24th February 2025

Adult-onset Still’s disease (AOSD)

Overview of AOSD

AOSD can be thought of as being on the same continuum as systemic-JIA. It is a rare, muti-system inflammatory disorder, affecting males and females equally, with a bimodal incidence in the late teens/early 20s and the late 40s/early 50s. The cause is unknown, though there is thought to be a genetic preponderance in patients with certain HLA subtypes. It can be triggered by pregnancy, and the index presentation may occur in the postpartum period. Various infections have also been identified as triggers, including viral (CMV, EBV, Coxsackie) and bacterial (Mycoplasma pneumoniae and Chlamydia pneumonia) infections.

The pathophysiology of the response seen in AOSD is similar to that in RA, being mediated by lymphocytes and a ‘cytokine storm’ thought to involve IFN-ɣ, TNF-ɑ and IL-6, among other markers. The principles of treatment and, indeed, the agents used are similar to those used in RA and systemic-JIA, including in the case of secondary HLH, usually guided by a Rheumatologist. There are three patterns of AOSD, with an approximately equal split: monophasic (a single episode with remission within one year); polycyclic systemic (recurrent flares with periods of remission, typically separated by years); and chronic articular (mainly affecting the joints causing a severe, destructive and disabling arthritis).

Signs and symptoms of AOSD

The clinical features are varied and often non-specific, making the diagnosis a challenge and so requiring a low index of suspicion:

• Fever – sudden-onset daily fevers up to 40℃, typically in the late afternoon/early evening, which settle without antipyretics in a majority of cases. Fever is the most common first symptom.
• Rash – typically a salmon-pink macular or maculopapular rash of the trunk and limbs, appearing whilst febrile and then disappearing. This occurs in around 70% of cases.
• Arthritis – classically mild, oligoarticular and transient but may evolve into a severe, symmetrical polyarthropathy. The wrists, knees and ankles are mainly affected, but the shoulders, elbows, hands and hips may also be involved.
• Pharyngitis – occurs in approximately 70% of cases, particularly if an infective trigger is thought likely.
• Hepatomegaly, splenomegaly and/or lymphadenopathy – occurs in approximately 50% of cases.
• Serositis – in approximately one-third of cases, pleuritis and pericarditis occur, their signs and symptoms adding to the confusing constellations of clinical features possible at presentation.

AOSD has considerable overlap with many other conditions, some of which also have multi-system manifestations, and so, in a similar manner to JIA, AOSD is a diagnosis of exclusion.

Investigation of AOSD

There is no specific diagnostic test for AOSD. Inflammatory markers such as CRP and ESR are often elevated, and there is typically leucocytosis with thrombocytosis and normocytic anaemia. Key to the diagnosis is a grossly elevated ferritin (>1000 ng/ml with a glycosylated fraction <20% giving a 90% specificity). An elevation in bilirubin, transaminases, and lactate dehydrogenase is also common. In cases of secondary HLH (approximately 40% of cases), pancytopaenia and DIC can occur (associated with a drop in ESR, low fibrinogen, high triglycerides and a markedly raised ferritin). This condition has a significant morbidity and mortality and so timely diagnosis is crucial. Gold standard is identifying haemophagocytosis in bone marrow aspirates, but features may also be evident on a blood film.

The Yamaguchi criteria were created from retrospective data and have a 93.5% sensitivity for AOSD. These include signs, symptoms and laboratory investigations. Diagnosis requires five or more criteria (two of which should be major criteria) without any of the exclusion criteria:

Table 3 Yamaguchi criteria for AOSD

X-rays in AOSD show non-specific joint space narrowing without erosions (and ankylosis over time), and so may help diagnostically but will not be as key to making the diagnosis as having a low index of suspicion clinically and requesting the appropriate laboratory investigations (particularly to exclude other conditions and screen for multi-system involvement).

Management of AOSD

NSAIDs are used as antipyretics and as analgesics for arthritic pain. The mainstay of treatment is immunosuppression, first-line being oral corticosteroids and then intravenous methylprednisolone in severe cases. If AOSD is refractory, then DMARDs are initiated, inducing remission in around 70% of cases. Methotrexate, azathioprine, hydroxychloroquine, ciclosporin and tacrolimus are used as corticosteroid-sparing agents. There is evidence for the use of IVIG in refractory cases, during pregnancy and in life-threatening secondary HLH. Biologics such as anakinra (an anti-IL-1𝛃 drug) and tocilizumab (an anti-IL-6 drug) can also be used, though anti-TNF-ɑ drugs such as adalimumab and etanercept have reportedly led to secondary HLH and paradoxical AOSD flares in case reports. The choice of initial agent and, indeed, the decision to escalate agents will depend on disease severity and the degree of organ involvement at that time.

References

• Clunie, G, Wilkinson N, Nikiphorou E, Jadon D. Oxford Handbook of Rheumatology. Fourth Edition. Oxford: Oxford University Press; 2018
• Savic S & Al-Hakim A. Adult-Onset Still’s Disease [Internet]. BMJ Best Practice. BMJ Publishing Group; 2023 [Cited 2023 December 3]. Available from: https://bestpractice.bmj.com/topics/en-gb/3000317