Dose Adjustment of Methotrexate Administered Concomitantly with Golimumab for Rheumatoid Arthritis in Japanese Real-World Clinical Settings.

INTRODUCTION: The combination of methotrexate (MTX) with biological disease-modifying antirheumatic drugs (bDMARDs) is a recommended treatment option for rheumatoid arthritis (RA) patients showing an inadequate response to MTX monotherapy. However, the adequate dose of MTX, especially in long-term treatment with bDMARDs/MTX combination therapy, remains under-addressed. Since RA patients require long-term treatment, we examined the effects of using golimumab (GLM) in the long run as well as its persistency and associated factors. METHODS: We used the Japan Medical Data Center Inc. (JMDC) administrative claims data of 489 patients receiving GLM therapy for calculating the persistency in patients with constant, reduced, or escalated MTX dosing. The factors associated with GLM persistency were assessed using Cox proportional hazard modeling, controlling for the dose adjustment of concomitant MTX, age, sex, RA disease period, and the initial dose of GLM or concomitant MTX during GLM/MTX combination therapy. RESULTS: During GLM/MTX combination therapy, up to 52% of patients were reported to experience dose adjustments of concomitant MTX treatment (i.e., dose reduction and escalation in 34% and 18% of patients, respectively). Persistency was similar in the MTX dose-reduction patients and the MTX dose-constant patients. In the Cox proportional hazard model, no significant differences were observed in association with GLM persistency, including with respect to MTX dose adjustment. CONCLUSIONS: GLM prescription was continued in 80% or more (1 year) and 50% or more (3 years) of RA patients receiving reduced concomitant MTX dosing, suggesting that MTX dose adjustment (including MTX reduction) could be considered in GLM/MTX combination therapy.

Safety and efficacy of infliximab in the treatment of refractory uveoretinitis in Behçet's disease: a large-scale, long-term postmarketing surveillance in Japan.

BACKGROUND: Infliximab, an anti-tumor necrosis factor-alpha antibody, has been reported to have excellent efficacy for refractory uveoretinitis in Behçet's disease (RUBD), and was approved for this indication in Japan. However, the long-term safety profile and efficacy in real-world clinical settings in patients with RUBD have not been fully clarified. The BRIGHT study, a prospective, large-scale, long-term postmarketing surveillance (PMS) study, was conducted to investigate the long-term safety and efficacy of infliximab in Japanese patients with RUBD. METHODS: All patients with RUBD who started infliximab treatment between January 2007 and January 2010 were enrolled. Safety was evaluated every 6 months for up to 24 months after initiation of therapy in 656 patients, and efficacy was evaluated in 650 patients. Patient characteristics were compared using the chi-square or Fisher's exact test. The frequency of ocular attacks before and after infliximab treatment was compared using the Wilcoxon signed-rank test. Independent associated factors for safety or efficacy were identified using multiple logistic regression analysis. A two-sided p value <0.05 was considered significant. RESULTS: Among the 656 patients evaluated for safety, 555 (84.6%) completed the 24-month study period. The incidence of adverse drug reactions (ADRs) and serious ADRs were 32.32% and 6.10%, respectively, and the safety profile was comparable to that of Japanese PMS of infliximab for other diseases. The most common ADRs and serious ADRs were infections (11.89% and 3.66%). Tuberculosis was reported in two patients, and Pneumocystis jirovecii in one. Identified independent associated factors for infections were comorbid respiratory disease, history of allergic disease, and concomitant use of glucocorticoids. Although infusion reactions were observed in 11.13% of patients, most were non-serious. The response rate at 24 months by physician global assessment was 80.7%. Median frequency of ocular attacks per 6 months significantly decreased compared with that before infliximab treatment (2.0 to 0.0), and corrected visual acuity was maintained during the study. CONCLUSIONS: Infliximab treatment had good tolerability and efficacy in Japanese patients with RUBD in this large-scale, long-term PMS. Infliximab treatment seemed to be a good treatment option for RUBD in real-world clinical settings. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000027733 . Retrospectively registered on 6 June 2017.

High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study.

BACKGROUND: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. METHODS: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: "low/low-C" (RF < 55 IU/ml, anti-CCP < 42 U/ml), "high/high-C" (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. RESULTS: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 µg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. CONCLUSIONS: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00691028 . Retrospectively registered on 3 June 2008.

Efficacy and safety of dose escalation of infliximab therapy in Japanese patients with psoriasis: Results of the SPREAD study.

Although infliximab is approved for psoriasis, its efficacy is reduced over time in some patients. The aim of this phase III trial is to evaluate efficacy and safety of infliximab dose escalation in Japanese psoriasis patients with loss of efficacy to standard-dose therapy. Patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis or psoriatic erythroderma who showed loss of efficacy to standard-dose therapy received infliximab dose escalation (10 mg/kg every 8 weeks) from weeks 0 to 32. Loss of efficacy was defined as not maintaining 50% reduction in the Psoriasis Area and Severity Index (PASI 50) after achieving PASI 75. Efficacy and safety were evaluated up to week 40. Fifty-one patients received dose escalation and 43 completed the study. PASI 75 and median improvement rate of PASI score at week 40 were 44% and 70.0%, respectively, showing efficacy in skin symptoms. Efficacies in quality of life, nail psoriasis and joint pain were also obtained. Median serum infliximab level increased from less than 0.1 to 1.1 µg/mL from weeks 0 to 40, showing positive correlation between efficacy and serum infliximab level at week 40. Favorable efficacy was observed in patients with detectable serum infliximab levels (≥0.1 µg/mL) at baseline. Incidences of adverse events, serious adverse events, serious infections and serious infusion reactions were 92%, 10%, 4% and 0%, respectively. No marked difference was observed in both efficacy and safety among psoriasis types. No new safety concerns were observed. Infliximab dose escalation was effective and well-tolerated in psoriasis patients with loss of efficacy to standard-dose therapy, suggesting that dose escalation may be a useful therapeutic option for these patients.

Prediction of clinical response after 1 year of infliximab therapy in rheumatoid arthritis based on disease activity at 3 months: posthoc analysis of the RISING study.

OBJECTIVE: To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). METHODS: Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. RESULTS: Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, > 50% of patients continuing 3 mg/kg therapy would not be able to achieve REM or LDA at W54. However, even in patients with high or moderate disease activity at W14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. CONCLUSION: Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy.

Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). METHODS: Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). RESULTS: In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 µg/ml) at 3 and 6 mg/kg but were greater than 2 µg/ml at 10 mg/kg, whereas the levels were approximately 1 µg/ml for each dosage group in TNF-low patients. CONCLUSION: In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab.

MEN4901/T-0128, a new camptothecin derivative-carboxymethyldextran conjugate, has potent antitumor activities in a panel of human tumor xenografts in nude mice.

PURPOSE: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. EXPERIMENTAL DESIGN: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. RESULTS: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d x 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d x 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. CONCLUSIONS: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.