. J Thorac Cardiovasc Surg. 1995;109:183-184.

3. Van Aken E, Van Landegem W, Van de Abeele G, De Bleecker J. Myasthenia gravis and sarcoidosis: report of two cases. Clinical Neurol Neurosurg. 1996; 98(4):320.

4. De Bleecker J, vanAken L, van Landegem W, van den Abeele G, Cuvelier C. Myasthenia gravis and sarcoidosis: report of 2 cases. Eur Neurol. 1996; 36:326–327.

5. Volpe C, Gorji N, Melato M, Maffessanti M. Myasthenia gravis relapse associated with sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 2000; 17:87–88.

6. Nishida H, Tanaka Y, Nakao N, Ibi T, Sahashi K. A case of myasthenia gravis following sarcoidosis and Hashimoto’s thyroiditis. Rinsho Shinkeigaku. 2000; 40(8):797-800.

7. Bonnet F, Dubuc J, Morlat P et al. Sarcoïdose et comorbidité : étude rétrospective de 32 observations. Rev Med Interne. 2001; 22: 619-623.

8. Rozsa C, Kis G, Komoly S, Anselmo V, Esik O, Lang I et al. Myasthenia in a patient with sarcoidosis and schizophrenia. Ideggyogy Sz. 2004; 57:242-244.

9. Kurukumbi M, Weir RL, Kalyanam J, Nasim M, Jayam-Trouth A. Rare association of thymoma, myasthenia gravis and sarcoidosis : a case report. J Med. 2008; 2:245.

10. Spengos K, Vassilopoulou S, Christou Y, Manta P. Sarcoidosis in a case of MuSK-positive myasthenia gravis. Neuromuscular Disorders. 2008; 18: 890–891.

11. Gascón-Bayarri J, Mañá J, Martínez-Yélamos S, Murillo, R. Reñé O, Rubio F. Neurosarcoidosis. Eur J Intern Med. 2011 doi:10.1016/j.ejim.2011.08.019

12. Zamecnik J, Ambler Z, Ehler E, Simkova L, Mazanec R, Schutzner J. Granulomatous myopathy in patients with sarcoidosis and myasthenia gravis. Cesk Patol. 2006; 42:175–181.

13. Gdynia HJ, Mogel H, Kuhnlein P. et al. Diagnosis and differential diagnosis of granulomatous myositis. Nervenarzt. 2008; 79:407–474.

O, Lang I et al. Myasthenia in a patient with


Queens Hospital Center, Mount Sinai School of Medicine, Jamaica, New York

Corresponding author: Dr. P. O. Ochieng. Email:

Case Report An atypical case of systemic lupus erythematosus presenting as � eeting hemorrhagic pleural e� usion with normal complement level

Ochieng PO and Abrudescu A

Abstract

Background: Systemic lupus erythe-matosus (SLE) is a multisystem disease that can be a diagnostic conundrum. Case report: We describe a patient who presented with recurrent � eeting exudative and hemorrhagic pleural e� usion. It took multiple visits over 3 months and renal biopsy to con� rm the diagnosis of SLE. Management: The patient was treat-ed with immunosuppression. Results: She had a favorable clinical response and continues to be followed up as an outpatient.Conclusion: Systemic lupus erythe-matosus can be di� cult diagnosis to make as it may present with atypical features.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease with a myriad of presentation. The varying manifestations and progression make SLE a potential diagnostic challenge. We present an atypical case of SLE that was a diagnostic enigma.

Case report

Forty fi ve year old black female fi rst presented in March 2011 with acute onset right side pleuritic chest pain and fever. She reported a dry cough and no other symptom. At admission, she was in mild respiratory distress with respiratory rate of 20/min with the rest of the vitals normal. Chest exam was consistent with right pleural effusion and the rest of systemic examination was normal. Haemogram revealed normocytic anemia and leucocytosis. Urea, creatinine and electrolytes were within normal limits. Hepatic panel was unremarkable except for low protein and albumin. Chest X-ray (CXR)

revealed right pleural effusion (Figure 1). On thoracocentesis the pleural fl uid was hemorrhagic and exudative with parameters as shown in Table 1. Pleural cytology and microbiology tests were negative. Antinuclear antigen (ANA) was positive with speckled pattern and titre of 1:160. Other connective tissue markers (Anti-Double strand DNA antibodies, anti-smith antibody, anti-Ro, anti-La and Rheumatoid factor) were negative. Hepatitis B and C and HIV screening were negative. Complement 3 and 4 levels were within normal limits with levels of 129 mg/dl and 29 mg/dl respectively. She was treated as with antibiotics for community acquired pneumonia with para pneumonic effusion and she improved and was discharged home. In May 2011, she returned to the Emergency room with three days history of left side pleuritic chest pain and dyspnea. The pain was similar to her pain on previous admission but she had no fever or cough on this admission. Examination was consistent with left pleural effusion which was confi rmed on CXR (Figure 2). Chest CT scan revealed pulmonary emboli in the left main pulmonary artery with no lung infarct and left pleural effusion (Figure 3). Pleural fl uid was exudative and hemorrhagic with parameters on table 1. Pleural cytology revealed reactive mesothelial cells and no malignant cells and microbiology studies were negative. Repeat connective tissue work-up was again negative except for ANA titers that increased to 1:640. Complement 3 and 4 levels were normal at 79 mg/dl and 29 mg/dl respectively. Antiphospholipid and anti-beta 2 glycoprotein were negative. Urinalysis revealed proteinuria and 24 hour urine protein was 4.1g. Right kidney biopsy was consistent with membranous nephritis classifi ed as lupus nephritis WHO class V (microscopy- glomerular capillary loops thickening with subepithelial spikes and no endocapillary proliferation or crescents. Electron microscopy- podocyte effacement with intramembranous, transmembranous and subepithelial immune deposits and

Ochieng PO and Abrudescu A, Abrudescu A


proliferation of basement membrane around the deposits. Immunopathology- glomerular capillary wall and mesangial nodular IgM/IgG and C3 depositis with tubular basement membrane, interstitium and blood vessel sparing) On follow-up, to discuss the renal biopsy results in June 2011, the pleural effusion had resolved spontaneously

and proteinuria had improved (to 0.8g proteinuria in 24 hours) but she had developed atypical desquamating rash with malar distribution (Figure 4). At this point she was treated with steroids. On follow-up she had improvement of proteinuria and resolution of her rash. She continued with follow-up at the outpatient clinic.

Table 1: Pleural fluid analysis results

Date PH prot alb ldh gluc RBC WBC neut lymp mon mes mQ

22/3/11 7.43 3.8(ser 6)Mg/dl

1.8(ser 2.2) mg/dl

150(ser 179)mg/dl

90 mg/dl

1020/ml

2600/ml

69% 21% 3% 1% 6%

13/5/11 7.2 4.1(ser 5.7) mg/dl

1.7(ser 1.9) mg/dl

584 (ser 206)

116 mg/dl

2210/ml

2640/ml

86% 9% 5%

Key to abbreviations: Prot = Total protein, alb = Albumin, ldh = Lactate dehydrogenase, glu = Glucose, RBC = Red blood cells, WBC = White blood cells, neut = Neutrophils, lymph = Lymphocytes, mon = Monocytes, mes = Mesothelial cells and mQ = Macrophages

Figures 1 to 4: 1 (upper left) CXR in March, 2 (upper right) CXR in May, 3 (lower left) Chest CT scan in May and 4 (lower right) facial rash in June

Afr J Rheumatol 2013; 1(1): 8-1241

Discussion

Although our patient did not meet the criteria for SLE during the first two admissions, she eventually had at least four of the diagnostic criteria including serositis, renal manifestation, positive ANA and malar rash. This took about 3 months from the initial presentation and underscores the fact that the American College of Rheumatology criteria was developed as a research criterion and not a clinical criterion. Pleuropulmonary manifestations of SLE are vast entailing pleural, parenchymal, bronchial, pulmonary vasculature and diaphragmatic pathologies1. Pleural effusions have been recorded in up to 50% of patients with SLE with this number increasing to over 90% at autopsy 2, 3. The fleeting nature of her pleural effusion that was initially on the right then left is not uncommon in SLE but hemorrhagic nature of the pleural effusion makes this case atypical. Only a few cases of hemorrhagic pleural effusion of SLE have been reported in literature with prevalence not documented. Other differential diagnoses considered for the pleural effusion included Pseudo-meigs’ syndrome and pseudo-pseudo meigs’ or Tjalma’s syndrome but these were considered less likely with no ascites noted on imaging 4, 5. Occult malignancy including lymphoma were also explored as a differential diagnosis with negative work-up. Pathophysiology of SLE is postulated to entail uncontrolled autoreactivity of B and T lymphocytes leading to the production of autoantibodies against self-directed antigens and tissue destruction. The loss of self tolerance is an evolving area of medical knowledge and probably involves genetic factors, deficiency of regulatory T cells and B cells, hormonal factors and environmental factors 6. Complement system is central in this pathogenesis process. Studies have revealed that reduced levels of hemolytic complement, C1q, C4, C3 in pleural fluid from lupus patient when compared to pleural effusions due to other conditions even after adjustment for the total protein content of the pleural fluid7. This makes this case atypical considering the

normal complement levels during active serositis on both admissions. This normal complement is hard to explain and underscores the fact that knowledge on the complexity pathophysiology of SLE is in evolution. Another interesting phenomenon was paradoxical decline, albeit mild, in level of complement after the pleural effusion resolved and the proteinuria improved.

Conclusion

Differential diagnosis of SLE should be retained even in atypical cases particularly if no alternative diagnosis is made. It may also present with features not consistent with the conventional clinical and laboratory features.

References

1. Orens JB, Martinez FJ, Lynch JP III. Pleuropulmonary manifestation of systemic lupus erythematosus. Rheum Dis Clin North Am. 1994; 20:159-193.

2. Alarcon-Segovia D, Alarcon DG. Pleuropulmonary manifestations of systemic lupus erythematosus. Dis Chest. 1961; 39: 7-17.

3. Keane MP, Lynch JP III. Pleuropulmonary manifestation of systemic lupus erythematosus. Thorax. 2000; 55:159-166.

4. Tjalma WAA. Ascites, pleural effusion and CA 125 elevation in an SLE patient, either a Tjalma syndrome or, due to the migrated Filshie clips, a pseudo-Meigs syndrome. Gynecol Oncol 2005; 97: 288–291.

5. Schmitt R, Weichert W, Schneider W, Luft FC, Kettritz R. Pseudo-pseudo Meigs’ syndrome. Lancet. 2005; 366: 1672.

6. Cuchacovich R, Gedalia A. Pathophysiology and clinical spectrum of infections in systemic lupus erythematosus. Rheum Dis Clin N Am. 2009; 35: 75–93.

7. Mitra B, Sengupta P, Saha K, Sarkar N, Pal J. Systemic lupus erythematosus presenting with recurrent pleural effusion without any systemic manifestation. JAPI. 53: 1073-1076

Figures 1 to 4: I (upper left) CXR in March, 2 (upper right) CXR in May, 3 (lower left) Chest CT scan in May and 4(lower right) facial rash in june


proliferation of basement membrane around the deposits. Immunopathology- glomerular capillary wall and mesangial nodular IgM/IgG and C3 depositis with tubular basement membrane, interstitium and blood vessel sparing) On follow-up, to discuss the renal biopsy results in June 2011, the pleural effusion had resolved spontaneously

and proteinuria had improved (to 0.8g proteinuria in 24 hours) but she had developed atypical desquamating rash with malar distribution (Figure 4). At this point she was treated with steroids. On follow-up she had improvement of proteinuria and resolution of her rash. She continued with follow-up at the outpatient clinic.

Table 1: Pleural fluid analysis results

Date PH prot alb ldh gluc RBC WBC neut lymp mon mes mQ

22/3/11 7.43 3.8(ser 6)Mg/dl

1.8(ser 2.2) mg/dl

150(ser 179)mg/dl

90 mg/dl

1020/ml

2600/ml

69% 21% 3% 1% 6%

13/5/11 7.2 4.1(ser 5.7) mg/dl

1.7(ser 1.9) mg/dl

584 (ser 206)

116 mg/dl

2210/ml

2640/ml

86% 9% 5%

Key to abbreviations: Prot = Total protein, alb = Albumin, ldh = Lactate dehydrogenase, glu = Glucose, RBC = Red blood cells, WBC = White blood cells, neut = Neutrophils, lymph = Lymphocytes, mon = Monocytes, mes = Mesothelial cells and mQ = Macrophages

Figures 1 to 4: 1 (upper left) CXR in March, 2 (upper right) CXR in May, 3 (lower left) Chest CT scan in May and 4 (lower right) facial rash in June

Afr J Rheumatol 2013; 1(1): 8-1241

Discussion

Although our patient did not meet the criteria for SLE during the first two admissions, she eventually had at least four of the diagnostic criteria including serositis, renal manifestation, positive ANA and malar rash. This took about 3 months from the initial presentation and underscores the fact that the American College of Rheumatology criteria was developed as a research criterion and not a clinical criterion. Pleuropulmonary manifestations of SLE are vast entailing pleural, parenchymal, bronchial, pulmonary vasculature and diaphragmatic pathologies1. Pleural effusions have been recorded in up to 50% of patients with SLE with this number increasing to over 90% at autopsy 2, 3. The fleeting nature of her pleural effusion that was initially on the right then left is not uncommon in SLE but hemorrhagic nature of the pleural effusion makes this case atypical. Only a few cases of hemorrhagic pleural effusion of SLE have been reported in literature with prevalence not documented. Other differential diagnoses considered for the pleural effusion included Pseudo-meigs’ syndrome and pseudo-pseudo meigs’ or Tjalma’s syndrome but these were considered less likely with no ascites noted on imaging 4, 5. Occult malignancy including lymphoma were also explored as a differential diagnosis with negative work-up. Pathophysiology of SLE is postulated to entail uncontrolled autoreactivity of B and T lymphocytes leading to the production of autoantibodies against self-directed antigens and tissue destruction. The loss of self tolerance is an evolving area of medical knowledge and probably involves genetic factors, deficiency of regulatory T cells and B cells, hormonal factors and environmental factors 6. Complement system is central in this pathogenesis process. Studies have revealed that reduced levels of hemolytic complement, C1q, C4, C3 in pleural fluid from lupus patient when compared to pleural effusions due to other conditions even after adjustment for the total protein content of the pleural fluid7. This makes this case atypical considering the

normal complement levels during active serositis on both admissions. This normal complement is hard to explain and underscores the fact that knowledge on the complexity pathophysiology of SLE is in evolution. Another interesting phenomenon was paradoxical decline, albeit mild, in level of complement after the pleural effusion resolved and the proteinuria improved.

Conclusion

Differential diagnosis of SLE should be retained even in atypical cases particularly if no alternative diagnosis is made. It may also present with features not consistent with the conventional clinical and laboratory features.

References

1. Orens JB, Martinez FJ, Lynch JP III. Pleuropulmonary manifestation of systemic lupus erythematosus. Rheum Dis Clin North Am. 1994; 20:159-193.

2. Alarcon-Segovia D, Alarcon DG. Pleuropulmonary manifestations of systemic lupus erythematosus. Dis Chest. 1961; 39: 7-17.

3. Keane MP, Lynch JP III. Pleuropulmonary manifestation of systemic lupus erythematosus. Thorax. 2000; 55:159-166.

4. Tjalma WAA. Ascites, pleural effusion and CA 125 elevation in an SLE patient, either a Tjalma syndrome or, due to the migrated Filshie clips, a pseudo-Meigs syndrome. Gynecol Oncol 2005; 97: 288–291.

5. Schmitt R, Weichert W, Schneider W, Luft FC, Kettritz R. Pseudo-pseudo Meigs’ syndrome. Lancet. 2005; 366: 1672.

6. Cuchacovich R, Gedalia A. Pathophysiology and clinical spectrum of infections in systemic lupus erythematosus. Rheum Dis Clin N Am. 2009; 35: 75–93.

7. Mitra B, Sengupta P, Saha K, Sarkar N, Pal J. Systemic lupus erythematosus presenting with recurrent pleural effusion without any systemic manifestation. JAPI. 53: 1073-1076

.

Afr J Rheumatol 2013; 1(1): 4545 Afr J Rheumatol 2013; 1(1): 8-1253

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The African Journal of Rheumatology is published biannually by the The African League of Associations for Rheumatology (AFLAR). The journal aims to publish papers on basic and clinical research in rheumatism and arthritis and be a vessel of sharing knowledge a close the globe. Original research work, reviews, case reports and other relevant scientific work will be published in the journal on the understanding that the work submitted will not be under consideration in any other journal. This must be stated by the authors when submitting papers.All submitted papers will be acknowledged and are peer reviewed. The journal will strive to communicate to the authors the verdict of the reviewers within three months from date of submission. Papers should be submitted to; The Editor, African Journal of Rheumatology, P. O. Box 29727 – 00202, Nairobi, Kenya. Email: [email protected] on patients and volunteers require informed consent and this must be clearly stated in the paper. Authors of this kind of papers must as well state

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