Impact of Interleukin-1 Blockade on the Development of Macrophage Activation Syndrome in Still Disease: Incidence and Diagnostic Validity of the EULAR/ACR/PRINTO 2016 MAS Classification Criteria

Abstract

Objective: To evaluate the applicability of the 2016 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR)/Paediatric Rheumatology International Trials Organisation (PRINTO) macrophage activation syndrome (MAS) classification criteria in patients with Still disease and systemic juvenile idiopathic arthritis (sJIA-SD) treated with interleukin-1 (IL-1)-targeted therapy and to assess the incidence of MAS in this context.

Methods: We analyzed retrospective and prospective data from Dutch patients with sJIA-SD (diagnosis 2008-2017, n = 54) and data from a nationwide prospective Dutch cohort and intervention study (diagnosis 2017-2022, n = 66). From these cohorts, MAS episodes developing in patients with sJIA-SD treated with IL-1-targeted therapy (anakinra or canakinumab) with at least two years of follow-up were selected. Clinical and laboratory data were extracted from the electronic patient files.

Results: A total of 22 patients experienced 29 MAS episodes while receiving IL-1-targeted treatment. Seven patients had recurrent MAS episodes (not all while receiving IL-1 blockade). The 2016 criteria for MAS in sJIA-SD were met for 28 of 29 MAS episodes (97%). Within the prospective nationwide cohort starting anakinra as first-line monotherapy, the incidence rate of MAS in the first two years of disease was 18% (12 of 66 patients, with 11 of 12 while receiving IL-1 inhibition). This incidence is comparable to that observed in historical glucocorticoid-treated patients. Half of MAS episodes occurred within three months after diagnosis, and Epstein-Barr virus was the most common identifiable trigger.

Conclusion: Although first-line anakinra in new-onset sJIA-SD has demonstrated high response rates, our data suggest the incidence of MAS in the first two years of disease is not reduced. Patients appear to be particularly at risk early in disease. Importantly, our data show that the EULAR/ACR/PRINTO 2016 MAS classification criteria remain applicable to patients receiving IL-1-targeted therapy.

Figure 1

The canonical laboratory features of the EULAR/ACR/PRINTO MAS criteria and cytokine levels over time. (A) Ferritin, (B) thrombocyte, (C) AST, (D) triglyceride, (E) fibrinogen, (F) IL‐18, (G) galectin‐9, and (H) CXCL10 measurements per patient at sJIA‐SD diagnosis and per episode: one month, two weeks, and one week before MAS; MAS diagnosis (start of MAS treatment); and three days, one week, two weeks, one month, and two months after MAS therapy initiation. Blue dots indicate the median, and bars indicate interquartile range. Gray dots indicate individual measurements. The red dashed line indicates the threshold of the EULAR/ACR/PRINTO MAS criteria. The green dashed line indicates the clinical reference values. Maximum n at sJIA‐SD diagnosis is 22 patients, and maximum n at MAS diagnosis is 29 episodes. ACR, American College of Rheumatology; AST, aspartate aminotransferase; IL, interleukin; MAS, macrophage activation syndrome; PRINTO, Paediatric Rheumatology International Trials Organisation; SD, Still disease; sJIA, systemic juvenile idiopathic arthritis.

Figure 2

Patients are most at risk for MAS in the first three months of diagnosis. Percentage of the ESTIS cohort with MAS over time (days since diagnosis up to two‐year visit). The red dot indicates an MAS episode under IL‐6 pathway–targeted treatment (tocilizumab), blue dots indicate MAS episodes under anakinra treatment, and green dots indicate MAS episodes under canakinumab treatment. The gray dashed line indicates the time point when 50% of the first MAS episodes occurred. Total number of patients in the prospective ESTIS cohort = 66; total number of patients with MAS = 12. ESTIS, Early Stop of Targeted Treatment in Children with Systemic Juvenile Idiopathic Arthritis; IL, interleukin; MAS, macrophage activation syndrome.