Integration of genetics and miRNA-target gene network identified disease biology implicated in tissue specificity.

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA-target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA-target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10-8). Our result highlighted that miRNA-target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.

Efficacy and safety of secukinumab in Japanese patients with active ankylosing spondylitis: 24-week results from an open-label phase 3 study (MEASURE 2-J).

Objective: Secukinumab, a fully human monoclonal antibody that neutralizes interleukin-17A, improved the signs and symptoms of ankylosing spondylitis (AS) in three Phase 3 global studies (MEASURE 1, 2, and 3). Here, we describe the efficacy and safety results through Week 24 of a study of secukinumab in Japanese patients with active AS.Methods: In this multicenter, open-label, single arm, 52-week study, 30 AS patients self-administered secukinumab 150 mg subcutaneously at baseline, Weeks 1, 2, 3, and 4, and every 4 weeks thereafter. The primary efficacy endpoint was ASAS 20 response at Week 16. Overall safety and tolerability were assessed beyond Week 24 up to the data reporting cut-off date.Results: The ASAS 20 response rate was 70% (21/30) at Week 16, which was sustained to Week 24. Secukinumab was effective in various clinical outcomes including patient's global assessment of disease activity, spinal pain, nocturnal pain, physical function, spinal mobility, and CRP level. Comparable ASAS 20 and 40 responses were observed regardless of previous anti-TNF therapy. Secukinumab was well-tolerated with a safety profile consistent with previous reports.Conclusion: Secukinumab 150 mg provided sustained improvement in the signs and symptoms of Japanese AS patients through 24 weeks, with no new or unexpected safety signals.

A large observational cohort study of rheumatoid arthritis, IORRA: Providing context for today's treatment options.

Real-world evidence, based on real-world data from routine clinical treatment, is becoming increasingly important for providing high-quality medical care. Large-scale cohort studies can provide useful access to some of this real-world evidence, as shown by the IORRA (Institute of Rheumatology, Rheumatoid Arthritis) cohort in Japan. This large cohort study of patients with rheumatoid arthritis (RA) has been surveying enrolled participants since its inception in 2000. In the last 19 years, it has served as a database for a wide range of research in areas including transitions in medical care at the clinical level, changes in therapeutic drugs, approaches to comorbidities, developments in pharmacoeconomics, and the effects of genomic information on treatment options. This research has resulted in the publication of 133 articles in English to date. IORRA monitors changes in the management of RA, and has quantified over time the daily experience of clinicians who provide routine medical care. Such observational databases, which reflect the reality of daily clinical practice, will become increasingly important and may provide a model for similar research in other disease areas.

Age and female gender associated with periodontal disease in Japanese patients with rheumatoid arthritis: Results from self-reported questionnaires from the IORRA cohort study.

Objectives: This study aimed to evaluate the prevalence of, and the factors associated with, periodontal disease in Japanese patients with rheumatoid arthritis (RA).Methods: Patients with RA enrolled in the Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort completed three self-administered questionnaires including questions about recent gingival bleeding during toothbrushing, a recent diagnosis of periodontitis by a dentist, and any history of periodontitis. Logistic regression analyses were used to evaluate associations with clinical variables for each questionnaire.Results: Among 5600 Japanese patients with RA, 31.0%, 18.3%, and 20.4% of patients self-reported recent gingival bleeding during toothbrushing, a recent diagnosis of periodontitis by a dentist, and a history of periodontitis, respectively. In multivariate models, younger age, fracture history, Japanese Health Assessment Questionnaire-Disability Index (JHAQ-DI), and prednisolone dosage were significantly (p < .05) associated with recent gingival bleeding during toothbrushing. Older age, female gender, and ever-smoker status were significantly correlated with a recent diagnosis of periodontitis.Conclusion: Many Japanese patients with RA experience gingival bleeding during toothbrushing and are diagnosed with periodontitis. Age, female gender, ever-smoker status, fracture history, JHAQ-DI, and prednisolone dosage appeared to be associated with periodontal disease in Japanese patients with RA.

Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis.

Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.

Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor.

OBJECTS: Although the association of cigarette smoking (CS) with susceptibility to rheumatoid arthritis (RA) has been established, the impact of CS on anticitrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) levels in RA has yet been clear, especially in relation to shared epitope (SE) alleles. METHODS: A total of 6239 subjects, the largest Asian study ever, from two independent Japanese cohorts were enrolled. Precise smoking histories, levels of ACPA and RF, and HLA-DRB1 allele status were withdrawn from databases. Associations between CS and high ACPA or RF levels, defined by the top quartiles, were evaluated. The effect of HLA-DRB1 alleles on the association was further investigated. RESULTS: CS at RA onset conferred the risks of high levels of both antibodies, especially RF (OR 2.06, p=7.4×10-14; ACPA, OR 1.29, p=0.012), suggesting that RF level is more sensitive to CS than ACPA level. The patients who had quitted CS before RA onset showed a trend of decreased risks of developing high levels of ACPA or RF, and the risks steadily decreased according to the cessation years. The association of CS with high ACPA level was observed only in subjects carrying SE alleles, while the association of high RF level was observed regardless of SE. CONCLUSIONS: CS confers the risks of high autoantibody levels in RA in different manners; CS interacts with SE alleles on ACPA level, while CS impacts on RF level despite SE allele. These data suggest novel distinct production mechanisms of RF and ACPA.

Hypouricaemic effects of yoghurt containing Lactobacillus gasseri PA-3 in patients with hyperuricaemia and/or gout: A randomised, double-blind, placebo-controlled study.

PURPOSE: Lactobacillus gasseri PA-3 (PA-3) has been previously shown to decrease serum uric acid (SUA) levels in subjects with increased SUA. In this study, we investigated whether PA-3 is also capable of decreasing SUA levels in patients with hyperuricaemia and/or gout. METHODS: Twenty-five patients with hyperuricaemia and/or gout completed this study. Urate-lowering drugs were discontinued for 12 weeks (week -4 to week 8). After flushing of urate-lowering drugs for 4 weeks (week 0), patients were randomised equally to receive diets containing yoghurt beverages with PA-3 or without PA-3 for a duration of 8 weeks (week 8). The intention to treat (ITT) population included all subjects who were randomised, and the per-protocol (PP) population included subjects who completed the experiment with compliance. We evaluated SUA levels at the end of the study as well as changes in SUA levels in comparison to week 0. RESULTS: In both ITT and PP analyses, there were no significant differences in SUA levels or in the changes in SUA levels compared to week 0 between the two groups. However, in a sub-population whose SUA levels at week 0 were within one SD of the mean of the whole PP population, changes in SUA levels in the group consuming PA-3-containing yoghurt were significantly lower than those of the control group (p = .0378). CONCLUSION: PA-3-containing yoghurt improves SUA levels, even in patients with hyperuricaemia and/or gout.

Factors associated with decreasing serum 25(OH)D among Japanese patients with rheumatoid arthritis: Results from the IORRA cohort study.

OBJECTIVE: The aim of this study was to investigate factors that predict a decrease in serum 25(OH)D among Japanese patients with rheumatoid arthritis (RA). METHODS: In 2011 and 2013, serum 25(OH)D was evaluated in the same 2534 Japanese patients with RA (2179 women and 355 men) who participated in the Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort study. A vitamin D deficiency was defined as serum 25(OH)D levels <20 ng/mL. Predictive factors resulting in decreased serum 25(OH)D over a 2-year period were evaluated using multivariate logistic regression. RESULTS: The prevalence of vitamin D deficiency was 73.3% in 2011 and 68.2% in 2013. Serum 25(OH)D levels decreased by >5 ng/mL from 2011 to 2013 in 224 (8.8%) patients. A serum 25(OH)D decrease of >5 ng/mL was significantly associated with female gender, younger age, and disuse of bisphosphonates among all patients, and younger age, higher Japanese health assessment questionnaire disability index (JHAQ-DI), increased tender joint counts, and disuse of bisphosphonates and/or active vitamin D3 among women with RA. CONCLUSION: Female gender, younger age, JHAQ-DI, tender joint counts, and disuse of bisphosphonates and/or active vitamin D3 appear to be associated with a decrease in serum 25(OH)D in Japanese patients with RA.

Stepwise dose increase of febuxostat is comparable with colchicine prophylaxis for the prevention of gout flares during the initial phase of urate-lowering therapy: results from FORTUNE-1, a prospective, multicentre randomised study.

OBJECTIVES: To determine whether febuxostat with stepwise dose increase is as useful as colchicine prophylaxis in reducing gout flares during the initial introduction of urate-lowering therapy in patients with gout in comparison with febuxostat with no dose titration. METHODS: In this prospective, multicentre, randomised open-label comparative study, patients were randomised to group A (stepwise dose increase of febuxostat from 10 to 40 mg/day), group B (fixed-dose febuxostat 40 mg/day plus colchicine 0.5 mg/day) or group C (fixed-dose febuxostat 40 mg/day) and observed for 12 weeks. Gout flare was defined as non-steroidal anti-inflammatory drug use for gout symptoms. RESULTS: A total of 255 patients were randomised, and 241 patients were treated. Among the treated patients, gout flares were experienced by 20/96 (20.8%) in group A, 18/95 (18.9%) in group B and 18/50 (36.0%) in group C. The incidence of flare was significantly lower in groups A and B than that in group C (P=0.047 and P=0.024, respectively), although the differences were not significant after correction for multiple comparisons. No significant difference was noted between the incidence of gout flare in groups A and B. CONCLUSIONS: Our data suggested that stepwise dose increase of febuxostat and low-dose colchicine prophylaxis effectively reduced gout flares in comparison with fixed-dose febuxostat alone. Stepwise dose increase of febuxostat may be an effective alternative to low-dose colchicine prophylaxis during the introduction of urate-lowering therapy. TRIAL REGISTRATION NUMBER: UMIN 000008414.

Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population.

BACKGROUND: HLA-DRB1 is the strongest susceptibility gene to rheumatoid arthritis (RA). HLA-DRB1 alleles showed significant non-additive and interactive effects on susceptibility to RA in the European population, but these effects on RA susceptibility should vary between populations due to the difference in allelic distribution. Furthermore, non-additive or interactive effects on the phenotypes of RA are not fully known. We evaluated the non-additive and interactive effects of HLA-DRB1 alleles on RA susceptibility and anticitrullinated protein/peptide antibody (ACPA) levels in Japanese patients. METHODS: A total of 5581 ACPA(+) RA and 19 170 controls were genotyped or imputed for HLA-DRB1 alleles. Logistic regression analysis was performed for both allelic non-additive effects and interactive effects of allelic combinations. The significant levels were set by Bonferroni's correction. A total of 4371 ACPA(+) RA were analysed for ACPA levels. RESULTS: We obtained evidence of non-additive and interactive effects of HLA-DRB1 on ACPA(+) RA susceptibility (p=2.5×10-5 and 1.5×10-17, respectively). Multiple HLA-DRB1 alleles including HLA-DRB1*04:05, the most common susceptibility allele in the Japanese, showed significant non-additive effects (p≤0.0043). We identified multiple allelic combinations with significant interactive effects including a common combination with the European population as well as novel combinations. Additional variance of ACPA(+) RA susceptibility could be explained substantially by heterozygote dominance or interactive effects. We did not find evidence of non-additive and interactive effects on levels of ACPA. CONCLUSION: HLA allelic non-additive and interactive effects on ACPA(+) RA susceptibility were observed in the Japanese population. The allelic non-additive and interactive effects depend on allelic distribution in populations.

Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort.

OBJECTIVES: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice. METHODS: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD. RESULTS: A total of 470 RA patients who had initiated a bDMARD (IFX: n = 98, ETN: n = 181, TCZ: n = 90, and ADA: n = 101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation. CONCLUSION: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD.

Dental treatments, tooth extractions, and osteonecrosis of the jaw in Japanese patients with rheumatoid arthritis: results from the IORRA cohort study.

This study aimed to evaluate dental treatments, tooth extractions, and osteonecrosis of the jaw (ONJ) in Japanese patients with rheumatoid arthritis (RA). Patients with RA enrolled in our cohort completed self-administered questionnaires, which included questions regarding their dental treatments, tooth extractions by dentists during the past 6 months, and past history of ONJ. The history of ONJ was validated with the patients' medical records. Logistic regression was used to determine the association of variables with dental treatments and tooth extractions during the past 6 months. Among 5695 Japanese patients with RA who responded to the questionnaires (mean age, 61.0 years; 85.6 % female), 2323 patients (40.8 %) and 378 patients (6.6 %) reported having had dental treatments and tooth extractions performed by a dentist within the past 6 months, respectively. In multivariate models, advanced age was significantly (P < 0.0001) associated with both dental treatments and tooth extractions during the prior 6-month period, and ever smoking was significantly (P = 0.023) correlated with tooth extractions during that time. Among patients who reported a history of ONJ, we confirmed five cases of ONJ with patient medical records. The prevalence of ONJ was 0.094 % among all RA patients and 0.26 % among female RA patients ≥65 years of age (n = 1888). Our data suggest that more than a few Japanese patients with RA have dental complications that require care by dentists, and that Japanese rheumatologists and dentists should cooperate to improve dental health in patients with RA.

Incidence of comprehensive hospitalization due to infection, cardiovascular disease, fractures, and malignancies in patients with rheumatoid arthritis.

To comprehensively analyze the overall incidence of hospitalization for comorbidities in patients with rheumatoid arthritis (RA). We prospectively analyzed overall hospitalizations for comorbidities using the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. The incidence of hospitalized comorbidity was calculated. Risk factors for the most frequent hospitalized comorbidities were determined by multivariate logistic regression analysis. Among 5519 RA patients contributing 5336.5 person-years of observation, 435 incidences of hospitalized comorbidity [8.15/100 person-years; 95% confidence interval (CI) 7.40-8.95] were confirmed. The most frequent cause of hospitalized comorbidity was infection (1.52/100 person-years), primarily respiratory system infection (0.77/100 person-years), followed by malignancy (1.03/100 person-years), extra-articular manifestations (0.78/100 person-years), bone fracture (0.77/100 person-years), and acute coronary syndrome (0.22/100 person-years). Death occurred in 0.34/100 person-years (95% CI 0.20-0.53), and in 94.4% of cases the cause of death was the same as that of admission. The risk factors for the most frequent cause of hospitalization, hospitalized infection, were age [odds ratio (OR) 1.03; 95% CI 1.00-1.05], serum albumin level (OR 0.30; 95% CI 0.13-0.69), and corticosteroid use (prednisone > 5 mg/day; OR 3.66; 95% CI 1.81-7.35), but not methotrexate or biological agent use. The present study determined the overall burden of hospitalized comorbidities in patients with RA. These comprehensive data on hospitalized comorbidities may provide a basis for future improvements in the treatment of RA.

Pharmacoeconomic analysis of biological disease modifying antirheumatic drugs in patients with rheumatoid arthritis based on real-world data from the IORRA observational cohort study in Japan.

OBJECTIVES: To evaluate the cost-effectiveness of biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: We used a state-transition model and parameters were determined from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study on 421 patients who had failed at least one DMARD and started either 1 of 4 bDMARDs (bDMARD group; adalimumab, etanercept, infliximab, and tocilizumab) or methotrexate (control group). bDMARD group was evaluated as two groups: sequence of any 1 of 4 bDMARDs with and without tocilizumab. The incremental cost-effectiveness ratios (ICERs) for bDMARD group were estimated using base-case analysis, probabilistic sensitivity analysis (PSA) and scenario sensitivity analyses. RESULTS: ICERs of bDMARD group with or without tocilizumab were $38,179 and $48,855, respectively. By PSA, these sequences had respective probabilities of 86.8% and 75.1% of falling below the assumed cost-effectiveness threshold of $50,000 in Japan. Scenario sensitivity analyses showed that the best population for initiating bDMARD was RA patients less than 50 years old with Japanese version of HAQ between 1.1 and 1.6 and using tocilizumab as the bDMARD. CONCLUSION: bDMARDs were cost-effective for RA patients based on a real-world setting in Japan.

Successful delivery in a patient with clinically amyopathic dermatomyositis during pregnancy despite first-trimester acute exacerbation of interstitial lung disease.

A 37-year-old woman with rheumatoid arthritis and interstitial lung disease (ILD) developed clinically amyopathic dermatomyositis (CADM) after achieving pregnancy through in vitro fertilization. She was given oral prednisolone, which improved her respiratory status, and delivered a healthy baby at 35 weeks' gestation. There are few reports of successful outcomes for CADM during pregnancy; to the best of our knowledge, this is the first report of successful delivery in a patient with both CADM and ILD.

The minimally important difference for the Japanese version of the health assessment questionnaire in patients with rheumatoid arthritis in daily practice.

OBJECTIVE: To validate the minimally important difference (MID) of physical function using the Japanese version of the Health Assessment Questionnaire (J-HAQ) in a cohort of rheumatoid arthritis (RA). METHODS: Patients who participated in a cohort study in both October 2008 and April 2009 were analyzed. Patients self-rated their change in overall status over 6 months using a 5-point Likert scale ("much better", "somewhat better", "same", "somewhat worse", or "much worse"). The MID for J-HAQ score was defined as the mean J-HAQ score change in patients who rated themselves "somewhat better". An effect size (ES) of 0.2-0.5 was considered to be suitable for MID. RESULTS: A total of 4560 patients were analyzed. The mean (standard deviation [SD]) MID for J-HAQ score was -0.06 (0.29), corresponding to an ES of 0.08. As exploratory analysis, 1999 patients with a J-HAQ score ≥0.5 and 28-joint disease activity score (DAS28) ≥ 2.6 at baseline were assessed. The mean (SD) MID for J-HAQ score of these patients was 0.13 (0.01), corresponding to an ES of 0.21. CONCLUSIONS: The MID for J-HAQ score was 0.13 in patients with baseline J-HAQ score ≥0.5 and DAS28 ≥ 2.6. The MID for J-HAQ score was influenced by disease status and functional disability.

Risk factors associated with the occurrence of proximal humerus fractures in patients with rheumatoid arthritis: a custom strategy for preventing proximal humerus fractures.

To our knowledge, no prior report focused on the risk factors for proximal humerus fractures in patients with rheumatoid arthritis. The purpose of this study was to evaluate the association between potential risk factors and the occurrence of proximal humerus fractures in patients with rheumatoid arthritis. A total of 11,907 patients with rheumatoid arthritis were enrolled in our observational cohort rheumatoid arthritis study between 2000 and 2012. Self-reported proximal humerus fractures were verified using the patients' medical records. Cox proportional hazard models were used to analyze the independent contribution of risk factors to the occurrence of proximal humerus fractures. During follow-up (mean 5.6 years), 92 proximal humerus fractures were verified in 91 patients. Multivariate Cox regression analyses estimated that the hazard ratios of sustaining a proximal humerus fracture were 1.37 for every 10-year increase in age [95 % confidence interval (CI) 1.10-1.70; P < 0.01], 1.95 for increases in serum C-reactive protein levels (mg/100 mL; 95 % CI 1.15-3.34; P < 0.05), 2.13 for a history of fractures (95 % CI 1.34-3.40; P < 0.01), 1.07 for the daily prednisolone dose (per mg; 95 % CI 1.01-1.13; P < 0.05), and 1.97 for oral bisphosphonate use (95 % CI 1.20-3.23; P < 0.01). Better control of rheumatoid arthritis with a smaller daily prednisolone dose in elderly patients with a history of fractures may be important for preventing proximal humerus fractures.

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

Effectiveness of tacrolimus in comparison with methotrexate or biologics in propensity score-matched patients with rheumatoid arthritis.

OBJECTIVE: To analyze the effectiveness of tacrolimus (TAC) in comparison with methotrexate (MTX) or biologics in propensity score (PS)-matched rheumatoid arthritis (RA) patients. METHODS: RA patients with moderate or high disease activity as defined by the 28-joint disease activity score (DAS28) and who had completed at least two successive biannual RA cohort surveys were analyzed. Patients were assigned in a stepwise fashion to one of four groups (Biologics, MTX, TAC, or Control) according to medication changes during a 6-month period. A PS was generated for each of three conditions (Biologics, MTX or Control group versus the TAC group, respectively), followed by the assignment of PS-matched patients. At 1 year, the DAS28 in each treatment versus TAC group was analyzed using a mixed effect model with repeated measures. RESULTS: Compared with the respective PS-matched TAC group, the difference in DAS28 at 1 year was -0.398 [95% confidence interval (CI) - 0.660 to -0.136, p < 0.005] in the Biologics group (N = 120), -0.045 (95% CI -0.222 to 0.133, p = 0.622) in the MTX group (N = 465), and 0.182 (95% CI 0.010 to 0.353, p < 0.05) in the Control group (N = 462). CONCLUSION: TAC may provide a potential therapeutic option for RA patients with moderate to high disease activity.

Longer operative time is the risk for delayed wound healing after forefoot surgery in patients with rheumatoid arthritis.

OBJECTIVES: Forefoot deformities are common in patients with rheumatoid arthritis (RA) and often require operative treatment. There is a high rate of delayed wound healing after foot surgery, especially among patients with RA. The aim of this study was to identify risk factors of delayed wound healing in RA patients who had undergone forefoot surgery. METHODS: This study was a retrospective observational study designed to analyze the outcomes of all consecutive RA patients who had undergone toe arthroplasty from April 2010 through May 2014 at a single institute. Putative risk factors for delayed wound healing were assessed using univariate logistic regression analysis. Variables with α = 0.1 were then subjected to stepwise multivariate logistic regression analysis. RESULTS: A total of 192 RA patients (192 feet) were included in this study. Delayed wound healing was seen in 40 feet (40/192 [20.8%]). A stepwise multivariate logistic regression analysis revealed that longer operative time was the risk factor associated with delayed wound healing in RA patients undergoing forefoot surgery (p = 0.028, odds ratio = 1.19 [per 10 min], 95% confidence interval [CI]: 1.07-1.32). CONCLUSIONS: This finding emphasizes the importance of preventing operative complications during forefoot surgery.