Quarter in review – Pediatric Rheumatology

Chandrika S Bhat MD, RCPCH Fellowship in Pediatric Rheumatology (Bristol, UK)
Consultant, Pediatric Rheumatology Services, Rainbow Children’s Hospital, Bangalore

Study in focus 1: Emerging Concepts and Treatments in Autoinflammatory Interferonopathies and Monogenic Systemic Lupus Erythematosus (1)

Patho-mechanisms and Classification

The article proposes a classification system for autoinflammatory interferonopathies based on the underlying genetic defects and their impact on IFN production and signaling. It emphasizes the divergent and shared mechanisms leading to IFN dysregulation, including:

Intracellular Nucleic Acid Sensing: Defects in nucleic acid metabolism result in the accumulation of self-DNA or RNA, activating sensors like cGAS and RIG-I, which stimulate IFN production.
Protein Homeostasis: Impaired proteasome function leads to the build-up of misfolded proteins, triggering stress responses that enhance IFN signaling.
Intracellular Transport: Mutations affecting vesicular transport can cause the mis-localization of nucleic acid sensors, leading to inappropriate IFN activation.

Therapeutic Advances

Understanding these patho-mechanisms has paved the way for targeted therapies. The article highlights the success of Janus kinase (JAK) inhibitors, which block IFN signaling, in treating conditions like AGS and SAVI. Additionally, research into inhibitors of the STING pathway and other components involved in IFN production offers promising avenues for personalized treatment strategies. In conclusion, the article underscores the importance of genetic and mechanistic insights in developing targeted therapies for autoinflammatory interferonopathies and monogenic SLE.

Study in focus 2: EULAR/PReS recommendations for the diagnosis and management of Still’s disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still’s disease (2)

Overarching Principles

Unified Disease Concept: The task force emphasizes that sJIA and AOSD are manifestations of the same disease entity, advocating for the singular designation “Still’s disease.”
Shared Decision-Making: Treatment strategies should be developed collaboratively between healthcare providers and patients or their guardians, ensuring personalized care.
Treat-to-Target (T2T) Approach: Regular assessment of disease activity is crucial, with therapy adjustments aimed at achieving clinically inactive disease (CID) and, ultimately, drug-free remission.
Prompt Recognition of Complications: Early detection and treatment of macrophage activation syndrome (MAS) and severe lung disease are vital due to their potential severity.

Specific Recommendations

Diagnostic Criteria: Utilize operational definitions to facilitate rapid diagnosis, focusing on hallmark features such as high spiking fevers and evanescent rash. Fever should be ≥39°C (102.2°F) for at least seven days.
Biomarker Assessment: Elevated serum interleukin-18 (IL-18) and S100 proteins (e.g., calprotectin) strongly support the diagnosis and should be measured when available.
Differential Diagnosis: Carefully exclude alternative conditions, including malignancies, infections, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders.
Defining Disease States: CID is characterized by the absence of disease-related symptoms and normal inflammatory markers (ESR or CRP). Remission is defined as maintaining CID for at least six months.
Treatment Targets: Establish intermediate goals to guide therapy:
- Day 7: Resolution of fever and >50% reduction in CRP.
- Week 4: No fever, >50% reduction in active joint count, normal CRP, and physician/patient global assessment scores below 20 on a 0–100 visual analog scale.
- Month 3: CID with glucocorticoid (GC) dosage reduced to <0.1 or 0.2 mg/kg/day.
- Month 6: CID achieved without GCs.
Therapeutic Strategy: Prioritize early initiation of IL-1 or IL-6 inhibitors to achieve and maintain treatment targets, minimizing prolonged GC use.
Biologic Disease-Modifying Antirheumatic Drugs (bDMARDs): Initiate IL-1 or IL-6 inhibitors promptly upon diagnosis.
Tapering Therapy: Once CID is maintained for 3–6 months without GCs, consider tapering bDMARDs cautiously.
Monitoring for Complications: Vigilantly screen for severe complications, including MAS and lung disease, throughout the disease course.
MAS Identification: Suspect MAS in patients with persistent fever, splenomegaly, elevated or rising serum ferritin, low cell counts, abnormal liver function tests, coagulopathy, or elevated triglycerides.
MAS Treatment: Employ high-dose GCs as initial therapy, with consideration of adjunctive treatments such as anakinra, ciclosporin, or interferon-γ inhibitors.
Lung Disease Screening: Actively assess for respiratory symptoms (e.g., clubbing, persistent cough, dyspnea) and conduct pulmonary function tests. Utilize high-resolution CT scans when clinically indicated.
Lung Disease Management: The presence of risk factors or established lung disease should not preclude the use of IL-1 or IL-6 inhibitors.
Referral to Expert Centers: Manage difficult-to-treat cases, severe MAS, or lung disease in collaboration with specialized centers experienced in Still’s disease.

These recommendations aim to standardize care, promote early intervention, and improve outcomes for patients with Still’s disease across all age groups. The emphasis on a unified disease concept, patient-centered care, and proactive management of complications reflects a comprehensive approach to this complex condition.

References

Goldbach-Mansky, R., Alehashemi, S. & de Jesus, A.A. Emerging concepts and treatments in autoinflammatory interferonopathies and monogenic systemic lupus erythematosus. Nat Rev Rheumatol 2025; 21: 22–45.
Fautrel B, Mitrovic S, De Matteis A, Bindoli S, Antón J, Belot A et al. EULAR/PReS recommendations for the diagnosis and management of Still’s disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still’s disease. Ann Rheum Dis 2024; 83(12):1614-1627.