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29631060 Comparison of adult spinal deformity patients with and without rheumatoid arthritis underg 2018 Oct BACKGROUND CONTEXT: Numerous studies have analyzed the impact of rheumatoid arthritis (RA) on the cervical spine and its related surgical interventions. However, there is a paucity of literature available conducting the same analyses in patients with non-cervical spine involvement. PURPOSE: The objective of this study was to compare patient characteristics, comorbidities, and complications in patients with and without RA undergoing primary non-cervical spinal fusions. STUDY DESIGN/SETTING: This is a retrospective national database review. PATIENT SAMPLE: A total of 52,818 patients with adult spinal deformity undergoing non-cervical spinal fusions (1,814 patients with RA and 51,004 patients without RA). OUTCOME MEASURES: The outcome measures in the study include patient characteristics, as well as complication and mortality rates. MATERIALS AND METHODS: Using the Nationwide Inpatient Sample from 2003 to 2014, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes were used to identify patients aged ≥18 years old with and without RA undergoing primary non-cervical spinal fusions. Univariate analysis was used to determine patient characteristics, comorbidities, and complication values for each group. Bivariate analysis was used to compare the two groups. Significance was set at p<.05. RESULTS: Patients with RA were older (p<.001), were more likely to be women (p<.001), had increased rates of osteoporosis (p<.001), had a greater percentage of their surgeries reimbursed by Medicare (p<.001), and more often had weekend admissions (p=.014). There was no difference in all the other characteristics. Patients with RA had higher rates of iron deficiency anemia, congestive heart failure, chronic pulmonary disease, depression, and fluid and electrolyte disorders (all, p<.001). Patients without RA had higher rates of alcohol abuse (p=.027). There was no difference in all the other complications. There was no difference in mortality rate (p=.99). Total complications were greater in patients with RA (p<.001). Patients with RA had higher rates of infection (p=.032), implant-related complications (p=.010), incidental durotomies (p=.001), and urinary tract infections (p<.001). No difference existed among the other complications. CONCLUSIONS: Patients with RA have an increased number of comorbidities and complication rates compared with patients without RA. Such knowledge can help surgeons and patients with RA have beneficial preoperative discussions regarding outcomes.
29455165 Community-deliverable exercise and anxiety in adults with arthritis and other rheumatic di 2018 Feb 17 BACKGROUND/PURPOSE: Given conflicting findings, the purpose of this study was to use the meta-analytic approach to examine the effects of exercise (aerobic, strength training or both) on anxiety in adults with arthritis and other rheumatic diseases (AORD). METHODS: Randomised controlled exercise intervention trials ≥4weeks in adults ≥18 years of age with osteoarthritis, rheumatoid arthritis or fibromyalgia were included. Studies were located by searching eight electronic databases, cross-referencing and expert review. Dual selection and data abstraction of studies were performed. Hedge's standardised effect size (ES) was calculated for each result and pooled using the recently developed inverse heterogeneity model. Two-tailed z-alpha values ≤0.05 and non-overlapping 95% CI were considered statistically significant. Heterogeneity was estimated using Q and I(2) with alpha values ≤0.10 for Q considered statistically significant. Small-study effects were examined using funnel plots and Egger's regression test. In addition, the number needed to treat (NNT), percentile improvement and meta-regression were conducted. RESULTS: Of the 639 citations screened, 14 studies representing 926 initially enrolled participants (539 exercise, 387 control) met the criteria for inclusion. Length of training (mean±SD) averaged 15.8±6.7 weeks, frequency 3.3±1.3 times per week and duration 28.8±14.3 min per session. Overall, statistically significant reductions in anxiety were found (exercise minus control changes ES=-0.40, 95% CI -0.65 to -0.15, tau(2)=0.14; Q=40.3, P=0.0004; I(2) =62.8%). The NNT was 6 with a percentile improvement of 15.5% and an estimated 5.3 million inactive US adults with AORD improving their anxiety if they started exercising regularly. Statistically significant small-study effects were observed (P<0.0001). CONCLUSIONS: Exercise is associated with reductions in anxiety among adults with selected types of AORD. However, a need exists for additional, well-designed, randomised controlled trials on this topic. PROSPERO REGISTRATION NUMBER: CRD42016048728.
30229926 Population Pharmacokinetics and Exposure-Response Relationship of Intravenous and Subcutan 2019 Feb Abatacept population pharmacokinetics (PK) and exposure-response (E-R) models for selective efficacy end points were developed using phase 2 and 3 study data in patients with rheumatoid arthritis treated with abatacept (intravenous [IV] or subcutaneous [SC]), followed by simulations. Two efficacy end points were assessed in the E-R analyses: Disease Activity Score in 28 joints (DAS28) and American College of Rheumatology response criteria for 20/50/70% improvement (ACR20/50/70). The analyses were performed with data from 11 clinical studies for the population PK analysis and from 3 clinical studies for the E-R analyses (DAS28 and ACR20/50/70). The PK of abatacept were time invariant and can be described by a linear 2-compartment model with first-order elimination and with zero-order IV infusion or first-order absorption for SC abatacept. Baseline body weight was the only clinically meaningful covariate; that is, abatacept clearance and volume of central compartment increased with increasing baseline body weight. Steady-state trough concentration (C(minss) ) of abatacept was identified as the best exposure predictor of DAS28 response compared with other exposure measures. In addition, the E-R relationship was the same for IV and SC abatacept. Similar results were confirmed in the ACR20/50/70 E-R analyses. Efficacy responses increased with increasing C(minss) and a near-maximal response was associated with C(minss) ≥10 μg/mL. The model-based analyses confirmed that the weight-tiered ∼10 mg/kg IV and fixed 125 mg SC abatacept dosing regimens are comparable and achieved plateau responses, by delivering C(minss) ≥10 μg/mL in RA patients across all body weights.
29717034 Magnetic Resonance Imaging of Bilateral Hands Is More Optimal Than MRI of Unilateral Hands 2018 Jul OBJECTIVE: To explore the advantages of magnetic resonance imaging (MRI) of bilateral hands in rheumatoid arthritis (RA). METHODS: Consecutive patients with active RA were recruited for clinical assessments, radiographs, and MRI of bilateral hands. Bilateral hands were scanned simultaneously on 3.0 T whole-body MRI system and were scored on synovitis, osteitis, and bone erosion according to the RA MRI scoring (RAMRIS) system. RESULTS: Among 120 patients included, wrist bones and metacarpophalangeal joint (MCPJ) 2 proximal showed bone erosion in early RA. The second to fifth metacarpal bases and the second to fourth MCPJ distal showed more bone erosion in mid-stage or late-stage RA. When MRI of dominant unilateral hand was analyzed, MRI synovitis and osteitis in 5% of wrists and 3 MRI features in 5-14% of MCPJ were misdiagnosed (McNemar test, all p < 0.05). There were 46% wrist synovitis, 29-52% MCPJ2-5 synovitis, 45% wrist osteitis, and 20%-34% MCPJ2-5 osteitis not detected by joint tenderness and/or swelling. When the clinically more severe hand was selected for MRI of unilateral hand according to physical examination, MRI synovitis in 5% of wrists and 3 MRI features in 7-15% of MCPJ were misdiagnosed (all p < 0.05). Scatter plots and linear regression analyses were used to illustrate RAMRIS between dominant or selected hand (Y values) and nondominant or nonselected hand (X values). All linear models were markedly different from a Y = X linear model, indicating the dominant or clinically more severe hand could not represent the contralateral hand to evaluate RAMRIS. CONCLUSION: MRI of bilateral hands is more optimal than MRI of the unilateral hand in RA.
29142026 A Systematic Review of Quality Measures for Inflammatory Arthritis. 2018 Feb OBJECTIVE: To conduct a systematic review and quality appraisal of quality measures for inflammatory arthritis, including rheumatoid arthritis (RA), spondyloarthritis, psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). METHODS: Embase, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from January 1, 2000, to October 23, 2016, using Medical Subject Headings terms for inflammatory arthritis and quality measures. A "grey literature" search of international arthritis organizations and quality measure libraries was also conducted. Two reviewers independently considered the papers for inclusion, with disagreements resolved by consensus. A modified guideline appraisal tool (AGREE II) was used to appraise the measure development process, which determined final inclusion. Measures were abstracted in duplicate and categorized into themes, measure type, and domains of quality. RESULTS: Thirteen measurement sets were included from 4 countries (United States, Canada, United Kingdom, Netherlands) and 1 European consortium. They included 10 sets on RA and 1 each for PsA, inflammatory arthritis, and JIA. There were 161 unique individual measures (136 process, 20 structure, and 5 outcome). Major themes included assessment, medications, and comorbidities. Measure development methods were varied, including RAND/University of California, Los Angeles appropriateness methodology, prioritization exercises, or other modified-Delphi methods. Inclusion of patients occurred in 77% of development groups. Discussion of barriers to measurement was infrequent. CONCLUSION: Inflammatory arthritis quality measures cover a diversity of themes encompassing process, structure, and outcomes of care across the 6 domains of quality. However, between organizations, measure development is not standardized. Local assessment of measurement feasibility before use outside the original development context is recommended.
29611083 Regional differences in baseline disease activity and remission rates following golimumab 2018 May GO-MORE (NCT00975130) was a large open-label, multinational, multicenter, prospective phase 3 trial evaluating add-on therapy with golimumab in biologic-naïve patients with active rheumatoid arthritis (RA). The objective of this post hoc analysis was to examine regional differences in baseline disease activity and remission rates following golimumab treatment for RA. This was a planned, descriptive post hoc analysis of data from the GO-MORE trial. Baseline disease activity and remission were defined as moderate or severe based on EULAR criteria. This analysis included 3280 participants from the GO-MORE trial. All participants included in this analysis had high or moderate disease activity at baseline. At baseline, high disease activity was least common in Europe (71.0%), Canada (77.0%), and the Middle East (78.2%) and most common in Latin America (90.7%), South Africa (91.5%), and Asia (92.5%). Month 6 remission rates were highest in South Africa (29.1%), Europe (27.9%), and the Middle East (27.3%) and lowest in Canada (19.7%), Latin America (17.2%), and Asia (15.0%). Higher rates of remission in each geographical region generally corresponded with lower baseline disease activity. We suspect that access to care and implementation of the treat-to-target strategy were the most important determinants, but this apparent relationship needs to be confirmed in further studies that include a statistical analysis of prognostic indicators.
29579371 Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis. 2018 Jul Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast-like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset-specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early-stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.
29546668 Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti- 2018 Sep As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Pfizer) of tofacitinib (TOF; Xeljanz(®)) to submit evidence of the drug's clinical and cost-effectiveness in the treatment of rheumatoid arthritis (RA) after the failure of conventional disease-modifying antirheumatic drugs (cDMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost-effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for TOF is based predominantly on four randomised controlled trials (RCTs) comparing the efficacy of TOF against placebo. Three RCTs investigated TOF in combination with methotrexate (MTX), and one RCT investigated TOF monotherapy. All four RCTs compared TOF with placebo plus cDMARDs, one RCT also included adalimumab as a comparator. The study population in the four RCTs comprised patients who were MTX inadequate responders or cDMARD inadequate responders (cDMARD-IR). The company performed network meta-analyses (NMA) to assess the relative efficacy of TOF compared with biologic DMARDs (bDMARDs) in patients who were cDMARD-IR or bDMARD-IR with moderate-to-severe RA for European League Against Rheumatism (EULAR) response and change in the Health Assessment Questionnaire Disability Index at 6 months. The company's NMA concluded that TOF had comparable efficacy to bDMARDs currently recommended by NICE. The company submitted a de novo model that assessed the cost-effectiveness of TOF versus its comparators in six different populations: (1) cDMARD-IR with severe RA; (2) cDMARD-IR with severe RA for whom MTX is contraindicated or not tolerated; (3) bDMARD-IR; (4) bDMARD-IR for whom rituximab (RTX) is contraindicated or not tolerated; (5) bDMARD-IR for whom MTX is contraindicated or not tolerated; and, (6) cDMARD-IR with moderate RA. According to the company's economic analyses, in cDMARD-IR with severe RA, TOF plus MTX dominates or extendedly dominates most comparators, whilst TOF monotherapy is slightly less effective and less expensive than its comparators, with the cost saved per quality-adjusted life year (QALY) lost always higher than £50,000. In bDMARD-IR with severe RA, RTX plus MTX dominated TOF plus MTX, but in patients for whom RTX was not an option, TOF plus MTX dominated all comparators included in the analysis (four comparators recommended by NICE were not included). In cDMARD-IR with moderate RA, the cost per QALY for TOF in combination with MTX or as monotherapy compared with a sequence of cDMARDs was estimated to be greater than £50,000/QALY. The ERG identified a number of limitations in the company's analyses, including use of a fixed-effects model in the NMA and the use of treatment sequences in the cost-effectiveness model which did not reflect NICE recommendations. These limitations were addressed partly by the company during the clarification round and partly by the ERG. The exploratory analyses undertaken by the ERG resulted in similar conclusions: (1) TOF plus MTX was dominated by RTX plus MTX; (2) TOF in combination with MTX or as monotherapy dominates or extendedly dominates some of its comparators in cDMARD-IR and bDMARD-IR with severe RA for whom RTX plus MTX was not an option; and (3) in cDMARD-IR with moderate RA, the cost per QALY of TOF in combination with MTX or as a monotherapy versus cDMARDs was in excess of £47,000. The NICE Appraisal Committee consequently recommended TOF plus MTX as an option for patients whose disease has responded inadequately to intensive therapy with a combination of cDMARDs only if (1) disease is severe [a Disease Activity Score (DAS28) of more than 5.1] and (2) the company provides TOF with the discount agreed in the Patient Access Scheme (PAS). TOF plus MTX is also recommended as an option for adults whose disease has responded inadequately to, or who cannot have, other DMARDs, including at least one bDMARD, only if (1) disease is severe, (2) they cannot have RTX, and (3) the company provides TOF with the discount agreed in the PAS. For patients who are intolerant of MTX, or where MTX is contraindicated, TOF monotherapy is recommended where TOF plus MTX would be recommended.
29882210 Sarilumab for Previously-Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Revi 2018 Dec As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Sanofi Genzyme) of sarilumab (SAR; Kevzara(®)) to submit evidence of its clinical effectiveness and cost-effectiveness for previously treated moderate or severe rheumatoid arthritis (RA). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical effectiveness and cost-effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for SAR was based predominantly on five randomised controlled trials comparing the efficacy of SAR against adalimumab, tocilizumab or placebo. The clinical effectiveness review identified no head-to-head evidence on the efficacy of SAR against all the comparators within the scope. Therefore, the company performed three network meta-analyses (NMAs) in two different populations: two in patients who had had an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARDs) (one for combination therapies and one for monotherapies) and the other one in patients who had had an inadequate response to tumour necrosis factor inhibitors (TNFis). The company's NMAs concluded that SAR in combination with cDMARDs or as monotherapy has a statistically superior efficacy to cDMARDs and a comparable efficacy to most biologic disease-modifying antirheumatic drugs (bDMARDs) in both populations. The company submitted a Markov model that assessed the cost-effectiveness of SAR from the perspective of the National Health Service (NHS) and Personal Social Services in seven different populations: (1) patients with severe RA who have had an inadequate response to cDMARDs (cDMARD-IR); (2) cDMARD-IR patients with severe RA for whom methotrexate (MTX) is contraindicated or not tolerated; (3) patients with severe RA who have had an inadequate response to a TNFi (TNFi-IR); (4) TNFi-IR patients with severe RA for whom rituximab (RTX) is not an option; (5) TNFi-IR patients with severe RA for whom MTX is contraindicated or not tolerated; (6) TNFi-IR patients after RTX; and (7) cDMARD-IR patients with moderate RA whose 28-joint Disease Activity Score (DAS28) is between 4.0 and 5.1. The company's economic evaluation resulted in incremental cost-effectiveness ratios (ICERs) lower than £20,000 per quality-adjusted life year (QALY) gained for SAR in combination with MTX or as monotherapy versus its comparators when the comparators were less effective, and it resulted in cost savings higher than £60,000 per QALY lost when SAR was less effective, except in TNFi-IR patients who are RTX eligible (where the ICER for SAR + MTX compared with RTX + MTX was £130,691 per QALY gained) and in patients with moderate RA and a DAS28 of > 4.0 (where the ICER of SAR + MTX compared with MTX was £38,254 per QALY gained). Following a critique of the model, the ERG undertook exploratory analyses after applying two changes to the company's model: (1) use of a latent class approach to model Health Assessment Questionnaire Disability Index (HAQ-DI) progression for patients on cDMARDs; and (2) amendment of the company's modelling of patient progression from moderate to severe RA. The ICERs estimated by the ERG's exploratory analyses for SAR + MTX increased to £171,466 per QALY gained when compared with RTX + MTX in TNFi-IR patients who are RTX eligible, and to £63,438 per QALY gained when compared with MTX in patients with moderate RA and a DAS28 of > 4.0. The Appraisal Committee concluded that SAR in combination with MTX or as monotherapy is a cost-effective use of NHS resources in the considered populations, except in TNFi-IR patients who are RTX eligible and in patients with moderate RA and a DAS28 of > 4.0.
29736870 Can we predict thrombotic tendency in rheumatoid arthritis? A thromboelastographic analysi 2018 Sep The higher incidence of arterial and venous events is well established in patients with rheumatoid arthritis (RA). Our aim here was to investigate whether there is a prothrombotic state in RA patients by using rotational thromboelastometry (ROTEM) method and to demonstrate whether the disease variables play a role in this process. A total of 85 patients who met the 2010 RA classification criteria were consecutively included in the study. The patients with RA who have been using antiaggregant, anticoagulant, or nonsteroidal anti-inflammatory drugs (NSAIDs) and had a history of arterial or venous thromboembolism were excluded from the study. Their complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, D-dimer, and lipid profiles were measured, DAS-28 disease activation scores were calculated, and simultaneous ROTEM analysis was performed to determine the predisposition to thrombosis. Of the ROTEM parameters, clotting time (CT, seconds (s)), clot formation time (CFT, s), and maximum clot firmness (MCF) were evaluated. Having a shorter CT and/or CFT in intrinsic (I) or extrinsic (E) pathway and/or a longer MCF compared to the healthy controls was considered as "predisposition to hypercoagulability". The mean age of the 85 RA patients were 54.12 ± 13 years, and 77.6% of the patients were female (n = 66). Of the patients, 52.9% (n = 45) were using methotrexate (MTX) ± hydroxychloroquine (HCQ) ± corticosteroid (CS), while 43.5% (n = 37) were using anti-tumor necrosis factor (TNF) ± MTX. Active steroid usage was ongoing in 64.7% of the patients (n = 55). When evaluated according to DAS-28, in those with higher disease activity, a shorter I-CFT and greater I-MCF were determined (p = 0.020 and p = 0.033, respectively). In those with higher disease activity based on the correlation analysis, I-CFT and E-CFT were shorter and I-MCF and E-MCF were longer, indicating a higher predisposition to thrombosis. Using linear regression, variables with a major effect on ROTEM parameters were identified as DAS-28, CRP, and platelet count. As the first study in the literature, we identified that disease activation is the most important risk factor for prothrombotic state in RA patients irrespective of the drugs used. ROTEM can be used in clinical practice to predict thrombotic events in RA patients.
29327326 IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells. 2018 May IL-11 has been detected in inflamed joints; however, its role in the pathogenesis of arthritis is not yet clear. Studies were conducted to characterize the expression and functional significance of IL-11 and IL-11Rα in rheumatoid arthritis (RA). IL-11 levels were elevated in RA synovial fluid (SF) compared to osteoarthritis (OA) SF and plasma from RA, OA and normal individuals (NLs). Morphologic studies established that IL-11 was detected in lining fibroblasts and macrophages in addition to sublining endothelial cells and macrophages at higher levels in RA compared to NL synovial tissues. Since IL-11Rα was exclusively expressed in RA fibroblasts and endothelial cells, macrophages were not involved in IL-11 effector function. Ligation of IL-11 to IL-11Rα strongly provoked fibroblast infiltration into RA joint, while cell proliferation was unaffected by this process. Secretion of IL-8 and VEGF from IL-11 activated RA fibroblasts was responsible for the indirect effect of IL-11 on endothelial cell transmigration and tube formation. Moreover, IL-11 blockade impaired RA SF capacity to elicit endothelial cell transmigration and tube formation. We conclude that IL-11 binding to endothelial IL-11Rα can directly induce RA angiogenesis. In addition, secretion of proangiogenic factors from migrating fibroblasts potentiated by IL-11 can indirectly contribute to RA neovascularization.
28803184 Association of Asthma with Rheumatoid Arthritis: A Population-Based Case-Control Study. 2018 Jan BACKGROUND: T(H)1 and T(H)2 cells have counterregulatory relationships. However, the relationship between asthma, a T(H)2-predominant condition, and risk of systemic inflammatory diseases such as rheumatoid arthritis (RA), a T(H)1 condition, is poorly understood. OBJECTIVE: We aimed to determine whether asthma was associated with increased risks of incident RA among adults. METHODS: We conducted a retrospective population-based case-control study that examined existing incident RA cases and controls matched by age, sex, and registration year from the general population in Olmsted County, Minnesota, between January 2002 and December 2007. We performed comprehensive medical record reviews to ascertain asthma status using predetermined asthma criteria. The frequency of a history of asthma before the index date was compared between cases and controls. Logistic regression models were used to adjust for confounding factors. RESULTS: We enrolled 221 RA cases and 218 controls. Of the 221 RA cases, 156 (70.6%) were females, 207 (93.7%) were white, the median age at the index date was 52.5 years, and 53 (24.0%) had a history of asthma. Controls had similar characteristics except that 35 of 218 controls (16.1%) had a history of asthma. After adjustment for sex, age, smoking, body mass index, socioeconomic status, and comorbidity, asthma was significantly associated with increased risks of RA (adjusted odds ratio, 1.74; 95% CI, 1.05-2.90; P = .03). CONCLUSIONS: Despite the counterregulatory relationship between T(H)1 and T(H)2 cells, patients with asthma had a significantly higher risk of developing RA than healthy individuals.
29264794 High frequency of mutant thiopurine S-methyltransferase genotypes in Mexican patients with 2018 Apr Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are treated with immunosuppressive purine analogs, 6-mercaptopurine/6-thioguanine/azathiopurine, which are inactivated by thiopurine S-methyltransferase (TPMT). Non-synonymous polymorphisms in TPMT are associated with increased risk of adverse effects in patients treated with thiopurines. This study aimed to determine the frequency of the most common mutant TPMT alleles in Mexican patients with SLE (a prototype autoimmune disease) and RA (one of the most common autoimmune diseases in Mexico). Five hundred fifty-three consecutive patients from Central Mexico with SLE (178) and RA (375) were included. Subjects were genotyped to identify TPMT*2 (rs1800462), TPMT*3A (rs1800460 and rs1142345), TPMT*3B (rs1800460), and TPMT*3C (rs1142345) mutant alleles. DNA samples were assayed with the 5' exonuclease technique and TaqMan probes. Mutant alleles were detected in 6.2 and 5.2% of SLE and RA cases, respectively. Of note, 12.4% of SLE cases and 10.1% of RA cases carried mutant genotypes. Among those, the null genotype (TPMT*2/*3A, 0.3%) and the TPMT*3B (0.5%) and TPMT*3C (1.0%) alleles were found in RA, but not SLE cases. Mexican SLE cases displayed the highest frequency of mutant TPMT genotypes worldwide. TPMT genotyping should be performed for Mexican patients with SLE and RA before prescribing purine analogs.
30187188 Co-Delivery of Teriflunomide and Methotrexate from Hydroxyapatite Nanoparticles for the Tr 2018 Sep 5 PURPOSE: The present investigation was aimed at developing Teriflunomide (TEF) and Methotrexate (MTX) loaded hydroxyapatite nanoparticles and increasing tolerability towards combination therapy against rheumatoid arthritis by reducing hepatotoxicity. METHODS: Drug-loaded HAp-NPs were synthesized by wet-chemical precipitation method and optimized by Box-Behnken experimental design. The developed NPs were subjected to in vitro and in vivo characterization. In-vivo pharmacodynamics and biochemical studies were performed on adjuvant- induced arthritis model treated with different formulations; MTX-TEF-SOL, TEF-HAp-NP, MTX-HAp-NP, TEF-MTX-HAp-NP, FOLITRAX-10 and AUBAGIO. RESULTS: The size of the optimized formulations, TEF-HAp-NP and MTX-HAp-NP, was found to be 224.3 ± 83.80 nm and 268.3 ± 73.86 nm with drug loading 53.11 ± 0.84% and 67.04 ± 1.12% respectively. In vitro release of TEF from TEF-HAp-NP (70.41 ± 1.22%) and MTX from MTX-HAp-NP (82.43 ± 1.31%) up to 24 h revealed sustained release pattern. Results of the arthritic assessment study showed a significant (P < 0.05) reduction in ankle diameter (61.30 ± 7.42) and arthritis score (2.35 ± 0.24) with a marked restoration of ankle joint micro-architecture in TEF-MTX-HAp-NP treated group. During Hepatotoxicity studies, liver histopathology revealed that the formulation MTX-TEF-HAp-NP was least hepatotoxic with less hepatocyte swelling and fibrous connective tissue proliferation while Folitrax-10 was found to be most hepatotoxic. Biochemical studies revealed that Folitrax-10 significantly (P < 0.05) increased the GOT (313.64 ± 16) and GPT level (334.46 ± 13) while insignificant (P > 0.05) change in GOT (263.68 ± 17) and GPT (229.38 ± 10) level was recorded with TEF-MTX-HAp-NP. CONCLUSIONS: We report that the subcutaneous delivery of TEF-MTX-HAp-NP was most effective as it successfully reduced the dosage by half for maximizing therapeutic efficacy and minimizing side effects. Graphical Abstract ᅟ.
29907674 Feasibility of Measurement and Adherence to System Performance Measures for Rheumatoid Art 2018 Nov OBJECTIVE: To test the feasibility of reporting on 4 national performance measures for patients with rheumatoid arthritis (RA) in 5 different models of care. METHODS: The following performance measures were evaluated in 5 models of care: waiting time (WT) to rheumatologist consultation, percentage of patients seen in yearly followup (FU), percentage taking disease-modifying antirheumatic drugs (DMARD), and time to starting DMARD. All models aimed to improve early access and care for patients with RA. RESULTS: A number of feasibility issues were encountered in performance measure evaluation because of differences in site data collection and/or the duration of the model of care. For example, while 4/5 programs maintained clinical or research databases, chart reviews were still required to report on WT. Median WT for care in 2015 varied by site between 21 and 75 days. Yearly FU rates could only be calculated in 2 sites (combined owing to small numbers) and varied between 83% and 100%. Percentage of patients taking a DMARD and time to DMARD could be calculated in 3 models, and rates of DMARD use were between 90% and 100%, with median time to DMARD of 0 days in each. CONCLUSION: Our review has shown that even in models of care designed to improve access to care and early treatment, data to document improvements are often lacking. Where data were available for measuring, deficits in WT performance were noted for some centers. Our results highlight a need to improve reporting processes to drive quality improvement.
28972441 Efficacy and safety of infliximab: A comparison with other biological disease-modifying an 2018 Jul OBJECTIVES: The intensification of infliximab (IFX) treatment, involving escalation of the dose and shortening of interval, was approved in Japan in July 2009. We consider IFX intensification therapy to be preferable for patients with treatment-resistant active rheumatoid arthritis (RA). We retrospectively compared the efficacy of IFX with that of other bDMARDs in methotrexate (MTX)-resistant patients. METHODS: Patients who satisfied the following criteria were enrolled: (i) those who started bDMARDs between February 2011 and December 2016, and (ii) those who required bDMARDs after 180 d of MTX treatment. We compared 33 patients who had been treated with IFX (IFX group) and 146 who had received other bDMARDs treatment (non-IFX group). RESULTS: IFX was administered at a dose of 6.98 mg/kg/8-week equivalent at 52 weeks. Clinical disease activity index clinical remission (CDAI-CR) was achieved in 49 of the 179 patients at 52 weeks and 13 of these 49 patients received IFX. Logistic regression analysis showed that treatment with IFX was an important variable for the achievement of CDAI-CR at 52 weeks (odds ratio 2.69, 95% confidence interval 1.13-6.42). The severity and frequency of adverse events did not differ. CONCLUSION: Intensification of IFX was effective and well tolerated for MTX resistant patients.
30327328 How to treat patients with rheumatoid arthritis when methotrexate has failed? The use of a 2019 Jan OBJECTIVES: To compare consecutive disease modifying antirheumatic drug (DMARD)-treatment regimes in daily practice in patients with rheumatoid arthritis (RA) who failed on initial methotrexate, while using a multiple propensity score (PS) method to control for the spurious effects of confounding by indication. METHODS: Patients with newly diagnosed RA who had failed initial treatment with methotrexate were selected from METEOR, an international, observational registry. Subsequent DMARD-treatment regimens were categorised as: (1) conventional synthetic DMARD(s) (csDMARD(s)) only (143 patients), (2) csDMARD(s)+glucocorticoid (278 patients) and (3) biological DMARD (bDMARD)±csDMARD(s) (89 patients). Multiple PS that reflect the likelihood of treatment with each treatment-regime were estimated per patient using multinomial regression. Linear mixed model analyses were performed to analyse treatment responses per category (Disease Activity Score (DAS)) after a maximum follow-up duration of 6 and 12 months, and results were presented with adjustment for the multiple PS. RESULTS: After 6 months, follow-up PS-adjusted treatment responses yielded a change in DAS per year (95%  CI) of -2.00 (-2.65 to -1.36) if patients received a bDMARD; of -0.96 (-1.33 to -0.59) if patients received csDMARD(s)+glucocorticoids and of -0.73 (-1.21 to -0.25) if patients received csDMARDs only. These changes were -0.91 (-1.23 to -0.60); -0.43 (-0.62 to -0.23) and -0.39 (-0.66 to -0.13), respectively after 1  year of follow-up. CONCLUSIONS: In this analysis of worldwide common practice data with adjustment for multiple PS, patients with RA who had failed initial treatment with methotrexate monotherapy had a better DAS-response after a subsequent switch to a bDMARD-containing treatment regimen than to a regimen with csDMARD(s) only, with or without glucocorticoids.
29592917 Serious infection across biologic-treated patients with rheumatoid arthritis: results from 2018 Jun OBJECTIVES: To compare the incidence of serious infection (SI) across biologic drugs used to treat rheumatoid arthritis (RA) using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA). METHODS: The BSRBR-RA is a prospective observational cohort study. This analysis included patients with RA starting a new biologic. The primary outcome was SI defined as an infectious event requiring admission to hospital, intravenous antibiotics or resulting in death. Event rates were calculated and compared across biologics using Cox proportional hazards with adjustment for potential confounders. Secondary outcomes were the rate of infection by organ class and 30-day mortality following infection. RESULTS: This analysis included 19 282 patients with 46 771 years of follow-up. The incidence of SI was 5.51 cases per 100 patient years for the entire cohort (95% CI 5.29 to 5.71). Compared with etanercept, tocilizumab had a higher risk of SI (HR 1.22, 95% CI 1.02 to 1.47) and certolizumab pegol a lower risk of SI (HR 0.75, 95% CI 0.58 to 0.97) in the fully adjusted model. The 30-day mortality following SI was 10.4% (95% CI 9.2% to 11.6%). CONCLUSIONS: The rate of SI was lower with certolizumab pegol than etanercept in the primary analysis but the result was no longer significant in several sensitivity analyses performed suggesting residual confounding may account for the observed difference. From these results, it would be wrong to conclude that certolizumab pegol has a lower rate of SI than other biologics; however, the risk does not appear to be significantly higher as has previously been suggested.
29336365 IL1F7 Gene Polymorphism Is not Associated with Rheumatoid Arthritis Susceptibility in the 2018 Jan 20 BACKGROUND: Interleukin (IL)-37, also called IL1F7, is a natural inhibitor of inflammatory and immune responses. It is involved in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the role of IL1F7 gene polymorphism in RA susceptibility in a large cohort of patients. METHODS: Five selected single-nucleotide polymorphisms in IL1F7 genes (rs2723186, rs3811046, rs4241122, rs4364030, and rs4392270) were genotyped by TaqMan Allelic Discrimination in Northern Chinese Han population. The allele and the genotype were compared between patients with RA and healthy controls. Association analyses were performed on the entire data set and on different RA subsets based on the status of the anti-cyclic citrullinated peptide antibody and the rheumatoid factor by logistic regression, adjusting for age and gender. RESULTS: Trend associations were detected between rs2723186, rs4241122, rs4392270, and RA in Stage I (160 patients with RA; 252 healthy controls). Further validation in Stage II comprised 730 unrelated patients with RA (mean age: 54.9 ± 12.6 years; 81.6% females) and 778 unrelated healthy individuals (mean age: 53.5 ± 15.7 years; 79.5% females). No significant differences in the distributions of alleles and genotypes were observed between the case and control groups in both the entire set and the different RA subsets. Disease activity and age of RA onset were also not associated with genotype distributions. CONCLUSION: IL1F7 gene polymorphism does not significantly influence RA susceptibility in the Northern Chinese Han population.
28214596 Early non-response to certolizumab pegol in rheumatoid arthritis predicts treatment failur 2018 Jan OBJECTIVES: To compare different early clinical criteria of non-response determined at three months as predictors of clinical failure at one year in patients with rheumatoid arthritis starting therapy with certolizumab pegol. METHODS: Data were derived from a randomised Phase III clinical trial in patients with rheumatoid arthritis who failed to respond to methotrexate monotherapy. Patients included in this post-hoc analysis were treated with certolizumab pegol (400mg qd reduced to 200mg qd after one month) and with methotrexate. The study duration was twelve months. Response at three months was determined with the American College of Rheumatology-50, Disease Assessment Score-28 ESR, Health Assessment Questionnaire and the Clinical Disease Activity Index. The performance of these measures at predicting treatment failure at twelve months defined by the American College of Rheumatology-50 criteria was determined, using the positive predictive values as the principal evaluation criterion. RESULTS: Three hundred and eighty two patients were available for analysis and 225 completed the twelve-month follow-up. At Week 52, 149 (38.1%) patients met the American College of Rheumatology-50 response criterion. Positive predictive values ranged from 81% for a decrease in Health Assessment Questionnaire- Disability index score since baseline >0.22 to 95% for a decrease in Disease Assessment Score-28 score since baseline≥1.2. Sensitivity was≤70% in all cases. Performance of these measures was similar irrespective of the definition of treatment failure at 12months. CONCLUSIONS: Simple clinical measures of disease activity can predict future treatment failure reliably and are appropriate for implementing treat-to-target treatment strategies in everyday practice.