**5.3 Malignancies**

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).

The Role of Tocilizumab in the Treatment of Rheumatoid Arthritis 59

diseases, lifestyle diseases, etc.) is treated or controlled as well as possible before and during administration of biological agents. This not only stops stimulation of the production of inflammatory cytokines from factors other than RA, but also serves to reduce adverse events, which results in better efficacy and safety. This also directly improves physical

The standard dosage of TCZ for the treatment of RA is 8 mg/kg every 4 weeks. The serum TCZ concentrations 4 weeks after 3 doses are greater than 1 mg/mL, which is an effective dose, in about 80% of patients. However, this means that the serum TCZ concentrations are not sufficiently high in approximately 20% of patients. In these patients, increasing the dosage of TCZ and/or shortening the dosage interval may improve efficacy. Indeed, during clinical trials, it was observed that arthritis improved following the first dose but returned after 3 weeks in several patients. This suggested that the blood level could not be maintained over the 4-week period. I thus decided to give the second dose after an interval of 3 weeks following the first. By doing this, none of the patients suffered repeat deterioration by the time of the second dose in symptoms that had improved following the first, and no additive adverse effects were observed. A shorter dose interval at the start may be thought to be perfectly reasonable in terms of maintaining blood levels of biologics. In

The subjects of this analysis were patients who met the 1987 revised criteria for the classification of RA from ACR. Patients were included in the analysis if they started treatment with TCZ for the first time after 16 April 2008 (the date of insurance approval in Japan) (Table 2). This is an extension of a previous study (Hirabayashi et al, 2010). Data were collected until 20 March 2010. More than 23 and 51 weeks had elapsed since the first administration of TCZ in all 101 and in 70 patients, respectively. To reduce adverse events, any comorbidity was treated or controlled as well as possible before giving TCZ. All patients had a thoracic CT scan and were tested for the tuberculin reaction (or QuantiFERON ®), anti-streptolysin O (ASO), anti-streptokinase (ASK), treponema pallidum haemagglutination (TPHA), hepatitis B surface antigen (and anti-hepatitis B core antigen antibody), anti-hepatitis C virus antibody, and -D-glucan in order to screen for infections. If tooth plaque or caries were present, I arranged for assessment and treatment by a dentist. If chronic rhinorrhea or nasal blockage was seen, the patient was assessed and treated by an otolaryngologist. Patients were asked whether they had hemorrhoids. Patients were

Among the various therapies being used by the patients in the three months before they received TCZ, infliximab was discontinued at least one month before, adalimumab at least one week before, and etanercept at least 4 days before the new treatment commenced. Salazosulfapyridine, bucillamine, sodium aurothiomalate and mizoribine were discontinued upon initiating TCZ. The patients continued on MTX, tacrolimus and steroids at the same dose levels as before at least until dose 3 of TCZ. Then, MTX and tacrolimus were tapered off until 6 months after. The steroid dose was decreased slowly to avoid steroid withdrawal syndrome. There were no users of auranofin, D-penicillamine, hydroxychloroquine,

function irrespective of disease activity (Radner et al., 2010).

practice, this administration method is used for infliximab and abatacept.

**6.2 Clinical efficacy and safety in our experience** 

required to abstain from smoking.

minocycline or lobenzarit disodium.

**6.2.1 Patients** 
