RESUMO
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.
Assuntos
Síndrome de Behçet/tratamento farmacológico , Infliximab/uso terapêutico , Vigilância de Produtos Comercializados/tendências , Retinite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/tratamento farmacológico , Adolescente , Adulto , Idoso , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiologia , Fármacos Dermatológicos/farmacologia , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Infliximab/farmacologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Retinite/diagnóstico , Retinite/epidemiologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Uveíte/diagnóstico , Uveíte/epidemiologia , Adulto JovemRESUMO
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.
Assuntos
Anticorpos Antiproteína Citrulinada/sangue , Antirreumáticos/sangue , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Fator Reumatoide/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Infliximab/sangue , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosAssuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Humanos , Infliximab , Interleucina-6/sangue , Metotrexato/administração & dosagem , Indução de RemissãoRESUMO
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.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue , Adulto , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/sangue , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Métodos Epidemiológicos , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
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.