Rapid Onset of Efficacy of Baricitinib in Chinese Patients with Moderate to Severe Rheumatoid Arthritis: Results from Study RA-BALANCE.

INTRODUCTION: Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with rheumatoid arthritis (RA). This report aims to analyze the onset time of baricitinib in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate. METHODS: This post hoc analysis evaluated clinical improvements of Chinese patients treated with baricitinib 4 mg once daily compared with placebo, based on data from a phase 3 study RA-BALANCE. Efficacy measures including American College of Rheumatology 20% (ACR20) response, ACR core set values, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28) using high-sensitivity C-reactive protein (hsCRP), DAS28-erythrocyte sedimentation rate, Simplified Disease Activity Index, Clinical Disease Activity Index, DAS28-hsCRP ≤ 3.2 response (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 (except for FACIT-F evaluated every 4 weeks). A logistic regression model and an analysis of covariance model were used to analyze treatment comparisons of categorical and continuous measures, respectively. RESULTS: Statistically significant (p ≤ 0.05) improvements were observed as early as week 1 or 2 for the baricitinib group compared to placebo in almost all main efficacy measures. For other outcomes including 66 swollen joint count, 68 tender joint count, FACIT-F, and DAS28-hsCRP ≤ 3.2 response rate, differences were evident (p ≤ 0.05) by week 4 in the baricitinib group compared with placebo. Significant improvements in all efficacy measures were sustained through 24 weeks. CONCLUSIONS: Baricitinib demonstrated a rapid onset of efficacy on ACR20 response, ACR core set values, disease activity, and patient-reported outcome improvements in Chinese patients from RA-BALANCE. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02265705.

Interaction analysis between BLK rs13277113 polymorphism and BANK1 rs3733197 polymorphism, MMEL1/TNFRSF14 rs3890745 polymorphism in determining susceptibility to rheumatoid arthritis.

Two pairwise genetic interactions (B cell lymphocyte kinase (BLK) rs13277113,B cell scaffold protein with ankyrin repeats 1 (BANK1) rs3733197and BLK rs13277113 membrane metalloendopeptidase like 1 (MMEL1)/ tumor necrosis factor receptor superfamily member 14 (TNFRSF14) rs3890745) have been demonstrated in determining susceptibility to rheumatoid arthritis (RA) without replication, thus this study was performed to examine whether abovementioned genetic polymorphisms were associated with RA and further tests were performed to see whether aforementioned genetic interactions existed in RA among Chinese population. A total of 328 patients with RA and 449 healthy control subjects were included in the current study. The polymorphisms were genotyped using the ligase detection reaction-polymerase chain reaction (LDR-PCR) technology. The association of RA with each polymorphism was analyzed by multivariate logistic regression model. Interaction analysis was done by multiple methods. Significant difference in genotype distribution of BLK rs13277113 polymorphism between RA patients and healthy controls was found (p = 1.01 × 10-2). The major allele A of BLK rs13277113 polymorphism was significantly increased in RA patients compared with controls (OR = 1.36, 95% CI = 1.08-1.71, p = 9.27 × 10-3). Significant association of RA with the major allele A of BLK rs13277113 polymorphism under dominant model was also detected (OR = 2.74, 95% CI = 1.42-5.29, p = 2.73 × 10-3). However, we did not find significant association between neither BANK1 rs3733197 polymorphism nor MMEL1/TNFRSF14 rs3890745 polymorphism and RA. Non-significant evidence was found for neither additive nor multiplicative interaction for these two pairwise genetic polymorphisms (BLK rs13277113-BANK1 rs3733197; BLK rs13277113-MMEL1/TNFRSF14 rs3890745). Significant association of RA with G allele of BANK1 rs3733197 polymorphism was only found among individuals carrying A/A genotype of the BLK rs13277113 polymorphism (OR = 1.49, 95% CI = 1.01-2.18, p = .04). In summary, our results indicated that the BLK rs13277113 polymorphism was involved in the genetic background of RA in Chinese population and the association of BANK1 rs3733197 polymorphism with RA was dependent on the genotype of BLK rs13277113 polymorphism, highlighting B-cell response implicated in the pathogenesis of RA.

A study on associations of single-nucleotide polymorphisms within H19 and HOX transcript antisense RNA (HOTAIR) with genetic susceptibility to rheumatoid arthritis in a Chinese population.

OBJECTIVE: The purpose of our study was to examine whether the H19 rs2839698, rs217727, and HOX transcript antisense RNA (HOTAIR) rs12826786 polymorphisms were associated with genetic susceptibility to rheumatoid arthritis (RA) in a Chinese population. METHODS: A total of 777 participants were enrolled in this study, including 328 RA patients and 449 healthy controls. The H19 rs2839698, rs217727, and HOTAIR rs12826786 polymorphisms were detected by the ligase detection reaction-polymerase chain reaction (LDR-PCR) technology. RESULTS: No significant difference in genotype distribution between RA patients and healthy controls was found (P = 0.38 for rs2839698; P = 0.79 for rs217727; P = 0.39 for rs12826786). The difference in allele frequencies between RA patients and controls was also non-significant (rs2839698 T versus C, P = 0.23, odds ratio (OR) = 1.15, 95% confidence interval (CI) = 0.92-1.43; rs217727 C versus T, P = 0.55, OR = 1.07, 95% CI = 0.87-1.32; and rs12826786 T versus C, P = 0.32, OR = 1.14, 95% CI = 0.88-1.47). We have also evaluated the relationships of above-mentioned polymorphisms with risk of RA under dominant model and recessive model, but non-significant evidence was found. No significant evidence was detected for the relationships of H19 rs2839698, rs217727, and HOTAIR rs12826786 polymorphisms with risk of different serotypes of RA. CONCLUSIONS: Our results indicated that H19 rs2839698, rs217727, and HOTAIR rs12826786 polymorphisms might not be involved in the genetic background of RA in Chinese.

Associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with genetic susceptibility to rheumatoid arthritis: a meta-analysis.

The aim of our study was to conduct a meta-analysis to assess whether combined evidence shows associations between C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and genetic susceptibility to rheumatoid arthritis (RA). A total of 11 articles involving 20 comparisons were included, containing 12 comparisons for the MTHFR C677T polymorphism and 8 comparisons for the MTHFR A1298C polymorphism. Significant evidence was detected for the association of RA susceptibility with the MTHFR C677T polymorphism T allele under allelic contrast and dominant model in Asians (T versus C, OR = 1.300, 95 % CI = 1.104-1.531, p = 0.002; TT + CT versus CC, OR = 1.495, 95 % CI = 1.187-1.882, p = 0.001). Significant association between RA susceptibility and the MTHFR A1298C polymorphism A allele under recessive model was found in the overall meta-analysis (AA versus AC + CC, OR = 1.281, 95 % CI = 1.048-1.565, p = 0.016). Our meta-analysis results demonstrate that the MTHFR C677T polymorphism is involved in the genetic susceptibility of RA in Asians, and the MTHFR A1298C polymorphism is associated with genetic susceptibility to RA in the overall population. Given the paucity of studies, especially in non-Asian populations, further studies with larger sample sizes are required to elucidate the role of MTHFR polymorphisms in the genetic basis of RA in different ethnic populations.

[The efficacy and safety of low-dose rituximab in treatment of primary Sjögren's syndrome with thrombocytopenia].

OBJECTIVE: To investigate the clinical efficacy and safety of low-dose rituximab (RTX) for patients in primary Sjögren's syndrome (pSS) with thrombocytopenia. METHODS: Four pSS patients, 2 with refractory thrombocytopenia and 2 with glucocorticoid-dependent thrombocytopenia, were treated with rituximab at 100 mg, intravenous, weekly for a total of two cycles, together with prednisone 1 - 2 mg×kg(-1)×d(-1), and the counts of platelets and B-cells were evaluated. RESULTS: Efficacy of treatment was observed in all patients. The counts of platelets, at (3 - 39) × 10(9)/L baseline, increased in 1 - 2 weeks, and went up to (107 - 241) × 10(9)/L in 3 - 8 weeks. Sustained remission had been achieved for 27 - 52 weeks. The doses of prednisone were tappered to 3.75 - 7.50 mg/day in 12 weeks. One patient who relapsed at the 27th week (platelet count 47 × 10(9)/L), was retreated with 100 mg of RTX and still had good efficacy. The counts of B-cells reduced to (0.007 - 0.010) × 10(9)/L, but they did not achieved the depletion. There were no severe adverse events during RTX therapy. CONCLUSIONS: Our study has shown good efficacy and tolerability of low-dose RTX for pSS with thrombocytopenia. Low-dose RTX allows for reduction in corticosteroid doses and B-cells, while large-scale randomized double-blind controlled trials are needed to confirm the results.

[The serum levels of cytokines in patients with rheumatoid arthritis associated interstitial lung disease and their clinical significance].

OBJECTIVE: To study the clinical significance of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases (TIMPs) and transforming growth factor beta 1 (TGF-beta1) in the serum of patients with rheumatoid arthritis (RA) associated interstitial lung disease (ILD). METHODS: Twenty-nine patients with RA only (the RA group) and 28 patients with RA associated ILD (the RA-ILD group) were included in the study. Patients in the RA-ILD group were divided into 2 subgroups, 16 in the early RA-ILD group and 12 in the late RA-ILD group. Twenty-nine healthy volunteers served as the control group. ELISA was used to detect the levels of MMP-9, TIMP-1, TGF-beta1 in the serum of the three groups. RESULTS: The TIMP-1 levels of both the RA and the RA-ILD groups [(645 +/- 220) microg/L, (536 +/- 188) microg/L] were significantly higher than that of the control group [(392 +/- 92) microg/L, F = 15.221, P < 0.01]. The TGF-beta1 level of the RA-ILD group [(13.1 +/- 10.0) microg/L] was significantly higher than those of the control group and the RA group [(3.9 +/- 2.9) microg/L, (2.4 +/- 1.7) microg/L, F = 26.455, P < 0.01]. There was no difference in the TIMP-1 level between RA-ILD and RA groups, the TGF-beta1 level between the control group and the RA group, the MMP-9 level and MMP-9/TIMP-1 ratio among the three groups. The TIMP-1 level in the late RA-ILD group [(690 +/- 110) microg/L] was higher than that of the early RA-ILD group [(420 +/- 147) microg/L, t = -5.347, P < 0.01]. The TGF-beta1 level in the late RA-ILD group [(17.9 +/- 8.2) microg/L] was higher than that of the early RA-ILD group [(9.5 +/- 9.9) microg/L, t = - 2.39, P < 0.05]. The MMP-9/TIMP-1 ratio of the late RA-ILD group (0.9 +/- 0.1) was lower than that of the early RA-ILD group (1.2 +/- 0.4, z = 4.307, P < 0.01). There was no statistic significance in the MMP-9 level between the early and the late RA-ILD groups [(537 +/- 309) microg/L, (595 +/- 110) microg/L, t = - 1.397, P = 0.174]. CONCLUSIONS: TGF-beta1, can be used as a diagnostic marker of ILD in RA patients and it also reflects the pathological change of the lung. The decrease of MMP-9/TIMP-1 ratio in RA patients with ILD can reflect the severity degree of lung pathological changes.