What is the treatment and management approach for a patient with suspected Still's disease, a rare autoimmune disorder?

Treatment and Management of Still's Disease

IL-1 or IL-6 inhibitors should be initiated as early as possible once the diagnosis of Still's disease is established, as this represents the highest level of evidence for achieving rapid glucocorticoid-free clinical inactive disease and improving long-term outcomes. 1

Initial Treatment Strategy

First-Line Biologic Therapy

• Start an IL-1 inhibitor (anakinra or canakinumab) or IL-6 inhibitor (tocilizumab) immediately upon diagnosis to avoid prolonged systemic glucocorticoid use and achieve the treatment target. 1, 2
• Early initiation of these biologics leads to high rates of rapid glucocorticoid-free clinical inactive disease and may decrease the percentage of patients developing a persistent disease course. 1
• Canakinumab is the only FDA-approved biologic specifically for Still's disease (AOSD). 3

Role of Glucocorticoids

• Glucocorticoids may be used initially for severe systemic manifestations but should be rapidly tapered as biologics take effect. 1, 2
• The goal is to minimize glucocorticoid exposure given the significant burden of long-term high-dose use. 1

Treatment Targets and Timeline

The 2024 EULAR/PReS guidelines establish specific sequential targets using a treat-to-target approach: 1, 4

• Day 7: Resolution of fever and reduction of CRP by >50% 1
• Week 4: No fever, reduction of active joint count by >50%, normal CRP, and physician/patient global assessment <20 on 0-100 VAS 1
• Month 3: Clinical inactive disease (CID) with glucocorticoids <0.1-0.2 mg/kg/day 1
• Month 6: CID without glucocorticoids 1
• Ultimate goal: Drug-free remission (defined as ≥6 months of CID) 1

Monitoring Schedule

• Assess disease activity at each target timepoint (day 7, week 4, month 3, month 6) with inflammatory markers (CRP, ESR), complete blood count, serum ferritin, and liver function tests. 4
• Continue regular monitoring during remission/maintenance phase, adapting frequency to disease activity. 4

Management of Life-Threatening Complications

Macrophage Activation Syndrome (MAS)

MAS is a severe and potentially fatal complication requiring immediate recognition and treatment: 1

• Suspect MAS with: Persistent fever, splenomegaly, elevated/rising ferritin, inappropriate cytopenias, abnormal liver function tests, elevated triglycerides. 4
• First-line treatment: High-dose glucocorticoids remain the mainstay. 1
• Second-line options: Ciclosporin is well-established; IL-1 or IFNγ inhibitors should be used in patients who fail high-dose glucocorticoids or considered at MAS onset for severe/life-threatening cases. 1, 5
• Maintain vigilance with appropriate periodic blood screening and tight monitoring of at-risk patients. 1

Still's Lung Disease (LD)

This emerging complication has been observed more frequently over the past decade and can lead to severe respiratory failure and death: 1

• Risk factors: Younger age at onset, Down's syndrome, occurrence of MAS (especially recurrent), high serum IL-18 levels, and HLA DRB1*1501 carriage. 1
• Screening: Perform high-resolution CT scan in any patient with clinical concerns; use pulmonary function tests and pulse oximetry (especially continuous overnight in children); echocardiography to detect pulmonary hypertension or myocarditis. 1, 4
• Critical management principle: IL-1 and IL-6 inhibitors should NOT be withdrawn in patients with lung disease, as withdrawal does not improve LD in most patients and exposes them to severe flares (potentially with MAS) and the burden of high-dose glucocorticoids. 1
• Consider adding T cell-directed immunosuppression to IL-1/IL-6 blockers in patients at high risk for or developing LD, though direct evidence is limited. 1
• JAK inhibitors have shown benefit in isolated case reports. 1

Difficult-to-Treat Patients

For patients who fail IL-1 and IL-6 inhibitors, those with severe/recurrent MAS, or those with lung disease: 1

• Manage in collaboration with Still's disease expert centers (in Europe through ERN-RITA). 1
• Therapeutic strategies may include: Repeated intra-articular glucocorticoid injections, periodic glucocorticoid pulses, JAK inhibitors, combination of conventional and biologic DMARDs, and novel IL-18 or IFNγ inhibitors. 1
• Intermediate targets may be less ambitious for these complex patients. 1

Key Clinical Pitfalls

Common Diagnostic Challenges

• Still's disease diagnosis is typically reached by exclusion while investigating fever of unknown origin. 3
• Carefully exclude malignancies, infectious diseases, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders before confirming diagnosis. 1
• Use operational definitions: Fever ≥39°C for ≥7 days, transient salmon-pink rash coinciding with fever spikes, musculoskeletal involvement (arthralgia/myalgia; overt arthritis supportive but not necessary), and high inflammation (neutrophilic leukocytosis, elevated CRP and ferritin). 1

Biomarker Utilization

• Marked elevation of serum IL-18 and/or S100 proteins (calprotectin) strongly supports diagnosis and should be measured if available. 1, 2
• Extremely elevated serum ferritin is characteristic but nonspecific. 2, 6

Treatment Timing

The most critical pitfall is delaying biologic therapy—early initiation is associated with better outcomes and may prevent progression to chronic disease patterns. 1, 7