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ID PMID Title PublicationDate abstract
30511573 Resveratrol Alleviates Rheumatoid Arthritis via Reducing ROS and Inflammation, Inhibiting 2018 Dec 12 Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting joints and is featured by chronic synovial inflammation and angiogenesis. We employed a bovine type-II collagen (BIIC)-induced Sprague-Dawley rat arthritis model and an in vitro RA model based on interleukin (IL)-1β-stimulated rat synovial cells (RSC-364) to explore the preventive effect of resveratrol on RA and the underlying mechanisms. We found that resveratrol ameliorated BIIC-elicited synovitis and RA-related pathological hallmarks such as inflammatory cell infiltration and angiogenesis in the synovial tissue. Also, BIIC-stimulated rats displayed increased serum levels of proinflammatory cytokines and reactive oxygen species (ROS), as manifested by elevated serum malonaldehyde contents combined with reduced superoxide dismutase activity. It is noteworthy that resveratrol abolished BIIC-induced ROS and inflammation, confirming the antioxidative and anti-inflammatory actions of resveratrol in the context of RA. Furthermore, immunoblotting indicated that resveratrol downregulated the increase in the levels of hypoxia-inducible factor-1α (HIF-1α) and that of the activated phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in IL-1β-stimulated RSC-364 cells. Moreover, we observed that resveratrol-treated RSC-364 cells displayed both G(0)/G(1) cell-cycle arrest and enhanced levels of apoptosis. Altogether, the present evidence established the preventive role of resveratrol in RA progression. Mechanistically, resveratrol inhibits MAPK signaling pathways, likely by reducing ROS accumulation, to suppress the inflammatory response and cell proliferation and to provoke cell apoptosis in the synovial tissue, along with mitigation of HIF-1α-mediated angiogenesis. Thus resveratrol appears to hold great potential for clinical translation as a novel RA therapeutic.
30289538 Immediate treatment with tumour necrosis factor inhibitors in synthetic disease-modifying 2018 Oct 1 OBJECTIVE: To establish clinical consensus for the optimal placement of TNF inhibitor (TNFi) in DMARDs-naïve RA patients. METHODS: The steering group was composed of 15 Italian rheumatologists expert in the field of RA, who proposed and selected by consensus the clinically relevant questions on the role of TNFi treatment in DMARDs-naïve RA patients. The question was rephrased according to the population, intervention, comparison and outcome statement. The available scientific evidence on this topic were collected by updating the systematic literature reviews used for the EULAR 2013 recommendations up to January 2016. The aspects evaluated in the studies concerned clinical efficacy, radiographic structural damage and safety. After the systematic literature review the expert panel formulated a consensus statement, and a modified Delphi panel evaluated the level of agreement between panellists (strength of recommendation). RESULTS: From a total of 1080 records we have included 6 studies, 2 randomized clinical trials and 4 open-label extension trials. Evidence from publications generated three statements for the final consensus document. The systematic literature review and the consensus statements developed showed that, for patients with early RA and in the presence of a treat-to-target strategy, the immediate use of anti-TNFi compared with an early (within 12 weeks) step-up to anti-TNF therapy did not confer a significant advantage regarding clinical, functional and radiographic outcomes. CONCLUSION: The most appropriate placement of the TNFi therapy in the treatment algorithm of early RA still remains a challenging clinical question that needs to be further addressed.
29760159 Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rhe 2018 Sep OBJECTIVE: To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA). METHODS: In U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, 'MTX+') and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to 'MTX+'. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model. RESULTS: Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to 'MTX+'. DAS28 (adjusted OR (OR(adj)) 2.1, 95% CI 1.4 to 3.2), current smoking (OR(adj) 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (OR(adj) 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively. CONCLUSION: Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up 'MTX+' in DMARD-naive patients with new-onset RA. TRIAL REGISTRATION: NCT01034137; Post-results, ISRCTN26791028; Post-results.
29712771 IgG Immunocomplexes Sensitize Human Monocytes for Inflammatory Hyperactivity via Transcrip 2018 Jun 15 Prevalence of circulating immunocomplexes (ICs) strongly correlates with rheumatoid arthritis (RA) in humans. Deposits of IgG-ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. In this study, we present evidence that IgG-ICs precipitated from RA sera sensitized human monocytes for a long-lasting inflammatory functional state, characterized by a strong TNF-α response to cellular proteins representing damage-associated molecular patterns and microbe-derived pathogen-associated molecular patterns. Importantly, plate-coated human IgG (a mimic of deposited IC without Ag restriction) exhibited a similarly robust ability of monocyte sensitization in vitro. The plate-coated human IgG-induced functional programming is accompanied by transcriptomic and epigenetic modification of various inflammatory cytokines and negative regulator genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed a signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG-ICs in vivo. Thus, the ability of IgG-ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages toward inflammation may render them key players in the development of RA.
29324391 siRNA-mediated c-Rel knockdown ameliorates collagen-induced arthritis in mice. 2018 Mar Previous studies have shown that inflammatory mediators involved in the development of rheumatoid arthritis (RA) are regulated by the Rel/nuclear factor-κB (Rel/NF-κB) transcription factor family. c-Rel, a member of the Rel/NF-κB family that is preferentially expressed by immune cells, is a risk factor for several inflammatory diseases including RA. In the current study, we investigated whether targeting c-Rel can be used to treat collagen-induced arthritis, an animal model for RA. c-Rel specific siRNA (siRel) delivered by nanoparticles was used to knockdown the expression of c-Rel. Our results showed that siRel treatment significantly ameliorated collagen-induced arthritis. Further study revealed that c-Rel expression in the dendritic cells and macrophages from mice treated with siRel was significantly down-regulated. Consistent with the phenotypical result, the expression of inflammatory cytokines TNF-α, IL-1β, IL-6, IL-12 and IL-23 by peritoneal macrophages and splenocytes were significantly decreased. In addition, attenuated systemic and collagen-specific Th1 and Th17 immune responses were observed. Furthermore, we found that the expression of inflammatory cytokines was significantly down-regulated and the infiltration of CD3(+) T cells and F4/80(+) macrophages was markedly reduced in hind paws of mice treated with siRel. Collectively, our study provides strong evidence that siRNA-mediated c-Rel knockdown can suppress the development of collagen-induced arthritis in mice. Therefore, blocking c-Rel may represent an attracting strategy for the treatment of human rheumatoid arthritis.
30022333 Discontinuation of non-anti-TNF drugs for rheumatoid arthritis in interventional versus ob 2018 Nov PURPOSE: Although randomized controlled trials (RCTs) are the gold standard for the assessment of clinical outcomes, long-term extension trials (LTEs) and observational cohorts may help generate evidence. Our goal was to compare the discontinuation rates of abatacept, rituximab, and tocilizumab in rheumatoid arthritis (RA) reported in different study designs. METHODS: A systematic review was conducted with searches in PubMed, Scopus, and the Cochrane Library, plus a manual search, for RCTs, LTEs, and observational cohorts reporting discontinuation rates by any of three causes (all-cause, inefficacy, adverse events). Meta-analyses with sensitivity analyses and meta-regressions were conducted. RESULTS: Of the 111 studies included, 74 were RCTs (n = 55) or LTEs (n = 17) reporting data on abatacept (n = 33), rituximab (n = 10), and tocilizumab (n = 31) and 37 were observational cohort studies (abatacept = 11, rituximab = 8, tocilizumab = 18). The follow-up duration did not differ among the study designs. Discontinuation rates were similar among the drugs but varied among the study designs. Discontinuation rates were significantly higher in cohort studies than those in interventional studies for the three drugs. Sensitivity analyses could not identify patient characteristics associated with these differences. Meta-regression analyses demonstrated no correlation between study follow-up duration and discontinuation rates. CONCLUSIONS: The discontinuation rates reported for non-anti-TNF drugs varied relative to the study design in which they were investigated. Regulatory agencies, price-setting entities, and evidence-gathering researchers should consider the effect of the real-life environment in their decisions and conclusions.
29496226 How is symptom flare defined in musculoskeletal conditions: A systematic review. 2018 Oct OBJECTIVE: To systematically review the definitions for "flare" in musculoskeletal conditions, the derivation processes, and validation of definitions for the 12 most burdensome musculoskeletal conditions. METHODS: A literature search was conducted in MEDLINE, EMBASE, CINAHL, AMED, PsycInfo and Lilacs to identify studies that investigated derivation or validation of a flare definition, which we considered as a phrase or group of domains. RESULTS: Reports of derivation of flare definitions were identified for 9/12 musculoskeletal conditions. Validation of flare definitions was initiated for 4/12. For each condition, different derivation and validation methods have been used, with variable levels of consumer involvement, and in some cases different groups have worked on the process in parallel. Although some flare definitions began simply as "symptom worsening" or "change in treatment", most evolved into multidimensional definitions that include: pain, impact on function, joint symptoms, and emotional elements. Frequently initial attempts to create phrase to define the term flare evolved into consensus on the breadth of domains involved. Validation has compared flare definitions/domains against measures of disease activity, clinicians' diagnosis, response to drug therapy, or a combination. CONCLUSION: This review suggests that greater characterisation and definition of flares in musculoskeletal conditions are linked to the inclusion of multiple perspectives, multifaceted domains and compound comparators for their validation. Further work is required to optimise and test the derived definitions for most musculoskeletal conditions. As some elements are disease-specific, flare definitions cannot be extrapolated to other conditions. Research regarding flare in back pain (most burdensome disease) is limited.
29853189 Identifying MRI-detected inflammatory features specific for rheumatoid arthritis: two-fold 2019 Feb OBJECTIVE: MRI-detected inflammation is considered of diagnostic value for rheumatoid arthritis (RA), but its evaluation involves a time-consuming scoring of 61 joint-level features. It is not clear, however, which of these features are specific for RA and whether evaluating a subset of specific features is sufficient to differentiate RA patients. This study aimed to identify a subset of RA-specific features in a case-control setting and validate them in a longitudinal cohort of arthralgia patients. METHODS: The difference in frequency of MRI-detected inflammation (bone marrow edema, synovitis, and tenosynovitis) between 199 RA patients and 193 controls was studied in 61 features across the wrist, metacarpophalangeal, and metatarsophalangeal joints. A subset of RA-specific features was obtained by applying a cutoff on the frequency difference while maximizing discriminative performance. For validation, this subset was used to predict arthritis development in 225 clinically suspect arthralgia (CSA) patients. Diagnostic performance was compared to a reference method that uses the complete set of 61 features normalized for inflammation levels in age-matched controls. RESULTS: Subset of 30 features, mainly (teno)synovitis, was obtained from the case-control setting. Validation in CSA patients yielded an area of 0.69 (95% CI: 0.59-0.78) under the ROC curve and a positive predictive value (PPV) of 31%, compared to 0.68 (95% CI: 0.60-0.77) and 29% PPV of the reference method with 61 features. CONCLUSION: Subset of 30 MRI-detected inflammatory features, dominated by (teno)synovitis, offers a considerable reduction of scoring efforts without compromising accuracy for prediction of arthritis development in CSA patients.
30324407 Increased risk of sudden sensory neural hearing loss in patients with rheumatoid arthritis 2019 Mar To evaluate the association between sudden sensorineural hearing loss (SSNHL) and rheumatoid arthritis (RA) among a national sample cohort from Korea. Data were collected from 2002 through 2013 for individuals aged ≥ 20 years in the Korean National Health Insurance Service (NHIS)-National Sample Cohort. We extracted the data from RA patients (n = 7619) and 1:4-matched controls (n = 30,476) and analyzed the occurrence of SSNHL. Matching was performed based on age, sex, income, region of residence, and medical history. RA was diagnosed based on International Classification of Disease-10 (ICD-10) codes (M05 or M06) and prescriptions for the antirheumatic drugs. SSNHL was diagnosed based on the relevant ICD-10 code (H912). Among the SSNHL participants, we included only those who had undergone an audiometry exam (claim codes: E6931-E6937, F6341-F6348) and received treatment with steroids. The crude and adjusted hazard ratios (HRs) were calculated using Cox-proportional hazard models, and the 95% confidence intervals (CIs) were determined. Subgroup analyses based on age and sex were also performed. The rate of SSNHL in the RA group (0.8% [62/7619]) was higher than that in the control group (0.6% [177/30,476], P = 0.021). The crude and adjusted HRs for SSNHL were 1.40 (95% CI = 1.05-1.87) and 1.39 (95% CI = 1.04-1.86), respectively, in the RA group (each P < 0.05). The relationship between RA and SSNHL was observed primarily in patients aged ≥ 50 years and men. The risk of SSNHL is higher in patients with RA.
30381121 [Xinfeng capsule improves pulmonary function of rats with rheumatoid arthritis by inhibiti 2018 Jul Objective To observe the effect of Xinfeng capsule (XFC) on PKC/NF-κB pathway in the lung tissue of adjuvant arthritis (AA) rats. Methods Rats were divided into normal control(NC) group, model control(MC) group, XFC group, and leflunomide group (LEF). Except the NC group, the other three groups were induced into AA models with complete Freund's adjuvant (CFA). The XFC [0.34 g/(kg.d), 1 mL/100 g) or LEF 0.05 mg/(kg.d)] was administrated from day 19 after the injection of CFA by gavage, once a day for 30 days. Pulmonary function was observed. The levels of IL-6, IL-12, IL-10, IL-17, IL-35 and matrix metalloproteinases (MMP)-9 were detected by ELISA. Ras-associated C3 botoxin substrate 1 (Rac-1), PKC, NF-κBp65 mRNA were detected by real-time quantitative PCR. The levels of Rac-1, PKC, NF-κBp65 proteins were determined by Western blot analysis. The expression and distribution of PKC and NF-κB in the lung tissues were analyzed by immunohistochemical staining. Results The pulmonary function parameters such as FEV1, FEF50, FEF75 and peak expiratory flow (PEF) in the XFC group were significantly higher than those in the MC group. The expression of IL-10, IL-35 in the serum increased, and IL-6, IL-17 and MMP-9 decreased. Compared with the MC group, the expression of PKC, NF-κBp65 and Rac-1 decreased in the XFC group. Conclusion XFC improves the lung function by inhibiting the PKC/NF-κB pathway and balancing the cytokine network.
30333289 [Association of short-term efficacy for infliximab in rheumatoid arthritis with plasma con 2018 Sep 28 To investigate the correlation between peripheral concentration of infliximab (IFX) or anti-IFX antibody titers and short-term therapeutic effect of IFX in patients with active rheumatoid arthritis (RA).
 Methods: Twenty patients with active RA were treated with combination of methotrexate (MTX), leflunomide (LEF) with IFX, and the clinical and laboratory index and the side effects were recorded before and after IFX treatment. Twenty healthy subjects were chosen as a control group.
 Results: After 14-week treatment, patients were categorized into good, moderate or no responders according to EULAR remission criteria. There were no significant differences in peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels among the 3 groups, and there were no significant correlations among ΔDAS28-CRP, peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels.
 Conclusion: Peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels can not be used as reliable predictive index for short-term effect of IFX in active RA.
29671191 Rheumatoid arthritis is associated with increased in-hospital mortality in asthma exacerba 2018 Jul The relationship between RA and asthma has been yielding conflicting results, with most recent studies showing a possible positive association. The study aims at the outcomes of adult patients hospitalized for asthma exacerbation in those with and without RA. We used data from the National Inpatient Sample (NIS) for the period of 2012-2014. ICD 9 code was used to identify the diagnosis. Our primary outcome was in-hospital mortality. Our secondary outcome was total asthma exacerbation hospitalizations, length of stay, and total hospital charges. Compared to those without RA, RA was associated with increased hospitalizations for asthma exacerbation (unadjusted OR 1.29, p < 0.001; adjusted OR 1.06, p = 0.002), more respiratory and systemic comorbidities, increased in-hospital mortality (unadjusted OR 1.89, p = 0.001; adjusted OR 1.60, p = 0.020), length of stay (4.5 vs 3.8; unadjusted p < 0.001, adjusted p < 0.001), and total hospital charges (30,149 vs 26,247; unadjusted p < 0.001, adjusted p = 0.048). Our study was the first to demonstrate that RA is associated with increased in-hospital mortality, length of stay, and cost using a national inpatient database. We hypothesize that in asthmatic patients with concurrent RA, their asthma may represent a distinctive subgroup that is more severe and carries a poorer prognosis, which deserves more attention and future investigation.
29861659 The Effects of MicroRNAs on Key Signalling Pathways and Epigenetic Modification in Fibrobl 2018 MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level via direct binding to the 3'-untranslated region (UTR) of target mRNAs. Emerging evidence shows that miRNAs play crucial roles in controlling and modulating immune system-related diseases. This review focuses on the role played by miRNAs in fibroblast-like synoviocytes (FLS), which is a key cellular component within synovia, during the establishment and maintenance of rheumatoid arthritis (RA), a systemic inflammatory autoimmune disease. It also provides an overview and classification of known functional miRNAs in RA FLS and summarizes the potential uses of these small molecules in RA diagnosis and treatment.
29955612 Chemokine C-C Motif Ligand 4 Gene Polymorphisms Associated with Susceptibility to Rheumato 2018 Chemokine C-C motif ligand 4 (CCL4) gene is a chemokine-encoding gene, and the polymorphism of CCL4 gene has been shown to predict risk of various diseases. We want to investigate whether the single nucleotide polymorphisms (SNPs) of the CCL4 gene can predict the risk of rheumatoid arthritis (RA). Between 2007 and 2015, we recruited 217 patients diagnosed with RA and 371 control participants. Comparative genotyping of the rs1634507, rs10491121, and rs1719153 SNPs was performed. When compared with participants with the A/A genotype of rs1719153, those with the A/T genotype were less likely to develop RA, as were those with the A/T+T/T genotype. The protective effect of the T-containing genotype was even more prominent among females. Those with A/T in rs1719153 were 56% less likely to develop RA compared with females with A/A; a similar protective effect was seen for females with the A/T+T/T genotype compared with those with A/A. The GTEx database revealed that patients carrying the T/T genotype had lower levels of CCL4 gene expression than those carrying the A/A genotype. These results indicate that the nucleotide T over the rs1719153 is associated with decreased CCL4 gene expression and decreased risk for RA.
29495940 Fragmented hyaluronan has no alarmin function assessed in arthritis synovial fibroblast an 2018 Feb Hyaluronan (HA) is a large polymer and an important component of the extracellular matrix. During homeostasis, high molecular mass HA is the predominant form, but upon inflammation, degradation products of HA accumulate. These HA fragments (HA-fs) have been reported to possess pro-inflammatory activities and thus act as alarmins, notifying immune cells of danger via TLR4 and CD44. HA is found in large quantities in synovial joint fluid. In order to reveal a potential role of HA-fs in arthritis pathogenesis, the in vitro effects of HA of various molecular masses (from 1680 kDa to oligosaccharide HA) on synovial fibroblasts and chondrocytes from rheumatoid arthritis patients, and on peripheral blood mononuclear cells from healthy donors, were investigated. TLR4 and CD44 surface expression was confirmed by immunocytochemistry, and cell activation was determined based on cytokine and chemokine production. While the cell types investigated expressed TLR4 and CD44, no increased release of IL-1ß, IL-6, IL-8, IL-10, IL-12 or TNF-α was detected after HA stimulation. Similarly, HA did not enhance activation after priming cells with low doses of LPS or by forming complexes with LPS. Hence, this study does not support the common view of HA-fs being pro-inflammatory mediators and it is not likely that HA-fs generated during arthritis contribute to disease pathogenesis.
29620639 The role of leptin in osteoarthritis. 2018 Apr BACKGROUND: The pathogenesis of osteoarthritis (OA) is not clear; leptin may be related to its pathogenesis. METHODS: We reviewed articles on leptin in OA, chondrocytes, and in vitro experiments. It is concluded that leptin may lead to OA via some signaling pathways. At the same time, the concentration of leptin in vitro experiments and OA/rheumatoid arthritis (RA) patients was summarized. RESULTS: Leptin levels in serum and synovial fluid of OA/RA patients were higher than normal person. In the condition of infection and immunity, serum leptin levels in the peripheral blood significantly increase. Because of the close relationship between obesity, leptin, and OA, it is crucial to study the effects of weight loss and exercise intervention on serum leptin levels to improve the symptoms of OA patients. CONCLUSION: Treatment for leptin-increased obesity may be a treatment for OA. The role of leptin in OA cannot be ignored and needs to be further studied.
30092680 The three-year efficacy of iguratimod in clinical daily practice in patients with rheumato 2019 Sep Objectives: To assess the middle-term outcome of iguratimod (IGU) in rheumatoid arthritis (RA) patients. Methods: Sixty-nine RA patients (14 males and 55 females, mean age of 64.0 years) receiving IGU-containing therapies were enrolled. We divided these patients into three groups based on the treatment at the baseline: an IGU group, a methotrexate (MTX) plus IGU group, and a biologics plus IGU group. The baseline characteristics and clinical course were evaluated over three years. Predictive factors associated with the achievement of low disease activity (LDA) were statistically analyzed. Results: The survival rate of IGU therapy at 3 years was 40.6%. The disease activity was significantly decreased in the IGU group and MTX plus IGU group compared with the baseline. Furthermore, 38 patients (55.1%) were in remission or had LDA at 3 years. The patient gender, use of prednisolone (PSL) and DAS28-CRP at baseline were the factors associated with the achievement of remission or LDA at three years. Conclusion: IGU was effective without MTX or bDMARDs as well as in combination with MTX. A female gender, no use of PSL and a low DAS28-CRP at the initiation of IGU were associated with clinical remission or LDA achievement at three years.
30100102 Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders. 2018 Nov Dysregulation of innate immunity accompanied by excessive interferon production contributes to autoimmune disease. However, the mechanism by which the immune response is modulated in autoimmune disorders is largely unknown. Here we identified loss-of-function mutations of OTUD1 associated with multiple autoimmune diseases. Under inflammatory conditions, inducible OTUD1 acts as an immune checkpoint and blocks RIG-I-like receptors signaling. As a deubiquitinase, OTUD1 directly interacts with transcription factor IRF3 and removes the K63-linked poly-ubiquitin chains on IRF3 Lysine 98, which inhibits IRF3 nuclear translocation and transcriptional activity. In contrast, OTUD1 mutants impair its suppressive effects on IRF3 via attenuating the OTUD1 deubiquinase activity or its association with IRF3. Moreover, we found FOXO3 signaling is required for OTUD1 induction upon antigenic stimulation. Our data demonstrate that OTUD1 is involved in maintaining immune homeostasis and loss-of-function mutations of OTUD1 enhance the immune response and are associated with autoimmunity.
29439289 Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheuma 2018 Jun OBJECTIVE: The 24-week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate-to-severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks. METHODS: In this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week). At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group). Efficacy, safety, and immunogenicity were evaluated up to 52 weeks. RESULTS: The full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group). The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study. ACR20 response rates ranged from 73.4% to 78.8% at week 52. Radiographic progression was minimal and comparable across treatment groups. The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition. CONCLUSION: SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment-emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy.
29572291 Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal 2018 Jun OBJECTIVE: To determine whether a 2-week methotrexate (MTX) discontinuation after vaccination improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA). METHODS: In this prospective randomised parallel-group multicentre study, patients with RA on stable dose of MTX were randomly assigned at a ratio of 1:1 to continue MTX or to hold MTX for 2 weeks after 2016-2017 quadrivalent seasonal influenza vaccine containing H1N1, H3N2, B-Yamagata and B-Victoria. The primary outcome was frequency of satisfactory vaccine response, defined as greater than or equal to fourfold increase of haemagglutination inhibition (HI) antibody titre at 4 weeks after vaccination against ≥2 of four vaccine strains. Secondary endpoints included seroprotection (ie, HI titre ≥1:40) rate, fold change in antibody titres. RESULTS: The modified intention-to-treat population included 156 patients in the MTX-continue group and 160 patients in the MTX-hold group. More patients in MTX-hold group achieved satisfactory vaccine response than the MTX-continue group (75.5% vs 54.5%, p<0.001). Seroprotection rate was higher in the MTX-hold group than the MTX-continue group for all four antigens (H1N1: difference 10.7%, 95% CI 2.0% to 19.3%; H3N2: difference 15.9%, 95% CI 5.9% to 26.0%; B-Yamagata: difference13.7%, 95% CI 5.2% to 22.4%; B-Victoria: difference 14.7%, 95% CI 4.5% to 25.0%). The MTX-hold group showed higher fold increase in their antibody titres against all four influenza antigens (all p<0.05). Change in disease activity was similar between groups. CONCLUSIONS: A temporary MTX discontinuation for 2 weeks after vaccination improves the immunogenicity of seasonal influenza vaccination in patients with RA without increasing RA disease activity. TRIAL REGISTRATION: NCT02897011.