Approach

​There are currently no internationally agreed guidelines for the treatment of adult-onset Still disease (AOSD). The German Society of Rheumatology published a guideline for diagnosis and treatment of AOSD in 2022.[2]​ Both this guideline and published expert recommendations suggest a stepwise approach, depending on the disease course and response to treatment. The overall aims of treatment are to:[4]

  • Achieve clinical and biochemical remission of the disease. This should include resolution of symptoms (e.g., fevers, rash, and joint pains) in addition to normalization of the markers of disease activity (e.g., C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], and ferritin).

  • Prevent organ damage and serious complications such as macrophage activation syndrome (MAS).

Treatment depends on clinical context.

  • For patients with AOSD who are being investigated and managed in the outpatient setting, take a stepwise approach from corticosteroids to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and newer biologic agents depending on response.[6]​ If the patient responds well to corticosteroids but symptoms persist or recur when corticosteroid therapy is tapered, aim to add a second therapy as a corticosteroid-sparing agent.[73]

  • For those in extremis (e.g., in ICU) specialist opinion and more rapid use of biologic agents may be required.[2][4][6]

Initial management

Nonsteroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief

Offer NSAIDs to provide temporary symptomatic relief.[1]​​[2][4]​​[74]

  • High-dose indomethacin or ibuprofen have been shown to be effective in managing inflammatory symptoms in some patients. Overall, however, NSAIDs are often ineffective in people with AOSD with a high rate of adverse events reported.[1]​​[74]

  • Even in patients who benefit, avoid prolonged use of NSAIDs due to the risk of gastrointestinal bleeding and renal impairment, particularly in older patients.[74]

  • NSAIDs may increase the risk of cardiovascular thrombotic events and serious gastrointestinal events.

Note that NSAIDs can be used for short-term symptomatic relief at any stage of treatment for AOSD.[2]

Assess disease activity to determine the need for additional treatment. Base your assessment on a combination of:[2]

  • Clinical symptoms and signs (e.g., arthritis, fever, organ involvement)

  • Laboratory results (serum ferritin, CRP, ESR).

Systemic corticosteroids

Treat patients who are diagnosed with AOSD and experiencing active disease with systemic corticosteroids as the first-line therapy.[2] Coprescribe gastrointestinal protection (proton-pump inhibitor) and bone protection (calcium and vitamin D) according to your local protocols.

  • The condition should be highly responsive to corticosteroids, with significant clinical and biochemical improvement typically occurring within a few days.[1][36] The rate of effectiveness for corticosteroids has been reported at between 38% and 95% in different studies.[2]

  • Studies have shown that higher initial doses of prednisone provide quicker clinical resolution and reduce the risk of disease relapse.[36][75]​​

  • Intravenous pulse-dose corticosteroids are often administered if there is severe visceral (organ) involvement or MAS.[1]​​[4]​​[5][36]

Though corticosteroids provide rapid and sustained improvement in both articular and systemic AOSD, aim to avoid prolonged therapy due to the risk of adverse effects. These include diabetes, hypertension, osteoporosis, weight gain, and Cushing syndrome.[74]

  • If resolution of symptoms and biochemical markers is achieved, aim to slowly taper the corticosteroid dose after 4-6 weeks.[1] It is important to taper the dose slowly as quick reductions can lead to disease relapse.

    • For successfully treated patients, aim to slowly taper the corticosteroid dose to cessation before eventually trialing a period off other therapies to assess for clinical remission.

  • If inflammation persists despite corticosteroid therapy or relapse occurs following the corticosteroid taper, add a corticosteroid-sparing agent (see Second-line therapies below for more details).

AOSD can be monophasic and therefore treatment with corticosteroids may be all that is required to manage patients with the disease.

  • However, up to 45% of patients become corticosteroid dependent and require second-line therapy with corticosteroid-sparing agents (i.e., conventional synthetic DMARDs and/or biologic agents).[24]​​[36]

Second-line therapies

Conventional synthetic disease-modifying antirheumatic drugs (DMARDs)

In patients who are corticosteroid dependent or who relapse when the corticosteroid dose is tapered, conventional synthetic DMARDs are the usual second-line treatment used as corticosteroid-sparing therapy, enabling a tapering of the corticosteroid dose.[2][4][73]

Start patients on methotrexate.[4]

  • In one study of 26 patients with AOSD, methotrexate allowed 69% of participants to attain complete remission and 39% to discontinue corticosteroids.[76]

  • Although patients with AOSD can often have deranged liver enzymes, methotrexate can still be prescribed in these instances but ensure close monitoring of transaminases.[77]

Although other conventional synthetic DMARDs - such as cyclosporine, azathioprine, leflunomide, and hydroxychloroquine - may be considered, there is as yet little evidence for their benefits in patients with AOSD.[1][73][78][79]

Biologic agents for refractory AOSD

Around 17% to 32% of patients do not respond to high-dose corticosteroids and conventional synthetic DMARDs, a condition termed refractory AOSD.[4][78][80]​ Biologic agents are the next step in management for this group.

Consider the use of IL-1 inhibitors (e.g., anakinra, canakinumab) or IL-6 inhibitors (e.g., tocilizumab) in patients with refractory AOSD.[1][4][78]

  • Anakinra, canakinumab, and tocilizumab have generally been shown to be highly effective for refractory AOSD, often with rapid and sustained clinical and biochemical responses. These medications have favorable safety profiles and significant numbers of patients achieve clinical remission and/or significant corticosteroid dose reductions.[81][82][83][84][85]

  • The choice between anakinra, canakinumab, and tocilizumab depends on local experience and availability and it is possible to switch from one to another if the first option chosen does not work well. Check your local guidelines.

Tumor necrosis factor (TNF)-alpha inhibitors (e.g., infliximab or adalimumab) have been shown to achieve clinical remission, though at a lower rate than the alternatives.[4] Consider these only after at least one interleukin inhibitor has been tried without success, particularly if the patient has a chronic articular pattern of disease.​[80][83][86]​​

Anakinra and canakinumab are licensed in Europe for people with AOSD, whereas only canakinumab is currently licensed for AOSD in the US. Other biologics are used off-label.

The conventional synthetic DMARD is usually continued alongside the biologic agent, although occasionally it may need to be stopped owing to adverse effects.

Request rapid specialist input for any patient in extremis (e.g., those in ICU or experiencing the serious complication of MAS).

  • Intravenous systemic corticosteroids and immediate use of biologic agents may be required to achieve disease control.

Early use of biologic agents for high disease activity

Consider using a biologic, particularly an IL-1 inhibitor, as the preferred initial corticosteroid-sparing therapy for any patient whose clinical symptoms/signs and laboratory results show high disease activity.[2][4][6]​​​

  • Assess disease activity based on a combination of:[2]

    • Clinical symptoms and signs (e.g., arthritis, fever, organ involvement)

    • Laboratory results (serum ferritin, CRP, ESR)

  • Anakinra and canakinumab are increasingly preferred to conventional synthetic DMARDs as second-line therapy (after corticosteroids) in patients with moderately or highly active disease. It is likely this approach will become standard in future, depending on availability and local protocols. Check your local guidelines.

    • Most evidence for the use of biologic agents in AOSD has come from studies in patients who are resistant to conventional synthetic DMARDs although cohort studies have shown that anakinra is also effective as a treatment option prior to the use of conventional immunosuppressants.[2]

It is likely that over time biologic agents will replace conventional synthetic DMARDs as the preferred second-line agents for all patients with AOSD.[74]

  • Biologic agents have fewer severe adverse effects than methotrexate and achieve a more rapid clinical response, enabling patients to reduce their dependence on corticosteroids.[2][5]​​

Complications of AOSD

Serious and potentially life-threatening complications of AOSD can occur as a first presentation or at a later stage in management. Macrophage activation syndrome (MAS) is the most significant of these although patients can also present with life-threatening or organ-threatening visceral involvement without MAS.[1][4][5][6]

Be aware that MAS and other complications of AOSD have their own treatment protocols and require specialist management.[4] 

Always evaluate the possibility of MAS if the patient has risk factors for this serious complication.[2]

  • Key risk factors for MAS include high clinical disease activity, and laboratory markers such as high serum ferritin, cytopenia (particularly leukopenia), and elevated triglyceride levels.[2]

  • MAS has been reported to affect up to 15% of people with AOSD and it has a high mortality rate.[4]

Other serious complications of AOSD include:[2]

  • Perimyocardial disease such as pericarditis, pericardial effusion, and cardiomyopathy

  • Interstitial lung disease

  • AA amyloidosis. This is a rare complication but important to exclude in patients with persistently active AOSD.

Intravenous pulse-dose corticosteroid treatment (e.g., methylprednisolone) is often administered to patients who have significant organ dysfunction or MAS, transitioning to an oral corticosteroid after a few days.[1][4][5][36]​​ The clinical response is usually very rapid.[4]

Early use of biological agents may also be needed.[2][4][6]​​ An IL-1 inhibitor is recommended as an add-on to corticosteroid therapy in AOSD-related MAS that fails to respond to corticosteroid therapy alone, with the strongest evidence supporting the use of anakinra.[87][88][89][90]

In patients who have organ involvement without MAS, an IL-1 inhibitor or an IL-6 inhibitor is often used, with the choice between anakinra, canakinumab, and tocilizumab depending on local experience and availability.[3][4]​ It is possible to switch from one to another if the first option chosen does not work well. Check your local guidelines.​​

Monitoring on therapy

Ensure ongoing monitoring under specialist care, which should include regular clinical assessment of bloods including CBC, CRP, ESR, eGFR, transaminases, ferritin, and coagulation tests.[91]

There are a number of scoring systems that are in clinical use and that can help with disease monitoring. Examples include Pouchot score, adapted American College of Rheumatology (ACR) response criteria, and the more recently proposed Still activity score.[92][93] The choice of scoring system depends on local preference and expertise. With further research, it is hoped that one universal scoring system for disease activity will be adopted.

Specific monitoring is required for drugs used to manage AOSD; consult your local drug formulary for more information.

Discontinuing therapy

AOSD can be monocyclic (19% to 44%), recurrent/polycyclic (10% to 41%), or chronic and progressive (35% to 67%).[91]

  • Both monocyclic and polycyclic courses involve flares of symptoms and possibly years of subsequent clinical remission.

  • Therefore, once good clinical control is achieved, tapering and discontinuation of treatment is an appropriate aim although there is not yet any standardized protocol or consensus on how this should be done.[91] 

  • Ensure patients are managed under specialist care if possible and aim to slowly taper corticosteroids to cessation, followed thereafter by trials of conventional synthetic DMARDs and biologic agents.

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