Adult-Onset Still’s Disease

Janaki Patel, M.D.

Basic Information

Definition

Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder of unknown etiology. It is characterized mainly by daily high spiking fevers greater than 102° F, arthritis or arthralgias, and an evanescent salmon-colored skin rash, with an elevated serum ferritin. The temperature returns to normal between fever spikes and is usually the initial manifestation. Musculoskeletal symptoms are universal and eventually progress to destructive arthropathy, which is most commonly located in the knees, wrists, and ankles. As this is a systemic condition, there is a large variety of symptom presentations in affected individuals.

Synonyms

Adult Still’s disease
Wissler’s syndrome
Wissler-Fanconi syndrome
AOSD

ICD-10CM CODES
M06.1	Adult-onset Still disease

Epidemiology & Demographics

Incidence

22/10,000,000 in men, 34/10,000,000 in women

Peak Incidence

Age 16 to 35

Prevalence

1.5 cases per 100,000 to 1,000,000 population

Predominant Sex and Age

Roughly equal sex distribution, bimodal age range 15 to 25 and 36 to 46

Genetics

Relative risk ranging from 2.1 to 2.9 associated with HLA B17, B18, B35, and DR2. Cytokine production is thought to be implicated in the pathogenesis: IL6, IL2, interferon gamma, and tumor necrosis factor alpha (TNF-α)

Risk Factors

Infectious triggers have been suggested, and suspected bacterial pathogens include Yersinia enterocolitica and Mycoplasma pneumoniae.

Physical Findings & Clinical Presentation

•

Triad (occurring in 75%-95% of patients): High spiking fevers, characteristic rash, and arthritis/arthralgias.
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Fever is >102° F, transient, quotidian in pattern, usually in the late afternoon/early evening.
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Rash is typically evanescent, salmon pink, and maculopapular. It is usually located on the trunk and proximal extremities, but it can involve the palms and soles (and occasionally the face). The rash often accompanies fever and resolves when the patient is afebrile.
•

Arthritis is symmetric and destructive, involving the wrists, knees, and ankles. Fusion of the wrist joints is characteristic of AOSD.
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Nonspecific symptoms: pharyngitis, myalgias, lymphadenopathy, splenomegaly, and serositis, including pleuritis and pericarditis.

Etiology

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None identified, but genetic factors and infectious triggers have been proposed

Diagnosis

Differential Diagnosis

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Infection, malignancy, or autoimmune disorders
1. 1.
  
  Infection: Hepatitis, rubella, CMV, EBV, mumps, coxsackie virus, adenovirus
2. 2.
  
  Neoplasms: Leukemia, lymphoma, angioblastic T cell lymphoma, solid cancers, myeloproliferative disorders
3. 3.
  
  Autoinflammatory: Schnitzler syndrome, Sweet syndrome, sarcoid, hemophagocytic lymphohistiocytosis
4. 4.
  
  Rheumatologic: Rheumatoid arthritis, reactive arthritis, systemic lupus erythematosus, dermatomyositis/polymyositis, periarteritis nodosa (PAN)
5. 5.
  
  Periodic fever syndromes: Familial Mediterranean fever (FMF), TNF receptor–associated periodic syndrome (TRAPS)

Diagnostic Criteria

This is a diagnosis of exclusion made only in the absence of other clinical conditions that present in a similar fashion.

Multiple potential diagnostic criteria have been proposed in the evaluation of patients suspected of having adult-onset Still’s disease. The Yamaguchi criteria are the most widely used and have 93.5% sensitivity.

Yamaguchi criteria:

Major Criteria

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Arthralgia >2 weeks
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Fever >102.2° F; >1 week
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Nonpruritic salmon rash
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WBC >10,000 with 80% granulocytes

Minor Criteria

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Sore throat
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Lymphadenopathy
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Hepatomegaly/splenomegaly
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LFT abnormalities
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Negative ANA and RF

Exclusion criteria: infections, malignancies, and rheumatic diseases

Diagnosis: 5 criteria with at least 2 major criteria

Laboratory Tests

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CBC generally demonstrates leukocytosis with a predominance of polymorphonuclear leukocytes.
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ANA and RF results are usually within normal levels in AOSD, whereas ESR/CRP are often markedly elevated in virtually all patients.
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ALT/AST and LDH are elevated in at least 75% of patients.
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Ferritin can be markedly elevated beyond the level expected for a typical inflammatory process (as much as 70% of patients).
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Normocytic anemia with hemoglobin <10 g/dl and reactive thrombocytosis.

Imaging Studies

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Radiographs are not helpful at early onset of symptoms; helpful if chronic.
1. •
  
  Early changes could show soft tissue swelling, joint effusions, and/or periarticular osteopenia.
2. •
  
  Classic finding is nonerosive narrowing of carpometacarpal (CMC) and intercarpal joint space of wrist. This can eventually lead to ankylosis.
3. •
  
  X-ray findings are seen in only 40% of patients, however.
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Radionuclide bone scan and MRI with gadolinium may be helpful for early diagnosis.

Treatment

Acute General Rx

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Aspirin and NSAIDs at full doses are used initially to control arthritic symptoms.
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Systemic glucocorticoids are often required to control systemic inflammation in more severe disease.

Chronic Rx

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In patients with persistent symptoms, steroid-sparing immunomodulatory agents are often required.
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Oral or injectable methotrexate is often added to control chronic disease, specifically the arthritis symptoms.
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TNF-inhibitors including etanercept and infliximab can be effective at controlling symptoms.
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Anti-IL6 (tocilizumab) and anti-IL1 (anakinra) may also be effective in controlling disease activity.

Disposition

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Three distinct patterns of clinical course:
1. 1.
  
  Self-limited/monocyclic pattern: systemic symptoms of fever, rash, serositis, hepatosplenomegaly predominate for a few weeks to months; remission in 1 year
2. 2.
  
  Intermittent/polycyclic pattern: recurrent fevers with or without articular symptoms lasting from a few weeks up to 2 years; may have complete remission between flares that could be years apart
3. 3.
  
  Chronic articular pattern: severe articular presentation leading to joint destruction; more disability, worst prognosis

Referral

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Rheumatology for diagnosis and treatment
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Dermatology for evaluation and possible biopsy of rash

Pearls & Considerations

Comments

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AOSD is a diagnosis of exclusion.
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Evanescent rash often dissipates when the patient is afebrile; it is therefore important to do a skin exam while the patient is febrile.
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Suspect AOSD when ferritin levels >3000 ng/ml in clinical context when bacterial and viral infections are excluded.

Ferri – Adult-Onset Still’s Disease