What is the recommended treatment approach for Still's disease, including first‑line nonsteroidal anti‑inflammatory drugs, corticosteroids, disease‑modifying antirheumatic drugs, and biologic agents?

Treatment of Still's Disease (Adult-Onset Still's Disease)

For Adult-Onset Still's Disease (AOSD), most patients will require corticosteroids at some point in their disease course, with NSAIDs alone controlling disease in only 7-15% of patients; methotrexate should be added for steroid-refractory disease or to enable steroid tapering, and biologic agents—particularly IL-1 inhibitors (anakinra, canakinumab) or IL-6 inhibitors (tocilizumab)—should be initiated early in patients with inadequate response to conventional therapy. 1, 2

Initial Treatment Approach

First-Line Therapy: NSAIDs and Corticosteroids

• NSAIDs as monotherapy are effective in only 7-15% of patients with AOSD, making them insufficient as sole therapy for most patients 1

• Indomethacin and naproxen are preferred over salicylates as more useful class representatives 1

• Corticosteroids are required in 76-95% of patients at some point during their disease course 1

  • 89% of patients require prednisone at some point, with 46% requiring maintenance treatment 1
  • The need for steroids increases with disease pattern: 57% for self-limited, 67% for intermittent, and 77% for chronic articular AOSD 1

• High-dose prednisone should be limited to 6 months for NSAID-refractory systemic disease presenting with persistent anemia, pericarditis, serositis, and elevated liver enzymes 1

• IV pulse methylprednisolone can be used for disease refractory to oral prednisone 1

Critical Pitfall

Maintenance doses of 10-15 mg/day prednisone for arthritic symptoms have been associated with severe joint destruction despite steroid treatment in some patients, emphasizing the need for additional disease-modifying therapy 1

Second-Line Therapy: Disease-Modifying Antirheumatic Drugs

Methotrexate as Preferred DMARD

Methotrexate is the preferred conventional DMARD for patients requiring additional therapy beyond NSAIDs and corticosteroids 1, 2

• Low-dose MTX (mean 11.5 mg/week) achieves 88% response rate with 78% entering complete remission 1
• MTX enables prednisone dose reduction by 69%, with 42% of patients able to discontinue prednisone entirely 1
• Polyarthritis is particularly susceptible to MTX treatment, often resolving completely 1
• The effect on non-articular manifestations is less well-defined 1

When to Add DMARDs

DMARDs should be reserved for cases where:

• The combination of NSAIDs and steroids fails 1
• Reduction in steroid requirement is desired due to lack of tolerance or adverse events 1
• 34% of patients require additional remittive treatment to maintain disease control 1

Other Conventional DMARDs

Other antirheumatic agents show modest success with overall response rates of approximately 40% 1:

• Gold: 6/8 responders (75%) 1
• Penicillamine: 4/6 responders (67%) 1
• Hydroxychloroquine: 0/3 responders (0%) 1
• Azathioprine: 0/1 responders (0%) 1

Biologic Therapy: The Modern Standard

When to Initiate Biologics

The 2024 EULAR/PRES recommendations and recent evidence support earlier use of biologics in AOSD management 2, 3, 4

• First-line biological DMARD therapy shows 7.20 times greater odds of achieving sustained, event-free remission compared to conventional synthetic DMARDs (50% vs 12% at week 72) 3
• Biologics should be considered for patients with inadequate response to NSAIDs and corticosteroids, particularly before prolonged high-dose steroid exposure 2, 3

IL-1 Inhibitors: Highly Effective Option

Anakinra (100 mg subcutaneously daily) demonstrates rapid and sustained efficacy 1, 2, 5:

• Clinical improvement seen within days to weeks 1
• Complete remission rate of 73% (95% CI 58-84%) 5
• Corticosteroid discontinuation achieved in 47% (95% CI 18-78%) 5
• Effective even in patients who failed TNF inhibitors 1

Canakinumab is the only FDA-approved biologic for AOSD treatment 6:

• Complete remission rate of 77% (95% CI 29-97%) 5
• Corticosteroid discontinuation in 34% (95% CI 6-81%) 5

IL-6 Inhibitors: Alternative First-Line Biologic

Tocilizumab shows excellent efficacy 1, 2, 5:

• Complete remission rate of 80% (95% CI 59-92%) 5
• Corticosteroid discontinuation in 57% (95% CI 29-81%) 5
• Marked decrease in CRP, defervescence, and improvement in arthralgia 1

TNF Inhibitors: Less Preferred

Infliximab appears more effective than etanercept for AOSD 1:

• Infliximab induced 4 complete and long-lasting remissions 1
• Etanercept produced only 1 complete remission 1
• Treatment failures occurred equally with both agents, particularly in childhood-onset disease 1
• TNF inhibitors are generally less effective than IL-1 or IL-6 inhibitors for AOSD 2, 4

Treatment Algorithm

Step 1: Initial Therapy

• Trial of scheduled NSAIDs (indomethacin or naproxen preferred) 1
• Add corticosteroids if inadequate response within 2-4 weeks 1, 2
• Use high-dose prednisone for severe systemic features, but limit to 6 months 1

Step 2: Steroid-Dependent or Refractory Disease

• Add methotrexate (target dose ≥15 mg/week) to enable steroid tapering 1
• Consider early biologic therapy (IL-1 or IL-6 inhibitor) for patients with high disease activity or poor prognostic features 2, 3, 4

Step 3: Inadequate Response to Conventional Therapy

• Initiate biologic DMARD: IL-1 inhibitor (anakinra or canakinumab) or IL-6 inhibitor (tocilizumab) 2, 5, 3
• Continue methotrexate as combination therapy when possible 2

Step 4: Biologic Failure

• Switch to alternative biologic with different mechanism of action 1, 2
• Consider infliximab if TNF inhibition is chosen 1
• Studies show higher proportion of patients previously treated with biologics have lower rates of corticosteroid discontinuation 5

Special Considerations

Macrophage Activation Syndrome (MAS)

MAS is the most severe complication requiring immediate recognition and treatment 2, 6:

• Monitor for persistent fever, splenomegaly, elevated/rising ferritin, inappropriately low cell counts, abnormal liver function tests 2
• Treatment must include high-dose glucocorticoids 2
• Add anakinra, ciclosporin, and/or IFN-γ inhibitors as part of initial MAS therapy 2
• MAS can occur even during disease remission, particularly with concurrent infection 2

Lung Disease

• Actively screen for clinical symptoms (clubbing, persistent cough, shortness of breath) and perform pulmonary function tests 2
• IL-1 or IL-6 inhibitors are not contraindicated in patients with Still's lung disease based on available data 2

Treatment Tapering

• Achieve clinically inactive disease on glucocorticoids before initiating biologic tapering 2
• The ultimate goal is drug-free remission, which is realistic for a substantial proportion of patients with modern therapies 2

Key Evidence Gaps and Cautions

• Most evidence comes from case series and retrospective studies rather than randomized controlled trials 1, 5
• Three randomized controlled trials of biologics did not show statistically significant benefits, though meta-analyses demonstrate high remission rates 5
• Serious infections occurred with high-dose MTX (40-50 mg/day), including Legionella pneumonitis and cerebral nocardiosis 1
• Infliximab has been associated with rare serious side effects including infusion reactions, recurrent infections, pneumonitis, heart failure, and fulminant hepatitis in hepatitis B patients 1