What is the next step in managing a patient with Still's disease who is not responding to 500 mg of methylprednisolone (corticosteroid)?

Management of Still's Disease Refractory to High-Dose Methylprednisolone

Add IL-1 inhibition (anakinra) or IL-6 inhibition (tocilizumab) immediately, with anakinra preferred as first-line biologic therapy due to superior safety profile and efficacy in controlling both systemic and articular manifestations. 1

Immediate Next Steps

First-Line Biologic Addition

• Anakinra is the preferred biologic agent when adding to corticosteroids for refractory Still's disease, with the most reassuring safety profile among biologics and proven efficacy even in critically ill patients 1
• Anakinra should be dosed higher than standard (>1-2 mg/kg/day), potentially with repeated intravenous dosing for severe disease 1
• IL-6 inhibitors (tocilizumab) are equally effective but carry higher rates of serious adverse events and infections compared to IL-1 inhibition 1
• The 2024 EULAR/PRES guidelines strongly recommend prioritizing IL-1 or IL-6 inhibitors to avoid prolonged systemic glucocorticoid use, based on overwhelming real-world evidence 1

Critical Consideration: Rule Out Macrophage Activation Syndrome (MAS)

• Before escalating therapy, actively assess for MAS, which occurs in 15-20% of Still's disease patients and can develop at any time, including during treatment 1
• If MAS is present or impending, continue high-dose methylprednisolone (15-30 mg/kg/day, maximum 1g/infusion) and add:
  • Ciclosporin (oral or IV) as first additional agent 1
  • Anakinra at high doses (intravenous repeated dosing) 1
  • Emapalumab (anti-IFN-γ antibody) for severe MAS failing standard therapy, though not yet approved in Europe 1
  • Combination therapies with multiple agents on background of high-dose glucocorticoids are often necessary for severe MAS 1

Treatment Algorithm for Non-MAS Refractory Disease

Step 1: Add Biologic Immediately

• Anakinra (preferred): Start at doses >2 mg/kg/day, consider IV dosing 1
• Tocilizumab (alternative): 8 mg/kg IV every 4 weeks, may increase to every 2 weeks based on response 2
• Both agents control systemic manifestations (fever, rash) and articular disease while enabling glucocorticoid tapering 1

Step 2: Add Methotrexate as Steroid-Sparing Agent

• Methotrexate 11.5 mg/week (range 7.5-17.5 mg) allows 69% reduction in daily prednisone dose 3
• 88% of patients respond to methotrexate, with 85% able to taper prednisone when MTX added 1, 3
• Methotrexate + low-dose glucocorticoids represents standard first-line therapy per ACR guidelines, but in your refractory case, add it alongside biologics 4, 5

Step 3: If Biologics Fail

• Ciclosporin as second-line agent, particularly valuable in resource-limited settings 1, 4
• Alternative biologics: Switch from IL-1 to IL-6 inhibitor or vice versa 1
• JAK inhibitors (ruxolitinib, baricitinib) have case report evidence in refractory cases 1
• Abatacept may be considered after failure of anti-TNF and anti-IL-1 therapies 6

Treatment Targets and Monitoring

Sequential Targets (for newly diagnosed or relapsing patients)

• Day 7: Resolution of fever, CRP reduction >50% 5
• Week 4: No fever, active joint count reduction >50%, normal CRP, physician/patient global assessment <20/100 5
• Month 3: Glucocorticoid dose ≤0.1 mg/kg/day (adults) or ≤0.2 mg/kg/day (children) 1
• Month 6: Clinically inactive disease on minimal therapy 1

Key Monitoring Points

• IL-6 inhibitors may blunt CRP increase, making CRP less reliable for monitoring disease activity or detecting MAS 1
• Monitor for infectious complications, which are more frequent with IL-6 inhibition than IL-1 inhibition 1
• Regular laboratory monitoring including complete metabolic panels required with tocilizumab 2

Critical Pitfalls to Avoid

• Never maintain high-dose glucocorticoids (10-15 mg/day prednisone) long-term for arthritis control, as this leads to severe joint destruction despite steroid treatment 1, 5
• Do not delay biologic therapy: The "window of opportunity" is within 3 months of symptom onset; early biologic initiation prevents persistent chronic course 5
• Maintain high suspicion for MAS throughout the disease course, as it can develop abruptly at any time—at onset, during diagnostic workup, during biologic treatment even when disease is well-controlled, or during drug tapering 1
• Avoid using tocilizumab or other biologics after insufficient immunosuppression, as this may paradoxically trigger MAS; ensure adequate methylprednisolone therapy first 7
• Do not rely on NSAID monotherapy or glucocorticoids alone, as 85-93% of patients require advanced treatment 5

Special Situations

If Tuberculosis History Present

• Methotrexate + glucocorticoids preferred over biologics due to substantial TB reactivation risk with IL-1/IL-6 inhibitors 4
• Cyclosporine carries lower TB reactivation risk than biologics 4
• Anakinra may be used only after: completed TB treatment, negative latent TB testing, and initiated TB prophylaxis 4

If Lung Disease Present

• IL-1 or IL-6 inhibitors are not contraindicated in patients with Still's disease-related lung disease 5
• Actively screen for lung disease with clinical symptoms (clubbing, persistent cough, dyspnea) and pulmonary function tests 1

Combination Therapy Strategy

• Tocilizumab after adequate methylprednisolone pulse therapy represents safe and effective approach for severe disease 7
• Combination of high-dose glucocorticoids + anakinra + methotrexate achieves prolonged remission in refractory cases 1
• Multiple agents on background of high-dose glucocorticoids should be considered as initial therapy for severe presentations 1