Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including Creactive protein (CRP). We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathologic significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R and the proportion of sIL-6R saturated with tocilizumab after tocilizumab administration in patients with RA and Castleman disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after tocilizumab administration in both RA and Castleman disease. As long as free tocilizumab was detectable, sIL-6R was saturated with tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R-mediated consumption of IL-6 was inhibited by the unavailability of tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity. (Blood. 2008;112:3959-3964)

Objective. To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis Methods. CIA was induced by immunizing twice at a 3-week interval with bovine type I1 collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined.Results. In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14.Conclusion. IL-6 produced after CII immunization appears to play an essential role in the immunity to (CIA).

We present safety and efficacy data from Japanese clinical studies on monotherapy with tocilizumab (TCZ), a humanized anti-interleukin 6 receptor monoclonal antibody, in which 601 patients with moderate to severe rheumatoid arthritis, with a total of 2188 patient-years (pt-yr) exposure, were enrolled. The median treatment duration was 3.8 years. The incidence of adverse events (AEs), including abnormal laboratory test results, was calculated as 465.1 per 100 pt-yr. The most common serious adverse events (SAEs) were infections (6.22 per 100 pt-yr). There was no increase in the frequency of AEs or SAEs with long-term treatment. Abnormalities in the laboratory test results, such as increases in lipid parameters or abnormal liver function parameters, were common, but most were mild and there were no SAEs related to them. At baseline, 546 patients (90.8%) were taking corticosteroids; of these, 77.8% were able to decrease their corticosteroid dose during the study period, while 35.2% discontinued corticosteroids altogether. In the patients treated longer than 5 years, 91.3, 73.0, and 51.3% met the ACR20, ACR50, and ACR70 response criteria, respectively, and 59.7% met the DAS remission criterion (DAS28 <2.6) at 5 years. In conclusion, based on these results, TCZ has shown good tolerability and high efficacy during long-term treatment.

In the present study, we examined the preventive effect of anti-mouse IL-6 receptor (IL-6R) antibody, MR16-1, on the development of autoimmune kidney disease in female NZB/W F1 (BWF1) mice. Immunological tolerance to MR16-1 or isotype-matched control antibody, KH-5, was induced by the simultaneous administration of anti-CD4 MoAb in mice. Thereafter, mice were intraperitoneally given 0.5 mg of MR16-1, 0.5 mg of KH-5 or saline once a week from 13 to 64 weeks of age. MR16-1 treatment dramatically suppressed proteinuria and prolonged the survival time of BWF1 mice. Only one out of 10 mice died with high levels of proteinuria throughout the experiment. MR16-1 almost completely suppressed the production of IgG forms of anti-DNA and anti-TNP antibodies, but not the IgM forms of these antibodies. In particular, all IgG subclasses (IgG1, IgG2a, IgG2b and IgG3) of anti-DNA antibody production were significantly suppressed. Moreover, serum IgG1, IgG2a and IgG3 levels in MR16-1-treated mice were lower than those in saline- and KH-5-treated mice, whereas serum IgM and IgA levels were not influenced. In conclusion, MR16-1 potently suppressed the development of autoimmune disease in BWF1 mice, and this was attributed to its effect of specific suppression of IgG class antibody production.

TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare.