Background/Purpose:

Systemic-onset juvenile idiopathic arthritis (s-JIA) is a subtype of chronic childhood arthritis that is characterized by a spiking fever, rash, and arthritis. About 7% of s-JIA patients develop macrophage activation syndrome (MAS), a potentially fatal complication. Although several biologic therapies have dramatically improved the prognosis of s-JIA, the risk of developing MAS under biologic therapy seems not vanished because there are several reports of MAS associated with etanercept and canakinumab in patients with s-JIA.

To evaluate the prevalence of MAS in patients with s-JIA under the treatment of tocilizumab.

Methods:

During the post-marketing surveillance of tocilizumab conducted by Chugai Pharmaceutical Co. Ltd. in Japan from 2008 to 2012, a total of 394 patients was registered. Tocilizumab, 8 mg/kg, was administered to the patients every 2 weeks, and routine investigations including CBC, CRP/ESR, D-dimer, liver function tests, creatinine, urinary beta 2-microglobulin, total cholesterol/triglyceride, and serum ferritin were determined before each infusion. Among them, 23 patients (5.8%) were diagnosed by the pediatrician in attendance with MAS, suspected MAS, or hemophagocytic syndrome; and then clinical course and laboratory data of the patients were reported as severe adverse events. Data were analyzed by the members of the Safety Evaluation Committee. Data were provided by Chugai Pharmaceutical Co. Ltd.

Results:

The Committee investigated the clinical manifestations and the changes of laboratory data along with the time course of each patient reported. Three patients were defined as definitive MAS (0.76%), 2 patients as EB virus-associated hemophagocytic syndrome (0.51%). Among other 18 patients, 11 patients (2.8%) were defined as probable MAS because the patients’ information including laboratory data was incomplete. Seven patients (1.8%) were judged as possible MAS or non-MAS because the treatment intervention for MAS was too early to define as MAS, or other diseases such as infectious disease, and hemolytic-uremic syndrome were suspected. Among 8 out of 14 patients defined as definitive or probable MAS, clinical manifestations were quite different from those seen in MAS on conventional therapy were. One patient died due to multi-organ failure, and none experienced sequelae.

Conclusion:

The frequency of definitive MAS under the tocilizumab therapy is estimated as 0.76%, and possible MAS as 2.8% (total 3.6%). Since the development of MAS in s-JIA patients under the conventional therapy was reported to be 6.8% ~ 13%, tocilizumab may have reduced the frequency of MAS developing in s-JIA. However, the clinical symptoms/signs such as fever, rash and an anguish look were not apparent in about half of the patients, and the inflammatory markers such as CRP and ESR were suppressed owing to the inhibition of IL-6 by tocilizumab. Taken together, physical examination and laboratory tests should be carefully taken at each visit in patients on tocilizumab in order to detect deadly MAS incipiently.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/reported-macrophage-activation-syndrome-in-patients-with-systemic-onset-juvenile-idiopathic-arthritis-treated-with-tocilizumab/