Tomomi Tsuru

Mechanism‐based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study)

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.

Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab

Abstract Objectives. To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castlemans disease (CD) during tocilizumab therapy. Methods. 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. Results. 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 titer < 40-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. Conclusion. Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.

Safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus: Results from a phase 1/2 randomized study

Abstract Objectives: This 12-week, randomized, double-blind, placebo-controlled, multicenter phase 1/2 study (NCT01449071) assessed the safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus despite standard of care. Methods: Twenty patients were randomized 1:1:1:1:1 to placebo or one of four epratuzumab dose regimens (100 mg every other week [Q2W], 400 mg Q2W, 600 mg every week [QW], or 1200 mg Q2W) administered during an initial 4-week dosing period. Adverse events (AEs), pharmacokinetics and pharmacodynamics were assessed. Results: Nineteen of 20 patients completed the study. All placebo patients and 13 of 16 epratuzumab patients reported ≥1 AE, 2 of 16 epratuzumab patients reported a serious AE. Cmax and AUCτ increased proportionally with dose after first and last infusion, t1/2 was similar across groups (∼13 days). Epratuzumab treatment was associated with decreased CD22 mean fluorescence intensity in total B cells (CD19+CD22+) and unswitched memory B cells (CD19+IgD+CD27+). Small-to-moderate decreases were observed in total B cell (CD20+) count. Conclusions: Epratuzumab was well-tolerated, with no new safety signals identified. The pharmacokinetics appeared linear after first and last infusions. Treatment with epratuzumab was associated with CD22 downregulation and with small-to-moderate decreases in total B cell count.

Okadaic acid enhances human T cell activation and phosphorylation of an internal substrate induced by phorbol myristate acetate

Okadaic acid is a potent tumor promoter and an inhibitor of serine/threonine-specific protein phosphatases. We studied the effect of okadaic acid in human T cell activation and phosphorylation of internal substrates. Okadaic acid at up to 4 nM enhanced phorbol myristate acetate (PMA)-induced proliferation and CD25 (IL-2 receptor, p55) expression, although it showed no activation by itself. Okadaic acid induced hyperphosphorylation of a 60 kDa protein in T cells as well as non-T cells, as reported in fibroblasts and keratinocytes. Preincubation with 4 nM okadaic acid enhanced PMA induced phosphorylation of the 80 kDa protein, an internal substrate of protein kinase C in T cells. These results suggest that okadaic acid inhibited dephosphorylation of protein kinase C specific substrates, and as a result, enhanced T cell activation mediated by protein kinase C pathway.

Impact of methotrexate dose on efficacy of adalimumab in Japanese patients with rheumatoid arthritis: Results from registered data analyses

Abstract Objective: Upper limit of methotrexate (MTX) for patients with rheumatoid arthritis (RA) was recently increased from 8 to 16 mg/week in Japan. We therefore examined the effect of concomitant MTX dose on the efficacy of adalimumab (ADA) in clinical practice. Method: Sixty-one consecutive RA patients treated with ADA were followed for minimum 52 weeks and retrospectively compared by MTX dose; patients receiving concomitant MTX of 10 mg/week or more (MTX ≥10 mg group) and <10 mg/week (MTX <10 mg group). Disease activity and remission were evaluated by the disease activity score 28 (DAS28) criteria. Results: The MTX ≥10 mg group consistently showed better improvement in DAS28 and resulted in more patients (52.8%) with DAS28-remission compared with the MTX <10 mg group (26.1%). Multivariate analysis showed that MTX ≥10 mg had a significant effect on DAS28 remission with odds ratio of 5.12. ADA retention rate was 72.2% in MTX ≥10 mg group compared with 52.0% in MTX <10 mg group. Discontinuation of ADA due to adverse events were comparable in the MTX ≥10 mg and MTX <10 mg groups (11.1% vs. 12.0%). Conclusions: These findings support the critical role of concomitant MTX in the efficacy of ADA, and recommend use of MTX ≥10 mg in Japanese RA patients.

Ultrasonographic efficacy of biologic and targeted synthetic DMARDs therapy in RA from multicenter RA ultrasound prospective cohort in Japan

To explore the variables associated with initial favorable power Doppler (PD) ultrasound (US) response induced by biologic and targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs) in patients with rheumatoid arthritis (RA).

Urinary C4 excretion in systemic lupus erythematosus

The fourth component of complement (C4) in urine was measured in 19 patients with systemic lupus erythematosus (SLE). Urinary C4 was detectable in all SLE patients using an enzyme linked immunosorbent assay. In 11 of 13 patients whose urinary C4 was serially measured, a decrease of urinary C4 was found in parallel with a decrease of disease activity of SLE. In the remaining 2 patients, the amount of C4 increased preceding a flare-up of the disease. The measurement of urinary C4 may be useful in evaluating the disease activity of SLE in individual patients and sometimes in predicting the flare-up of the disease. The specific hemolytic activity of excreted C4 and Western blotting analysis showed that urinary C4 consisted mainly of degraded fragments of C4. In two cases, camostat, a serine protease inhibitor, rapidly decreased the urinary C4 excretion, suggesting that the complement activation occurred in the glomerulus in lupus nephritis.

Sex Differences in mRNA Expression of Reduced Folate Carrier-1, Folypolyformyl Glutamate Synthase, and γ-Glutamyl Hydrolase in a Healthy Japanese Population

Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well known, but little is known about those differences in relation to therapeutic response. Reduced folate carrier‐1 (RFC‐1), folypolyformyl glutamate synthase (FPGS), and γ‐glutamyl hydrolase (GGH) are important transporters and enzymes that convert methotrexate (MTX) in the body. This study investigated the sex differences in mRNA expression of RFC‐1, FPGS, and GGH in 190 unrelated healthy Japanese people. The genotypes and mRNA expression were determined using the real‐time PCR method. Significant differences between men and women were observed in RFC‐1, FPGS, and GGH mRNA expression. The mRNA expression of FPGS and GGH was greater in women than that in men, but the expression of RFC‐1 was less in the former than the latter. In stratified analysis by genotype, significant differences in sex‐specific mRNA expression were observed in G/G of FPGS, C/C of GGH 452, and C/C of GGH –401. All showed greater mRNA expression in women than in men. In the 5 single‐nucleotide polymorphisms RFC‐1 80G>A, RFC‐1 –43T>C, FPGS 1994G>A, GGH 452C>T, and GGH –401C>T examined, the FPGS 1994 G/G (1.46‐fold), GGH 452 C/C (2.16‐fold), and GGH –401 C/C (2.68‐fold) genotypes showed significantly higher mRNA expression in women than in men. Healthy Japanese adults in this study showed sex‐specific differences in mRNA expression that differed among RFC‐1, FPGS, and GGH. Therefore, the relationship between genetic polymorphisms and mRNA expression including sex differences might contribute to the variation in the efficacy/toxicity of MTX in patients with RA.