Comparison of the efficacy and safety of tocilizumab, sarilumab, and olokizumab in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study compared the relative efficacy and safety of olokizumab, tocilizumab, and sarilumab in rheumatoid arthritis (RA) patients who were intolerant or responding inadequately to methotrexate (MTX). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab, tocilizumab, and sarilumab in RA patients who were intolerant or responding inadequately to MTX. RESULTS: Six RCTs comprising 4439 patients met the inclusion criteria. Tocilizumab, sarilumab, olokizumab, and adalimumab treatments achieved a significant American College of Rheumatology 20% (ACR20) response rate compared with placebo. However, tocilizumab was associated with the most favorable surface area using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that tocilizumab treatment had the highest probability of providing the best ACR20 response rate, followed by sarilumab, olokizumab every 2 weeks (Q2W), olokizumab Q4W, adalimumab 40 mg, and placebo. The ACR50 and 70 response rates showed a distribution pattern similar to that of the ACR20 response rate. However, olokizumab Q4W had a higher ranking probability than olokizumab Q2W. The SUCRA rating showed that the placebo was the best intervention with the least adverse events (AEs) and withdrawal due to AEs, followed by interleukin­6 inhibitors. CONCLUSION: Tocilizumab, sarilumab, and olokizumab are more effective than adalimumab and have similar efficacy and safety in RA patients with inadequate responses to MTX.

Comparative efficacy and safety of tumor necrosis factor inhibitors and their biosimilars in patients with rheumatoid arthritis having an insufficient response to methotrexate : A network meta-analysis.

OBJECTIVE: This study aimed to compare the effectiveness and safety of tumor necrosis factor inhibitor (TNFI) biosimilars to TNFI originators in patients with active rheumatoid arthritis (RA) who responded inadequately to methotrexate (MTX). METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) to compare the effectiveness and safety of TNFI biosimilars to TNFIs in patients with RA who had not responded adequately to MTX. RESULTS: A total of 18 RCTs (8 adalimumab, 7 infliximab, and 3 etanercept) comprising 4039 patients randomized to TNFI biosimilars and 3905 to TNFI treatment were included. The American College of Rheumatology 20% improvement (ACR20) response rate was significantly higher for TNFI biosimilar-treated patients than for TNFI-treated patients (odds ratio, OR 1.140, 95% confidence interval, CI 1.031-1.261, P = 0.011); however, subgroup analysis by the TNFI type showed that the ACR20 response rates were not different among the biosimilars of adalimumab, infliximab, and etanercept compared with the originators. The ACR50 response rate was significantly higher for TNFI biosimilar-treated patients than for TNFI treated patients (OR 1.096, 95% CI 1.001-1.200, P = 0.047). Subgroup analysis by the TNFI type showed that the ACR50 response rates did not differ among the biosimilars of adalimumab and infliximab compared with the originators; however, the ACR50 response rate was significantly higher in etanercept biosimilar-treated patients than in etanercept-treated patients (OR 1.406, 95% CI 1.111-1.780, P = 0.005). No significant difference was observed between the TNFI biosimilars and TNFIs as per ACR70. There was no significant difference in the number of patients who experienced adverse events (AEs) between TNFI biosimilars and TNFIs (OR 0.961, 95% CI 0.876-1.055, P = 0.402); however, subgroup analysis by the TNFI type showed that the adalimumab biosimilar caused fewer AEs than adalimumab (OR 0.865, 95% CI 0.756-0.989, P = 0.034). Serious AEs and withdrawals due to AEs did not differ between TNFI biosimilars and TNFIs. CONCLUSION: This meta-analysis showed that TNFI biosimilars had an overall comparable efficacy and safety profile compared with their originators in RA patients.

Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis.

WHAT IS KNOWN AND OBJECTIVE: Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed. METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA. RESULTS AND DISCUSSION: Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo. WHAT IS NEW AND CONCLUSION: All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.

Vitamin D receptor FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma: a meta-analysis.

PURPOSE: The purpose of this study was to examine whether vitamin D receptor (lVDR) polymorphisms are associated with susceptibility to melanoma. METHODS: A meta-analysis was carried out to investigate the association between the VDR FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma. RESULTS: A total of 11 studies were evaluated, which included 4,413 patients and 4,072 controls (all European). The meta-analysis revealed no association between melanoma and the BsmI B allele (odds ratio/OR=0.901, 95% confidence interval/CI=0.783-1.036, p=0.144). However, an association was shown between melanoma and the Bb+bb genotype (OR=0.868, 95% CI=0.767-0.982, p=0.025). No association was noticed between melanoma and FokI polymorphism (OR for the F allele=1.016, 95% CI=0.869-1.189, p=0.839). Moreover, melanoma risk was not associated with the TaqI, ApaI, and EcoRV polymorphisms (OR for the T allele=0.986, 95% CI=0.842-1.156, p=0.864; OR for the A allele=0.949, 95% CI=0.842-1.069, p=0.388; OR for the E allele=0.993, 95% CI=0.875-1.126, p=0.911, respectively). CONCLUSIONS: This meta-analysis demonstrated that the VDR BsmI polymorphism is associated with susceptibility to melanoma in Europeans, suggesting that carrying the VDR BsmI B allele may be a protective factor against melanoma development.

Genome-wide pathway analysis in pancreatic cancer.

PURPOSE: The purpose of this study was to identify candidate single-nucleotide polymorphisms (SNPs) that might play a role in susceptibility to pancreatic cancer, elucidate their potential mechanisms, and generate SNP-to-gene-to-pathway hypotheses. METHODS: A genome-wide association study (GWAS) dataset of pancreatic cancer that included 496,959 SNPs from 3,851 pancreatic cancer patients and 3,934 control subjects of European descent was used in this study. The Identify candidate Causal SNPs and Pathways (ICSNPathway) method was applied to the GWAS dataset. RESULTS: ICSNPathway analysis identified 18 candidate SNPs, 11 genes (including HNF1A and HNF4G), and 30 pathways, which revealed 11 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was one wherein rs2230739 alters the role of ADCY9 in various pathways and processes, including cyclase activity, phosphorus oxygen lyase activity, hsa04912, hsa04540, hsa04020, and hsa00230 (0.010 ≤ p < 0.001; 0.038 ≤ false discovery rate (FDR) ≤ 0.016). The second strongest mechanism was that rs16859886 modulates ADCY10 to affect its role in pathways including cyclase activity, phosphorus oxygen lyase activity, nucleobase, nucleoside, and nucleotide metabolic processing, and hsa00230 (0.010 ≤ p < 0.001; 0.038 ≤ FDR ≤ 0.016). CONCLUSIONS: By using the ICSNPathway to analyze pancreatic cancer GWAS data, 18 candidate SNPs, 11 genes (including ADCY9, ADCY10, HNF1A, and HNF4G), and 30 pathways were identified that might contribute to the susceptibility of patients to pancreatic cancer.

CTLA-4 +49 A/G and -318 C/T polymorphisms and susceptibility to multiple sclerosis: a meta-analysis.

OBJECTIVE: The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, and -318 C/T polymorphisms confer susceptibility to multiple sclerosis (MS). METHODS: A meta-analysis of the associations between the CTLA-4 +49 A/G and -318 C/T polymorphisms and MS. RESULTS: A total of 23 separate comparisons from 19 studies of the CTLA-4 +49 A/G polymorphism and 10 comparisons (8 studies) of the CTLA-4 -318 C/T polymorphism were considered. Meta-analysis showed no association between MS and the CTLA-4 +49G allele in the analysis of all study subjects (OR = 1.026, 95% CI = 0.967-1.089, p = 0.395). Stratification by ethnicity indicated no association between the CTLA-4 +49G allele and MS in Caucasians, Asians, or Arabs. Meta-analysis showed no association between RA and the CTLA-4 -318C allele in all study subjects (OR = 0.909, 95% CI = 0.704-1.175, p = 0.467). In addition, meta-analysis stratified by ethnicity revealed no association between MS and the CTLA-4 -318 C/T polymorphism in Caucasian, Asian, or Arab populations. CONCLUSIONS: This meta-analysis of published studies did not find an association between the CTLA-4 +49 A/G and -318 C/T polymorphisms and susceptibility to MS in Caucasian, Asian, and Arab populations.

Korean Observational Study Network for Arthritis (KORONA): establishment of a prospective multicenter cohort for rheumatoid arthritis in South Korea.

OBJECTIVES: The object of this study was to introduce the KORean Observational study Network for Arthritis (KORONA) registry with an emphasis on the design of the Korean rheumatoid arthritis (RA) national database, as well as to provide an overview of the RA patients who are currently registered in KORONA. METHODS: The KORONA was established in July 2009 by the Clinical Research Center for Rheumatoid Arthritis (CRCRA) in South Korea. KORONA is based on a prospective protocol and standard, defined data collection instruments. Demographic and clinical features, laboratory and radiologic data, health-related outcomes, treatment side effects, resource utilization, and health behaviors of the RA cohort patients are recorded in a database. RESULTS: A total of 23 institutions, which are about 38% of the rheumatologic departments at tertiary academic hospitals across South Korea, are part of KORONA. The quality control of data collection and management has been performed through annual monitoring and auditing, staff training, and providing standard operation protocol by the executive committee of CRCRA. As of 31 December 2010, 4721 patients with established RA were included in KORONA, because an annual survey had started to be performed in July 2010. CONCLUSIONS: KORONA is the first nationwide Korean RA-specific cohort and it will provide valuable "real-world" information for Korean RA patients.