Abstract

Multicentric Castleman’s disease (MCD) is an atypical lympho- proliferative disorder which is closely associated with dysregulated overproduction of interleukin-6 (IL-6). In the previous report, we showed that the humanized anti-IL-6 receptor monoclonal antibody, tocilizumab (formerly called MRA), was therapeutically effective for the patients with MCD and the safety profile was acceptable relative to the clinical benefit. We also found that serum IgE levels were elevated in some patients with Castleman’s disease, which also decreased by IL-6 blocking therapy, suggesting that IL-6 may be involved in IgE production in vivo. To examine whether or not IL-6 serves as a regulator for IL-4, a major class switching factor for IgE, in vivo, we analyzed serum IL-4 as well as IgE levels in patients with MCD before and after the blockade of IL-6 actions utilizing humanized anti-IL-6 receptor monoclonal antibody in the 4-month clinical trial. Twenty-eight patients with MCD were enrolled and received intravenously 8 mg/kg of tocilizumab every two weeks for a total of 4 months. In fifteen of twenty-eight patients, 5–20 mg/day of prednisolone was used 4 weeks prior to study dosing, but the dosage of each patient was not changed during treatment. Serum IL-4 and IgE levels as well as inflammatory markers were monitored. This study complied with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice guidelines. All patients gave written informed consent before participating in this study. Tocilizumab treatment improved the systemic inflammatory manifestations and laboratory markers such as CRP and fibrinogen as we previously reported. Before tocilizumab treatment, serum IL-4 and IgE levels were elevated (median 14.9 pg/mL, range 2.8–228 pg/mL and median 995 IU/mL, range 12–8000 IU/mL, respectively, n=28). Serum IL-4 levels gradually decreased by tocilizumab treatment (median 8.0 pg/mL, range 2.0–257 pg/mL at 6 weeks, n=28, p<0.005 vs. pretreatment; median 6.0 pg/mL, range 2.0–75.6 pg/mL at 16 weeks, n=28, p<0.0001, respectively). Serum IgE levels also significantly decreased at 6 weeks but not at 16 weeks (median 590 IU/mL, range 6–7000 IU/mL at 6 weeks, p<0.005; median 605 IU/mL, range 5.9–16000 IU/mL at 16 weeks, n.s, respectively). In association with the decrease in serum IL-4 and IgE levels, disease activity of atopic dermatitis improved in the patients with atopic dermatitis. IgE RAST scores for Japanese cedar also significantly decreased. IL-6 has been reportedly to direct the differentiation of IL-4-producing T helper cell 2 (Th2), in vitro, but the in vivo action of IL-6 has been controversial. Our findings clearly indicate that IL-6 regulates the IL-4 production, in vivo, and may serve as a regulator not only for B cell differentiation but also for class switching to IgE.

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