Tocilizumab modifies clinical and laboratory features of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Abstract

Background: This study aimed to determine the influence of tocilizumab (TCZ) in modifying the clinical and laboratory features of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Furthermore, we assessed the performance of the 2016 MAS classification criteria for patients with s-JIA-associated MAS while treated with TCZ. Methods: A panel of 15 pediatric rheumatologists conducted a combination of expert consensus and analysis of real patient data. Clinical and laboratory features of s-JIA-associated MAS in 12 TCZ-treated patients and 18 untreated patients were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented full-blown MAS. Results: Clinically, the TCZ-treated patients with s-JIA-associated MAS were less likely febrile and had significantly lower ferritin, triglyceride, and CRP levels than the untreated patients with s-JIA-associated MAS. Other laboratory features of MAS including lower platelet counts and lower fibrinogen were more pronounced in TCZ-treated patients. The TCZ-treated patients with s-JIAassociated MAS were less likely to be classified as MAS based on the MAS classification criteria (25% vs 83.3%, p < 0.01). This is ascribed to the absence of fever or insufficient ferritin elevation, compared with the untreated patients. Conclusion: TCZ could modify the clinical and laboratory features of s-JIA-associated MAS. When evaluating the s-JIA patients while treated with TCZ, it is not applicable to use MAS classification criteria. Care must be taken to not underdiagnose MAS based on the MAS classification criteria.

COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy

“…As a consequence of the abovementioned pathogenic scenario linking iron, inflammation and infections, there is the need to find a possible therapeutic strategy to prevent CRS and onset of fibrosis occurring particularly in patients with COVID-19. The progress in understanding the critical role of pro-inflammatory cytokines in the pathogenesis of other hyperferritinemic syndromes such as MAS-HLH and AOSD has led to pilot the use of anti-cytokine agents, resulting in an increasing number of successful case reports in patients who were unresponsive to conventional treatments [ 93 ]. The inhibition of IL-1 (with the use of anakinra and canakinumab) and IL-6 (mainly with tocilizumab) showed a strong efficacy compared with placebo in several cohorts and randomized controlled trials in MAS-HLH and AOSD.…”

Macrophage activation syndrome and COVID-19

“…Anti-IL-6 treatment with specific blocker tocilizumab has also been suggested effective in attenuating clinical symptoms of MAS. Shimizu et al defined that patients with MAS showed significantly lower ferritin, CRP, triglycerol, fibrinogen, and aspartic aminotransferase serum levels when receiving tocilizumab treatment, indicating an alleviation of systemic inflammation [13]. However, the improvement in clinical and laboratory features of MAS may compromise MAS diagnosis.…”

Prognostic and predictive biomarkers in patients with COVID-19 treated with tocilizumab in a randomised controlled trial

“…High ferritin levels are thought to be a biomarker and a driver of disease severity in other clinical disorders characterised by abnormal macrophage activation and elevated IL-6 activity, such as cytokine release syndrome 26 and systemic juvenile idiopathic arthritis (sJIA). 27 In both conditions, patients benefit from tocilizumab treatment, and ferritin levels decrease after treatment in those with sJIA. 27 Although results are hypothesis-generating in this respect, the relationship between hyper-ferritinemia and elevated IL-6 levels in COVID-19 and other diseases provides a potential rationale for why ferritin was predictive for the effects of IL-6 pathway inhibition with tocilizumab in our study.…”

“…27 In both conditions, patients benefit from tocilizumab treatment, and ferritin levels decrease after treatment in those with sJIA. 27 Although results are hypothesis-generating in this respect, the relationship between hyper-ferritinemia and elevated IL-6 levels in COVID-19 and other diseases provides a potential rationale for why ferritin was predictive for the effects of IL-6 pathway inhibition with tocilizumab in our study. Additional investigation of biomarkers downstream of IL-6 and ferritin signalling, together with single-cell analysis of pulmonary cells, might further elucidate how high ferritin levels predict benefit from the inhibition of IL-6 activity in patients with severe COVID-19.…”