Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

severe disease: with severe organ dysfunction with or without signs of macrophage activation syndrome

1st line – specialist management

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ACUTE
|
severe disease: with severe organ dysfunction with or without signs of macrophage activation syndrome
1st line – 

specialist management

In some patients, the first presentation of adult-onset Still disease (AOSD) is with a serious and potentially life-threatening complication. 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, including for consideration of the need for escalation to critical care. This is regardless of whether they occur as a first presentation or a later complication.

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 and cytopenia (particularly leukopenia).[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.

Consider – intravenous corticosteroid

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ACUTE
|
severe disease: with severe organ dysfunction with or without signs of macrophage activation syndrome
Consider – 

intravenous corticosteroid

Treatment recommended for SOME patients in selected patient group

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

Primary options

methylprednisolone sodium succinate: 0.5 to 1 g intravenously once daily for 3 days, followed by oral prednisone course

and

prednisone: 40-60 mg orally once daily, following the completion of 3-day methylprednisolone course

Consider – biologic agent

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ACUTE
|
severe disease: with severe organ dysfunction with or without signs of macrophage activation syndrome
Consider – 

biologic agent

Treatment recommended for SOME patients in selected patient group

Early use of biologic agents may be needed in patients with life-threatening or organ-threatening disease.[2]​​[4][6]

An IL-1 inhibitor is recommended as an add-on 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]​ Be aware that MAS has a specific treatment protocol and requires specialist management, including potential need for escalation to critical care.

In patients who have organ involvement without MAS, an IL-1 inhibitor or an IL-6 inhibitor (e.g., tocilizumab) 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.

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]

  • 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 doses used for these patients may be higher than the licensed dose for this indication, and a specialist should be consulted for guidance on the most appropriate dose.

  • Most evidence for the use of biologic agents in people with 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 use of conventional immunosuppressants.[2]

Biologic agents are associated with serious infections and malignancy. They are contraindicated in patients with active infections. Use caution in patients at risk of chronic or recurrent infections or malignancy. Screen for tuberculosis before treatment.

Primary options

anakinra: consult specialist for guidance on dose

OR

canakinumab: consult specialist for guidance on dose

OR

tocilizumab: consult specialist for guidance on dose

Consider – nonsteroidal anti-inflammatory drug (NSAID)

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ACUTE
|
severe disease: with severe organ dysfunction with or without signs of macrophage activation syndrome
Consider – 

nonsteroidal anti-inflammatory drug (NSAID)

Treatment recommended for SOME patients in selected patient group

Offer an NSAID to provide temporary symptomatic relief as required.[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.

  • Use the lowest effective dose for the shortest effective treatment duration.

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

Primary options

indomethacin: 25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day

OR

ibuprofen: 300-800 mg orally three to four times daily, maximum 3200 mg/day

ONGOING

mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome

1st line – oral corticosteroid

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ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
1st line – 

oral corticosteroid

Treat patients who are diagnosed with AOSD and experiencing active disease with systemic corticosteroids as the first-line therapy.[2]

  • 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]​​

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 to 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.

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 disease-modifying antirheumatic drugs and/or biologic agents).[24][36]

Coprescribe gastrointestinal protection (proton-pump inhibitor) and bone protection (calcium and vitamin D) according to your local protocols.

Primary options

prednisone: 0.5 to 1 mg/kg/day orally initially, adjust dose according to response and gradually taper after 4-6 weeks

Consider – nonsteroidal anti-inflammatory drug (NSAID)

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ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
Consider – 

nonsteroidal anti-inflammatory drug (NSAID)

Treatment recommended for SOME patients in selected patient group

Offer an NSAID to provide temporary symptomatic relief as required.[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.

  • Use the lowest effective dose for the shortest effective treatment duration.

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

Primary options

indomethacin: 25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day

OR

ibuprofen: 300-800 mg orally three to four times daily, maximum 3200 mg/day

2nd line – conventional synthetic disease-modifying antirheumatic drug (DMARD)

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ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
2nd line – 

conventional synthetic disease-modifying antirheumatic drug (DMARD)

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

Start patients on methotrexate.[4]

  • 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]

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

  • Methotrexate can cause hepatotoxicity, pulmonary toxicity, gastrointestinal toxicity, and malignancy. Myelosuppression, aplastic anemia, and gastrointestinal toxicity have been reported when methotrexate is used in combination with some NSAIDs (particularly at high doses).

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]​​

Primary options

methotrexate: 7.5 to 25 mg orally/subcutaneously/intramuscularly once weekly on the same day of each week

Secondary options

cyclosporine modified: consult specialist for guidance on dose

Tertiary options

azathioprine: consult specialist for guidance on dose

OR

leflunomide: consult specialist for guidance on dose

OR

hydroxychloroquine sulfate: consult specialist for guidance on dos

Plus – oral corticosteroid

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ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
Plus – 

oral corticosteroid

Treatment recommended for ALL patients in selected patient group

After starting the conventional synthetic DMARD, aim to slowly taper the dose of the corticosteroid due to the risk of adverse effects from long-term use (e.g., diabetes, hypertension, osteoporosis, weight gain, and Cushing syndrome).​[2][4][74]

  • It is important to taper the dose slowly as quick reductions can lead to disease relapse.

Primary options

prednisone: 0.5 to 1 mg/kg/day orally, gradually taper according to response

Consider – nonsteroidal anti-inflammatory drug (NSAID)

Back
ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
Consider – 

nonsteroidal anti-inflammatory drug (NSAID)

Treatment recommended for SOME patients in selected patient group

Offer an NSAID to provide temporary symptomatic relief as required.[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.

  • Use the lowest effective dose for the shortest effective treatment duration.

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

Primary options

indomethacin: 25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day

OR

ibuprofen: 300-800 mg orally three to four times daily, maximum 3200 mg/day

3rd line – biologic agent

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ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
3rd line – 

biologic agent

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, adalimumab) have been shown to achieve clinical remission in patients with AOSD, though at a lower rate than IL inhibitors. 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.

Biologic agents are associated with serious infections and malignancy. They are contraindicated in patients with active infections. Use caution in patients at risk of chronic or recurrent infections or malignancy. Screen for tuberculosis before treatment.

Note that anakinra and canakinumab are increasingly preferred to conventional synthetic DMARDs as second-line options (after corticosteroids) in patients whose clinical symptoms/signs and laboratory results show highly active disease.[2][6] It is likely this approach will become standard in future, depending on availability and local protocol. Check local guidelines. See Management approach for more detail.

Primary options

anakinra: 100 mg subcutaneously once daily

OR

canakinumab: 4 mg/kg subcutaneously every 4 weeks, maximum 300 mg/dose

OR

tocilizumab: consult specialist for guidance on dose

Secondary options

adalimumab: consult specialist for guidance on dose

OR

infliximab: consult specialist for guidance on dose

Plus – oral corticosteroid

Back
ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
Plus – 

oral corticosteroid

Treatment recommended for ALL patients in selected patient group

After starting the biologic agent, aim to slowly taper the dose of the corticosteroid due to the risk of adverse effects from long-term use (e.g., diabetes, hypertension, osteoporosis, weight gain, and Cushing syndrome).​[2][4][74]

  • It is important to taper the dose slowly as quick reductions can lead to disease relapse.

Primary options

prednisone: 0.5 to 1 mg/kg/day orally, gradually taper according to response

Consider – conventional synthetic disease-modifying antirheumatic drug (DMARD)

Back
ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
Consider – 

conventional synthetic disease-modifying antirheumatic drug (DMARD)

Treatment recommended for SOME patients in selected patient group

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

Primary options

methotrexate: 7.5 to 25 mg orally/subcutaneously/intramuscularly once weekly on the same day of each week

Secondary options

cyclosporine modified: consult specialist for guidance on dose

Tertiary options

azathioprine: consult specialist for guidance on dose

OR

leflunomide: consult specialist for guidance on dose

OR

hydroxychloroquine sulfate: consult specialist for guidance on dose

Consider – nonsteroidal anti-inflammatory drug (NSAID)

Back
ONGOING
|
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
Consider – 

nonsteroidal anti-inflammatory drug (NSAID)

Treatment recommended for SOME patients in selected patient group

Offer an NSAID to provide temporary symptomatic relief as required.[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.

  • Use the lowest effective dose for the shortest effective treatment duration.

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

Primary options

indomethacin: 25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day

OR

ibuprofen: 300-800 mg orally three to four times daily, maximum 3200 mg/day

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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