**5.1 Synovitis**

56 Rheumatoid Arthritis – Treatment

increase the risk of de novo infection of tuberculosis. TCZ did not affect the humoral

Infusion reactions (any adverse event occurring during, or within 24 h after infusion) occurred in 5.6% of patients with TCZ (Jones et al., 2010). The majority occurred during the first two infusions, and no serious infusion reactions were reported. In the meta-analysis of TCZ monotherapy, total 133 infusion reactions were observed in 93 patients (Nishimoto et al., 2010). Most of them occurred within the first four infusions. Headache, increased blood pressure, and pruritus were common. Anaphylactic reactions were observed in 3 patients. In worldwide Roche clinical trials, the rate of malignancies in patients receiving TCZ was 11.6 events per 1000 patient-years while the rate in the patients receiving synthetic DMARDs was 17.7 events per 1000 patient-years (van Vollenhoven et al., 2010). As it usually takes several years before a malignant neoplasm grows to be clinically recognized after the appearance of the first malignant cell, TCZ may not have been involved in the

Decreases in the neutrophil count were commonly observed in patients receiving TCZ. In the meta-analysis of TCZ monotherapy, grade 2 (<1500–1000/µL) and grade 3 neutropenia (<1000–500/µL) were observed in 92 (15.3%) and 36 patients (6.0%), respectively (Nishimoto et al., 2010). However, the decreases were not progressive, and neither febrile neutropenia nor agranulocytosis occurred. There was no obvious association between decreases in neutrophils and the occurrence infections. Decreases in the neutrophil are probably due to inhibition of the biological effects of IL-6 on recruitment of neutrophils into peripheral blood, not due to myelosuppression. Transient or intermittent elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have often been observed in patients receiving TCZ. The incidence of elevations of AST or ALT in patients treated with TCZ monotherapy was no more than that in patients treated with MTX monotherapy (Jones et al., 2010). Prolonged exposure to TCZ therapy did not appear to be associated with an increased likelihood of developing increases in ALT or AST because the numbers of patients developing increased ALT or AST values was highest in the first 6 months of treatment (Australian Government, 2011). Mean total cholesterol (T-cho) rose upon treatment with TCZ, but showed no continuous increase. As high-density lipoprotein (HDL) also increased, the atherogenic index [(T-cho – HDL)/HDL] did not change. Small low-density lipoprotein (LDL), which may be proatherogenic, did not increase with TCZ treatment while both large very low density lipoprotein (VLDL) and small HDL increases were observed (McInnes et al., 2010). Inhibition IL-6 signaling decreases lipoprotein A serum levels which correlate with coronary heart disease (Schultz et al., 2010; Daneshet al., 2000). Treatment with TCZ

Gastrointestinal (GI) perforation occurred in 26 cases out of 4009 patients treated with TCZ in worldwide Roche clinical trials (van Vollenhoven et al., 2009). The rate of GI perforations was 2.8 events per 1000 patient-years with TCZ therapy while the rate in patients with RA who were exposed to corticosteroids was 3.9 events per 1000 patient-years. The majority of the patients who experienced GI perforations treated with TCZ were also receiving corticosteroids, NSAIDS, and MTX. GI perforations occur mainly in lower GI tract, and 16 of the 18 patients with colonic perforations had diverticulitis. Prevention of constipation is important not only to reduce the incidence of colonic perforations but also to improve quality of life. A case of multiple ulcers in the small and large intestines during TCZ therapy has been reported (Iwasa et al., 2011). In mice, Il-6 signal is necessary for the development of

response to influenza vaccination (Tsuru et al., 2008).

may not increase the risk of cardiovascular disease.

carcinogenesis of the malignancies found during TCZ treatment to date.

The characteristic pathophysiology of RA is the destruction of bone and cartilage due to "persistent" synovitis; however, the mechanism of this "persistence" is not yet clear. It is reported that an IL-17A-triggered positive-feedback loop of IL-6 expression is present in fibroblasts (Ogura et al., 2008). Moreover, IL-6 stimulates megakaryocytes to increase platelet counts and induces platelet activation (Oleksowicz et al., 1994; Kaser et al., 2009), while platelet-derived microparticles in turn prominently elicit IL-6, not TNF, from synovial fibroblasts (Boilard et al., 2010). These phenomena may be involved in "persistent" inflammation. TCZ is the only drug that can directly cut these positive-feedback loops.

## **5.2 Insulin resistance**

IL-6 is involved in the pathology of type II diabetes mellitus related insulin resistance (Fève & Bastard, 2009). The expression of IL-6 was markedly increased (up to 15-fold) in human fat cells from insulin-resistant individuals (Rotter et al., 2003). Inhibition of IL-6 signaling affects insulin resistance in a positive way (Schultz et al, 2010). A significant decrease of HbA1c was observed at only 1 month after TCZ treatment (Ogata et al., 2011a). Thus, TCZ may help to resolve insulin RA patients.
