Adult Onset Still’s DiseaseDz

Synonyms: Still disease, Adult-Still’s disease, systemic juvenile idiopathic arthritis (SoJIA), Wissler-Fanconi syndrome, subsepsis hyperallergica.

ICD-9 Code: 714.3
ICD-10 Code:  M06.1

Definition: AOSD is a systemic inflammatory disease that typically afflicts young adults. It is characterized by quotidian fevers, evanescent rashes, and chronic polyarthritis.

Etiology: Unknown. AOSD is the adult continuum of systemic juvenile arthritis (SoJIA) and likely shares a common etioilogy. Both exhibit the same manifestations, clinical course and response to treatment.  However, adults are more likely to complain of a prodromal sore throat, without proof of infection.  Hence,  because of the febrile onset and sore throat, AOSD has infrequently been associated with a variety of viral infections, including rubella, Epstein-Barr virus, Coxsackie B4, and mumps, although no single agent has been proven to inciting or pathogenic. AOSD appears to be an autoinflammatory syndrome as it shares many of the features seen in these disorders of the inate immune response and has been associated with excess production of IL-1 , IL-18 and IL-6.  While some periodic fevers have been linked to tumor necrosis factor (TNF) receptor gene mutations, AOSD has not.

Incidence: AOSD is uncommon. AOSD is the most common autoimmune cause of fever of unknown origin – occuring in 5% to 9% of FUO series. Most major medical centers should see one to two cases per year.

Demographics: Usual onset age is between 16 and 35 years (~75% of cases), with 10% presenting after age 50 years. Males and females are equally affected. AOSD has been reported worldwide, affecting all races and ethnic groups.

Cardinal Findings: Onset is often heralded by a prodromal sore throat (70%). Symptoms progress within 1 to 3 weeks. Nearly 90% of patients have the triad of quotidian fevers, evanescent rash, and arthritis. Quotidian (spiking, daily) fevers must be over 102° F, may be as high as 105°F and usually recur at the same time each day, usually late afternoon (3–6 PM) or late night (11 PM–2 AM).  The evanescent rash is faintly erythematous or salmon pink, maculopapular, and most evident with febrile episodes. It commonly appears on the trunk, neck, or extremities and may be associated with dermatographism, Koebner phenomenon (lesions arising at sites of trauma/pressure), pruritus, or urticaria. Fixed dermal plaques have been rarely described. Facial or palmar or plantar rashes are not part of the AOSD syndrome. Arthritis tends to predominate with time and behaves like rheumatoid arthritis, being polyarticular and involving the wrist, knee, ankle, and small joints of the fingers. As many as 25% of patients develop a chronic destructive polyarthritis. Other prominent manifestations (seen in >50% of patients) include myalgias, carpal ankylosis, weight loss (> 10% body weight), lymphadenopathy, hepatomegaly, splenomegaly, pleuritis and pericarditis.

Complications:  Growth disturbances in are seldom seen children and mostly those requiring  chronic steroid therapy. Chronic polyarthritis and/or erosive arthritis in 25-30% and is usually a prime determinant of long-term functional outcome.  The rare, macrophage activation syndrome is seen in a minority of SoJIA and AOSD patients. MAS may occur in the setting of many conditions including infection, malignancy or autoimmune conditions.  Such patients become acutely ill with very high fevers, hyperferritinemia, rapidly developing cytopenias and DIC.

Diagnostic Tests: No test is diagnostic. Patients with AOSD should be seronegative for rheumatoid factor (RF) and antinuclear antibody (ANA). Neutrophilic leukocytosis (WBC > 12.5), thrombocytosis, markedly elevated ESR (50% are >90 mm/hr and 90% are > 50 mm/hr) or C-reactive protein levels (> 2.0 mg/dl).  Frequently a dramatic drop in serum albumin will parallel a dramatic drop in hematocrit and weight loss.  Thus, hypoalbuminemia, elevated hepatic enzymes (primarily transaminases), and aldolase  elevations are seen in 60-75% of patients during active inflammatory phase of the disease.   Increased ferritin (another acute phase reactant) levels are half as common as elevations in ESR or CRP.  Nevertheless,  ferritin levels  >1,000 ng/mL are seen in 50% of patients, and very high levels (as high as 30,000 ng/mL) are occasionally seen.  Although radiographs are nondiagnostic, 50% of Still’s patients develop a distinctive pattern of pericapitate carpal ankylosis as they develop chronic polyarthritis over time.

Diagnostic Keys: This is a clinical diagnosis of exclusion. The evanescent rash and circadian fever (>102°F) that lasts weeks to months may be the most distinctive features of AOSD.

Diagnostic Criteria:  The diagnosis can be supported by the Yamaguchi criteria or the Cush criteria.   According to the Cush criteria (see table), a “Probable AOSD” diagnosis requires >10 points and 12-week disease/symptom duration.  A “Definite AOSD” diagnosis requires >10 points and > 6 month disease/symptom duration.

Differential Diagnosis: Acute viral infection (e.g., Epstein-Barr virus, rubella), dermatomyositis (DM),  reactive arthritis, inflammatory bowel disease, acute leukemias, and lymphoma are often mistaken for AOSD.  Less common possibilities include bacterial endocarditis, sarcoidosis, Sweet’s syndrome, tuberculosis, and granulomatous hepatitis.  Other forms of periodic fever and autoinflammatory syndromes may also mimic AOSD or SoJIA – these include Schnitzler syndrome, Muckle-Wells syndrome, Familial Mediterranean fever, TNF receptor–associated periodic syndrome (TRAPS), PAPA syndrome, PFAPA (Marshall) syndrome and hyper-IgD syndrome.

Therapy: Initially, NSAID therapy at antiinflammatory doses (e.g., naproxen 500 mg tid) can be used. Sustained-release indomethacin (75–225 mg/day) is effective in up to half of patients. Aspirin is seldom effective. Corticosteroids are often employed early during the inflammatory phase of the disorder and is especially indicated with daily fevers >104° F, markedly elevated hepatic enzymes, pleuritis, pericarditis, pericardial tamponade, pneumonitis and those resistant to NSAIDs. High-dose prednisone (40–80 mg/day) is necessary to control the systemic manifestations. Although oral DMARD therapy with methotrexate (MTX) (15–25 mg/wk), hydroxychloroquine, azathioprine, or cyclosporine. has been used to limit steroid exposure, most patients with systemic disease (fever, serositis, rash, etc) should be put on an IL-1 inhibitor (anakinra) or an IL-6 inhibitor (tocilizumab) as brisk responses are common and possibly diagnostic.  Anakinra has a short half-life (6 hrs) and should be given nightly as the circadian spike in IL-1 is usually after midnight. Patients who are partially controlled with anakinra 100 mg qhs may benefit from higher doses of 200 mg qhs. If tocilizumab (anti–IL-6 receptor antibody) is used, the doses are different than that used in rheumatoid arthritis. In AOSD and SoJIA patients with active systemic disease the usual dose of tocilizumab is 8 mg/kg/day and is given every 2 weeks for 8-12 weeks and then give 8 mg/kg every 4 weeks.  Children less than 30 kg may be dosed higher at 12 mg/kg/day using the same frequency of delivery. TNF inhibitor use should not be considered in those with active systemic disease but may be very effective in treating the chronic polyarthritis AOSD or SoJIA. Antecdotal use of colchicine, IVIG, abatacept, rituximab and the TNF inhibitors has been limited to refractory cases.  Cyclosporine should be promptly used in patients with the macrophage activation syndrome.

Prognosis: Flares of systemic disease may last from 6 to 24 months. In most, the clinical course displays either intermittent bouts of systemic disease or chronic arthritis (less than one-third). Death is uncommon (9% of cases) and results from complications of therapy (usually corticosteroids), pericardial tamponade, hepatic failure, or disseminated intravascular coagulation.

BIBLIOGRAPHY

Cush JJ. Adult onset Still’s disease. Bull Rheum Dis 2000;49:1–4. PMID: 11100625 

Cush JJ, Medsger TA, Christy WA, et al. Adult-onset Still’s disease: clinical course and outcome. Arthritis Rheum 1987;30:186–194.  PMID: 3827959 

De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2385-95. PMID: 23252525

Cush JJ. Autoinflammatory syndromes.  Dermatol Clin. 2013;31:471-80. PMID: 23827249