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To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman's disease (CD) during tocilizumab therapy.Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine. Antibody titers were measured every 4 weeks for a total of 12 weeks after vaccination.In the tocilizumab group, seroprotective titers (40-fold or more) were obtained in 36/38(95%) for A(NC), 35/38(92%) for A(HIR) and 32/38(84%) for B(MAL). In the patients with baseline antibody titer40-fold, 11/11(100%), 7/8(88%) and 18/20(90%) patients showed four-fold or more increase in the titer from baseline to A(NC), A(HIR) and B(MAL), respectively. Patients using TNF inhibitors and/or DMARDs showed similar responses. Pneumococcal antibody titers increased at least two-fold in more than 9 of 12 serotypes, which continued for longer than 12 weeks in all the patients.Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy and toxicity has not yet been determined. To establish personalized MTX therapy in Japanese patients with rheumatoid arthritis, we performed a preliminary study for predicting better methotrexate efficacy including single-nucleotide polymorphisms (SNPs) for MTX-related transporters/enzymes. Methods Disease control status (good or poor) was judged by the number of Disease Activity Scores (DAS28) of A, RFC1 –43 T > C, FPGS 1994G > A, GGH 401C > T, MTHFR 1298A > C, and TYMS 3'-UTR (−6/+6) was performed using the real-time PCR system. Results Seven of 21 patients were judged as good responders in terms of disease control, and the remainder as poor responders. For 0–3 months after starting MTX administration, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 96.0 mg and 25.4 and 118.0 mg and 23.4, respectively. For 0–6 months, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 192.0 mg and 51.0 and 214.0 mg and 47.6, respectively. Statistically significant differences between the 2 groups in the 0–6-month period were observed in DAS28 AUC improvement and index R. A slight tendency for a correlation between G/G genotypes and A allele genotypes in RFC1 80 genotypes was observed, although it did not reach statistical significance. Conclusion This study suggested that aggressive RA treatment with MTX from the early period of administration is necessary to obtain a good response after 6 months, although no SNPs predicting a better treatment response to MTX were identified.

A multicenter, open-label, dose-escalation phase 1/2 study was undertaken to evaluate the optimal subcutaneous tocilizumab dose that would result in exposure comparable to the intravenous tocilizumab 8-mg/kg approved dose in patients with rheumatoid arthritis. A pharmacokinetic and biomarker approach was used to estimate the clinical optimal dose regimen of subcutaneous tocilizumab. Safety and efficacy of subcutaneous tocilizumab were assessed as secondary end points. Patients received subcutaneous tocilizumab at 81 mg every 2 weeks (q2w) (n = 8), 162 mg q2w (n = 12), or 162 mg weekly (qw) (n = 12) for 24 weeks. 88% of 162-mg q2w patients and 100% of 162-mg qw patients maintained mean serum trough tocilizumab concentrations of ≥1 µg/mL, and had exposure comparable with the approved intravenous tocilizumab dose of 8 mg/kg; this resulted in normalized C-reactive protein levels and improvement in ACR20/50/70 responses. The most common adverse events were abnormal laboratory results, which were mild in severity. Anti-tocilizumab antibodies were detected in a few patients in the 81-mg q2w and 162-mg qw groups. In conclusion, coupled with efficacy and tolerability results, the appropriate dose of subcutaneous tocilizumab was determined to be 162 mg q2w for Japanese patients.