Adult-onset Still disease (ORPHA:829)
A rare inflammatory multisystem disorder characterized clinically by four cardinal signs: fever of unknown origin, arthralgia or arthritis, hyperleucocytosis, and typical skin rash.
Epidemiology
Prevalence and incidence data are difficult to determine given the broad, non-specific clinical presentation of adult-onset Still disease (AOSD). The estimated prevalence of AOSD is more than 1/100,000 population. There is a slightly higher number of affected women than affected men.
Clinical description
AOSD primarily affects young adults, although older patients have been reported. The presenting features are variable and may include high fever (>39°C) with daily spikes, sore throat or pharyngitis, arthralgia or arthritis (>65% of patients), transient maculopapular rash, and more rarely myalgia, lymphadenopathy, hepatosplenomegaly, and serositis. Arthritis may involve any joint and can migrate in early disease and then stabilize with time. Arthralgia is usually correlated with fever spikes. Rash mostly consists of transient, small, discrete, salmon-pink, non-pruritic macules or maculopapules that often occur concomitantly with fever and generally spare the face, palms and soles of the feet. Pleuritis or pericarditis are commonly found. Patients may lose weight and have a generally poor overall health status. Three different disease courses have been described: self-limited, systemic course with a single flare and complete remission within 2 to 4 weeks, intermittent course with recurrence of systemic or articular flares after remission of 2 weeks to 2years, and a primarily articular chronic course (with erosions in a 1/3 patients). Some affected individuals have a history of systemic juvenile idiopathic arthritis.
Etiology
The etiology of AOSD and its underlying pathogenetic mechanisms are not known. No risk factors for the disease have been identified so far, but environmental factors are suspected. Several infectious conditions have been reported to be associated with onset of the disease (e.g. Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, Coxsackie virus, hepatitis A, B, and C viruses, and Mycoplasma pneumoniae).
Diagnostic methods
The non-specific clinical features of AOSD make diagnosis difficult. No serological marker is currently available. AOSD is a diagnosis of exclusion. Two sets of classification criteria, Yamaguchi and Fautrel, exist. Major diagnostic criteria include arthralgia for more than 2 weeks, intermittent high fever for more than 1 week, characteristic rash, and white blood cell count above 10,000. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, abnormal liver function tests, and negative rheumatoid factor and ANA. Elevated ferritin is often found and may assist in diagnosis, especially if it is associated with a low level of glycosylated ferritin.
Differential diagnosis
Many other inflammatory, neoplastic, and infectious conditions with a similar presentation must be ruled out in order to diagnose AOSD. Differential diagnoses include infections (endocarditis, occult infections, secondary syphilis, viral rash), malignancies (lymphoma) or autoimmune diseases (such as polyarteritis nodosa, vasculitis, or polymyositis).
Genetic counseling
AOSD is a sporadic non-inheritable disease and genetic counseling is therefore not needed.
Management and treatment
The aim is to achieve complete remission and prevent joint damage through treatment. Treatment-free remission is possible but the risk of relapse remains present throughout life Multidisciplinary rounds in contact with a reference center are highly recommended. The mainstay of first-line treatment is prednisone, and most guidelines tend to recommend an early association with biologic therapies (anti-IL1 agents (anakinra, canakinumab), and anti-IL-6 agents (tocilizumab)), in order to allow a rapid tapering of prednisone and hence prevent steroid-induced complications. Methotrexate and tumor necrosis factor blockers may be used in chronic articular forms, but have limited efficacy in systemic forms. Regular clinical and biological monitoring (initially tight) is necessary.
Prognosis
The overall prognosis is generally good, but acute life-threatening manifestations may occur in rare cases. The most classical complication is macrophage activation syndrome but blood coagulation disorders, fulminant hepatitis, cardiac and pulmonary complications may occur. Some patients with chronic disease and major joint involvement may have significantly altered quality of life, but this tends to disappear thanks to a better and earlier management with biologics.

                            Last update: 
                            October 2019


                            - Expert reviewer(s): 
                            Pr Bruno FAUTREL  - Dr Stéphane MITROVIC