july--september, 2004

Journal of Pakistan Association of Dermatologists

Volume 1 4, Number 3 July-September, 200 4 Editor Ijaz Hussain Associate Editors Farhana Muzaffar Zahida Rani Faria Asad

Advisory Board Ashfaq Ahmed Khan Atif Hasnain Kazmi Badr S. Dhanani Hasina Thawerani Iqbal Chowdhry Iqbal Tareen Khadimullah Kakakhel Muhammad Jahangir Naeem Iqbal S. M. Azam Bokhari S.M. Shamim Sabrina Suhail Pal Simeen Ber Rahman Tahir Saeed Haroon

Editorial Board Ahsan Hameed Amor Khachemoune Arfan ul Bari Muhammad Arif Maan Ghulam Mujtaba Ian MacColl Jameel A. Shaheen Khalid Hussain Khawar Khurshid Muhammad Khalid Naseema Kapadia

Nasser Rashid Dar Pervaiz Iqbal Shahbaz A. Janjua Shahbaz Aman Tahir Anees Tahir Jamil Ahmad Tariq Rashid Tariq Zaman Yasmeena Khan Zarnaz Wahid Zohra Zaidi

Publication Manager Mr. Omar Abdul Aziz

JPAD, the official journal of Pakistan Association of Dermatologists is published quarterly, four issues per volume and one volume per year (ISSN 1560-9014). The journal is recognized by Pakistan Medical and Dental Council and is indexed in College of Physicians and Surgeons Pakistan MEDLIP; Ulrich’s International Periodical Directory, USA; ExtraMED, London; EMBASE/Excerpta Medica, The Netherlands; and Index Medicus, WHO Alexandria, Egypt.

Subscription A complimentary copy of the journal is provided to all PAD members. Subscription rates per volume are Rs. 1000.00 for Pakistan, £80.00 for UK and $120.00 for US and rest of the world. Copyright 2003 Any material published in JPAD is copyright of Pakistan Association of Dermatologists.

Journal of Pakistan Association of Dermatologists

Volume 1 4, Number 3 July-September, 200 4 Contents Editorial The guardian of the genome: p53 107 Shahbaz A. Janjua Original articles Cutaneous manifestations of systemic lupus erythematosus in Pakistani children 110 Farhana Muzaffar Cutaneous leishmaniasis in Sadda, Kurram Agency, Pakistan 114 Sahibzada Mahmood Noor, Dildar Hussain Olive oil: an effective emollient for lichen simplex chronicus 118 Syed Muhammad Shamim, Kishwar Sultana, Fareeda Islam, S.I Ahmed Family history of psoriasis and recent infectious disease are risk factors for the first episode of acute guttate psoriasis 124 Shahzana Naqqash , Tameez-ud-deen, Shahid Naqqash, Abdul Quddus Butt Review articles

Porokeratosis : A review of unique group of keratinizing disorders 130 Arfan ul Bari, Simeen Ber Rahman Management of atopic dermatitis: a review 140 Amer Ejaz, Naeem Raza

Stat corner Biostatistics – I: Introduction, role and application in medicine 148 Tariq Zaman, Abbas Raza

Case reports Dyskeratosis congenita in a Saudi boy: an uncommon genodermatosis 153 A. Y. Saadeldin, Satti A. Satti, Ali S. Dammas

Nevoid psoriasis: an uncommon blaschkolinear dermatosis 157 Arfan ul Bari, Simeen Ber Rahman Quiz Generalized pustular rash of acute onset 161 Asher Ahmed Mashood News 164 Information for authors 165

Journal of Pakistan Association of Dermatologists 2004; 14: 107-9.

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Address for Correspondence Dr. Shahbaz A. Janjua, MD, Ayza Skin and Research Center, Lalamusa, Pakistan Email: [email protected]

Editorial The guardian of genome: p53 Shahbaz A. Janjua

Ayza Skin and Research Center, Lalamusa, Pakistan

Cancer is essentially a genetic disorder. So far, more than one hundred cancer related genes have been discovered, several of which are implicated in the natural history of cancer because they have constantly been found mutated.1 The mutations could be inherited or acquired. Inherited mutations that predispose individuals to cancer formation are termed germline, while acquired mutations that contribute to tumor development are known as somatic. Mutations that occur in critical growth regulatory genes resulting in variations in cellular proliferation and survival, subsequently contribute to the selection of dominant tumor populations. Oncogenes and tumor suppressor genes make two broad classes that become mutated contributing to cancer formation. Cancer-promoting genes or oncogenes were originally identified as viral genes that "transform" a normal cell into a malignant cell. Normal counterparts to these viral oncogenes in the human genome, well known as proto-oncogenes, have been detected, most of which function as growth-signaling molecules that become mutated and are perpetually "turned on”. Tumor suppressor genes, on the other hand, negatively regulate cell growth or promote

cell death. Both copies of the tumor suppressor gene must be inactivated for complete loss of function unlike oncogenes. One group of tumor suppressor genes restricts cellular growth by inhibiting the cell cycle and cell division, down-regulating growth signals, or promoting cell death while the second group does not directly participate in growth regulation, but rather maintains the integrity of the human genome. The p53 tumor-suppressor gene is the most striking example that is mutated in about half of almost all types of cancer arising from a wide spectrum of tissues.1 The p53 gene is located on the long arm of chromosome 17 and contains 11 exons spanning some 20000 bp of genomic sequence. The gene encodes a 53 kd nuclear phosphoprotein of 393 amino acid residues which is well known as p53 protein. The p53, also termed as guardian of the genome (as it protects DNA integrity in response to cytotoxic stress, including radiation), was discovered in the late 1970s.2,3 It has been implicated in the control of the cell cycle, DNA repair and synthesis, cell differentiation, genomic plasticity, and programmed cell death.4,5 The activity of the p53 tumor-suppressor protein has a key role in controlling both cancer and aging. It would be pertinent to note here that underactivity of p53 encourages the growth of cancer, and overactivity can accelerate the aging process.

The guardian of genome: p53 Shahbaz A. Janjua

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The p53 protein which is synthesized after the infliction of DNA damage, functions to protect the cells from malignant transformation by causing cell-cycle arrest at the G1 phase until the DNA damage has been repaired. Once the damage is repaired, p53 is degraded. As mentioned earlier, a loss of this protective influence occurs in approximately 50% of human tumors in which p53 is inactivated by a mutation in its gene or by the binding of proteins encoded by viral or cellular oncogenes.6 The mutations result in reduced binding of the p53 with the damaged DNA and subsequent accumulation of mutated p53 in the cell nuclei of the affected cells to the extent that it becomes detectable by routine immunocytochemistry.7 This makes it the most frequently inactivated protein in human cancer and therefore an important pathway to target for cancer therapy. In addition to representing the most common genetic defects in human cancer, the spectrum of p53 mutations has characteristic fingerprints that can be correlated with the DNA damage specific to certain definitive causes of cancer (e.g. UV-B radiation, aflatoxin, and oxidative processes).8 The mutated forms of p53 may also interact with different sets of transcription sites, resulting in increased proliferation of cells because p53 is also a transcription factor.9 Mutations in the p53 gene have been observed in many actinic keratoses, basal cell carcinomas, and squamous cell carcinomas, and in a small proportion of malignant melanomas. Specific types of pyrimidine transitions have pointed to a role for UV light in these mutations.7

The correlation between the incidence of squamous cell carcinoma and mutations in p53 tumor suppressor genes has been well characterized.10 The chief risk factor for squamous-cell carcinoma, is exposure to ultraviolet light which is highly mutagenic, partly as a consequence of the characteristic pyrimidine dimer premutagenic lesions it generates in DNA.11 Of all the experimentally examined mutagens, ultraviolet radiation leaves the most distinctive fingerprint in DNA: unrepaired cytosine dimers induce tandem mutations, in which two adjacent cytosine residues (cytosine-cytosine) are replaced by two thymine bases (thymine-thymine), an event that occurs very rarely unless there is exposure to ultraviolet radiation. Three of the first 15 mutations discovered in the p53 gene of squamous-cell carcinomas of the skin were just such tandem substitutions, directly incriminating both exposure to ultraviolet light as the cause of damage to the p53 gene and the loss of tumor-suppressor function in the development of the cancers.10 It would be interesting to note that p53 is not an oncogene and the mutated forms may not necessarily result in an oncogenic process. It was evident from the description of p53 mutations in at least two nonmalignant hyperproliferative processes including keloid and rheumatoid arthritis.12,13 It has also been hypothesized that p53 mutations predispose cells to hyperproliferation, resulting in keloid formation because p53 mutations have been noted in the keloid fibroblasts.12


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The most challenging task is the development of drugs to mimic p53 tumor-suppressor function that is being aided by rapid advances in studies of p53 molecular mechanisms. The failure of chemotherapy and resistance to radiotherapy has been attributed to multidrug-resistance gene, MDR1, which confers cross-resistance to hydrophobic natural-product cytotoxic drugs making that treatment ineffective. It has been demonstrated that the expression of MDR1 is up-regulated by certain mutants of p53.9,14 Then the role of normal functioning p53 in allowing time for the repair of radiation-induced DNA damage during the G1 phase of the cell cycle, suggests that the response to radiotherapy or chemotherapy may depend in part on the status of p53 in tumors before treatment. A full clinical analysis of various types of tumors still remains to be explored to learn whether treatment is more or less successful, depending on the type of p53 alteration in the primary tumor, and whether different treatments and treatment schedules should then be selected on the basis of the involvement of p53. References

1. Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993; 329: 1318-27.

2. Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature 1979; 278: 261-3.

3. Linzer DI, Levine AJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 1979; 17: 43-52.

4. Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature 1991; 351: 453-6.

5. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 Mutations in human cancers. Science 1991; 253: 49-53.

6. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in p53 tumor suppression gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994; 54: 4855-78.

7. McNutt NS, Saenz-Santamaria C, Volkenandt M et al. Abnormalities of p53 protein expression in cutaneous disorders. Arch Dermatol 1994; 130: 225-32.

8. Gasparro FP. p53 in dermatology. Arch Dermatol 1998; 134: 1029-32.

9. Dittmer D, Pati S, Zambetti G et al. Gain of function mutations in p53. Nat Genet 1993; 4: 42-6.

10. Brash DE, Rudolph JA, Simon JA et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A 1991; 88: 10124-8.

11. Drobetsky EA, Grosovsky AJ, Glickman BW. The specificity of UV-induced mutations at an endogenous locus in mammalian cells. Proc Natl Acad Sci U S A 1987; 84: 9103-7.

12. Saed GM, Ladin D, Olson J et al. Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing. Arch Dermatol 1998; 134: 963-7.

13. Firestein GS, Nguyen K, Aupperle KR et al Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. Am J Pathol 1996; 149: 2143-51.

14. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science 1992; 255: 459-62.

Cutaneous manifestations of SLE in Pakistani children Farhana Muzaffar

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Address for Correspondence Dr. Farhana Muzaffar, Assistant Professor of Dermatology, The Institute o f Child Health/Children’s Hospital, Lahore

Original article Cutaneous manifestations of systemic lupus erythematosus in Pakistani children Farhana Muzaffar

Department of Dermatology, Institute of Child Health/Children Hospital, Lahore.

Abstract Background Systemic lupus erythematosus (SLE) is a multisystem disease of autoimmune

etiology. Cutaneous changes are seen in more than two -third of patients. Objectives The present study was planned to evaluate cutaneous manifes tations of SLE in children. Patients and methods Fifteen cases of SLE were collected from the Department of Pediatric Dermatology, Children Hospital, Lahore. The diagnosis was based on American Rheumatism Association criteria. Cutaneous changes were recorded on a predevised pro forma. Results Age of onset was 5-13 years in 14 (93.3%) children. One case of neonatal LE was seen. There were 8 (53.3%) females and 7 (46.7%) males. Malar rash was present in 10 (66.6%), photosensitivity in 8 (53.3%), diffuse hair loss in 6 (40%), hyperpigmentation in 5 (33.3%), vascular lesions in 5 (33.3%), mucosal lesions in 3 (20%), nail changes in 2 (13.3%), bullous lesions in 1 (6.7%), livedo reticularis in 1 (6.7%), and rheumatoid nodules in 1 (6.7%). The single case of NLE had generalized scaly lesions. Conclusion Cutaneous changes in children are different from those seen in adults. Female preponderance was not seen in children. Photosensitivity and vascular lesions were less frequent while the discoid rash was rare. Peripheral gangrene, chilblain and Raynaud’s phenomenon were not seen. Neonatal LE was a rare entity. Key words SLE, neonatal LE, cutaneous manifestations.

Introduction

Systemic lupus erythematosus (SLE) is a multisystem disease of autoimmune etiology. Integument is affected in more than two-third of cases.1-3 Cutaneous changes constitute four of 11 criteria of American Rheumatism Association (ARA) for the diagnosis of SLE. The disease usually affects adult females. Childhood SLE is a rare entity with an incidence of 10-20 in 100000 white

Caucasian children with a male to female ratio of 1:4.5 between the ages of 6 and 18 years.4 It is reported that 15-17% of all patients with SLE, the disease starts before 16 years. Rarely the babies born to mothers with lupus may develop LE called neonatal lupus erythematosus (NLE), due to passive transfer of maternal autoantibodies to fetus . Cutaneous changes of all types occur in 60-90% of children at any time during the course of illness whereas these are seen in 60-78% of cases at the time of diagnosis.4 Hence, the recognition of cutaneous changes of SLE is very important in the early diagnosis of this potentially dangerous


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disease which, otherwise may be missed by an unwary physician. Many local studies 5-7 address the subject in adult patients with SLE; however, scanty data are available on the topic in children of Pakistani origin. The present study was conducted to evaluate the cutaneous manifestations of SLE in Pakistani children.

Patients and methods

This descriptive study was conducted at the Department of Pediatric Dermatology, Institute of Child Health/Children Hospital, Lahore, from 1st January, 2003 to 31st December, 2003. Fifteen children of SLE (diagnosed on the basis of ARA criteria) were enrolled in the study. A detailed history and physical examination were recorded. The relevant hematological, biochemical and immunological profile, radiological work-up and skin biopsy were carried out. Cutaneous changes were further subdivided as specific (histopathological changes characteristic of LE) and non specific. Results During the one-year period, 15 patients were diagnosed, 14 children had SLE and one had neonatal LE. There were 8 female (53.3%) and 7 (46.7%) male children, with male to female of 1:1.1. Age of onset ranged from 5-13 years in 14 children with SLE. The frequency of LE-specific lesions and LE-nonspecific lesions is shown in Table 1 and 2, respectively. LE-specific included malar rash (Figure 1), mucosal ulcers (Figure 2) and photosensitivity. Oral mucosa was affected in 3 and genital in 2 patients (Table 3).

Table 1 Frequency of different LE-specific lesions in 15 case of SLE. Lesions n (%) Malar rash 10 (66.7) Photosensitivity 8 (53.3) Psoriasiform lesions of subacute LE

1 (6.7)

Table 2 Dis tribution of different LE-nonspecific lesions Lesions n (%) Vascular lesions Telangiectasia 5 (33.3) Microinfarcts 2 (13.3) Purpura 2 (13.3) Chronic ulcers 2 (13.3) Bullous Erythema multiforme 1 (6.7) Livedo reticularis 1 (6.7) Pigmentary changes Hyperpigmentation 5 (33.3) Hypopigmentation 1 (6.7) Hair changes Diffuse alopecia 6 (40) Lupus hair 1 (6.7) Others Ragged cuticle 2 (13.3) Ichthyosis 2 (13.3) Sclerodactyly 1 (6.7) Erythematous papules 1 (6.7) Rheumatoid nodules 1 (6.7)

Table 3 Mucosal sites affected (n=15) Mucosae affected n (%) Lips 3 (20) Palate 3 (20) Buccal mucosa 3 (20) Genital mucosa 2 (13.3) Chronic discoid lesions were not seen in any case. The single case of NLE had generalized psoriasiform eruption (Figure 3). She was the first baby of a 24-year-old mother who was found to be anti-Ro positive. She had fever, skin rash, hepatosplenomegaly and cardiac disease. Histopathology from the back showed changes compatible with LE. The baby was also anti-Ro positive. Amongst nonspecific lesions vascular manifestations were the most frequent

Cutaneous manifestations of SLE in Pakistani children Farhana Muzaffar

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Figure 1 Malar rash, photosensitive generalized maculopapular eruption and non-cicatricial alopecia in a child with SLE.

Figure 3 Generalized psoriasiform eruption in the female infant with neonatal LE.

(Figure 4). The frequency of other types of lesions is shown in Table 2. Peripheral gangrene, chronic ulcer, chilblain, and Raynaud’s phenomenon were not seen. Discussion The present study affirms the high prevalence of cutaneous changes in SLE patients. However, the frequency was 100% in our series than previously reported4 since all of our cases were collected from the dermatology out-patient clinic. Secondly, a diverse spectrum of cutaneous changes can be seen. We noticed an equal sex ratio whereas

Figure 2 Ulcers over lips and buccal mucosa. Face and neck is als o affected.

Figure 4 Bilateral purpuric eruption on the legs of a girl. Mild scaling is also evident.

previous reports give a female preponderance.4 Malar rash was the most frequent finding. This is in accordance with the previous reports.4,8,9 Malar rash is seen in 30-80% of patients and it is present in 22-60% of cases at the time of diagnosis.4 The incidence of malar rash increases with disease progression.9 Photosensitivity was rare in our series. Similarly, none of our patients had discoid lesions. Table 4 depicts the comparison of cutaneous changes in our patients with that by Font et al.8 The difference between two can be due to different racial background. Psoriasiform eruption seen in the single patient of NLE was in consonance with literature.4 This signifies that a psoriasiform eruption in an infant in the


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Table 4 Comparis on with study in children. Lesions Present

study (2003) (n=15)

Font et al. [4] Spain, 2004 (n=34)

Malar rash 66.7 44% Photosensitivity 53.3% 23% Oral ulcers 20% 9% Psoriasiform lesions of SCLE

6.7% -

Livedo reticularis 6.7% 3% Table 5 Comparis on with study in adults. Lesions Present

study (2003) (n=15)

Rabbani et al. [5] Pakistan, 2003 (n=34)

Malar rash 66.7 31% Photosensitivity 6.7% 33% Vascular lesions 33.3% 20% Mucosal lesions 20% 20% Pigmentary changes 33.3% 22% Discoid rash - 15% presence of systemic features should not be taken lightly. Table 5 compares the cutaneous changes in children of our series with those in Pakistani adults. In comparison to adults, malar rash, photosensitivity and vascular lesions were more frequent whereas discoid lesions are seen more frequently. Our results conclude that cutaneous changes in children are different from those seen in adults. Female preponderance is not seen in children. Photosensitivity is less frequent. Discoid rash is rare. Peripheral gangrene, chronic ulcer, chilblain, and Raynaud’s phenomenon were not seen. Neonatal LE is a rare entity.

References

1. Cervera R, Khamashta MA, Font J et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1000 patients. Medicine 1993; 72: 113-24.

2. Costallat LT, Coimbra AM. Systemic lupus erythematosus : clinical and laboratory aspects to age at onset. Clin Exp Rheumatol 1994; 12: 603-7.

3. Tucker LB, Menon S, Miller LC et al. Adult and childhood-onset systemic lupus erythematosus: a comparison of onset, clinical features, serology, and outcome. Br J Rheumatol 1995; 34: 866-72.

4. Silverman ED, Eddy A. Systemic lupus erythematosus in childhood and adolescence. In: Maddison P, Isenberg D, Woo P, Glass D, eds. Oxford Textbook of Rheumatology. Oxford: Oxford University Press; 1993. p. 756-71.

5. Kapadia N. Cutaneous changes in systemic lupus erythematosus (dissertation). Karachi: College of Physicians and Surgeons; 1994.

6. Ahmed TA, Ikram N, Hussain T et al. Clinical and laboratory features of SLE in Pa kistani patients. J Pak Med Assoc 2002; 52: 12-5.

7. Rabbani MA, Shah SM, Ahmed A. Cutaneous manifestations of systemic lupus erythematosus in Pakistani patients. J Pak Med Assoc 2003: 53: 539-41.

8. Font J, Cervera R, Espinosa G et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunologic findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis 1998; 58: 456-9.

9. Rood MJ, ten Cate R, van Suijlekom-Smit LW et al. Childhood-onset SLE: clinical presentation and prognosis in 31 patients. Scand J Rheumatol 1999; 28: 222 -6.

Cutaneous leishmaniasis in Sadda…. Sahibzada M. Noor and Dildar Hussain

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Address for Correspondence Dr. Sahibzada Mahmood Noor, 32, New Colony, Hango Road, Kohat, Pakistan Email: [email protected]

Original article Cutaneous leishmaniasis in Sadda, Kurram Agency, Pakistan Sahibzada Mahmood Noor, Dildar Hussain

Tehsil Headquarter Hospital, Sadda, Parachinar

Abstract Background Cutaneous leishmaniasis (CL) is endemic in the tribal belt bordering

Afghanistan .This study was carried out to determine the demographic and clinical pattern of the disease in Sadda , Kurram Agency. Patients and methods CL patients presenting to leishmaniasis clinic of Tehsil Headquarter Hospital, Sadda from 1st November, 2003 to 30thMarch, 2004 were included in the study. The patients were diagnosed clinically and confirmed by laboratory confirmation of parasites in a Giemsa-stained smear prepared from the lesion. All important clinical details were recorded on a specially designed proforma and patients were registered for the purpose of treatment and a card was issued to them for subsequent visits and follow up. Results A total of one hundred and fifty patients with 325 lesions were seen during a period of five months. Dry type of cutaneous leishmaniasis was seen in 120 (80%) patients and wet type was noted in 30 (20%) patients. Most of the lesions (98%) were present on exposed parts of the body. Sixty (40%) patients had one and 75 (50%) had two lesions. More than two lesions were seen in 10% of patients. Eighty per cent of sufferers were less than 30 years of age. The disease was more common in males (70%). Family history was positive in 45 (30%) patients. History regarding traveling to Afghanistan was negative in most of the patients (98%). Conclusion CL is endemic in this part of tribal belt. Both type of CL is prevalent among the local p opulation. Key words Cutaneous leishmaniasis, Sadda

Introduction Cutaneous leishmaniasis (CL) is a chronic granulomatous infection of reticuloendothelial cells of skin caused by the protozoan parasite Leishmania.1 Although, the infection occurs in all continents, it is endemic in tropical and subtropical countries. In Pakistan, the disease is endemic in Sindh and Baluchistan provinces.2 It has also been reported from Multan, Dera Ghazi Khan

and Chakwal districts in the province of Punjab.3 In NWFP, the disease has been reported from District Dir,4 Kohat,5 and Afghan refugees settlements. In Afghanistan and Pakistan two Leishmania species; L. tropica causing dry type of lesions and L. major producing wet type of lesions are mainly seen. 6 Visceral leishmaniasis has been reported from district Dir in NWFP.7 Cutaneous leishmaniasis is called saal dana in Afghanistan and areas of NWFP where it is endemic (saal=year, dana=lesion). CL has been common in parts of Afghanistan for centuries .6 During Soviet occupation of Afghanistan, tribal


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belt bordering Afghanistan was the home to millions of Afghan refugees, and Kurram Agency in Federally administered tribal area (FATA) had the largest population of Afghan refugees. These war-related population movements and environmental destruction have caused a large increase in the CL prevalence in tribal belt bordering Afghanistan. CL spread to refugee camps in FATA of Pakistan and is now transmitted locally in these areas.8 Kurram Agency is divided into three parts Upper Kurram, lower Kurram and central Kurram. Sadda is the headquarter of the lower Kurram with a population of half a million. Due to increase in the prevalence of cutaneous leishmaniasis in Sadda, a Leishmaniasis Clinic was established in 2001 where patients are diagnosed on the basis of smear for parasites and treated with pentavalent antimonial compounds. This study was conducted to determine the demographic and clinical pattern of cutaneous leishmaniasis in patients presenting to leishmaniasis clinic of Tehsil head quarter hospital Sadda. Patients and methods This study was carried out in the Leishmaniasis Clinic of Tehsil headquarter hospital (THQ), Sadda, Kurram agency from 1st November 2003 to 30th April, 2004. One hundred and fifty patients with clinically suspected leishmaniasis presenting to the Leishmanias is Clinic of THQ hospital, Sadda, Parachinar were included in the study. Clinical features including age, gender, nationality, site and number of the lesions, family history, inquiry regarding visit to Afghanistan were recorded on a register. The lesion was examined clinically and diagnosis was confirmed by the presence of amastigotes

of Leishmania in a Giemsa-stained smear from the edge of the lesion. Smear examination is the earliest and sole method to confirm the clinical diagnosis in an endemic area. In our study only smear positive cases were included in the study. All the cases were registered and a card was issued for the purpose of treatment and follow -up. Patients were treated according to WHO recommendations with either sodium stib ogluconate or meglumine antimonate.

Results

A total of 150 patients were seen in the clinic during a period of 4 months from 1st November, 2003 to 30th March, 2004. There were 105 (70%) males and 45 (30%) females. Although disease was prevalent in all age groups (range 1-60 years), 83% of the patients were less than 30 years of age. Dry type of leishmaniasis was seen in 120 (80%) patients while wet type was noted in 30 (20%) patients Table 1. The duration of lesion ranged from 4 weeks to 3 months. The lesions were situated on the exposed parts of the body face, hands and feet. Face was the commonest site involved and trunk the least Table 2. Family history of leishmaniasis was positive in 22 patients. None of the patients reported traveling to Afghanistan. Majority of patie nts were local whereas 17 patients were Afghan refugees. The total number of lesions in all the patients was 325. Sixty patients (40%) had one lesion, 75 (50%) had two lesions and 15 (10%) had more than two lesions. The maximum number of lesions i.e. 6 was seen in brother and sister who were from Sherinao, a small village next to Pak-Afghan border in Afghanistan Table 3.

Cutaneous leishmaniasis in Sadda…. Sahibzada M. Noor and Dildar Hussain

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Table 1 Age and gender of the study population (n=150)

Age (years) n (%)

0-10 30 (20)

11-20 48 (33)

21-30 40 (27)

31-40 11 (7.3)

51-60 9 (6)

Table 2 Anatomical distribution of lesions (n=325) Site n (%) Face 103 (32) Hands 82 (25) Forearms 48 (15) Feet 58 (17.8) Legs 26 (8) Trunk 7 (2.2) Total 325 (100)

Table 3 Frequency of number of lesions (n=325) Number of lesions n (%)

1 60 (40) 2 75 (50) 3 4 (2.7) 4 1 (0.7) 5 3 (2) 6 2 (1.3) Discussion Cutaneous leishmaniasis is a world wide problem and is endemic in Afghanistan for centuries. It is of clinical importance because of its chronicity and its potential for local destruction and disfigurement. The disease is commonly known as saal-dana in parts of Afghanistan and trib al areas where it is endemic .8 Sporadic cases of cutaneous leishmaniasis were seen in Afghan refugees living in this area as evidenced by the presence of healed lesions in Afghan refugees. The disease has been endemic in Afghanistan for a long time. 8 The present outbreak in this part of tribal belt can be linked to large scale movement of refugees across the border and environmental destruction as a

result of massive bombing carried out in this area that disturbed the ecology. Initially the disease was localized to Afghan refugees but gradually it involved the local population, which was non immune to the disease as reported from other parts of country.8

In the present study, both types of cutaneous leishmaniasis were seen, although dry type of lesions were more common (80%). In contrast Rab et al.9 reported wet type of lesions from Baluchistan whereas another study from Multan10 reported dry type of lesions. The occurrence of both type of cutaneous leishmaniasis may be due to presence of L. major as well as L. tropica in this region.

Almost all the patients were local except two patients who were admitted in the hospital with extensive lesions referred from Afghanistan. This signifies that the disease is locally endemic. Afghan refugees living in Sadda are provided health facilities by Project Directorate Health for Afghan refugees, having separate centers for provision of health facilities to Afghan refugees.

Most of the patients were from poor socioeconomic background living in congested houses having mud-lined walls with poor sanitary conditions. Family history of involvement was positive in 30% of cases.

Lesions were found mainly on exposed parts of the body because these are easily accessible sites for the sandflies to bite. The duration of lesions ranged from 4 weeks to three months. The disease was more common in 11-20 years age group.


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Smear for Leishman-Donovan bodies is the sole method available to confirm these cases. Patients presenting with unusual lesions with negative smear were referred to tertiary level hospitals for diagnosis and management. Unusual clinical variants of cutaneous leishmaniasis have been reported from other endemic areas.11 Due to lack of facilities and trained personnel, the disease is overdiagnosed and many skin ailments are wrongly treated as leishmaniasis.

Conclusion

Cutaneous leishmaniasis is endemic in this part of tribal area bordering Afghanistan. It is for first time that cutaneous leishmaniasis has been reported from this area. The disease can be controlled by elimination of sand flies and improving sanitary conditions.

References

1. Kubba R, Gindan YA. Leishmaniasis. Dermatol Clinic 1989; 7 :331-50.

2. Jaffrany M, Haroon TS. Cutaneous leishmaniasis in Pakistan. Biomedica 1992; 8: 39-44.

3. Ayub S, Mujtaba G, Khalid M, Bhutta R. Profile of patients of cutaneous

leishmaniasis in Multan. J Pak Med Assoc 2001; 50: 279-81.

4. Rahim F, Jamal S, Raziq F et al. An outbreak of cutaneous Leishmanias is in a village of District Dir, N.W.F.P. J Postgrad Med Inst 2003 ;17: 85-8.

5. Mashood AM. Diagnostic yield of various traditional laboratory investigations in the diagnosis of cutaneous leishmaniasis. J Pak Assoc Dermatol 2004; 14: 59-63.

6. World Health Organization (WHO). Report of Committee. The Leishmaniasis: World Health Tech Rep Ser 701, 1984.

7. Rahim F, Rehman F, Ahmed S, Zada B. Visceral Leishmaniasis in District Dir, N.W.F.P. J Pak Med Assoc 1998; 48: 162 -4.

8. Rowland M, Munir A, Durrani N et al. An outbreak of cutaneous leishmaniasis in an Afghan refugee settlement in north-west Pakistan. Trans R Soc Trop Med Hyg 1999; 93: 2.

9. Rab MA, Azmi FA, Iqbal J et al. Cutaneous leishmaniasis in Baluchistan: reservoir, host and sandfly vector in Uthal, Lasbela. J Pak Med Assoc 1996; 36: 134-8.

10. Mujtaba G, Khalid M. Cutaneous Leishmaniasis in Multan, Pakistan. Int J Dermatol 1998; 37: 843-6.

11. Raja KM, Khan AA, Hameed A, Rahman SB. Unusual clinical variants of cutaneous leishmaniasis in Pakistan. Br J Dermatol 1998; 139 : 111-3.

Olive oil: an effective emollient for LSC S. M. Shamim et al.

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Original article Olive oil: an effective emollient for lichen simplex chronicus Syed Muhammad Shamim, Kishwar Sultana*, Fareeda Islam, S.I Ahmed

Department Pharmacology and Therapeutics, Karachi Medical & Dental College, Karachi * Department Anatomy, Hamdard College of Medicine & Dentistry, Hamdard University, Karachi Department of Pharmacy, Hamdard University, Karachi

Abstract Background Olive belongs to the family of Oleacae. Olive oil is being used increasingly in

different systemic diseases. In dermatology, it is primarily used as a vehicle but it can have many other potential uses. Objectives We tested the efficacy of topical olive oil in the treatment of lichen simplex chronicus. Patients and methods Forty male and female patients suffering from lichen simplex chronicus affecting nape of the neck, arms, back of the legs and ankle. Patients were followed up weekly for four weeks. Pruritus and dryness were scored on a 4-grade scale i.e. none, slight, moderate and severe at baseline and on each follow up visit. Results Significant improvement in pruritus and dryness was noticed in all age groups and both sexes. Conclusions Olive oil is effective in controlling dryness and pruritus in lichen simplex chronicus. Key words Olive oil, emollient, lichen simplex chronicus.

Introduction The plant Olive (Zaitoon in Arabic and Urdu) belongs the family Oleacae. The olive oil is nutritive, emollient, demulcent, laxative, allays the irritation of digestive organs and alimentary canal. Olive oil is used for edible purpose, relieves general debility and weakness in all age groups. It relieves constipation and is beneficial when used in fistula and anal fissures. It is useful to relieve rheumatic pain, paralysis, sciatica. It softens the body when

massaged and it was considered remedy of haemorrhoids, skin diseases, according to Ibn-ul-Qim as mentioned by Ghaznavi. 1,2 The olive oil produces freshness, keeps alertness, removes the worms from the gut, gives vigour in old age2 It is known that Mediterranean diet represents a useful and effective mean for prevention of arteriosclerosis.3 Effect of olive oil on cardiovascular disease were evaluated and the findings suggested that polyphenolic compounds found in olive oil are endowed with several biologic activities that may contribute to lower incidence of coronary heart disease in Mediterranean area,4 It is useful in modifying disease activity in systemic lupus erythematosus5 and rheumatoid arthritis .6

Address for Correspondence Prof. Syed Muhammad Shamim Department Pharmacology and Therapeutics, Karachi Medical & Dental College, Karachi


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In dermatology, olive oil has many uses. Besides its use as a vehicle in different topical preparations,7 it is also effective in alopecia, seborrhoea capitis, lustreless hair, oral aphthae and burns.2 The experimental work showed its potential benefits in psoriasis.8 Olive oil or fish oil supplementation was also found to improve the symptoms of pruritus in patient of chronic renal failure.9 Lichen simplex chronicus (LSC) is a dermatosis in which lichenification, the hallmark of disease, occurs without any known precipitating factor.10 The disease is common world-wide and it usually affects adults of both sexes. Nape and sides of neck, around ankles, lower legs, thighs, extensor aspects of arms, and genital regions are the usually affected sites. Topical steroids with and without occlusion, intradermal steroid injections are usually used to treat. Considering the growing popularity of alternative medicine in dermatology world over, we aimed to test the efficacy and safety of olive oil in the treatment of this itchy disorder. Patients an d methods Forty male and forty female patients, age = 10 years, suffering from lichen simplex chronicus (diagnosed clinically) were collected from authors’ clinics and divided into different subgroups according to the age and sex as shown in Table 1. They were advised olive oil to apply on the affected parts (nape of the neck, arms, back of the legs and ankle) three times a day regularly. Dryness and pruritus were scored weekly for 4 weeks. The assessment score was assigned qualitatively as none, slight, moderate and severe. The pre- and post-treatment scores

Table 1 Subgroups of patients according to Group Age (years) n Male patients (n=40) 1. A 10-20 10 2. A1 21-30 10 3. A2 31-40 10 4. A3 41-50 10 Female patients (n=40) 5. B 10-20 10 6. B1 21-30 10 7. B2 31-40 10 8. B3 41-50 10

were compared for statistical significance. Results Tables 2-5 show the effect of olive oil therapy on dryness and pruritus in all subgroups. Effect on dryness Males Group A In this group, before treatment dryness was scored as moderate in 40% of the patients and severe in 60% . After four weeks , 70% rated as slight and 30% as moderate dryness (p<0.05).

Group A1 10% of the patients had moderate dryness while 90% had severe dryness before treatment. At week 4, 50% had slight and 50% had moderate dryness (p<0.05).

Group A2 Before treatment 10% of the patients had slight, 40% moderate, and 50% scored severe dryness. After 4 weeks of treatment, 80% rated slight and 20% moderate dryness (p <0.05).

Group A3 In 41-50 years group, before treatment 10% of the patients had slight, 40% had moderate and 50% had severe dryness. At the end of four weeks, 60% turned to slight while 40% turned to moderate (p <0.05).


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Table 2 Effect of olive oil treatment on dryness according to age group in male (n=40) Before therapy After treatment One week Two week Three week Four week Age group and severity of

clinical signs n (%) n (%) n (%) n (%) n (%) p value

Group A 10-20 years n=10 None - - - - - Slight - - - 6 (60) 7 (70) <0.05 Moderate 4 (40) 7 (70) 9 (90) 4 (40) 3 (30) Severe 6 (60) 3 (30) 1 (10) - - Group A1 21-30 years n=10 None - - - - - Slight - - 3 (30) 4 (40) 5 (50) <0.05 Moderate 1 (10) 3 (30) 5 (50) 6 (60) 5 (50) Severe 9 (90) 7 (70) 2 (20) Group A2 31-40 years n=10 None - - - - - Slight 1 (10) 1 (10) 1 (40) 4 (60) 8 (80) <0.05 Moderate 4 (40) 6 (60) 6 (50) 5 (40) 2 (20) Severe 5 (50) 3 (30) 3 (10) 1 (10) Group A3 41-50 years n=10 None - - - - - Slight 1 (10) 1 (10) 2 (20) 6 (60) 6 (60) <0.05 Moderate 4 (40) 6 (60) 8 (80) 4 (40) 4 (40) Severe 5 (50) 3 (30)

Table 3 Effect of o live oil treatment on dryness according to age group in females (n=40) After treatment Before

treatment One week Two week Three week Four week Age group and severity of clinical signs n (%) n (%) n (%) n (%) n (%) p value

Group B 10-20 years n=10 None - - - - - Slight - - - 1 (10) 2 (20) <0.05 Moderate 2 (20) 2 (20) 10 (100) 9 (90) 8 (80) Severe 8 (80) 8 (80) - -

Group B121-30 years n=10 None - - - - - Slight - - - - 5 (20) <0.05 Moderate 3 (30) 5 (50) 9 (90) 9 (90) 5 (70) Severe 7 (70) 5 (50) 1 (10) 1 (10) -

Group B2 31-40 years n=10 None - - - - - Slight 1 (10) 1 (10) 1 (10) 6 (60) 2 (20) <0.05 Moderate 3 (30) 8 (80) 9 (90) 4 (40) 8 (80) Severe 6 (60) 1 (10) - - -

Group B3 41-50 years n=10 None - - - - - Slight - - - 2 (20) 6 (60) <0.05 Moderate 5 (50) 7 (70) 9 (90) 7 (70) 4 (40) Severe 5 (50) 3 (30) 1 (10) 1 (10) -


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Females Group B Before treatment, 20% of the patients had moderate and 80% had severe dryness. After four weeks of therapy, 20% had slight and 80% had moderate signs dryness (p<0.05).

Group B1 30% patients had moderate and 70% had severe dryness before treatment whereas at week 4, 20% had slight, 70% had moderate and 10% had severe dryness (p<0.05).

Group B2 In this group, at baseline 10% patients had slight, 30% moderate and 60% severe dryness. At week 4, 20% had slight while 80% had moderate signs (p<0.05).

Group B3 50% of the patients had moderate while 50% had severe dryness. After four weeks of treatment, 60% had slight while 40% remained with moderate dryness (p<0.05).

Effect on pruritus Males Group A At baseline, 40% of the patients suffered from moderate and 60% from severe pruritus. At the end of treatment, 70% complained slight and 30% moderate pruritus (p<0.05).

Group A1 (21-30 years) Before treatment, 10% had moderate and 90% had severe itching while at the end of 4 weeks, 50% of the patients had slight and, 50% had moderate pruritus (p<0.05).

Group A2 In this group, 10% patients had slight pruritus before treatment, 50% had moderate while 40% had severe symptom. At the end of 4 weeks , 10% of the patients were symptom free while 80% were having slight pruritus and 10% moderate symptom (p<0.05).

Group A3 10% of the patients had slight pruritus , 40% moderate and 50% had severe. At the end of 4 weeks , 20% patients were symptom-free, 70% were left with slight itching and 10% with moderate itching (p<0.05).

Females Group B Before treatment, the pruritus was moderate in 20% of the patients, while 80% had severe symptoms. In contrast, at four weeks, 80% had slight symptom while 20% had moderate itching (p<0.05).

Group B1 The symptom of pruritus was moderate in 40% of patients and severe in 60%. At week 4, 60% of the patients had slight symptom while 40% had moderate (p<0.05).

Group B2 In 10% of the patients itching was slight, in 30% moderate and in 60% severe. With four weeks therapy, 10% had no pruritus, 80% left with slight symptoms and 10% with severe symptom (p<0.05).

Group B3 Before start of the treatment, 50% of patients had moderate pruritus while other 50% had severe symptom. After four weeks, 90% patients remained with slight itching and 10% remained with moderate symptom (p<0.05).

Safety profile None of the patient developed any cutaneous adverse effect. Discussion Steroids, topical or intralesional, have been the mainstay of treatment of LSC. No doubt being highly effective, steroids have many inherent, cutaneous and systemic, adverse


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Table 4 Effect of olive oil therapy on pruritus) according to age group in male (n=40) Before After treatment

Treatment One week Two week Three week Four week Age group and

severity of clinical signs n (%) n (%) n (%) n (%) n (%) p value

Group A 10-20 years n=10 None - - - - - Slight - - - 7 (70) <0.05 Moderate 4 (40) 7 (70) 9 (90) 10 (100) 3 (30) Severe 6 (60) 3 (30) 1 (10) - -

Group A1 21-30 years n=10 None - - - - - Slight - - 3 (30) 4 (40) 5 (50) <0.05 Moderate 1 (10) 3 (30) 6 (60) 6 (60) 5 (50) Severe 9 (90) 7 (70) 1 (10)

Group A2 31-40 years n=10 None - - - - 1 (10) Slight 1 (10) 1 (10) 4 (40) 6 (60) 8 (80) <0.05 Moderate 5 (50) 6 (60) 5 (50) 4 (40) 2 (10) Severe 4 (40) 3 (30) 1 (10)

Group A3 41-50 years n=10 None - - - 1 (10) 2 (20) Slight 1 (10) 1 (10) 2 (20) 5 (50) 7 (70) <0.05 Moderate 4 (40) 6 (60) 8 (80) 4 (40) 1 (10) Severe 5 (50) 3 (30)

Table 5 Effect of olive oil therapy on pruritus of the skin according to age group in females (n=40) After treatment Before

treatment One week Two week Three week Four week Age group and severity of clinical s igns n (%) n (%) n (%) n (%) n (%) p value

Group B 10-20 years n=10 None - - - - - Slight - - 4 (40) 7 (70) 8 (80) <0.05 Moderate 2 (20) 2 (20) 6 (60) 3 (30) 2 (20) Severe 8 (80) 8 (80) - - -

Group B1 21-30 years n=10 None - - - - - Slight - 2 (20) 2 (20) 5 (50) 6 (60) <0.05 Moderate 4 (40) 4 (40) 8 (80) 5 (50) 4 (40) Severe 6 (60) 4 (40) - - -

Group B2 31-40 years n=10 None - - - - 1 (10) Slight 1 (10) 1 (10) 5 (50) 9 (90) 8 (80) <0.05 Moderate 3 (30) 9 (90) 5 (50) 1 (10) 1 (10) Severe 6 (60) - - - -

Group B3 41-50 years n=10 None - - - - - Slight - 1 (10) 5 (50) 7 (70) 9 (90) <0.05 Moderate 5 (50) 6 (60) 5 (50) 3 (30) 1 (10) Severe 5 (50) 3 (30) - - -


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effects, so not really an ideal therapy.10 There is need and vacuum to find an alternative drug and the present study is an attempt to address this topic. Our results show that topical use of olive oil is effective in the treatment of lichen simplex chronicus. Scanty data are available on this subject. How does this improvement occur? In addition to the placebo ef fect, other mechanism s may be responsible. Olive oil is a good emollient which might help in breaking the itch-scratch-lichenification vicious cycle, the basic underlying pathophysiology in LSC. Different ingredients of olive oil may also be the other contributory factors. The major components of olive oil are monounsaturated oleic acid; squalene, tocopherols.11 These possess anti-inflammatory, anti-oxidant and scavenger properties. How far these mechanisms are helpful in LSC needs to be searched for. Placebo-controlled, double-blind studies are required to determine the comparative efficacy of olive oil in LSC. Olive oil was well-tolerated by our patients confirming that olive oil has low sensitizing potential. 12 In conclusion, olive oil appears to be effective in the treatment of lichen simplex chronicus; however, further investigations are required to confirm this.

References

1. Khan U, Saeed A, Alam MT, eds. Olea europaea. Karachi: University of Karachi; 1997. p. 314 -5.

2. Ghaznavi K, ed. Tibb-e-nabvi Aur Jadid Science. Lahore: Alfaisal publishers; 1992.

3. Jossa F, Macinic M. The Mediterranean diet in the prevention of arteriosclerosis research. Prog Med 1996; 87: 175-81.

4. Visioli F, Galli C. The effect of minor constituents of olive oil on cardiovascular disease: new findings. Nutr Rev 1998; 56: 142-7.

5. Walton AJ, Snaith ML, Ocniskar M et al. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis 1991; 50: 463-6.

6. Linos A, Kaklamanis E, Kontomerkosa A et al. The effect of olive oil and fish consumption on rheumatoid arthritis – a case control study. Scand J Rheumatol 1991; 20; 419-26.

7. Polaano MK, ed. Topical Skin Therapeutics. Edinburgh: Churchill Livingsstone; 1984.

8. Bjorneboe A, Smith AK, Bjorneboe GE et al. Effect of dietary supplementation with n-3 fatty acid on clinical manifestation of psoriasis. Br J Dermatol 1998; 118 : 77-83.

9. Pock LW. Essential fatty acid deficiency in renal failure. Can supplements really help? J Ann Diet Assoc 1997; 97: 5150 -3.

10. Burton JL, Holden CA. Eczema, lichenification and prurigo. In: Champion RH, Burton JL, Burns DA, Breathnach SM, eds. Rook/Wilkinson/Ebling Textbook of dermatology, 6th edn. London: Blackwell Science; 1998. p. 629-86.

11. Composition of olive oil. www.oliveoil. (accessed on 15.06.04).

12. Kranke B, Komericki P, Aberer W. Olive oil - contact sensitizer or irritant. Contact Dermatitis 1997; 36: 5-10.

Family history of psoriasis and recent infection…. Shahzana Naqqash et al.

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Original article Family history of psoriasis and recent infectious disease are risk factors for the first episode of acute guttate psoriasis Shahzana Naqqash, Tameez-ud-deen, Shahid Naqqash*, Abdul Quddus Butt

Dermatology Department, Rawalpindi General Hospital, Rawalpindi *ENT Department, POF Hospital, Wah Cantt

Abstract Background Psoriasis is a heterogeneous disease in its clinical expression. Both genetic

and environmental factors are thought to contribute to the pathogenesis. The association of guttate psoriasis with streptococcal pharyngitis is well accepted. The association of other risk factors is less well-defined. Objectives The aim of this study was to estimate the risk for guttate psoriasis with recent infections and to explore other potential risk factors like family history of psoriasis . Patients and methods This was a case-control study. Cases were patients with the first diagnosis ever of acute guttate psoriasis. Controls were patients newly diagnosed as having dermatologic conditions other than psoriasis and seen in the same outpatient services as the cases. Inclusion of cases and controls was restricted to patients up to 18 years of age. A total 35 cases (median age, 8 years) and 150 controls (median age, 12½ years) were included in the analysis. Results A significant difference was observed for a family history of psoriasis. 45.7% of patients with guttate psoriasis gave a family history of psoriasis in their first-degree relatives. The risk of psoriasis was also increased in subjects who reported a history of a recent infectious episode. The analysis by individual diagnosis pointed to acute pharyngitis as the disease with the strongest association. Twenty-seven patients (77.1%) gave a history of sore throat preceding the onset of guttate psoriasis. All of them had a throat swab performed, of these 20 had normal flora cultured. Only 6 had a positive culture and in these cases Lancefield group C ß-hemolytic streptococci were isolated. ASO titer was raised in 21 (60%) patients of guttate psoriasis . Conclusion The study confirmed that recent pharyngeal infection is a risk factor for guttate psoriasis. It also documented the strong association between guttate psoriasis and a family history of psoriasis Key words Guttate psoriasis, streptococcal pharyngitis, ASO titer

Introduction

Psoriasis is a chronic scaly and inflammatory skin disorder, the pathogenesis of which remains elusive, but genetic and environmental factors are thought to contribute. The disease process

comprises immune-mediated cutaneous inflammation and keratinocyte hyperproliferation, and many biochemical and immunological abnormalities have been identified.1 Psoriasis is a heterogeneous disease and various clinical subtypes can be differentiated. Guttate psoriasis is characterized by the eruption of small erythematous and scaling lesions over large areas of the skin surface 1-2

Address for Correspondence Dr. Shahzana Naqqash House No. 22, Ravi Road Wah Cantt, Pakistan.


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weeks after an episode of acute tonsillitis or pharyngitis.2 It represents a manifestation of psoriasis of an early age at onset and as such is more frequent than other varieties in children and young adults. It may arise on its own (acute guttate psoriasis) or may complicate existing, often quite limited, chronic plaque psoriasis (guttate flare of chronic plaque psoriasis). If left untreated, guttate psoriasis may clear spontaneously or may develop into chronic plaque psoriasis. It may recur, although the risk is not well-defined.3 Acute guttate psoriasis is associated with infections by Streptococcus pyogenes, and cross-reaction between skin and streptococcal antigens have been reported. The role of superantigens in the pathogenesis of psoriasis is a well-established and attractive hypothesis.4 Superantigens include viral and bacterial proteins that can stimulate T-cells to proliferate without prior intracellular processing by an antigen-presenting cell. The aim of our case-control study was to provide a quantitative estimate of the risk for guttate psoriasis associated a recent streptococcal throat infection.

Patients and methods

Our case-control study was conducted at dermatology department, Rawalpindi General Hospital, Rawalpindi, from Dec. 2002 to Dec. 2003. Entry criteria for cases were the first ever diagnosis of acute guttate psoriasis with no previous diagnosis of psoriasis. Guttate psoriasis was defined as the abrupt appearance of drop-like, round or oval orange-brown asymptomatic papules covered with scales and scattered over the

body. Controls were patients who were diagnosed for the first time in their life as having dermatologic conditions other than psoriasis. They were recruited in the same outpatient services. Inclusion of cases and controls was restricted to patients up to 18 years of age. A standardized interview was used to assess the disease onset in cases and controls. A total 35 cases of guttate psoriasis, satisfying entry criteria, and 150 controls were recruited. Information about family history of psoriasis in blood relatives (siblings and parents), and personal medical history was obtained from cases and controls using an identical structured questionnaire. Information on any infectious disease requiring at least one medical attendance during the three months before diagnosis was collected in cases and controls. Detailed history regarding sore throat was recorded, throat swabs were taken in relevant patients and ASO titre was determined in all cases and controls. Anthropometric measures including height and weight were also obtained. Results The patients with guttate psoriasis consisted of 23 female (65.7%) and 12 male (34.3%) subjects. The control population consisted of 90 (60%) female and 60 (40%) male subjects. The median age at diagnosis was 8 years in cases and 12½ years in controls. The distribution of cases and controls did not show any substantial differences in the distribution of gender. In 20 (57.1%) cases , lesions of guttate psoriasis were combined with classic plaque psoriasis. Diagnosis in the control group comprised the following: eczema 40 (26.7%), urticaria 30 (20%), scabies 50


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Table 1 Demographic data of s tudy population ad controls

Cases Controls Age (years) <5 6 30 5-10 14 70 10-18 15 50 Sex (male/female) 12/23 60/90 Family history of psoriasis (parents/siblings)

No 19 130 Yes 16 20 Recent infectious disease

No 8 125 Yes 27 25 ASO titre >200 IU ml-1 21 10 <200 IU ml-1 14 140 (33.3%), superficial mycosis 20 (13.3%) and acne 10 (6.7%). The distribution of cases and controls according to age, sex, family history of first degree relatives and history of previous and concomitant infection is presented in Table 1. A significant difference was observed for a family history of psoriasis. 16 cases (45.7%) had a family history of psorias is whereas only 20 of the control patients (13.3%) had a family history of psoriasis. The risk of psoriasis was also increased in subjects who reported a history of a recent infectious episode. The analysis by individual diagnosis pointed to acute pharyngitis as the disease with the strongest association. Twenty-seven (77.1%) patients gave a history of sore throat preceding the onset of guttate psoriasis. All of them had a throat swab performed, of these 20 had normal flora cultured. Only 6 had a positive culture and in these cases Lancefield group C ß-hemolytic streptococci were isolated. ASO titer was raised in 21 patients (60%), while it was raised in only 10 of 150 controls (6.66%). The clinical features of cases studied are given in Table 2.

Discussion This study provides the evidence that guttate psoriasis, in subjects without a previous diagnosis of psoriasis is strongly associated with a family history of psoriasis. This is in accordance with previous studies.5, 6 To avoid recall bias in the reporting of a family history of psoriasis, the study was restricted to newly diagnosed cases and controls. It is likely that genetic factors are involved. Familial cases of guttate psoriasis have been described5,7 and a highly significant association with HLA-Bw17 has been reported in guttate as well as in plaque psoriasis .8 Moreover, HLA-B13 has been linked to a history of severe streptococcal infection in these patients.9 A long held belief supported by fairly convincing clinical immunologic evidence associates guttate psoriasis with acute infection, particularly from S. pyogenes.10,11 Our study suggests that recent pharyngeal infection is associated with an increase in the risk for the first episode of guttate compared with subjects not reporting such a history, as 27 out of 35 patients (77.1%) gave the history sore throat within preceding three months, the infectious agent responsible found out to be S. pyogenes. In studies relying on bacteriologic culture, S. pyogenes has been isolated in a far higher proportion of guttate psoriasis patients ranging from 20% to 97%.12 Group A streptococci are thought to be responsible for majority of cases of streptococcal-induced pharyngitis, but strains of other serogroups, especially groups D and G, may occasionally be involved.13 Confirmation of streptococcal infection in guttate psoriasis may be difficult because patients are often seen in the convalescent phase when antibiotics have already been prescribed2 and throat swab cultures are more likely to be


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Table 2 Clinical features of guttate psoriasis

a Preceding onset pf psoriasis. b Normal antistreptolysin O titre is <200 IU ml-1. c n/d = not done. d GP = guttate psoriasis. e Normal = normal flora isolated. f CPP = chronic plaque psoriasis. g Lancefield group C ß-hemolytic streptococcus isolated. h Anti-DNase B

negative. Approximately 20% of group A streptococcal infected individuals do not respond by so that a negative titer alone streptococcal infection.14 Sixty per cent of subjects in this study had raised ASO titers at presentation while only six of 27 patients investigated with a throat swab had a positive streptococcal

throat culture. There are limited data available on the results of investigation into the association between streptococcal infection and guttate psoriasis; serological evidence of streptococcal infection was found in 19 of 33 (58%) with acute guttate psoriasis in one study.2 In another study Mallon et al.15 27twenty seven of 29 patients (93%) had raised ASO titer . In our

Subject Age (years)

Sex Family History

History of sore throat

Throat swab culture

ASO titre (IU ml -

1)b 1 1 m No Yes n/dc <200 2 7 f Yes Yes normale 800 3 9 m Yes Yes normal 400 4 9 f No Yes normal 300 5 8 f No Yes normal 250 6 2 f No No normal <200 7 14 f Yes Yes Gp C 400 8 7 m No No n/d 250 9 17 f Yes Yes normal 300 10 13 f Yes Yes normal 400 11 18 f Yes Yes normal <200 12 12 f No Yes normal 500 13 10 m Yes Yes Gp C 1200 14 9 f No Yes normal 800 15 2 f No Yes normal 600 16 5 m Yes Yes normal <200 17 3 f Yes No n/d <200 18 7 f Yes Yes n/d <200 19 13 m Yes Yes Gp Cg 1600 20 10 f No Yes normal 300 21 6 f No Yes n/d <200 22 8 m No Yes normal 1500 23 11 m No No n/d <200 24 15 f No Yes normal 500 25 3 f Yes Yes Gp C 800 26 7 f Yes No normal 400 27 5 f Yes Yes normal <200 28 14 m No Yes normal <200 29 16 f No Yes normal 300 30 17 m No Yes Gp C 800 31 10 f Yes No normal 400 32 6 f No Yes Gp C 1200 33 7 m No No n/d <200 34 11 f Yes Yes normal 800 35 3 m No No n/d <200


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study, 60% of patients with guttate psoriasis had raised ASO titer and 17.1% had positive culture of S pyogenes. It is unlikely that these are mere chance associations. There is evidence that an immunologic mechanism is involved in the triggering of guttate psoriasis by streptococcal infection. Stimulation of T-cells by streptococcal superantigens has been suggested.11,16,17,18 They bind directly to the major histocompatibility complex class II molecule on the antigen presenting cell and stimulate T cells that express certain T-cell receptors. This leads to polyclonal T-cell activation with release of immune cytokines such as interleukin-2, which are important in the pathogenesis of psoriasis.19 It is possible that streptococci contain antigenic substances recognized by psoriatic T-cells. Aiba et al.20 and Baker et al.21 reported the altered responses of peripheral blood mononuclear cells (PBLs) from psoriatic patients to streptococcal antigen in vitro. Furthermore, Baker et al.22 have reported the presence of streptococcal antigen-specific T-cells in guttate psoriasis lesions. Gabriel et al.23 confirmed the auto-immune components in guttate psoriasis, due to cross reactions between skin and streptococcal antigens . Keeping these studies in mind, and the strong association documented in our study, between guttate psoriasis and recent acute pharyngitis, it is important to search for and eliminate microbial infections in the treatment of psoriasis. In view of this many dermatologists have recommended using antibiotics for psoriasis particularly guttate type. Some dermatologists have also recommended tonsillectomy for psoriasis in patients with recurrent streptococcal pharyngitis. There is, currently, no firm evidence on which to base any recommendations for the routine

management of acute guttate psoriasis. Furthermore, it is not clear whether any intervention can effectively, prolong the duration of remission or prevent progression to chronic plaque psoriasis. More studies are needed with greater numbers of patients so that risk associations of psoriasis can be determined accurately, and optimal method for achieving clearance of psoriasis can be determined. References

1. Van de Kerkhof PCM. Boss JP, eds. Pathogenesis aspects of psoriasis. Clin Dermatol 1995; 13: 97-8.

2. Telfer NR, Chalmers RJ, Whale K, Colman G. The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol 1992; 128: 39-42.

3. Martin BA, Chalmers RJC, Telfer NR. How great is the risk of further psoriasis following a single episode of acute guttate psoriasis? Arch Dermatol 1996; 132: 717 -8.

4. Valdimarsson H, Baker BS, Jonsdottir I et al. Psoriasis: a T-cell mediated autoimmune disease induced by streptococcal superantigens? Immunol Today 1995; 16: 145-9.

5. Banno T, Fujisawa H, Stomi H et al. Psoriasis vulgaris and acute guttate psoriasis in a family. Int J Dermatol 2001; 40: 285-7.

6. Luigi N, Lorenzo P, Fabio P, Claude FC, and the psoriasis study group of the Italian Group for Epidemiological Research in Dermatology. Family history of psoriasis, stressful life events, and recent infectious disease are risk factors for a first episode of acute guttate psoriasis: Results of a case-control study. J Am Acad Dermatol 2001; 44: 433-8.

7. Bolton GG, Daniel CR. A family outbreak of acute guttate psoriasis . Arch Dermatol 1990; 126 : 1523-4.

8. Williams RC, Mckenzie AW, Roger JH, Joysey VC. HLA -A antigens in patients with guttate psoriasis. Br J Dermatol 1976; 95: 163-7.

9. Krain LS, Newcomer VD, Terasaki PI. HLA antigen in psoriasis [letter]. N Engl J Med 1973; 288: 1245.


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10. Wilson AG, Clark I, Heard SR et al. Immuno-blotting of streptococcal antigens in guttate psoriasis. Br J Dermatol 1993; 128: 151-8.

11. Leung DY, Travers JB Giorno R et al. Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest 1995; 96: 2106-12.

12. Tervaert WC, Esseveld H. A study of the incidence of haemolytic streptococci in the throat in patients with psoriasis vulgaris with reference to their role in the pathogenesis of this disease. Dermatologica 1970; 140: 282-90.

13. Stjernquist-Desatnik A, Prellner K, Christensen P. Clinical and laboratory findings in patients with acute tonsillitis. Acta Otolaryngol (Stockh) 1987; 104 : 351-9.

14. Johnson DR, Kaplan EL, Stramek J et al., eds. Laboratory diagnosis of group A streptococcal infections. Geneva: World Health Organization; 1996.

15. Mallon E, Bunce M, Savoie H et al. HLA-C and guttate psoriasis. Br J Dermatol 2000; 143: 1177-82.

16. Leung DY, Walsh P, Giorno R, Norris DA. A potential role for superantigens in the pathogenesis of psoriasis. J Invest Dermatol 1993; 100 : 225-8.

17. Lewis HM, Baker BS, Bokth S et al. Restricted T cell receptor V-beta gene usage in the skin of patients with guttate and chronic plaque psoriasis . Br J Dermatol 1993; 129 : 514-20.

18. Horiuchi N, Aiba S, Ozawa H et al. Peripheral blood lymphocytes from psoriatic patients are hyporesponsive to beta-streptococcal superantigens. Br J Dermatol 1998; 138 : 229-35.

19. Skov L, Baadsgaard O. Superantigens. Do they have a role in skin diseases? Arch Dermatol 1995; 131 : 829-32.

20. Aiba S, Tagami H. Proliferative responses of peripheral blood mononuclear cells from psoriatic patients to T lymphocyte-stimulating cytokines (IL -2, IL-3, IL-4 and granulocyte-macrophage colony-stimulating factor) and OK-432. Arch Dermatol Res 1989; 281 : 310-5

21. Baker BS, Powel AV, Malkani AK et al. Altered cell-mediated immunity to group A haemolytic streptococcal

antigens in chronic plaque psoriasis. Br J Dermatol 1991; 125 : 38-42.

22. Baker BS, Powles A, Garioch JJ et al. Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions. Br J Dermatol 1993; 128 : 493-9.

23. Villeda GG, Santamaria CLC, Perez LR et al. Recognition of Streptococcus pyogenes and skin autoantigens in guttate psoriasis. Arch Med Res 1998; 29: 143-8.

Porokeratosis: a review….. Arfan ul Bari and Simeen Ber Rahman

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Re view article Porokeratosis: a review of unique group of keratinizing disorder Arfan ul Bari, Simeen Ber Rahman*

Consultant Dermatologist, PAF Hospital, Sargodha * Dermatology Department, Military Hospital, Rawalpindi

Abstract Porokeratosis is a group of disorder of uncertain cause characterized by abnormal epidermal keratinization with the histologic finding of cornoid lamella. To date, five major clinical variants have been identified. This unique group of disorders of keratinization is reviewed here, with special reference to the differentiation of each component and their management. Key words Porokeratosis, porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminate, linear porokeratosis, punctate porokeratosis, cornoid lamella.

Introduction

Porokeratosis is a clonal disorder of keratinization characterized by one or more atrophic patches surrounded by a clinically and histologically distinctive ridge-like border called the cornoid lamella. Five clinical variants of porokeratosis are recognized: (i) classic porokeratosis of Mibelli (PM), (ii) disseminated superficial actinic porokeratosis (DSAP), (iii) porokeratosis palmaris et plantaris disseminate (PPPD), (iv) linear porokeratosis (LP), and (v) punctate porokeratosis (PP). Porokeratosis most commonly occurs in fair-skinned individuals and is relatively rare in darker-skinned races. PM and PPPD affect men twice as often as women. DSAP is three times more common in women compared with men and LP is seen with equal incidence in both sexes. PPPD and LP may be

seen at any age, from birth to adulthood, PM usually develops in childhood, DSAP generally develops in the third or fourth decade of life.1,2 Lesions may be found anywhere, including the mucous membranes, although they most commonly occur on the extremities.3-5 A verrucous variant that is localized to the buttocks and resembles psoriasis has been reported in several patients6. Several risk factors for the development of porokeratosis have been identified; these include genetic inheritance, ultraviolet radiation, and immunosuppression. Excessive natural or artificial ultraviolet radiation, electron beam therapy, and extensive radiation therapy are well-established trigger factors. Immunosuppression may induce new lesions or cause preexisting lesions to flare.2,7-10 The approach to treatment is individualized, based on the size of the lesion and the anatomical location, the functional and aesthetic considerations, the risk of malignancy, and the patient’s preference. Protection from the sun, use of emollients, and watchful observation for

Address for Correspondence Squadron Leader Dr. Arfan ul Bari, Consultant Dermatologist, PAF Hospital, Sargodha Ph# (off): 0451-5553307, (res): 0451-5553308 E mail: [email protected]


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signs of malignant degeneration may be all that is needed for many patients. Various medical and surgical modalities are also available. Excision is most appropriate when malignant degeneration develops. Cryotherapy, electrodesiccation and curettage are minimally invasive methods of inducing resolution for large numbers of lesions. Diamond fraise dermabrasion and laser therapy has also been used with conflicting reports of efficacy.11-16 The prognosis is generally excellent.2 Patients who develop PM or linear porokeratosis because of immunosuppression are at higher risk for the development of a squamous or basal cell carcinoma within the lesion. Linear porokeratosis is associated with a higher risk of malignant degeneration.17-19 PM circumferentially involving the digits may induce pseudoainhum.20 Patients must practice strict sun precautions and must periodically examine their skin for lesions suggestive of malignancy.

Historical Background

Porokeratosis was first described by Mibelli21 in 1893 as one or more localized, chronically progressive, hypertrophic irregular plaques with central atrophy and a prominent peripheral ridge. A more superficial disseminated form was described independently almost at the same time by Respighi22 and later by Andrews.23 A linear variant was added early in the last century.24 Disseminated superficial actinic porokeratosis25 was described in 1966 and porokeratosis palmaris et plantaris disseminate26 was added to the spectrum in 1971.

Etiology and Pathogenesis

The exact etiology of the various types of porokeratosis is unknown. An autosomal

dominant mode of inheritance has been reasonably well established for PM,27,28 PPPD,26 DSP, and DSAP.29 Linear porokeratosis has been observed in monozygotic twins.30 The similarities of clinical appearance and histopathology as well as the coexistence of different variants of porokeratosis in one patient or in several members of an affected family make a strong case for considering them different phenotypic expressions of a common genetic aberration.31,32 Risk factors for porokeratosis include genetic inheritance, ultraviolet light exposure, and immunosuppression. One study found that approximately 10% of patients who had undergone renal transplantation developed porokeratosis.1,7-10 An autosomal dominant mode of inheritance has been established for familial cases of almost all forms.

Classic porokeratosis (Mibelli) Autosomal dominant inheritance and immunosuppression are the usual causes.27,28 PM has also been seen following radiation therapy, at burn wounds, and at hemodialysis sites.33

Disseminated superficial (actinic) porokeratosis Sun exposure and/or artificial ultraviolet radiation exposure in a patient who is genetically predisposed cause DSAP. Exacerbations have been reported following prolonged sun exposure, repeated tanning bed exposure, electron beam radiation therapy, and therapeutic phototherapy or photochemotherapy for psoriasis.34,35 Drug-induced photosensitivity may play a role. Protection from ultraviolet radiation may lead to spontaneous resolution. Immunosuppression predisposes patients to both DSAP and nonactinic DSP.36 Because of this, a viral etiology has been hypothesized.


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Linear porokeratosis No definite inheritance pattern has been established. Loss of heterozygosity has been proposed as a genetic mechanism and may explain the higher risk of malignant degeneration seen in linear porokeratosis in comparison to other forms of porokeratosis.30,37

Porokeratosis palmaris et plantaris disseminate Familial PPPD is transmitted in an autosomal dominant mode with variable penetrance.26 Acquired PPPD may be caused by immunosuppression, or it may be a cutaneous marker of internal malignancy.38

Punctate porokeratosis This condition has no unique inheritance pattern and is usually associated with other forms of porokeratosis.39

Clinical Variants

1. Porokeratosis of Mibelli [Figure 1]

It generally starts in childhood as a small, asymptomatic or slightly pruritic lesion that expand over a period of years, but may develop during adulthood and enlarge rapidly, usually in the clinical setting of immunosuppression. Occasionally, patients have a history of an antecedent trauma, such as a burn wound. The lesion develops as a small, light brown, keratotic papule that slowly expands to form an irregularly shaped, annular plaque with a raised, ridgelike border. This border may be hypertrophic or verrucous and is usually greater than 1 mm in height. A thin furrow is typically seen in the center of the ridge, causing a Great Wall of China effect. The lesion is slightly hypopigmented or hyperpigmented, minimally scaly, slightly atrophic, hairless, and anhidrotic. The size may vary from a few millimeters to several centimeters. Lesions may be found

anywhere, including the mucous membranes, although they most commonly occur on the extremities.1,3,4-6,27,28,33

2. Disseminated superficial (actinic) porokeratosis [Figure 2]

Multiple, brown, annular, keratotic lesions that develop predominantly on the extensor surfaces of the legs and the arms characterize DSAP. They are usually asymptomatic, but they may itch slightly. Facial lesions are seen in approximately 15% of patients, and the face may be the only area of involvement. Patients are typically women in their third or fourth decade of life, with a history of excessive ultraviolet exposure. Patients may have a history of phototherapy for psoriasis.1,8,19,31,34,35

3. Non-actinic disseminated superficial porokeratosis

Non-actinic forms may be seen following electron beam total skin irradiation, organ transplantation, hepatitis C virus related hepatocellular carcinoma, HIV infection, renal failure, or in association with other causes of immunosuppression. Dozens of small, indistinct, light brown patches with a threadlike border are seen on the extensor surfaces of the arms and the legs. Non actinic DSP may have a generalized distribution, sparing the palms and the soles.34,40-

42

4. Linear porokeratosis [Figure 3]

During infancy or early childhood, a unilateral, linear array of papules and plaques with the characteristic raised peripheral ridge are seen unilaterally on an extremity, the trunk, and/or the head and neck area. The lesions commonly follow a dermatomal distribution. Multiple linear groups may be seen in one patient, typically on the same side. They may be seen in


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Figure 1 Porokeratosis of Mibelli over central face of an elderly person.

Figure 2 Disseminated superficial actinic porokeratosis over forearm.

Figure 3 Linear porokeratosis over hand.

Figure 4 Porokeratosis palmaris plantaris et disseminate lesions over planter region.

Figure 5 Porokeratosis palmaris plantaris et disseminate lesions over calf region.

association with other forms of porokeratosis. Individual lesions within the linear grouping have a well-developed border, often with a central furrow similar to that seen in classic PM. Clinical changes consistent with the development of a basal or squamous cell carcinoma are more common in linear porokeratosis than in other forms of porokeratosis.1,17,24,30,37


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5. Porokeratosis palmaris et plantaris disseminate [Figures 4, 5]

Small, relatively uniform lesions are first seen on the palms and the soles, and then they develop in a generalized distribution, including the mucosal membranes. The lesions may itch or sting, but they are usually asymptomatic. The onset is typically during adolescence or early adulthood, and males are affected twice as often as females. The lesions are small and superficial with a slightly hyperpigmented, atrophic center and a minimally raised peripheral ridge. Mucosal lesions are small, annular or serpiginous, and pale. Squamous cell carcinoma has been reported to develop within lesions of PPPD.1,26,38,43,44

6. Punctate porokeratosis

Multiple, asymptomatic, tiny, seed-like, hyperkeratotic papules with thin, raised margins develop on the palms and the soles during adulthood. Patients usually have other forms of porokeratosis as well, most commonly the linear or Mibelli types. Punctate porokeratosis may be clinically and histologically indistinguishable from punctate porokeratotic keratoderma, which may be a cutaneous sign of an internal malignancy.39,45,46

7. Verrucous /hyperkeratotic variant

A verrucous variant that is localized to the buttocks and resembles psoriasis has been reported in several patients. Several cases of hyperkeratotic variants of PM and DSAP have also bee described.47,48

8. Giant porokeratosis

Rarely the lesions of porokeratosis may be 10-20 cm in diameter and the surrounding wall raised 1 cm. Mostly found on the foot and are said to

have a high incidence of malignant transformation.32,49

9. Bullous porokeratosis

This has been described in association with disseminated superficial porokeratosis .50

10. Pruriginous porokeratosis

This variant has again been described in association with disseminated superficial porokeratosis .50,51

11. Zosteriform porokeratosis Porokeratotic lesions have rarely been seen in dermatomal pattern.52

12. Mutilating variant Mutilating and destructive lesions have been reported in PM.53,54

13. Malignant porokeratosis Any porokeratosis developing fatal malignancies may be regarded as malignant porokeratosis.55

Association with cutaneous malignancies

The exact molecular mechanism of carcinogenesis developing in various forms of porokeratosis remains unclear, but chromosomal instability and reduced immune surveillance with over expression of p53 are hypothesized to play a role in the development of cutaneous malignancies within porokeratosis. Sudden aggravation of DSP and DSAP should prompt a search for an underlying disease causing immunosuppression. Squamous cell carcinoma, Bowen's disease and basal cell epithelioma have been observed and are more likely in large isolated lesions of PM, but malignant transsformation has also been observed in DSP and DSAP and linear porokeratosis. Widespread metastases and fatal outcome have rarely been reported.1,2,7,19,56-60


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Histopathology [Figure 6, 7]

Porokeratoses are grouped because of their histologic hallmark, the cornoid lamella, and the resulting clinical features. It has been proposed that, in porokeratosis, a mutant clone of epidermal cells expands peripherally, leading to formation of a cornoid lamella at the boundary between the clonal population and normal keratinocytes and represents the pathologic substrate for the ridge-like border. The cornoid lamella arises in the interfollicular epidermis and may involve the ostia of hair follicles or sweat ducts, which have led to the misnomer porokeratosis. It consists of a tightly packed, thin column of parakeratotic cells extending through the entire thickness of the surrounding orthokeratotic stratum corneum. It occupies an indentation of the epidermis that is generally tilted away from the center of the lesion. The adjacent epidermis is hyperkeratotic and acanthotic to a variable degree. The granular layer is missing below the cornoid lamella, and single or clustered dyskeratotic cells and vacuolated keratinocytes are found at its base. The papillary dermis beneath the cornoid lamella contains a moderately dense inflammatory infiltrate and dilated capillaries. The center of the lesion is usually atrophic, with areas of liquefaction degeneration in the basal layer, colloid body formation, and flattening of rete ridges, whereas the dermis may be edematous or fibrotic with telangiectasia. In essence, similar histopathologic changes are encountered in all forms of porokeratosis. However, in DSP, DSAP and PPPD, the cornoid lamella is less pronounced or so minimal as to be difficult to recognize.1,21,60,61

Diagnosis and differential diagnosis

Diagnosis of porokeratosis is usually made with ease, both clinically and histopathologically. The

Figure 6 Characteristic histology showing two parallel column of compact parakeratotic/dyskeratotic cells (cornoid lamellae) indenting the underlying epidermis.

Figure 9 High power view of (cornoid lamellae) with absence of granular layer and liquefaction in basal layer.

continuous keratotic ridge cleaved by a longitudinal furrow, which surrounds the lesions both in the Mibelli type and the other variants, is quite diagnostic, as is the localization and distribution of lesions. Elastosis perforans serpiginosa can be similar to PM, but it consists of erythematous, keratotic papules and lacks the continuous ridge with its furrow. The superficial, disseminated types of porokeratosis may resemble actinic keratoses, stucco keratoses, flat seborrheic keratoses, or flat warts. Small, discrete lesions may be mistaken for lichen sclerosus et atrophicus, lichen planus, acrokeratosis verruciformis, and pityriasis rubra pilaris, but each of these others lacks the fine, slightly raised, threadlike border. Neoplastic


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disorders, such as cutaneous T cell lymphoma (CTCL), can mimic lesions DSAP or PM clinically. Histologically, the lesions lack a cornoid lamella and reveal infiltrates typical of CTCL. Punctate porokeratosis should be differentiated from punctate keratoderma and planter warts.1,6,62,63

Treatment

The optimal treatment modality must be selected depending on the lesion's size and localization, functional and aesthetic requirements, and the general condition of the patient. The lesion can recur with any therapeutic modality. Lubrication usually improves the symptoms in superficial forms of porokeratosis, as does keratolytic treatment of hyperkeratotic lesions. Topical 5-fluorouracil is highly effective in PM, linear porokeratosis, and in DSP and DSAP. Treatment must be continued until a brisk inflammatory reaction is obtained that seems to be a prerequisite for clearing and can occur as a delayed reaction. The use of oral retinoids has yielded conflicting results: whereas excellent results were obtained in some patients with DSAP, widespread PM, PPPD and linear porokeratosis, one must be aware that relapses usually follow several weeks or months after discontinuation of retinoid therapy. It has been pointed out that retinoids might have an inhibitory effect on cutaneous carcinogenesis in porokeratotic lesions. Circumscribed lesions of PM or linear porokeratosis may be excised and grafted or destroyed by cryotherapy, electrodessication, dermabrasion, or CO2 laser. All therapeutic measures that might increase the malignant potential of porokeratosis such as irradiation, immunosuppression, and excessive UV exposure should be avoided.11-16

Course and Prognosis

Prognosis is generally excellent in patients having no underlying immunosuppression and paucity of risk factors. Lesions may increase in size and number with time; while this may be an extremely slow process in PM, progression can be quite pronounced in DSP and particularly in DSAP after UV exposure. In immunocompromised patients, spontaneous fluctuations in severity and spontaneous remissions depending on the immune status have been described. Sudden aggravation of DSP and DSAP should prompt a search for an underlying disease causing immunosuppression. Malignant degeneration has been observed and is more likely in large isolated lesions of PM, but it has also been observed in DSP and DSAP and linear porokeratosis. Widespread metastases and fatal outcome have been reported. Several cases of giant PM in an acral location causing destruction of underlying soft tissue and bone and mutilation have been observed.17-20,53-55,64-66

References

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2. Raychaudhuri SP, Smoller BR. Porokeratosis in immunosuppressed and non immunosuppressed patients. Int J Dermatol 1992; 31: 781-2.

3. Mehregan AH. Porokeratosis of the face. J Am Acad Dermatol 1980; 3: 394-6.

4. Tangoren IA, Weinberg JM, Ioffreda M et al. Penile porokeratosis of Mibelli. J Am Acad Dermatol 1997; 36: 479-81.

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8. Cockerell CJ. Induction of disseminated superficial actinic porokeratosis by phototherapy for psoriasis . J Am Acad Dermatol 1991; 24: 301-2.

9. Macmillan AL, Roberts SOB. Porokeratosis of Mibelli after renal transplantation. Br J Dermatol 1974; 90: 45-51.

10. Wilkinson SM, Cartwright PH, English JS. Porokeratosis of Mibelli and immunosuppression. Clin Exp Dermatol 1991; 16: 61-2.

11. Thiers BH. The use of topical calcipotriene/calcipotriol in conditions other than plaque-type psoriasis. J Am Acad Dermatol 1997; 37: S69-71

12. Rabbin PE, Baldwin HE. Treatment of porokeratosis of Mibelli with CO2 laser vaporization versus surgical excision with split-thickness skin graft. A comparison. Dermatol Surg Oncol 1993;19: 199-202

13. Alster TS, Nanni CA. Successful treatment of porokeratosis with 585 nm pulsed dye laser irradiation. Cutis 1999; 63: 265-6.

14. McDonald SG, Peterka ES. Porokeratosis (Mibelli): Treatment with topical 5-fluorouracil. J Am Acad Dermatol 1983; 8: 107-10.

15. Danno K. Etretinate treatment in disseminated porokeratosis. J Dermatol 1988; 15: 440-4.

16. McCallister RE, Estes SA, Yarbrough CL. Porokeratosis plantaris, palmaris, et disseminata: Report of a case and treatment with isotretinoin . J Am Acad Dermatol 1985; 13: 598-603.

17. Sasaki S. Linear porokeratosis with multiple squamous cell carcinomas: Study of p53 expression in porokeratosis and squamo us cell carcinomas. Br J Dermatol 1996; 134: 1151-3.

18. Gray MH, Smoller BS, McNutt NS. Carcinogenesis in porokeratosis. Evidence for a role relating to chronic growth activation of keratinocytes. Am J Dermatopathol 1991; 13: 438-44.

19. Sasson M, Krain AD: Porokeratosis and cutaneous malignancy. A review. Dermatol Surg 1996; 22: 339-42

20. Ramesh V, Misra RS, Mahaur BS: Pseudoainhum in porokeratosis of Mibelli. Cutis 1992; 49: 129-30.

21. Mibelli V. Contributo allo studio della ipercheratosi dei canali studeriferi (porokeratosis). G Ital Mal Veneree Pelle 1893; 28: 313-5.

22. Respighi E. Di una ipercheratosi non ancora descritta. G Ital Mal Veneree Pelle 1893; 28: 356 7.

23. Andrews GC. Porokeratosis (Mibelli) disseminated and superficial type. Arch Dermatol Syphilol 1937; 36:1111-4.

24. Truffi M. Sur un cas de porokératose systemisée. Ann Dermatol Syphiligr 1905; 6: 521-3.

25. Chernosky ME: Porokeratosis: Report of twelve patients with multiple superficial lesions. South Med J 1966; 59 : 289-94.

26. Guss SB, Osbourn RA, Lutzner MA. Porokeratosis plantaris, palmaris, et disseminata: A third type of porokeratosis. Arch Dermatol 1971; 104: 366-73.

27. Gilchrest TC. Eleven cases of porokeratosis (Mibelli) in one family . J Cutan Genitourin Dis 1899; 17: 149-53.

28. Seghal VN, Dube B. Porokeratosis (Mibelli) in a family. Dermatologica 1967; 134: 219-24.

29. Anderson DE, Chernosky ME. Disseminated superficial actinic porokeratosis. Genetic aspects. Arch Dermatol 1969; 99: 408-12.

30. Guillot P, Taieb A, Fontan A. Porokératose de Mibelli linéaire chez des jumelles monozygotes. Ann Dermatol Venereol 1991; 118: 519-24.

31. Dover JS. Disseminated superficial actinic porokeratosis: Coexistence with other porokeratotic variants. Arch Dermatol 1986; 122: 887-9.

32. Lucker GP, Steijlen PM. The coexistence of linear and giant porokeratosis associated with Bowen's disease. Dermatology 1994; 189: 78-80.

33. Nova MP, Goldberg LJ, Mattison T, Halperin A. Porokeratosis arising in a burn scar. J Am Acad Dermatol 1991; 25: 354-6.

34. Ibbotson SH. Disseminated superficial porokeratosis: What is the association with


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ultraviolet irradiation? Clin Exp Dermatol 1996; 21: 48-50.

35. Hazen PG, Carney JF, Walker AE et al. Disseminated actinic porokeratosis: Appearance associated with photochemotherapy for psoriasis. J Am Acad Dermatol 1985; 12: 1077-8.

36. Fields LL, White-CR Jr; Maziarz-RT. Rapid development of disseminated superficial porokeratosis after transplant induction therapy. Bone Marrow Transplant 1995; 15: 993-5.

37. Hubler WR et al. Linear porokeratosis. Cutis 1974; 14: 61-3.

38. Patrizi A. Porokeratosis palmaris et plantaris disseminata: An unusual clinical presentation. J Am Acad Dermatol 1989; 21: 415-8.

39. Rahbari-H, Cordero AA, Mehregan-AH. Punctate porokeratosis: A clinical variant of porokeratosis of Mibelli. J Cutan Pathol 1977; 4: 338-41.

40. Hernandez MH, Lai CH, Mallory SB. Disseminated porokeratosis associated with chronic renal failure: A new type of disseminated porokeratosis? Arch Dermatol 2000; 136: 1568-9.

41. Park BS, Moon SE, Kim JA. Disseminated superficial porokeratosis in a patient with chronic liver disease. J Dermatol 1997; 24: 485-7

42. Kono T, Kobayashi H, Ishii M et al. Synchronous development of disseminated superficial porokeratosis and hepatitis C virus-related hepatocellular carcinoma. J Am Acad Dermatol 2000; 43: 966-8

43. Seishima M, Izumi T, Oyama Z, Maeda M. Squamous cell carcinoma arising from lesions of porokeratosis palmaris et plantaris disseminata. Eur J Dermatol 2000; 10: 478-80

44. Taub J, Steinberg M. Porokeratosis plantaris discreta: A previously unrecognized dermatologic entity. Int J Dermatol 1970; 9: 83-90.

45. Bianchi L, Orlandi A, Iraci S et al. Punctate porokeratotic keratoderma--its occurrence with internal neoplasia. Clin Exp Dermatol 1994 ; 19: 139-41.

46. Hunt SJ et al. Linear and punctate porokeratosis associated with end-stage liver

disease. J Am Acad Dermatol 1991; 25: 937-9.

47. Wallner JS, Fitzpatrick JE, Brice SL. Verrucous porokeratosis of Mibelli on the buttocks mimicking psoriasis. Cutis 2003; 72: 391-3.

48. Jang KA, Choi JH, Sung KJ, Moon KC, Koh JK. The hyperkeratotic variant of disseminated superficial actinic porokeratosis. Int J Dermatol 1999; 38: 204-6.

49. Sawai T, Hayakawa H, Danno K et al. Squamous cell carcinoma arising from giant porokeratosis: a case with extensive metastasis and hypercalcemia. J Am Acad Dermatol 1996; 34: 507-9.

50. Ricci C, Rosset A, Panizzon RG. Bullous and pruritic variant of disseminated superficial actinic porokeratosis: successful treatment with grenz rays. Dermatology 1999; 199: 328-31

51. Kang BD, Kye YC, Kim SN. Disseminated superficial actinic porokeratosis with both typical and prurigo nodularis -like lesions. J Dermatol 2001; 28: 81-5

52. Goldner R. Zosteriform porokeratosis of Mibelli. Arch Dermatol 1971; 104: 425-6.

53. Handa S. Mutilating lesions in porokeratosis of Mibelli. Dermatology 1995; 191: 162-4.

54. Rahbari H, Fazel Z; Mehregan AH. Destructive facial porokeratosis . J Am Acad Dermatol 1995; 33: 1049-50.

55. Rongioletti F, Rebora A. Disseminated porokeratosis with fatal metastatic squamous cell carcinoma: an additional case of "Malignant Disseminated Porokeratosis". Am J Dermatopathol 2002; 24: 144-8.

56. Khaskhely NM, Maruno M, Takamiyagi A et al. Disseminated Superficial Actinic Porokeratosis report of a case with electron microscopic observation, immunohistochemical and molecular biological analysis of P53 gene. J Pak Assoc Dermatol 2001; 11: 51-7.

57. Arranz-Salas I, Sanz-Trelles A, Ojeda DB. p53 alterations in porokeratosis J Cutan Pathol 2003; 30: 455-8.

58. Otsuka F, Nashiro K, Kobayashi K, Ishibashi Y. Chromosome abnormalities of porokeratosis -cultured epidermal keratinocytes. Comparison with those of


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cultured dermal fibroblasts. Cancer Genet Cytogenet 1991; 56: 163-9.

59. Otsuka F, Umebayashi Y, Watanabe S et al. Porokeratosis large skin lesions are susceptible to skin cancer development: Histological and cytological explanation for the susceptibility. J Cancer Res Clin Oncol 1993; 119: 395-400.

60. Ito M, Fujiwara H, Maruyama T et al. Morphogenesis of the cornoid lamella: histochemical, immunohistochemical, and ultrastructural study of porokeratosis. J Cutan Pathol 1991; 18: 247-56.

61. Reed RJ, Leone P. Porokeratosis -A mutant clonal keratosis of the epidermis. Arch Dermatol 1970; 101: 340-7.

62. Hsu WT, Toporcer MB, Kantor GR et al. Cutaneous T-cell lymphoma with

porokeratosis like lesions. J Am Acad Dermatol 1992; 27: 327-30.

63. Brenemann DL, Brenemann JC. Cutaneous T-cell lymphoma mimic king porokeratosis of Mibelli. J Am Acad Dermatol 1993; 29: 1046-58.

64. Tsambaos D, Spiliopoulos T: Disseminated superficial porokeratosis: Complete remission subsequent to discontinuation of immunosuppression. J Am Acad Dermatol 1993; 28: 651-2.

65. Zenarola P, Melillo-L; Lomuto-M et al. Exacerbation of porokeratosis: a sign of immunodepression. J Am Acad Dermatol 1993; 29: 1035-6.

Editor’s note

From the next issue of JPAD, the ‘QUIZ’ section will be replaced by

‘PHOTODERMDIAGNOSIS ’ section and it will be edited by Dr. Amor

Khachemoune, MD. The manuscripts should be submitted to:

Dr. Amor Khachemoune, MD. 1440 Beacon St # 508, Brookline MA 02445,

USA.

E-mail: [email protected].

Management of atopic dermatitis…. Amer Ejaz and Naeem Raza .

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Review article Management of atopic dermatitis – A review Amer Ejaz, Naeem Raza

Consultant Dermatologist, Combined Military Hospital, Malir, Karachi * Consultant Dermatologist, Combined Military Hospital, Abbottabad

Abstract Atopic dermatitis is a chronic relapsing and remitting disease, which afflicts mostly the young ones. The treatment of atopic dermatitis is very frustrating as no single therapeutic modality is satisfactory. The first breakthrough in its management came with the advent of topical steroids. We are still awaiting the next breakthrough. Much research is being done in this regard and the pick of the lot is topical immunotherapy. It may well prove to be the find of the decade in the management of atopic dermatitis. This article summarizes the established as well as unconventional therapeutic modalities which help the patients as well as which has evidence of successful use.

Key words Atopic dermatitis, management

Introduction

Atopic dermatitis is a chronic relapsing and remitting disorder, which usually starts in early childhood. It is frequently associated with elevated levels of serum IgE and a personal or family history of atopy i.e. allergic rhinitis, atopic dermatitis or asthma. The diagnosis is clinical and based on a combination of historic and morphologic finding, as there is no single distinguishing feature.1 Atopic dermatitis now affects 15% to 20% of children in developed countries, and prevalence in cities in developing countries undergoing rapid demographic changes is quickly following suit.2 The condition also creates a great financial burden for both the family and society.3 General measures Perhaps the most important consideration in the management of atopic dermatitis is

to educate the patient and family in certain realities of their disease. 1. The disease runs its own course and physicians can only moderate that course; the disorder is not curable but it is always possible to improve the patients' condition. 2. The skin must be kept moisturized. 3. It is crucial that trigger factors are avoided in order to prevent inflammation. a. Mild cleansing Routine everyday care of skin is an essential part of optimal patient management in atopic dermatitis. Xerosis, which is an integral part of atopic dermatitis, leaves the skin vulnerable to external insults, partly as a result of varying levels of barrier dysfunction. Cleansing removes dead surface cells, preparing skin to better absorb topically applied drugs/medication. Cleansers based on mild synthetic surfactants and/or emollients are ideal for these patients.4 b. Emollients Emollients and moisturizing creams are used to break the dry skin cycle and to maintain the smoothness of the skin. In the

Address for Correspondence Dr. Amer Ejaz, Consultant Dermatologist, Combined Military Hospital, Malir, Karachi Email: [email protected]


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vast majority of cases, improved bathing techniques and proper moisturizing can solve the problem. Patients need to avoid hot water, overuse of soap and unnecessary soaking and rubbing with washcloth and towel. Excessive frequency of bathing and hand washing should be discouraged. Most importantly, the skin hydration obtained from bathing should be retained by prompt application of an adequate moisturizer. The least expensive moisturizers are mineral oil and petrolatum etc. Moisturizers should be applied lightly after the bath and any excess removed with a cotton towel. Creams and lotions may be irritating and drying due to an evaporative effect. Greasy agents should be avoided in hot humid climate to prevent occlusive folliculitis. Similarly plastic wrap occlusion may also cause folliculitis.5 Recently it has been shown that ceramide deficiency is the putative cause of stratum corneum dysfunction. Ceramide-dominant, barrier repair emollient has been shown to be better than simple emollients.6 Established therapies

a. Antihistamines Oral antihistamines provide only marginal antipruritic benefit and much of the effect seems to be as a sleep aid. Doxepin is the most potent histamine antagonist and is very specific. So is hydroxyzine, which is one of the few shown to be effective in a controlled trial. However, relief of pruritus by non-sedating antihistamines has been refuted.7 Several studies demonstrate the efficacy of second and third generation anti histamines in relieving pruritus in atopic dermatitis .7,8 but double-blind placebo-controlled trial are lacking.6 Cetrizine, a second generation antihistamine, has been shown to possess anti-inflammatory properties, acting via

inhibition of leucocyte recruitment and activation, and by the reduction of ICAM-1 expression on keratinocytes.9,10

b. Topical steroids Topical corticosteroids have been the mainstay of treatment for atopic dermatitis over the past 40 years. Hydrocortisone was the first to be used; some 30 additional corticosteroid compounds have now been licensed for treatment of atopic dermatitis. Topical applications containing corticosteroid compounds vary greatly in potency. In general the more potent ones are associated with the greater risk of adverse effects. First application of potent topical steroids results in rapid clearance of the rash. The snag is that persistent application of a potent preparation will put the patient at risk of unwanted local effects on the skin. The development of side effects is directly proportional to the frequency of application of topical steroids. However, recent trials suggest that only once daily application can give optimal results,11 and maintenance treatment can be done effectively with only twice weekly application thus minimizing the side effects.12

c. UVA therapy Several studies have demonstrated the efficacy of UVA1 (340-400 nm) phototherapy for patients with severe atopic dermatitis. However, the optimum treatment dose has yet to be determined. Although in seminal investigations high UVA1 doses were used, comparable results were reported in recent studies with a medium-dose regimen.13 However, effectiveness is merely short term, limited, and is followed by recurrence of symptoms within a 3-month observation interval.14


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d. UVB therapy Recently, interest has been renewed in the narrow-band wavelength of UVB phototherapy for atopic dermatitis (TL-01 Lamp). Encouraging results have been reported. However, long-term follow-ups are required before this therapeutic modality is established as treatment of atopic dermatitis .15,16

e. Antibacterials Secondary bacterial infections are known to complicate atopic dermatitis, due to deranged skin barrier function and impaired immunological status. Staphylococcus aureus is the infecting organism in over 99% of episodes. It is nearly always penicillin-resistant. Cloxacillin and erythromycin are reasonable choices of treatment. Recent research has greatly contributed to our understanding of the pathophysiological potential of S. aureus superantigens in atopic dermatitis, suggesting that antibiotic therapy might be an important element in the therapeutic management of atopic dermatitis.17 Newer modalities

a. Cyclosporin Oral cyclosporin is now an established therapeutic modality in severe and recalcitrant atopic dermatitis. Several studies have shown that short-term treatment is effective and tolerable as the drug is tapered off before side effects set in. Dosage regimen of 3-5 mg/kg/day for 10 to 12 weeks is effective.18,19,20

b. Topical macrolactum immunomodulators The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other

inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable for topical therapy. Both substances inhibit the transcription of proinflammatory cytokine genes such as interleukin 2, which are dependent on the nuclear factor NF-AT. They block the catalytic function of calcineurin, which leads to the inhibition of the transport of the cytoplasmic component of NF-AT to the cell nucleus. Multicenter, randomized, double blind clinical trials with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis.21,22

c. Montelukast Cysteinyl leukotrienes have been shown to be important in the pathogenesis of allergen-induced (atopic) asthma and rhinitis. Skin manifestations of atopic dermatitis have been reported to improve with leukotriene antagonists. Double-blind placebo-controlled trials have shown moderate response to montelucast in severe atopic dermatitis.23,24,25

d. Photopheresis Recently, photopheresis was used as monotherapy in patients with intractable atopic dermatitis. A total of ten treatments were used with a two weekly interval. All patients showed clinical improvement as well as reduction in serum levels of eosinophil cationic proteins and total IgE.

26 Experimental modalities

a. Antifungals As fungal colonization is increased in atopic dermatitis, there is a rationale to use antifungals. Clinical improvement and decreased serum IgE were obtained in patients with positive Malassezia


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radioallergosorbent tests (RASTs), who were treated with oral ketoconazole. Some preliminary data suggested that oral itraconazole treatment in AD patients reduced the need for topical corticosteroids. Furthermore, besides its antifungal action, itraconazole in part relieves pruritus and inflammation.27

b. Balneotherapy Balneotherapy involves immersion of the patient in mineral water baths or pools. Bathing in water with a high salt concentration is safe, effective, and pleasant for healing and recovery. There are almost no side effects during and after treatment, and there is a very low risk to the patient's general health and well-being. The mechanisms by which broad spectrums of diseases are alleviated by spa therapy have not been fully elucidated.28 Such therapies are being used in many parts of Pakistan since ancient times. Many places are known for their hot springs and people travel from great distances to bathe in these waters.

c. Dinitrochlorobenzene A small uncontrolled pilot trial has suggested that contact sensitization to dinitrochlorobenzene and repeated weekly applications significantly improve the clinical status of severe atopic dermatitis in adults. The effects are thought to be due to topical immune modulation by dinitrochlorobenzene. Larger controlled studies of dinitrochlorobenzene treatment in atopic dermatitis are warranted.29

d. Intradermal Mycobacterium suspension Recently a small randomized, double blind and placebo controlled trial has shown improvement in childhood atopic dermatitis using intradermal injection of killed Mycobacterium vaccae (SRL 172).30

e. Naphthalan Naphthalan has long been known for its medicinal properties and beneficial effects in inflammatory diseases such as psoriasis, atopic dermatitis, and psoriatic dermatitis. Experience acquired to date in the use of naphthalan in the management of squamous dermatoses and atopic dermatitis has shown favorable results. It should be further investigated to confirm its usage in the treatment of these diseases.31

f. Probiotics Recent studies suggest that oral bacteriotherapy with probiotics might be useful in the management of atopic dermatitis. Lactobacillus GG (ATCC 53103), which is a human intestinal strain, promotes local antigen-specific immune responses (particularly in the IgA class), prevents permeability defects, and confers controlled antigen absorption, when given to infants with atopic eczema and cow's milk allergy as an extensively hydrolyzed whey formula containing (5 × 108 colony-forming units/gm formula). Thereby it promotes endogenous barrier mechanisms in patients with atopic dermatitis and food allergy by alleviating intestinal inflammation.32-34

g. Interferon gamma Recombinant human interferon gamma has been shown in a double-blind, placebo-controlled study to be a well-tolerated and effective agent in the long-term therapy of patients with AD, when given in a dose of 50 µg/m2 as daily self-administered subcutaneous injection for up to 24 months.35

h. Mycophenolate mofetil Mycophenolate mofetil is a new immunosuppressive drug that is used to prevent acute rejection of renal


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transplants. In doses of 2 or 3 g/d the drug is well tolerated, effective and safe in non responding atopic dermatitis.36 Complementary and alternative medicine

a. Acupuncture Acupuncture is an old therapeutic method that includes both needle and nonneedle acupuncture. Nonneedle acupuncture includes moxibustion, cupping, and acupressure. Acupuncture has been reported to be beneficial for the treatment of atopic dermatitis among many other skin conditions. A lack of controlled studies is the main drawback for this method of treatment. However, the experiences from experts in this field may offer us new ideas to resolve refractory disorders in dermatology.37

b. Traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative method of therapy that can be administered in oral, topical, or injectable forms. It emphasizes the importance of using many herbs that are combined in different formulations for each individual patient. In the future, perhaps a better understanding of TCM will be gained through more systematic analysis and controlled studies with a placebo arm.38,39

c. Homeopathic treatment Homeopathy is one of the commonest alternative methods of treatment being used these days by dermatologic patients. Conflicting results of this treatment modality have been reported. Randomized, blinded and placebo controlled trials are lacking in literature. Maybe a few good trials can settle this issue.40,41 d. Special silk fabric As it is well known, irritant factors aggravate childhood atopic dermatitis. A

special silk fabric (MICROAIR Dermasilk) has been developed to minimize such irritant reactions. It has been shown that wearing such fabric minimizes symptoms in atopic children.42

e. St. John's wort cream Recent investigations suggest an anti-inflammatory and antibacterial effect of hyperforin, which is a major constituent of Hypericum perforatum L. (Saint John's wort). A double-blind, placebo-controlled prospective study has shown a significant superiority of the hyperforin 1.5% cream compared to the vehicle in the topical treatment of mild to moderate atopic dermatitis. The therapeutic efficacy of the hypericum-cream, however, has to be evaluated in further studies with larger patient cohorts, in comparison to therapeutic standards i.e. glucocorticoids.43

f. Hypnosis Hypnosis is an alternative or complementary therapy that has been used since ancient times to treat medical and dermatologic problems. A wide spectrum of dermatologic disorders may be improved or cured using hypnosis as an alternative or complementary therapy, including atopic dermatitis.44

g. Oolong tea Standard treatment fails in many patients with recalcitrant AD skin lesions. Study results in animal models have demonstrated that the administrat ion of tea (i.e. green, black, or oolong46) suppressed type I and type IV allergic reactions. This hypothesis has been tested clinically in an open study and oolong tea has been found to be effective in atopic dermatitis, probably due to antiallergic properties of tea polyphenols.45


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h. Natural honey and beeswax A mixture of honey, olive oil and beeswax, all in equal proportions, applied topically, has been tested in a single blind, partially controlled study and found to be effective in the treatment of atopic dermatitis and psoriasis.46 Future The fact that so many new, exotic and alternative treatment modalities are being sought, shows the amount of research being done in the field of atopic dermatitis, on the other hand it also shows the failure of medical science to discover a cure for this debilitating condition. Many other therapies (may be too exotic) could not be included in this article due to space constraint. However, the clinch of the recent research in the field of atopic dermatitis is the development of topical immunotherapy. Tacrolimus and pimecrolimus are, maybe the therapeutic finds of this decade in the treatment of atopic dermatitis.47 The very concept of applying topical steroids with all the long-term ill effects will be changed. But till the time these topical immunomodulators become widely available, and also at lower cost, the mainstay of treatment remains emollients and topical steroids.

References

1. Schultz Larsen F. Atopic dermatitis: a genetic epidemiologic study in a population based twin sample. J Am Acad Dermatol 1993; 28: 719-23.

2. Williams H, Robertson C, Stewart A et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood. J Allergy Clin Immunol 1999; 103: 125-38.

3. Jenner N, Campbell J, Marks R. Morbidity and cost of atopic eczema in Australia. Australas J Dermatol 2004; 45: 16-22.

4. Subramanyan K. Role of mild cleansing in the management of patient skin. Dermatol Ther 2004; 17 (Suppl 1): 26-34.

5. Loden M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol 2003; 4: 771-88.

6. Chamlin S, Kao J, Frieden I et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: Changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002; 47: 198-208.

7. Klein PA, Richard AF. Clark RAF. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 1999; 135: 1522-5.

8. Imaizumi A, Kawakami T, Murakami F et al. Effective treatment of pruritus in atopic dermatitis using H1 antihistamines (second-generation anti-histamines): changes in blood histamine and tryptase levels. J Dermatol Sci 2003; 33: 23-9.

9. Portnoy JM, Dinakar C. Review of cetirizine hydrochloride for the treatment of allergic disorders. Expert Opin Pharmakother 2004; 5: 125-35.

10. Shimizu T, Nishihara J, Watanabe H et al. Cetirizine, an H1 receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti inflammatory action. Clin Exp Allergy 2004; 34: 103-9.

11. David JA. Topical corticosteroids in atopic dermatitis (editorial). BMJ 2003; 327: 942-3.

12. Berth-Jones J, Damstra RJ, Golsch S et al. Multinational Study Group. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomized double


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blind, parallel group study. BMJ 2003; 326: 1367-9.

13. Tzaneva S, Seeber A, Schwaiger N et al . High dose versus mediun dose UVA -1 phototherapy for patients with severe generalized atopic dermatitis. J Am Acad Dermatol 2001; 45: 503-7.

14. Abeck D, Schmidt T, Fesq H et al. Long-term efficacy of medium-dose UVA1 phototherapy in atopic dermatitis. J Am Acad Dermatol 2000; 42: 254-7.

15. Samson Yashar S, Gielczyk R, Scherschum L, Liun HW. Narrow band ultraviolet B treatment for vitiligo, pruritus, and inflammatory dermatosis. Photodermatol Photoimmunol Photomed 2003; 19: 164-8.

16. Grundmann-Kollmann M, Behrens S, Podda M et al. Phototherapy for atopic eczema with narrow-band UVB. J Am Acad Dermatol 1999; 40: 995-7.

17. Lubbe J. Secondary infections in patients with atopic dermatitis. Am J Clin Dermatol 2003; 4: 641-54.

18. Zaki I, Enerson R, Allen BR. Treatment of severe atopic dermatitis in childhood with cyclosporin. Br J Dermatol 1996; 135 (Suppl.48): 21-4.

19. Hakan G, Pekka E, Sakari R. Long term follow up of eczema patients treated with cyclosporin. Acta Derm Venereologica 1998, 78: 40-3.

20. Zouneveld M, De Rie MA, Beljaards R et al. The long-term safety and efficacy of cyclosporin in severe refractory atopic dermatitis: a comparison of two dosage regimens. Br J Dermatol 1996; 135 (Suppl.48): 15-20.

21. Bornhovd E, Burgdorf W, Wollenburg A. Macrolactum immunomodulators for topical treatment of inflammatory skin diseases. J Am Acad Dermatol 2001; 45: 736-43.

22. Abramovits W, Goldstein AM, Stevenson LC. Changing paradigms in dermatology: topical immunomodulators within a per mutational paradigm for the treatment of atopic and

eczematous dermatitis. Clin Dermatol 2003; 21: 383-91.

23. Broshtilova V, Antonov D, Bardarov E, Tsankov N. Severe erythrodermic atopic dermatitis treated with montelu kast. Skinmed 2003; 2: 134-6.

24. Yanase D, David-Bajar K. The leukotriene antagonist montelukast as a therapeutic agent for atopic dermatitis. J Am Acad Dermatol 2001; 44: 89-93.

25. Rackal JM, Vender RB. The treatment of atopic dermatitis and other dermatoses with leukotriene antagonists. Skin Therapy Lett 2004; 9: 1-5.

26. Heike IR, Billman-Eberwein C, Grewe M et al. Successful monotherapy of severe and intractable atopic dermatitis by photopheresis. J Am Acad Dermatol 1998; 38: 165-9.

27. Nikkels AF, Pierard GE. Framing the future of antifungals in atopic derma titis. Dermatology 2003; 206: 398-400.

28. Matz H, Orion E, Wolf R. Balneotherapy in dermatology. Dermatol Ther 2003; 16: 132-40.

29. Mills L, Mordan L, Roth H et al. Treatment of severe atopic dermatitis by topical immune modulation using dinitrochlorobenzene. J Am Acad Dermatol 2000; 42: 687-9.

30. Arkwright P, David T. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001; 107 : 531-4.

31. Alajbeg A, Vrzogic P, Ostrogovic Z. Naphthalan--a natural medicinal product. Acta Dermatovenerol Croat 2003; 11: 178-84.

32. Kalliomaki M, Salminen S, Poussa T et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomized placebo-controlled trial. Lancet 2003; 361: 1869-71.

33. Majamaa H, Isolauri E. Probiotics: A novel approach in the management of food allergy.


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J Allergy Clin Immunol 1997; 99: 179-85.

34. Rosenfeldt V, Benfeldt E, Nielsen SD et al. Effect of probiotic Lactobacillus strains in children with atopic dermatitis. J Allergy Clin Immunol 2003; 111: 389-95.

35. Stevens S, Hanifin J, Hamilton T et al . Long-term effectiveness of recombinant human interferon gamma therapy for atopic dermatitis despite unchanged serum IgE levels. Arch Dermatol 1998; 134: 799-804.

36. Pickenäcker A, Luger T, Schwarz T. Dyshidrotic eczema treated with mycophenolate mofetil. Arch Dermatol 1998; 134 : 899.

37. Chen CJ, Yu HS. Acupuncture, electrostimulation, and reflex therapy in dermatology. Dermatol Ther 2003; 16: 87-92.

38. Koo J, Desai R. Traditional Chinese medicine in dermatology. Dermatol Ther. 2003; 16: 98-105.

39. Koo J, Arian S. Traditional Chinese Medicine for the treatment of dermatologic disorders. Arch Dermatol 1998; 134: 1388-93.

40. Smolle J. Homeopathy in dermatology. Dermatol Ther 2003; 16: 93-7.

41. Itamura R, Hosoya R. Homeopathic treatment of

Japanese patients with intractable atopic dermatitis. Homeopathy 2003; 92: 108-14.

42. Ricci G, Patrizi A, Bendandi B et al. Clinical effectiveness of a silk fabric in the treatment of atopic dermatitis. Br J Dermatol 2004; 150: 127-31.

43. Schempp CM, Windeck T, Hezel S, Simon JC. Topical treatment of atopic dermatitis with St. John's wort cream-a randomized, placebo controlled, double blind half-side comparison. Phytomedicine 2003; 10 (Suppl 4): 31-7.

44. Shenefelt P. Hypnosis in dermatology. Arch Dermatol 2000; 136: 393-9.

45. Uehara M, Su giura H, Sakurai K. A trial of Oolong tea in the management of recalcitrant atopic dermatitis. Arch Dermatol 2001; 137: 42-3.

46. Al-Waili NS. Topic al application of natural honey, beeswax and olive oil mixture for atopic dermatitis or psoriasis: partially controlled, single-blinded study. Complement Ther Med 2003; 11: 226-34.

47. Shainhouse T, Eichenfield LF. Long-term safety of tacrolimus ointment in children treated for atopic dermatitis. Expert Opin Drug Saf 2003; 2: 457-65.

Biostatistics: Introduction…. Tariq Zaman and Abbas Raza

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Stat Corner Biostatistics - I: Introduction, role & applications in medicine

Tariq Zaman, Abbas Raza* Dermatology department, Allama Iqbal Medical College, Lahore. * Department of Medicine, King Edward Medical College, Lahore.

Understanding the fundamentals of biostatistics is essential for every clinician in order to plan a scientific study and interpret its results . Unfortunately, this area had been neglected at the level of undergraduate and postgraduate medical education in country. The terms like X2 test, student t test, p value, sensitivity, specificity etc. are very scary for clinicians and while going through a medical journal, the pages describing the statistical methods are generally skipped. As a part of CME activity for its readers, JPAD has started a series of articles covering this dry and boring topic. The authors have simplified the subject in a reader-friendly manner so that it is easy to comprehend and assimilate. (Editor).

“The fundamental gospel of statistics is to push back the domain of ignorance, prejudice, rule-of-thumb, arbitrary or premature decisions, tradition, and dogmatism and to increase the domain in which decisions are made and principles are formulated on the basis of analyzed quantitative facts.”….Robert W. Burgess Statistics is deeply engraved in our daily life e.g. the chances of being successful in a particular assignment or examination, and at a wider scale, success of a particular plan (e.g. healthcare) in a community or winning a war against enemy. All these issues are generally judged qualitatively. Calculating the risks, benefits and probabilities involved in mathematical terms is statistics. Present series of articles, which will regularly appear in successive issues of the journal, is written to make reader more effective in interpretation of research literature in medicine and be able to design research study and draw appropriate

statistical conclusions. This article is intended to give an introduction to biostatistics, its evolution through time and its role and applications in health sciences. Historical perspective From dawn of civilization to about AD 1000, medical treatment was directed against supposed etiologies, e.g., evil spirits, draining bad blood, etc. The first ever mention of statistical probabilities of an outcome is found in Talmud (AD 300). Hindu culture takes the credit of using numerical and decimal system, the foundation of statistics. Arabic mathematician, Khowarizmi, defined rules for adding, substracting, multiplying and dividing (AD 800). Huygen and John Grant (1660) advanced this knowledge further. Twentieth century saw an explosion of medical technology and treatment in the fields of surgery, medic ine and their subspecialties. It became increasingly necessary to standardize medical practice

Address for Correspondence Dr. Tariq Zaman, 210 G.T.Road, Baghban pura, Lahore.


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on sound scientific basis, and interpret the controversies in the treatment of similar conditions from growing body of evidence. In the mid-twentieth century, “Case Study” and “Case Series” were a common way to prove that a treatment was beneficial. Most research work done was anecdotal than scientific. James Lind, a Royal Navy surgeon, carried out first recorded randomized clinical trial in 1747, applying six dif ferent treatments for scurvy cure in sailors. It took 200 years before randomized controlled trials became the standard for evaluation of various therapeutic options.

Sir Ronald Fisher and Austin Bradford are remembered as fathers of modern statistics. They published a series of articles in “Lancet” and “British Medical Journal” (1937-1947)), reporting their randomized trials e.g. streptomycin vs. placebo in lung tuberculosis, and stressing upon introduction of biostatistics in medical curricula. Archic Chocrane, a British general practitioner started current movement of systematic statistical reviews of available evidence in medicine, thus laying the foundation of Evidence Based Medicine and Practice. Statistics and biostatistics The word “statistics” has originated from Latin words status (meaning ‘state') or statisticus (meaning ‘state affairs’) and has been used for the information useful for the state, e.g. information about size of population or armed forces, about amount of revenue, reserves or salaries, etc. etc. But now the term ‘statistics’ is used in two different contexts. Firstly, it is used as a synonym of data and refers to systematically arranged numerical facts and figures of any kind,

e.g. statistics regarding economics, business, industry, education, health, diseases, etc. They are collected from records, surveys or experiments. Secondly, the term statistics is used to refer a body of knowledge, a discipline or a branch of science. It is a science of figures. It deals with the principles and methods for collection, processing, analysis, presentation and interpretation of numerical data. It is an inferential science too, and helps us to draw reliable and valid inferences from the available data particularly in the fields of experimentation and research. It is a science of decision-making, and is the only way out to take decisions in the face of uncertainty. The term “biostatistics” is used for the statistics related to the biological sciences like biology, medicine or public health. So biostatistics refers either to the data arising out of the biological sciences or to the science that deals with the application of statistical methods to the data derived from these fields. Statistical methods fall into two broad categories, descriptive statistics and inferential statistics. Descriptive Statistics This branch of statistics deals with the summarization and description of data. It is the most basic form of statistics that lays the foundation for all statistical knowledge. The methods of descriptive statistics are used to consolidate the data in the form of tables, charts or graphs. They are also applied to compute the numerical quantities that provide information about the central tendency and spread of the data, e.g. mean, median, mode, standard deviation, variance, etc.


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Inferential Statistics It is the branch of statistics that deals with making inferences from the collected data. The methods of inferential statistics are applied to test statistical hypothesis and draw conclusions by computing confidence interval or statistical significance. They are used to estimate population parameters using data obtained from a sample from that population. Role of statistics in medicine Statistical analysis is a fundamental component of modern research in all disciplines of science, and medicine is no exception. In medical research the role of statistics starts from the planning phase in deciding study design, selecting sampling technique and formulating research methodology. The statistical tools have their application in data collection and its handling, analysis and interpretation. Statistical treatment of data is required to draw valid conclusions, which have to be evaluated in the light of statistical logic. Statistical methods are also helpful for comprehensible and effective presentation of research data and results. In addition, clear concepts of basic principles of biostatistics are also required to understand the data presented by others. “A knowledge of statistical methods is not only essential for those who present statistical arguments it is also needed by those on the receiving end.” …R.G.D. Allen Various statistical tools are extensively used in medical journals for description of data and for drawing conclusions from research findings. Knowledge of statistical methods is necessary to assess the validity of evidence in these articles. Understanding of principles and concepts of biostatistics is an essential prerequisite

to develop critical attitude towards research data and inferences presented at any forum or published in any scientific journal, newspaper or magazine. The clinicians also require some working knowledge of basic statistical techniques while evaluating clinical features, diagnosis, prognosis and management of their patients. In fact, neither medical practice nor research can be properly planned, executed or assessed without understanding the fundamentals of biostatistics. Application and uses of statistics in health sciences “A knowledge of statistics is like a knowledge of foreign languages or of algebra; it may prove of use at any time under any circumstances.”…Arthur L. Bowley The biostatistics has its application and uses in the following broad areas of basic medical sciences, applied medicine and public health:

• In def ining the normal of various body characteristic and their limits (range of normality) in a population, i.e. at what point these measures become ‘abnormal’ or ‘pathological’. For example, normal value and range of blood pressure, heart rate, weight, height, blood counts, serum biochemistry, etc.

• In finding the difference between means and proportions of normal variables (body characteristics) in two samples with different parameters or in the same sample at two places or in two different periods, e.g. difference between means of weight or height in various age, sex, racial or ethnic


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groups, or difference between heart rate or blood pressure at basal level and after exercise in the same sample.

• In finding the correlation between two variables. Whether one var iable increases or decreases proportionately with the other variable, and if so by how much. For example, correlation between age and weight, or between height and weight, etc.

• In determining the action, dosage and potency of a new drug in pharmacological studies. By statistical techniques the action of a drug is compared in animals or human volunteers with a placebo to determine whether it is due to the drug or by chance. Or the action of the new drug is compared with a standard drug or with various doses.

• In identifying and documenting the clinical features of diseases, e.g. signs, symptoms, course, prognosis, complications, etc. and their variability among various groups of patients or their association with various characteristics like age, sex, etc.

• In analyzing the sensitivity and specificity of various laboratory tests, clinical procedures or diagnostic criteria.

• In planning and conduct of clinical trials in a particular disease for efficacy and safety of a drug, surgical procedure, radiation or physiotherapy, etc.

• In evaluating the role of basic underlying factors in the causation of different ailments in the epidemiological studies. For example, determining the role of

contaminated water in diarrhea or dysentery by comparing the proportions of disease attacks in groups of individuals drinking boiled or unboiled water. Similarly, evaluation of the role of smoking in lung cancer or high cholesterol diet in ischemic heart disease, etc.

• In determining the usefulness of various public health programs. For example, evaluation of vaccination for a particular infection by comparing the proportions of attacks/deaths in vaccinated and unvaccinated subjects and by analyzing the statistical significance of the difference observed.

• In collecting the demographic, health and vital statistics, which are important indicators of health status of the community. They have a pivotal role in formulating health policy and in making future health plans.

In addition, application of statistical principles is necessary in many other areas of medicine and public health, like construction of life tables and survival rate calculation, risk specification, cost analysis, quality of life indices, etc. Latest trends in statistics Preceding decade has seen following developments in the clinical application of biostatistics in health care sciences: Evidence Based Medicine (EBM) Evidence Based Medicine has been defined as the “the conscientious, explicit and judicious use of best available evidence in making decisions about cases of individual patients”. It was realized in 1980s, that there were large variations in


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the treatment strategies offered to patients with similar ailments. For example, rates of prostatectomy (for benign hyperplasia), hysterectomy (for menorrghagia) and cataract surgery varied 2.5, 3.0 and 20 times respectively. Evidence based medicine started with the appreciation of the need for uniformity of treatment for same conditions. This uniformity is based upon statistical analysis of randomized controlled trials on the same subject. Meta-analysis Meta-analysis forms the basis of EBM. It involves inclusion of multiple studies according to preset inclusion and exclusion criteria in which the results from all the studies are pooled and analyzed statistically as if it were from one large study. The meta-analysis, also called as “Systematic Literature Review” explains the results quantit atively. In contrast the traditional “Literature Review” examines the relevant literature for general trends and patterns in a particular subject in qualitative terms only. Guidelines EBM clarifies one particular facet of disease management (e.g. thrombolysis in acute myocardial infarction). Comprehensive disease management requires treatment according to the best available evidence at each step till recovery. A disease may also not follow the typical pattern. Guidelines are formulated by a panel of experts of the particular disease. Literature is searched for each step of disease management, strength of evidence is judged, and a consensus is reached upon before publication of guidelines. Role of computer in statistics Mathematical calculations used in biostatistics have always been feared by

the non-statisticians including health professionals. Statistical analysis of any study is always considered to be the job of statistician. Computers and commercial statistical software packages have not only allayed the fear of mathematical calculations but also offer economy of time. Research worker can now apply the appropriate statistical methods to his research work himself with the help of these softwares. However, a sound knowledge of basic principles of biostatistics still remains mandatory to use these packages.

Conclusions The medical students, clinicians or research workers should not depend solely on the statistician for statistical analysis. They should learn the basic principles of biostatistics and should apply these methods correctly for unprejudiced assessment and management of the patients, for proper planning of scientific studies, for reinforcement of their own research conclusions and for critical evaluation of the work done by others.

Further reading

1. Bluman AG, ed. Elementary Statistics – step by step approach, 5th edn. Philadelphia : McGraw -Hill; 2004.

2. Coogan D, ed. Statistics in clinical medicine, 2nd edn. London: BMJ Publications; 1999.

3. Gaddis G, Gaddis M. Introduction to biostatistics; part II, the descriptive statistics. Ann Emerg Med 1990; 19: 309-15.

4. Krishnamurty GB, Kasovia-Schmitt P, Ostroff DJ, eds. Statistics – An interactive text for health and life sciences . London: Jones & Bartlett Publishers International; 1995.

5. Mann PS, editor. Introductory Statistics, 5th edn . Singapore: John Willy & Sons; 2004.


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Address for Correspondence Dr. Imad Yassin Saadeldin Consultant Pediatrician, King Fahad Hospital at Al-Baha, Al-Baha, PO Box 204, Al-Baha, Saudi Arabia. Tel.(Mobile):+966-53777041, Work: +966-7-725-4000 ext.-3730/3721 Fax:+966-725-4184/725-2188 E-mail: [email protected]

Case report Dyskeratosis congenita (DC) in a Saudi boy: an uncommon genodermatosis

A. Y. Saadeldin, Satti A. Satti, Ali S. Dammas

Pediatric & Neonatology Department, King Fahad Hospital at Al-Baha, Al-Baha, Saudi Arabia.

Abstract A 6-year-old Saudi boy presented to our hospital with severe thrombocytopenia. The patient was managed for a long time (6 years) as having chronic idiopathic thrombocytopenic purpura. Later on features consistent with dyskeratosis congenita were recognized by the authors. The main features were: skin manifestations, nail dystrophy, alopecia totalis, microcephaly and mental retardation. The condition was associated with acute necrotizing ulcerative gingivitis. At the age of 10, he developed pancytopenia and died at the age of 14 years from acute fulminant sepsis. Key words Dyskeratosis congenita, acute necrotizing ulcerative gingivitis, pancytopenia.

Introduction

Dyskeratosis congenital (DC) is a rare genodermatosis and multisystem disorder, characterized by cutaneous reticulated hyperpigmentation, nail dystrophy and mucous membrane les ions (ulcers, premalignant oral leucoplakia), and progressive pancytopenia.1 Bone marrow hypoplasia is frequent.2 The majority of cases (90%) are males.3 The age of presentation is between 5-15 years.4 The most common pattern of inheritance is X-linked recessive caused by mutations in the DKC1 gene.1 Autosomal dominant and recessive forms exist. The gene causing the X-linked recessive forms is located to Xq 28 and codes dyskerin, a 514 amino acid protein.5 80% of patients with DC

have progressive bone marrow (BM) failure, which is the major cause of death.6 Few of the patients die from pulmonary complications (e.g. fibrosis), and malignancy (acute myeloid leukemia and Hodgkin disease) .7

Case report

At the age of 6 years a Saudi boy presented to our hospital complaining of the following since the age of 6 months: chronic recurrent bleeding from gums, easy bruising following minor injuries, epistaxis and excessive tearing. During pregnancy his mother developed chicken pox. Delivery was normal with no problems. Developmental history revealed delayed speech and also other milestones. Parents were first degree cousins. There were nine siblings (7 males and 2 females) all were normal except one brother who died at the age of 3 years with similar complaint and physical picture as our patient and another 17-year-old brother with cutaneous hyperpigmentation, nail dystrophy and alopecia totalis but no

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hematological manifestations. There were seven maternal uncles who died in early childhood (the cause not known).

Physical examination Our patient was pale, microcephalic, with alopecia totalis and sparse hair of eyebrows and eye lashes (Figure 1), dystrophic nails of the hands (Figure 2) and feet, reticular skin with hyperpigmentation of the neck (Figure 3), upper chest and lower limbs, multiple purpuric spots with ecchymosis over the neck and bleeding spots in the gums, throat and uvula. The skin on extensor surfaces of upper and lower limbs and soles was hyperkeratotic. There were also subconjunctival haemorrhages (Figure 4). Dental caries with enamel hypoplasia was evident. Mouth examination showed: acute necrotizing ulcerative gingivitis (ANUG) with focal acute pseudomembranous candidiasis. No hepatosplenomegaly or lymphadenopathy detected, with normal joints and genitalia. Vital signs were normal. The weight, height and head circumference were all below the 3rd centile. Retinal hemorrhages in both eyes revealed by fundoscopy.

Investigations done on admission: 1. CBC: WBC: 8.6x109/l, HB: 7.2 g/dl, MCV: 100.0 fl, MCH: 31.2 pg, MCHC: 31.2 g/dl, RDW: 17.9 between 2-17x109/l, reticulocyte count of 1.6%. 2. Peripheral smear: macrocytic anemia with severe thrombocytopenia. 3. Prothrombin time (PT) and activated partial thromboplastin time (APTT): normal. 4. Chemistry was normal.

Later on the patient had frequent admissions in the pediatric department with severe anemia, severe thrombocytopenia and bleeding, mainly from gums. Lastly he presented in August, 2000 (at the age of 12 years) with high

Figure 1 Pale, microcephalic child with diffuse alopecia over scalp and sparse eyebrows and eye lashes

Figure 2 Dystrophic fingernails

Figure 3 Reticulate hyperpigmentation affecting the sides of neck.

Figure 3 Subconjunctival hemorrhage in the right eye.

fever, multiple oral ulceration and same previous physical changes. Investigations at this time revealed: 1. CBC: severe pancytopenia, ESR: 122mm/hr. 2. Peripheral smear: anisocytosis, normochromia, some macrocytes and few spherocytes. There was severe leucopenia


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with 51% lymphocytes and very low platelets count. 3. PT and APTT: still normal 4. Chemistry, urea and electrolytes and hepatitis panel were normal 5. Hb electrophoresis: HbA-97.9%, HbA2-2.1% 6. Chest X-ray and X-ray of limbs were normal. 7. Ultrasound (U/S) abdomen showed: coarse echo pattern of the liver. 8. Liver function tests were mildly disturbed. 9. High serum ferritin of 3216 ng/ml. 10. Bone marrow aspirate: showed a picture of aplastic anemia. 11. Septic screening was done many times, showed no bacterial growth. CT brain: showed mild cerebral atrophy.

Management The patient received many courses of prednisolone tablets since the age of 6 years in different hospitals before he was seen by the authors. He received also short courses of androgens: oxymethalone 60mg OD and androlone 25mg intramuscular every 2 weeks. During the last 8 years, our patient received many packed red blood cells and platelets transfusions due to severe anemia and thrombocytopenia, and many courses of parenteral and oral antibiotics, due to repeated systemic infections of the lower respiratory tract. Bone marrow transplantation was planned, but at the age of 14 years (in 2002) our patient presented with severe fulminant sepsis and in spite of extensive and aggressive management in our pediatric intensive care unit he expired after two days.

Discussion

Since the age of 6 years our patient had been admitted in the hospital due to bleeding per gums and skin and found to have severe thrombocytopenia. He was diagnosed and managed as having idiopathic thrombocytopenic purpura. This attracts the attention to physicians and

pediatricians of the importance of knowing such a rare condition like DC. We saw the patient for the first time when he was referred to our hospital at the age of 10 years, due to pancytopenia. At that time the following features were recognized: microcephaly, alopecia totalis with sparse hair of eye lashes and brows, dystrophic nails of the hands and feet, dermatologic features such as reticular hyperkeratotic skin and hyperpigmentation, which is the usual presentation in DC.1 He also presented with mucous membrane changes in the form of acute necrotizing ulcerative gingivitis (ANUG), which from literature review is found to be common in patients with immunodeficiency and HIV infection.8 ANUG is rare in DC. The patient was found to have bone marrow failure, which is considered to be a late manifestation of DC.2,9,10 Differential diagnosis to be considered is Hoyeraal-Hreidarsson syndrome, a severe infantile variant of DC, inherited as X-linked manner, in which there may be overlap with DC.1,11,12 The features of this syndrome include: intrauterine growth retardation, microcephaly, mental retardation, cerebral malformation, immunodeficiency and progressive bone marrow failure.1 Our patient presented with microcephaly, mental retardation and brain atrophy, which is not the usual presentation of classical DC.12

Other differential diagnoses are Rothmund-Thomson syndrome (short stature, skin telangiectasias, small hands and feet, hypoplastic thumbs with a high risk of osteosarcoma) and graft versus host disease.4 Our patient died at the age of 14 years with fulminant sepsis which is one of the leading causes of death in DC.13 Other causes of death include bone marrow failure6 and the development of malignancies, especially acute myeloid

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leukemia14 and squamous cell carcinoma, 2

which can occur on leucoplakia or normal mucous membranes and skin.7 As mentioned, there was one brother, who died at the age of 3 years, another 17 year-old brother, who is still living, both with similar features and 7 maternal uncles who died undiagnosed, in early childhood, suggesting an X-linked mode of inheritance. The patient received androgens for the bone marrow failure as there is about 50% response15 in many cases, but in our patient there was no improvement.

References

1. Yagamahi R, Kimyai-Asadi A, Rostamiani K et al. Overlap of dyskeratosis congenita with the Hoyeraal-Hreidarsson syndrome. J Pediatr 2000; 136 : 390-3.

2. Jacobs P, Saxe N, Gordon W, Nelson M. Dyskeratosis congenita: haematologic, cytogenetic, and dermatologic studies. Scand J Haematol 1984; 32: 461-8.

3. McKusick VA, ed. Mandelian inheritance in man, 11th edn. Baltimore : Johns Hopkins; 1994.

4. Chan EF. Dyskeratosis congenita. Nov.5.2001; eMedicine.

5. Connor JM, Gatherer D, Gray FC et al. Assignment of the gene for dyskeratosis congenita to Xq28. Hum Genet 1986; 72: 348-51.

6. Dokal I. Dyskeratosis congenita. Br. J Haematol 1999; 105: S11-5.

7. Baykal C, Buyukbabani N, Kavak A. Dyskeratosis congenita associated with Hodgkin disease. Eur J Dermatol 1998;.8: 385-7.

8. SC. HIV infection and periodontal disease. Ann R Australs Coll Dent Surg 2000; 15: 331-4.

9. Forni GL, Melevendi C, Japelli S, Rosore-Quortino A. Dyskeratosis congenita: unusual presenting features within kindred. Ped Hematol Oncol 1993; 10: 145-9.

10. Putterman C, Safadi R, Zlotogora J et al. Treatment of the manifestation of dyskeratosis congenita. Ann Hematol 1993; 66: 209-12.

11. Cossu F, Vulliamy TJ, Marrone A et al. A novel DKC1 mutation, severe combined immunodeficiency, and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome. Br J Ha ematol 2002; 119: 765-8.

12. Knight SW, Heiss NS, Vulliamy TJ: Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol 1999; 107: 335-9.

13. Davidson HR, Connor JM. Dyskeratosis congenita. J Med Genet 1988; 25: 843-6.

14. Knight S, Vulliamy T, Copplestone A et al. Dyskeratosis congenita (DC) registry: identification of new features of DC. Br J Haematol 1998; 103: 990-6.


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Case report Nevoid psoriasis: an uncommon blaschkolinear dermatosis Arfan ul Bari, Simeen Ber Rahman*

Consultant Dermatologist, PAF Hospital, Sargodha * Dermatology Department, Military Hospital, Rawalpindi

Abstract Nevoid or linear psoriasis is an uncommon form of psoriasis characterized by the linear or zosteriform distribution of the psoriatic lesions. It usually follows the lines of Blaschko with unilateral involvement. It is commonly confused clinically and histopathologically with verrucous epidermal nevus. We report a young male, who had linear psoriasis in a unilateral distribution over his shoulder and arm. He was diagnosed on clinical as well as histological ground and was managed on the lines of psoriasis. Key words Linear psoriasis, nevoid psoriasis, lines of Blaschko, inflammatory linear verrucous epidermal naevi.

Introduction

Psoriasis is a common chronic , genetic, noncontagious inflammatory skin disorder that appears in many clinico-morphological forms and can affect any part of the body. Nevoid or linear psoriasis is a rare variant of this common disorder and is characterized by a linear distribution of the psoriatic lesions. It follows the lines of Blaschko with unilateral involvement and usually occurs in young adults but has also been reported in childhood.1,2 The pathogenesis is unclear, but it could be explained as a result of the migration of cells harboring a somatic mutation following the lines of Blaschko during early embryogenesis .3,4 It was first described in 1951 by Leslie5 and Sobel.6 In psoriasis lesions in a

blaschkolinear distribution mostly occur together with scattered lesions, but occasionally they may be isolated and may present in a purely nevoid form following Blaschko’s lines, may koebnerize, or may superimpose an epidermal nevus.7,8 Very rarely it may coexist with another rare dermatosis that follows Blaschko's line, e.g. porokeratotic eccrine ostial and dermal duct nevus.9 Several clinical entities resemble nevoid psoriasis, and differential diagnosis is important. It is the inflammatory linear verrucous nevus (ILVEN) that is most commonly confused with linear psoriasis and a clear distinction between linear psoriasis vulgaris and (ILVEN) can be difficult because of the clinical and histopathologic similarities of the two conditions .10 An association of ILVEN with psoriasis vulgaris has also been reported.7 Lesions of the ILVEN are pruritic, most commonly occur on the legs, pelvis, and buttock, have early age of onset and female predominance. The congenital hemidysplasia with ichthyosiform nevus and limb deficiency

Address for Correspondence Squadron Leader Dr. Arfan ul Bari, Consultant Dermatologist, PAF Hospital, Sargodha Ph# (off): 0451-5553307, (res): 0451-5553308 E mail: [email protected]

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(CHILD) syndrome presents with verrucous plaques in a segmental distribution but other associated features clearly differentiate it. Lichen striatus and linear lichen planus also resemble nevoid psoriasis or ILVEN, however, their histology is quite distinct.10-12 Above clinical and histopathologic features clearly differentiate these disorders from linear psoriasis. In difficult to diagnose cases, involucrin immunohistochemistry can be a useful diagnostic tool to confirm diagnosis of nevoid psoriasis .13 Treatment with keratolytics and topical calcipotriol, topical steroids and other topical anti-psoriatic regimens lead to a s ignificant improvement.1,2 The purpose of reporting the case was to highlight the existence of nevoid or linear psoriasis as an entity.

Case report

A 25-year-old man, presented with a slightly pruritic, linear plaques over his left shoulder and adjacent arm. The lesions started appearing three years ago as small discrete papules and plaques roughly in a linear fashion on back of his right shoulder and arm and gradually progressed and coalesced to form large linear scaly plaques. He had no relevant personal or family history. On clinical examination, large erythematous scaly verrucous lesions were seen that were linearly distributed over back of his left shoulder axilla and outer aspect of the left upper arm (Figure 1 and 2). There were no lesions suggestive of psoriasis else where over his skin nails or scalp. Skin biopsy revealed classical histological features of psoriasis showing acanthosis with regular elongation of rete ridges, parakeratosis, Munro's microabscesses, spongiform pustules (Figure 3). There were no columns of hypergranulosis with orthokeratosis

Figure 1 Linear erythematous , scaly eruption affecting left axilla, shoulder ad upper arm.

Figure 2 Another view of linear hyperkeratotic, erythematous and scaly eruption.

Figure 3 Histopathology of the lesion, psoriasiform hyperplasia of epidermis along with Munro’s microabscesses.

alternating with columns of agranulosis with parakeratosis as we see in ILVEN.

Clinical examination and results of histopathology confirmed the diagnosis of unilateral nevoid or linear psoriasis. He


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was managed with topical anti-psoriatic ointment (containing tar, salicylic acid, topical steroid dispensed in emulsifying ointment).

Discussion

Psoriasis is one of a number of autoimmune diseases that display significant HLA associations (HLA-Cw6). However, only about 10% of Cw6-positive individuals develop disease, suggesting that other genetic and/or environmental factors must be involved. Several compelling lines of epidemiologic evidence indicate that psoriasis susceptibility is inherited, albeit not in a simple monogenic fashion, and that genetic, rather than environmental, factors are primarily responsible for the variability in inheritance of psoriasis. Taken together, these observations suggest that one or more loci in addition to HLA are necessary for the development of psoriasis. The number of additional loci is likely to be small, because i) the disease is very common ii) substantial excess risk of psoriasis is observed in first degree relatives, and iii) nevoid variants of psoriasis have been reported, suggestive of somatic mutation of a single gene during development.3,4 The existence of a linear psoriasis has frequently been a subject of debate. Several authors have disputed the existence of true line ar psoriasis and contend that many reports of linear psoriasis represent either inflammatory linear verrucous epidermal nevus (ILVEN) in a patient with psoriasis, a nevus, or even an invasion of ILVEN a by psoriasis as a manifestation of the isomorphic reaction.10,11 In contrast, some authors have a strong opinion that linear psoriasis is a separate entity. Therefore, before diagnosis, it should be differentiated clinically and histopathologically from

ILVEN. The criteria for the diagnosis of ILVEN established by Altman and Mehregan14 include early age of onset, 4 times more common among women than men, frequent involvement of the left leg, pruritus, psoriasiform appearance, persistence, and resistance to treatment. Among these criteria, a differential point is that the lesions of ILVEN take the form of intensely pruritic linear groups of excoriated eczematous papules, which proves extremely refractory to therapy. The histopathologic aspect of ILVEN is very similar to psoriasis, but is characterized by columns of hypergranulosis with orthokeratosis alternating with columns of agranulosis with parakeratosis. The case reported by us was clinically more suggestive of nevoid psoriasis rather than ILVEN, as the patient was male, the disease had late onset, and the lesions were not much pruritic and were distributed over upper half of the body (these features were against ILVEN). Moreover, the histology of the lesion revealed classical features of psoriasis and there were no alternating columns of hypergranulosis with orthokeratosis and agranulosis with parakeratosis. The response to anti-psoriatic treatment was satisfactory. Conclusion

Psoriasis may koebnerize in a linear fashion, may superimpose or invade an epidermal nevus but a nevoid form following Blaschko’s lines should be taken a separate entity.

References 1. Atherton DJ, Kahana M, Russel-Jones

R. Naevoid psoriasis. Br J Dermatol 1989; 120 : 837-41.

2. Saraswat A, Sandhu K, Shukla R, Handa S. Unilateral linear psoriasis with palmoplantar, nail, and scalp

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involvement. Pediatr Dermatol 2004; 21: 70-3.

3. Elder JT, Henseler T, Christophers E et al . Of genes and antigens: the inheritance of psoriasis. J Invest Dermatol 1994; 103: 150S-153S.

4. Happle R. Somatic recombination may explain linear psoriasis. J Med Genet 1991; 28: 337.

5. Leslie G. Linear psoriasis. Br J Dermatol 1951; 63: 262-263.

6. Sobel M. Linear psoriasis. Arch Dermatol Syph 1951; 63: 267-71.

7. Menni S, Restano L, Gianotti R, Boccardi D. Inflammatory linear verrucous epidermal nevus (ILVEN) and psoriasis in a child?. Int J Dermatol 2000; 39: 30-2.

8. Bondi EE. Psoriasis overlying an epidermal nevus. Arch Dermatol 1979; 115 : 624-5.

9. Yu HJ, Ko JY, Kwon HM, Kim JS. Linear psoriasis with porokeratotic eccrine ostial and dermal duct nevus. J Am Acad Dermatol 2004; 50: S81-3.

10. de Jong E, Rulo H, van de Kerkhof PC. Inflammatory linear verrucous epidermal nevus (ILVEN) versus linear psoriasis: a clinical, histological and immunohistochemical study. Acta Derm Venereol 1991; 71: 343-6.

11. Lee SH, Rogers M. Inflammatory linear verrucous epidermal naevi: a review of 23 cases. Austral J Dermatol 2001; 42: 252-6.

12. Grosshans EM. Acquired blaschkolinear dermatoses. Am J Med Genet 1999 6; 85: 334 -7

13. Ginarte M, Fernandez-Redondo V, Toriboi J. Unilateral psoriasis: a case individualized by means of involucrin . Cutis 2000; 65: 167-70.

14. Altman J, Mehregan AH. Inflammatory linear verrucous epidermal nevus. Arch Dermatol 1971; 104 : 385-9.


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Address for Correspondence Dr. Asher Ahmed Mashood, Consultant Dermatologist CMH, Peshawar Ph# 091 2016154, 091 271779 E-mail: [email protected]

Quiz

Generalized pustular rash of acute onset

Asher Ahmed Mashood Consultant Dermatologist, Combin ed Mil itary Hospital, Peshawar

Report of a case

A 23-year-old married lady reported in skin OPD with a generalized body rash and low-grade fever of 2 days duration. The patient suffered from renal colic three days prior to the development of the rash for which she received oral ampicillin. On examination, the skin of the whole body was erythematous. Over the background of erythema, there were multiple, superficial, pinpoint pustules, which were discrete and at places coalescing into sheets of pus (Figure 1).

Microscopic findings

The histopathological examination of the skin specimen revealed pustules within the stratum corneum. The epidermis showed acanthosis and spongiosis. The dermis showed mild edema and occasional extravasation of neutrophils and eosinophils.

Figure 1 Multiple discrete and coalescing pustules over a background of diffuse erythema. Dried squames are seen at places.

Generalized pustular rash of acute onset Asher A. Mashood

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Diagnosis Acute exanthemic pustulosis Discussion Acute exanthemic pustulosis is an eruption of generalized pustular rash over an erythematous background, all over the body especially the trunk.1 The rash occurs within 24-48 hours of the administration of the offending drug. The pustules are monomorphic, superficial and diffuse. The rash usually starts with fever and settles spontaneously with desquamation. Facial oedema, purpura, vesicles, blisters and erythema-multiforme like lesions may also be seen. The drugs implicated are ampicillin,2 amoxycillin,3 propicillin,4 cephadrine,5 cephalexin,6 cotrimoxazole,7 doxycycline,8 chloramphenicol, norfloxacin,9 ofloxacin, 10 streptomycin ,11 salazopyrine,12 pyrimethamine, frusamide, nitrazepam, itraconazole,1 diltiazem,13 captopril,14 enalapril,15 acetylsalicylic acid,16 naproxen,17 allopurinol,18 hydroxychloroquine,19 chlorpromazine,20 phenytoin, 21 and carbamezapine.22 The main differential diagnosis is pustular psoriasis.1,23 It can be differentiated from acute exanthemic pustulosis on both clinical and histological basis. The histopathological picture is identical to subcorneal pustular dermatosis, characterized by subcorneal pustules and mixed dermal infiltrate composed of neutrophils and eosinophils. Since it is a self-limiting disease, general measures like fluid and electrolyte balance, bladder care, prevention of infection, pain-killers, anti-pruritic tablets and some bland cream or lotion to reduce the discomfort are generally sufficient.

References

1. Manders SM, Heymann WR. Acute generalized exanthemic pustulosis. Cutis 1994; 54: 194-6.

2. Jay S, Kang J, Watcher MA et al. Localized pustular skin eruption. Localized pustular drug eruption secondary to ampicillin. Arch Dermatol 1994; 130: 787 -90.

3. Armster H, Schwarz T. Arzneimittelreaktion auf Amoxicillin unter dem blid eines toxischen pustuloderms. Hautarzt 1991; 42: 713-6.

4. Gebhardt M, Lusting A, Bocker T et al. Acute generalized exanthemic pustulosis (AGEP): manifestation of drug allergy to propicillin. Contact Dermatitis 1995; 33: 204-5.

5. Kalb RE, Grossman ME. Pustular eruption following administration of cephadrine. Cutis 1986; 38: 58-60.

6. Jackson H, Vion B, Levy PM. Generalized pustular drug rash due to cephalexin. Dermatologica 1988; 177 : 292-4.

7. MacDonald KJS, Green CK, Kenicer KJA. Pustular dermatosis induced by co-trimoxazole. Br Med J 1986; 293: 1279-80.

8. Trueb RM, Burg G. Acute generalized exanthemic pustulosis due to doxycycline. Dermatology 1993; 186 : 75-8.

9. Shelley ED, Shelly WB. The subcorneal pustular eruption; an example induced by norfloxacin. Cutis 1988; 42: 24-7.

10. Tsuada S, Kato K, Karasima T et al. Toxic pustuloderma induced by ofloxacin. Acta Derm Venereol (Stockh) 1993; 73: 382-4.

11. Kushimoto H, Aoki T. Toxic erythema with generalized follicular pustules caused by streptomycin. Arch Dermatol 1981; 117 : 444-5.

12. Gallais V, Grange F, De Bandt M et al. Toxidermie a la salazosulfapyridine. Erythrodermie pustuleuse et syndrome psedolympomateux: 2 observations. Ann Dermatol Venereol 1994; 121: 11-4.

13. Lambert DG, Dalac S, Beer F et al. Acute generalized exanthemic pustular dermatitis induced by diltiazem. Br J Dermatol 1988; 118: 308-9.


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14. Carroll J, Thaler M, Grossman E et al. Generalized pustular eruption associated with converting enzyme inhibitor therapy. Cutis 1995; 56: 276-8.

15. Ferguson JE, Chalmers RJ. Enalapril-induced toxic pustuloderma. Clin Exp Dermatol 1996; 21: 54-5.

16. Ballmer-Weber BK, Windmer M, Burg G. Acetylsalicylsaure-induzierte generalisierte pustulose. Schweiz Med Wochenschr 1993; 123: 542-6.

17. Grattan CEH. Generalized pustular drug rash due to naproxen. Dermatologica 1989; 179: 57-8.

18. Boffa MJ, Chalmers RJ. Allopurinol-induced toxic pustuloderma. Br J Dermatol 1994; 131: 447.

19. Lotem M, Ingber A, Segal R et al. generalized pustular drug rash induced by hydroxychloroquine. Acta

Derm Venereol (Stockh) 1990; 70: 250-1.

20. Burrows NP, Ratnavel RC, Norris PG. Pustular eruptions after chlorpromazine. Br Med J 1994; 309 : 97.

21. Kleier RS, Breneman DL, Boiko S. Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome. Arch Dermatol 1991; 127: 1361-4.

22. Commens CA, Fisher GO. Toxic pustuloderma following carbamazepine therapy. Arch Dermatol 1988; 124: 178 -9.

23. Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol 1994; 130 : 514-19.

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News

National events

2004

December 9-12, 2004 Silver Jubilee Conference of Pakistan Association of Dermatologists, Karachi. Organizing Chairman: Dr. Khurshid H. Alvi, Suite No. 11, 3rd Floor, Taj Medical Complex, M.A. Jinnah Road, Karachi, 74400 Pakistan Tel: +92 21 7789666 Fax: +92 21 7789677 E-mail: [email protected] [email protected] Website: www.pad.org.pk

Inauguration of De partmental Website and Teledermatology Unit, Department of Dermatology (Unit I), King Edward Medical College/Mayo Hospital, Lahore On 25 th August, 2004, official website and Teledermatology unit of Department of Dermatology (Unit I), Medical college/Mayo Hospital, Lahore) were inaugurated. Initially, only store-and-forward type of teleconsultation was started.

International events

2004

November 17-21 13th Congress of the European Academy of Dermatology and Venereology

Contact: Torello M. Lotti, Florence, Italy E-mail: [email protected] or

[email protected]

2005

February 3-6

4th South Asian Regional Conference of Dermatology, Venereology & Leprology DERMACON 2005 New Delhi, India Contact: Dr. Vijay K. Garg Tel: 020 7383 0266 E-mail: info @dermacon2005.com www.dermacon2005.com

October 12-15

European Academy of Dermatology and Venereology Congress (EADV) London, UK Contact: Marilyn Benham Tel: 020 7383 0266 E-mail: [email protected] www.eadv.org

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Information for Authors Manuscripts The JPAD agrees to accept manuscripts prepared in accordance with the “Uniform Requirements for Manuscript Submission to the Biomedical Journals” approved by the International Committee of Medical Journals Editors. Three copies of all material for publication should be sent to Dr. Ijaz Hussain, Editor, JPAD, Department of Dermatology, Mayo Hospital, Lahore, e-mail: [email protected] [email protected] Manuscripts should be printed on one side of paper only, with a 2.5 cm margin on either side, be double spaced, and bear the title of the paper, name and address of each author, together with the name of the hospital, laboratory or institution where the work has been carried out. The name and full address of corresponding author should be given on the first page. Pages should be numbered. Authors should keep a copy of the manuscript. In addition to the hard copy, an exact copy of the manuscript, containing all parts of the paper, must be submitted on high-density disk. The editor reserves the right to make corrections, both literary and technical, to the papers. Papers received are supposed to have been submitted exclusively to the Journal of Pakistan Association of Dermatologists and all authors must give a signed consent to publication in a letter sent with the manuscript. Authorship implies a significant contribution. In case of clinical trials, the names of pharmaceutical sponsors should be mentioned. Types of articles JPAD welcomes original and review articles, case reports, quizzes, items of correspondence etc. addressing any aspect of dermatology. The original article should be of about 2000 words, with no more than 6 tables or illustrations. Letters should not normally exceed 400 words and have more than 10 references. Parts of the paper The manuscript should be prepared as below. Title: In addition to the full title of the paper, a short version not more than 50 characters, for a running head, be provided. Author(s) details: Name(s) of the author(s) should be given as initial(s) followed by surnames, and should be clearly linked to the respective addresses by the use of symbols e.g. ∗ , †,‡ etc. Abstract: All articles other than correspondence should have an abstract. The original articles should have a structured abstract comprising of 4 subheadings: background, methods, results and conclusions. Keywords ≤ 5 should be provided to aid indexing. Main text: The main text should appear in the following sequence: introduction, methods, results, discussion, acknowledgments, references, tables and

legends for illustrations. Each section should begin on a new page. Generic names of the drugs should be used. Full names with abbreviations must be used given with the first mention, thereafter the abbreviation will be used. Abbreviations should be used for unwieldy names or where the names occur frequently. For all quantitative measurements the International System of Units (SI) should be used. References Only papers closely relevant to the author’s work should be referred to. References should be in the Vancouver style i.e. references should be written as unbracketed superscript numbers in the order in which they appear in the text e.g. ‘our previous reports1 and that of Cohen et al.2…..’. At the end of the article, references should give the name(s) and initials of author(s). If there are more than four authors, include the first three authors followed by et al., title of paper, title of the journal abbreviated in the standard manner (as published in the Index Medicus), year of publication, volume number, and first and final numbers of the article, e.g. Grattan C, Powell S, Humphreys F. Management and diagnostic guidelines for urticaria and angio-oedema. Br J Dermatol 2001; 144: 708-14. References to books should give the name(s) followed by initials of author(s) or editor(s), chapter (if relevant), book title, edition, place, publisher, year, and pages referred to e.g. Friedman WF, Child JS. Congenital heart disease in the adult. In: Fauci AS, Braunwald E, Isselbacher KJ et al., editors. Harrison’s principles of internal medicine. 14th edn. New York: McGraw-Hill; 1998. p. 1300-9. Tables There should be as few tables as possible and these should include only essential data. These should be printed on separate sheets and should be given Arabic numbers. No horizontal or vertical rules should be used. Avoid wordy, over-full tables. Legends should be provided. Illustrations Three sets of illustrations should be sent with each manuscript. Illustrations should be referred to in the text as ‘Figures’ and be given Arabic numbers. Each figure should be marked on the back with the name of the author(s), the title of the paper and the reference number used in the text. Orientation of the illustration should be indicated by marking the top with arrow. Photographs should be unmarked glossy prints. Diagrams should be on separate sheets and a legend should be provided for each illustration. Proofs Page proofs will be sent, without the original manuscript, to the corresponding author for proof correction and should be returned to the editor within three days. Major alterations from the text cannot be accepted. Any alterations should be marked, preferably in red.

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july--september, 2004