A56: Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Tocilizumab
Authors: Angelo Ravelli, Rayfel Schneider, Sheila Weitzman, Clare Devlin, Kaori Daimaru, Shumpei Yokota, Syuji Takei, Fabrizio De Benedetti
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA).[1] Changes in therapies, including biologics,[2, 3] may trigger MAS. Interleukin-6 (IL-6) plays a major pathogenic role in sJIA; data in animals suggest that high IL-6 levels contribute to the triggering of MAS.[4] Treatment with the IL-6 receptor inhibitor tocilizumab (TCZ) is very effective in patients with sJIA.[2] In this study, we investigated the rates and features of MAS occurring during TCZ treatment in patients with sJIA.



Methods:

Data were collected from patients with sJIA treated with TCZ in the international phase 3 trial (TENDER), 4 clinical trials in Japan, and the Japanese postmarketing surveillance (JPMS) program. Reported MAS events or disease flares associated with alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevations were collected. Worksheets with event information were assessed by an independent panel (2 pediatric rheumatologists, 1 pediatric hematologist with MAS expertise) overseen by the TENDER lead investigator. Cases were adjudicated as definite MAS, potential MAS, not MAS, or insufficient data.



Results:

The data set included 112 patients from TENDER (403.0 patient-years' [PY] exposure to TCZ), 149 patients from the Japanese trials (326 PY), and 366 patients from the JPMS program (523.9 PY). Of 31 cases reviewed, 22 events were adjudicated as definite or potential MAS: 5 from TENDER (3 definite, 2 potential), 6 from the Japanese trials (3 definite, 3 potential), and 11 from the JPMS program (5 definite, 6 potential). The rates/100 PY of definite/potential MAS were 1.24 (95% CI, 0.4–2.90) in TENDER, 1.84 (95% CI, 0.68–4.00) in the Japanese trials, and 2.10 (95% CI, 1.05–3.76) in the JPMS program. Features contributing to the adjudication of definite MAS are listed in the 1. All 11 events adjudicated as definite MAS met the preliminary MAS diagnostic guidelines.[6] All definite and potential MAS resolved with the exception of MAS in a patient from the Japanese phase 3 study who died after respiratory/cardiac arrest.


Table 1. Criteria for Adjudication of Cases as Definite MAS (n = 11)	Features of MAS	Patients for Whom These Features Led to Adjudication of Definite MAS n (%)mg


a

aThresholds for abnormal values were determined according to age and local guidelines.




	
Clinical signs	 	
Fever	6 (55)	
Rash	3 (27)	
Hemorrhage with purpura, hematuria	2 (18)	
Hepatomegaly	0 (0)	
Laboratory featuresa	 	
Elevated ALT/AST	11 (100)	
Thrombocytopenia	9 (82)	
Elevated ferritin	8 (73)	
Leukopenia	7 (64)	
Neutropenia	6 (55)	
Elevated lactate dehydrogenase	4 (36)	
Low fibrinogen	4 (36)	
Increased triglycerides	4 (36)	
Elevated D-dimers	3 (27)	
Low hemoglobin	4 (36)	
Elevated C-reactive protein	2 (18)	
Low erythrocyte sedimentation rate	2 (18)	



Conclusion:

The use of TCZ does not appear to be associated with increased risk for MAS in sJIA. There were no unusual clinical or laboratory features in these MAS cases.