**4. Safety and tolerability**

Infections are the most frequent adverse events during therapy with TCZ and other biologics or DMARDs. In the AMBITION study, TCZ monotherapy was compared with MTX monotherapy (Jones et al., 2010). Infection rates per patient year were similar (TCZ 1.06 vs MTX 1.09). In both groups, nasopharyngitis and upper respiratory tract infection were common. The common serious infections were pneumonia. Neither opportunistic infections nor tuberculosis were reported in the patients receiving TCZ. Similar results were observed in a meta-analysis of TCZ monotherapy in Japanese patients (Nishimoto et al., 2010). Long-term exposure did not increase the incidence of serious infections. TCZ may not

The Role of Tocilizumab in the Treatment of Rheumatoid Arthritis 57

lamina propria TH17 cells which may play a role in the maintenance of intestinal mucosal homeostasis (Atarashi et al., 2008). A causal relationship between TCZ and gastrointestinal

Experience with TCZ use in human pregnancy is very limited. Thirty-three pregnancies were reported in 32 patients (19 to 42 years) (Rubbert-Roth et al., 2010). Of the 32 patients, 26 received TCZ + MTX and 6 received TCZ monotherapy or TCZ + DMARD other than MTX. In patients who continued their pregnancies, TCZ and MTX were discontinued when the pregnancy was discovered. Of 11 term deliveries (2 received TCZ monotherapy, 9 received TCZ + MTX), 10 were of healthy newborns. One infant died of ARDS 3 days after emergency cesarean section. It is difficult to evaluate the safety of TCZ during pregnancy

In conclusion, clinical trials demonstrated that TCZ was generally well tolerated in patients with active RA. The incidence of adverse events of TCZ monotherapy is no more than that of MTX monotherapy. Also, the risk of adverse events is comparable with that of other biologics and the risk of serious infection may be less than that for TNF inhibitors (Campbell et al, 2011). There was no increase in the frequency of adverse events with long-term

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.

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

TCZ was originally planned as an anti-myeloma drug because TCZ suppressed growth of the IL-6-dependent myeloma cell line, KPMM2 (Mihara et al., 2005). In fact, in an RA patient with IgA-kappa type multiple myeloma, TCZ not only improved RA symptoms dramatically but also stabilized serum IgA levels for 13 months (Matsuyama et al,. 2011). TCZ decreases the serum levels of VEGF (Nishimoto et al., 2009b). This effect may interfere with the angiogenesis and growth of tumors. For example, the antitumor effect of TCZ for oral squamous cell carcinoma has been reported (Shinriki et al., 2009). Targeting of the IL-6

system may be beneficial in the treatment of malignancies (Hong et al., 2007).

perforation/ulceration should be addressed in future studies.

**5. The advantages, and potential advantages, of TCZ** 

from the current data.

**5.1 Synovitis** 

**5.2 Insulin resistance** 

**5.3 Malignancies** 

may help to resolve insulin RA patients.

treatment with TCZ (Nishimoto et al., 2010).

increase the risk of de novo infection of tuberculosis. TCZ did not affect the humoral response to influenza vaccination (Tsuru et al., 2008).

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 carcinogenesis of the malignancies found during TCZ treatment to date.

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 may not increase the risk of cardiovascular disease.

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 lamina propria TH17 cells which may play a role in the maintenance of intestinal mucosal homeostasis (Atarashi et al., 2008). A causal relationship between TCZ and gastrointestinal perforation/ulceration should be addressed in future studies.

Experience with TCZ use in human pregnancy is very limited. Thirty-three pregnancies were reported in 32 patients (19 to 42 years) (Rubbert-Roth et al., 2010). Of the 32 patients, 26 received TCZ + MTX and 6 received TCZ monotherapy or TCZ + DMARD other than MTX. In patients who continued their pregnancies, TCZ and MTX were discontinued when the pregnancy was discovered. Of 11 term deliveries (2 received TCZ monotherapy, 9 received TCZ + MTX), 10 were of healthy newborns. One infant died of ARDS 3 days after emergency cesarean section. It is difficult to evaluate the safety of TCZ during pregnancy from the current data.

In conclusion, clinical trials demonstrated that TCZ was generally well tolerated in patients with active RA. The incidence of adverse events of TCZ monotherapy is no more than that of MTX monotherapy. Also, the risk of adverse events is comparable with that of other biologics and the risk of serious infection may be less than that for TNF inhibitors (Campbell et al, 2011). There was no increase in the frequency of adverse events with long-term treatment with TCZ (Nishimoto et al., 2010).
