Dr. Ghazala Rasool Senior Registrar Medical Unit-II
Slide 3
Pyrexia of Unknown Origin In 1961 Petersdorf and Beeson defined
PUO as: Fever higher than 38.3 C (101 F) on several occasions
Persisting without diagnosis for at least 3 weeks At least 1 week's
investigation in hospital A new definition which includes the
outpatient setting (which reflects current medical practice) is
broader, stipulating: 3 outpatient visits or 3 days in the hospital
without elucidation of a cause or 1 week of "intelligent and
invasive" ambulatory investigation
Slide 4
Pyrexia of Unknown Origin In 75% cases of PUO, cause can be
determined with detailed investigations. In rest, cause remains
uncertain. Infections and malgnancies account for most PUOs (25-40%
of cases each) Autoimmune/ rheumatological disorders account for
10-20% cases.
Slide 5
Adult Onset Stills Disease Adult Stills disease is an
inflammatory disorder characterized by: Quotidian (daily) Fever
Arthritis Rash It is uncommon, as observed in many published case
series. It has been recognized as an important cause of the fever
of the unknown origin (FUO).
Slide 6
History It is named after the English physician George Still
(in 1896) who first described it in children. Stills disease has
become the eponymous term for systemic onset juvenile idiopathic
arthritis. In 1971,the term adult onset still disease was used to
describe a series of adult patients who: 1. did not fulfill the
criteria for rheumatoid arthritis but 2. who had features similar
to the children with systemic onset juvenile idiopathic
arthritis.
Slide 7
ETIOLOGY Unknown A variety of infectious triggers have been
suggested, including: Viral pathogens, Yersinia enterocolitica and
Mycoplasma pneumoniae It has also been suggested that genetic
factors are important, for example, human leukocyte antigen (HLA)-
B17, B18, B35, and DR2.
Slide 8
EPIDEMIOLOGY A retrospective French study estimated the annual
incidence of ASD to be 0.16 cases per 100,000 people. In a large
multicenter prospective study from tertiary care hospitals in
Turkey, Stills disease has been identified as the most common non
infectious inflammatory disease causing FUO in about 13.6% of their
patients. 1 1. Kucukardali Y, Oncul O, Cavuslu S, Danaci M, Calangu
S, Erdem H, Topcu AW, Adibelli Z, Akova M, Karaali EA, Ozel AM,
Bolaman Z, Caka B, Cetin B, Coban E, Karabay O, Karakoc C, Karan
MA, Korkmaz S, Sahin GO, Pahsa A, Sirmatel F, Solmazgul E, Ozmen N,
Tokatli I, Uzun C, Yakupoglu G, Besirbellioglu BA, Gul HC; Fever of
Unknown Origin Study Group. The spectrum of diseases causing fever
of unknown origin in Turkey: a multicenter study. Int J Infect Dis.
2008 Jan;12(1):71-9. Epub 2007 Jul 12. PubMed PMID: 17629532.
Slide 9
EPIDEMIOLOGY An equal gender distribution. There is a bimodal
age distribution, with: one peak between the ages of 15 and 25 and
the second between the ages of 36 and 46. However, patients older
than age 70 have been reported.
Slide 10
CLASSIFICATION CRITERIA There is no specific test or
combination of tests that can be used to establish the diagnosis of
ASD. At least seven sets of diagnostic criteria have been proposed.
However, the Japanese criteria, often termed the Yamaguchi
criteria, have the highest sensitivity in patients with a definite
diagnosis of ASD.
Slide 11
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YAMAGUSHI CRITERIA Major Criteria Minor Criteria Exclusion
Criteria Temperature > 39C (102.2F) for >1 wk Sore
throatInfections,especially sepsis Leukocytosis >10,000/mm 3 (
80% granulocytes) Lymphadenopathy and/orEpstein-Barr infection
Typical RashSplenomegaly or hepatomegaly Malignancy Arthalgias >
2wksAbnormal liver function studies, particularly elevations in AST
ALT LDH Inflammatory diseases Negative tests for ANA and rheumatoid
factor
Slide 13
AOSD should be considered if 5 criteria (2 of which being
major) are met. Once malignancies, infectious diseases and
rheumatological diseases have been excluded. The Yamaguchi criteria
have a sensitivity of 96% and specificity of 92%.
Slide 14
Slide 15
CLINICAL FEATURES FEVER Daily fever It is usually quotidian or
double-quotidian (two fever spikes per day). The temperature swings
can be dramatic, with changes of 4C occurring within four hours.
Complete defervescence is not required with these fevers, as fever
persists between spikes in approximately 20 percent of cases.
Slide 16
RASH The classic rash is Evanescent Salmon-colored Macular or
maculopapular eruption Transient that tends to occur with the
fever. Predominantly involves trunk and extremities (rarely involve
the palms, the soles and face). The Koebner phenomenon may be
present, in which the cutaneous eruption can sometimes be elicited
by stroking the skin. The rash is frequently misdiagnosed as a drug
reaction.
Slide 17
Evanescent rash
Slide 18
Slide 19
MUSCULOSKELETAL Arthralgia, arthritis, and myalgia are
universal features. Initially, the arthritis may be mild,
transient, and oligoarticular. However may evolve later into a more
severe and destructive polyarthritis Fusion of the wrist joints is
characteristic. The most commonly involved joints, in descending
order are: Knees Wrists Ankles Elbows Proximal interphalangeal
joints and shoulders
Slide 20
Clinical Features Pharyngitis Sore throat was noted in 69 %
percent. Lymphadenopathy Slightly tender, enlarged cervical lymph
nodes (one-half of patients). Splenomegaly / hepatomegaly
Pleuropericardial effusions, transient pulmonary infiltrates in 30
to 40 percent of patients. Myocarditis is a rare complication
Hematologic manifestations: pure red cell aplasia, DIC,
microangiopathic hemolytic anemia including, Reactive
hemophagocytic syndrome.
Slide 21
The Disease Complications It can include diverse complications,
affecting multiple organ systems. Moreover, the severity of the
organ involvement can vary considerably. The clinician should be
alerted to the existence of life- threatening AOSD complications,
namely: The macrophage activation syndrome. Disseminated
intravascular coagulopathy, thrombotic thrombocytopenic purpura,
Diffuse alveolar hemorrhage, and pulmonary arterial hypertension.
Fulminat hepatic failure.
Slide 22
REACTIVE HEMOPHAGOCYTIC SYNDROME It is termed as macrophage
activation syndrome when it occurs in AOSD. Rare but fatal
complication, may be underdiagnosed. A retrospective study reported
RHS in six (12 percent) out of 50 AOSD patients.
Slide 23
REACTIVE HEMOPHAGOCYTIC SYNDROME Hemophagocytic
lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory
condition caused by a highly stimulated but ineffective immune
system response. There is uncontrolled proliferation of T
lymphocytes and well-differentiated macrophages, leading to
widespread hemophagocytosis and cytokine overproduction
Slide 24
The diagnostic hallmark of RHS is the presence on bone marrow
examination of numerous, well-differentiated macrophages
(histiocytes) that are engaged actively in the phagocytosis of
hematopoietic elements
Slide 25
The Clinical Presentation of Macrophage Activation Syndrome
(MAS) Is generally acute and occasionally dramatic. Typically,
patients become: acutely ill with the sudden onset of non remitting
high fever, profound depression in all 3 blood cell lines, and
elevated serum liver enzyme levels, development of DIC.
Slide 26
Other Conditions associated with HLH HLH may also occur as a
secondary disorder in association with: severe infections,
malignancies, rheumatologic disorders, and some metabolic diseases.
This rare phenomenon was first ever diagnosed and reported in our
setup by our Dengue team in HFH, caused by Dengue co infection with
Malaria.
Slide 27
DISEASE COURSE Monophasic pattern Lasts only weeks to months,
completely resolving within less than a year. Intermittent pattern
one or more disease flares, with complete remissions between
episodes lasting from weeks up to one or two years. Subsequent
flares tend to be less severe and of shorter duration. Chronic
pattern Persistently active disease, in which articular symptoms
usually predominate. A potentially destructive arthritis may occur
in patients in this group.
Slide 28
INVESTIGATIONS No specific test or combination of tests that
can be used to establish the diagnosis of ASD. Raised ESR an CRP
are seen in virtually all patients Normocytic normochromic anemia
is seen in the majority of patients. Elevated ALT, AST, LDH are
seen in 75 percent of patients. Increased serum ferittin, exceeding
3000 ng/mL, is seen in 70 percent of patients
Slide 29
INVESTIGATIONS (continued) Immunologic studies the absence of
antinuclear antibodies and rheumatoid factor is one of the minor
criteria for ASD. Bone marrow examination may reveal hyperplasia of
granulocytic precursors. Radiographic findings nonerosive narrowing
of the carpometacarpal and intercarpal joint spaces of the wrists
often progresses to bony ankylosis (40%).
Slide 30
Serum Ferritin Markedly elevated serum ferritin concentrations
in as much as 70 percent of patients. More likely to be a
consequence of cytokine-induced synthesis by reticulo-endothelial
system or of hepatocyte damage with increased release.
Hyperferritinaemia is reported by some studies to be associated
with hisctiocyets hyperactivity The elevations correlate with
disease activity. A serologic marker to monitor the response to
treatment.
Slide 31
Glycosylated Ferritin Tends to be lower than in other rheumatic
disease. It may remain low both in the active phase of disease and
in remission. Both marked hyperferritinemia and a low fraction of
glycosylated serum ferritin also occur in the macrophage activation
syndrome Both the total serum ferritin and the glycosylated
fraction provide more diagnostic specificity for ASD than does
reliance upon either test alone.
Slide 32
Predictors of Chronic Disease and Unfavorable Outcome 1. The
development of a polyarthritis early in the course of ASD. 2.
Involvement of the shoulders or hips. 3. The need for more than two
years of systemic glucocorticoid therapy. Functional outcomes The
functional status of patients with ASD is generally good, even in
the setting of a chronic disease pattern.
Slide 33
TREATMENT Therapeutic decisions should be based upon the extent
and severity of organ system involvement. The principal options for
treatment are: NSAIDs Glucocorticoids Biologic agents DMARDs
Slide 34
NSAIDS Initial therapy with NSAIDs in patients with relatively
mild disease.
Slide 35
GLUCOCORTICOIDS If there is no response to several days of
starting NSAID. Patients with debilitating joint symptoms, or
internal organ involvement should be started on glucocorticoids
from the outset of therapy. Pulse glucocorticoids may be employed
initially in patients with life-threatening manifestations such as:
severe hepatic involvement, cardiac tamponade, disseminated
intravascular coagulation HPS
Slide 36
3BIOLOGICAL AGENTS No response to NSAIDs and glucocorticoids
within two to four weeks. a)ANAKINRA (recombinant human
interleukin-1 receptor antagonist b)RITUXIMAB (monoclonal antibody
) c) TUMOR NECROSIS FACTOR (TNF) inhibitors Experience with TNF
inhibitors remains limited to case reports Promising results have
been reported with etanercept, infliximab and adalimumab 4.DMARDS
when patients have either not responded sufficiently to NSAIDs,
glucocorticoids, or biologic agents METHOTRAXATE (Its most common
role is as a glucocorticoid- sparing agent) CYCLOSPORIN
Slide 37
Slide 38
Adult Onset Stills Disease in Pakistan A number of studies and
cases have been published internationally and also in Pakistan. A
retrospective study was conducted at Agha Khan Hospital Karachi
(1995-2005) to study the clinical characteristics of Stills disease
in a tertiary care hospital of Pakistan and compare it with similar
internationally published studies. 2 2. Abid N, Khalid AB. Adult
onset Stills disease in a tertiary care hospital of Pakistan. J Pak
Med Assoc. 2009 Jul;59(7):464-7. PubMed PMID: 19579736.
Slide 39
Results 13 patients with ASOD were identified. Fever (100%)
Arthralgia, myalgia (100%) Sore throat (53.8%) None of these
patients had rash with fever. Lab patterns were also studied which
were consistent with international data.
Slide 40
Conclusion Clinical characteristics of Stills disease in our
country are mostly similar to those seen in other regions.
Slide 41
Atypical Presentations of Stills Disease Worldwide Different
cases of atypical presentations of Stills disease have been
reported worldwide, of which two are worth mentioning.
Interestingly a case of Fulminant hepatic failure in a patient with
newly diagnosed Stills disease has been recently reported. 3 3.
Nalini Valluru, Venkata S. Tammana, Michael Windham, Eyasu Mekonen,
Rehana Begum, and Andrew Sanderson, Rare Manifestation of a Rare
Disease, Acute Liver Failure in Adult Onset Stills Disease:
Dramatic Response to Methylprednisolone Pulse TherapyA Case Report
and Review, Case Reports in Medicine, vol. 2014, Article ID 375035,
5 pages, 2014. doi:10.1155/2014/375035
Slide 42
A case of an eosinophilic pleural effusion as a novel and
unrecognized manifestation of active Stills disease was reported in
Greece in 2002. 4 4. Katerina M. Antoniou, George A.
Margaritopoulos, Ioannis Giannarakis, et al., Adult Onset Stills
Disease: A Case Report with a Rare Clinical Manifestation and
Pathophysiological Correlations, Case Reports in Medicine, vol.
2013, Article ID 981232, 4 pages, 2013.
doi:10.1155/2013/981232
Slide 43
Case Report A 39-year-old woman was admitted because of a non
itching macular-papular rash. In addition, the patient complained
of arthralgias, myalgias, fever of 38 degrees C, and night sweats.
On admission, a neutrophilic leukocytosis (23.6), An increase in
C-reactive protein (185 mg/l), Ferritin level of 1,740 microg/l
Liver enzymes were raised. Normal radiological and
echocardiographic findings. Repeated blood cultures were negative.
Antibiotic therapy was continued without any improvement.
Slide 44
In addition, acetaminophen and ibuprofen were given. Liver
function worsened and an icterus developed. A working diagnosis of
Still's disease was made. The patient was treated with high-dose
methylprednisone (250 mg/day for 3 days, then 100 mg/day). Liver
biopsy revealed subacute hepatitis with necrosis and accompanying
cholangitis. The prednisone therapy induced a fast remission and
improvement of liver function, liver transplantation was not
necessary. The patient is, 16 months after the incident, without
symptoms under prednisone 3 mg/day, and the liver function is
normal.
Slide 45
Conclusion Still's disease must be considered as part of the
differential diagnosis of acute liver failure, because an early
diagnosis and consequent therapy with prednisone may prevent the
need for liver transplantation.
Slide 46
Stills Disease: A Case Report with a Rare Clinical
Manifestation Pleuritis is the most common pulmonary manifestation,
and pleural effusions are usually exudative with a predominance of
neutrophils. A case of an eosinophilic pleural effusion as a novel
and unrecognized manifestation of active Stills disease was
reported in Greece in 2002.
Slide 47
A 51-year-old woman with a 15 days history of: Chest pain on
the left hemithorax, shortness of breath, evening fever (38.5C),
and diffuse arthralgias. On admission she was febrile (39.2C) and
tachypneic. On physical examination there were findings of left
sided pleural effusion. Laboratory findings included WBC count =
12000 cells, (ESR) = 33 mm/h. Chest radiography revealed left sided
pleural effusion. Empiric treatment with broad spectrum antibiotics
was commenced immediately.
Slide 48
Thoracocentesis revealed an eosinophilic pleural effusion (EPE)
(WBC = 5000, neutrophils = 38%, lymphocytes = 30%, and eosinophils
= 20%). A work up for diagnosis of EPE was undertaken. Blood,
urine, and sputum cultures, stains and cultures of bronchial wash
obtained and tuberculin skin testing were all negative for
infectious causes. CT scan of chest and abdomen, ultrasound of
abdomen, mammography, and FOB ruled out the presence of malignancy.
CT pulmonary angiography was negative for pulmonary embolism but
revealed a mild right pleural effusion as well
Slide 49
Rheumatoid factor, antinuclear antibodies, were negative. On
the fifth day of admission the patient became febrile again
(39.4C). There was no evidence suggestive for a connective tissue
disease.
Slide 50
The most plausible diagnosis based on clinical and laboratory
findings and exclusion of other possible causes of EPE was AOSD
(total 4 Yamaguchis criteria, 3 major). The patient was treated
with corticosteroids. She was discharged afebrile. Reevaluation
after 3 and 6 months showed marked improvement of the radiological
and clinical findings.
Slide 51
Take Home Message! In addition to common causes of PUO, there
are some uncommon causes as well and Adult onset stills disease is
an example in this regard.