Adult-Onset Still's Disease

What it is. Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder of the innate immune system, the adult counterpart of systemic juvenile idiopathic arthritis, and typically affects young adults. It is driven by the IL-1 beta/IL-18 and IL-6 cytokine axis. IL-18 (and IL-1) reflect inflammasome activation and disease activity, correlating with the Pouchot score, ferritin and CRP.

The classic tetrad. A very high ferritin in a febrile young adult should raise AOSD. The four features are:

• A daily (quotidian) spiking fever
• An evanescent salmon-pink macular rash, classically appearing with the evening fever spikes and fading between them
• Arthralgia or arthritis
• A markedly high serum ferritin, with a characteristically low glycosylated fraction

Supporting features. Sore throat, lymphadenopathy, hepatosplenomegaly, serositis and a neutrophilic leucocytosis complete the picture. ANA and rheumatoid factor are negative, and that seronegativity is a useful clue distinguishing AOSD from rheumatoid arthritis and lupus.

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A diagnosis of exclusion. Before settling on AOSD, rule out the serious mimics of a febrile young adult with a high ferritin: sepsis, malignancy (especially lymphoma) and other connective-tissue disease. The seronegativity and the very high ferritin with a low glycosylated fraction support the diagnosis, but they do not replace excluding infection and cancer.

The price is time. The median time to diagnosis was 4 months in one cohort of 57 patients. That is the cost of excluding sepsis and lymphoma first, and is why a patient may arrive already months into an undiagnosed febrile illness.

The Yamaguchi rule. Diagnosis needs at least 5 criteria, at least 2 of them major, and the exclusions must be satisfied.

The exclusions are infection (especially sepsis and EBV), malignancy (especially lymphoma) and other rheumatic disease (especially vasculitis).

The Fautrel alternative. This set adds a glycosylated ferritin fraction of 20% or less as a major criterion. Its other major items are fever of at least 39°C, arthralgia, transient erythema, pharyngitis and granulocytes of at least 80%; the minor items are a maculopapular rash and leucocytosis. It does not require exclusions and is more specific.

Grading activity. The Pouchot (systemic) score grades disease activity, giving roughly one point each for a list of systemic manifestations (fever, rash, serositis, organomegaly, leucocytosis, sore throat and so on). It correlates with ferritin and cytokine levels.

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The course is monocyclic, polycyclic (relapsing) or chronic articular. Naming the three is only half an answer. For an orthopaedic surgeon the question is which patients end up in the chronic articular group, because those are the only ones who reach an orthopaedic clinic, and it is a minority.

How the courses divide. Two retrospective cohorts give similar splits:

The destructive arthritis that gives the disease its orthopaedic relevance therefore affects about one patient in four to five. Most patients' disease is systemic and episodic rather than joint-destroying.

What predicts which course. In the 57-patient cohort a fever above 39.5 degrees predicted a monocyclic course, arthritis at presentation was associated with the chronic course, and thrombocytopenia with complicated disease. The loudest systemic presentation tends to burn out, while the patient whose joints are involved early is the one who goes on to chronic articular disease. Corticosteroid dependence occurred in 23 patients (45 percent) and was predicted by a low glycosylated ferritin, and the youngest patients had the highest risk of failing first-line treatment. These come from a single retrospective centre and are associations, not a validated prediction rule.

Ferritin. Ferritin was raised in 91 percent of the 82-patient cohort and tracks disease activity, but no validated absolute cut-off defines the diagnosis.

Complications and mortality. Macrophage activation syndrome is not a theoretical footnote: reactive haemophagocytic syndrome occurred in 8 of 57 patients (about 14 percent), with complications overall in 19. Mortality, by contrast, was low, with 3 deaths, none attributable to the disease itself.

What it is. Macrophage activation syndrome (MAS) is a secondary haemophagocytic lymphohistiocytosis complicating AOSD, a hyperferritinaemic cytokine storm. It is the feared complication: life-threatening, rapidly fatal if unrecognised, and a medical emergency.

The paradoxes. Suspect MAS when the inflammatory picture changes direction, in a patient whose ferritin soars further:

• New cytopenias (falling WBC, platelets and Hb), the opposite of the leucocytosis of AOSD
• A paradoxically falling ESR with a falling fibrinogen
• Rising triglycerides
• A soaring ferritin, often over 10,000
• Rising transaminases and LDH
• Hepatosplenomegaly, and coagulopathy or DIC
• Organ dysfunction

Confirming it. Haemophagocytosis may be seen on bone marrow, and soluble CD25 (IL-2 receptor) and sCD163 are raised. The HScore (reactive-haemophagocytosis score) and the 2016 EULAR/ACR MAS criteria help formalise the diagnosis.

Treatment. MAS needs urgent intensive treatment: high-dose corticosteroids (pulse methylprednisolone) with anakinra (IL-1 blockade), with or without ciclosporin, and etoposide for refractory or severe disease, plus intensive supportive care.

The orthopaedic footprint. The chronic articular form can cause a destructive arthritis. The classic pattern is a non-erosive-to-erosive carpal arthritis progressing to carpal/wrist ankylosis, a recognised Still's pattern, and hip or knee involvement sometimes needs arthroplasty.

Medical management is the mainstay. The ladder:

• NSAIDs for mild disease
• Corticosteroids for systemic flares
• Methotrexate as a steroid-sparing DMARD
• Increasingly, IL-1 (anakinra, canakinumab) and IL-6 (tocilizumab) biologics for refractory or chronic disease and for MAS

Around surgery. Any joint surgery is undertaken with the rheumatology team, optimising disease control and managing immunosuppression and steroids around the procedure.