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ID PMID Title PublicationDate abstract
28057661 Risk and severity of herpes zoster in patients with rheumatoid arthritis receiving differe 2017 Jan 5 OBJECTIVE: Increasing evidence indicates that the risk of herpes zoster (HZ) is elevated in rheumatoid arthritis (RA). Little is known about the epidemiology of HZ in patients with RA in Asia. The aim of this study was to determine the risk factors and outcomes of HZ among patients with RA. DESIGN: A case-control study. SETTING: A medical centre in Asia. PARTICIPANTS: A total of 9025 newly diagnosed and eligible patients with RA (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 714.0) during the period 2001-2014. Among them, 275 (3.05%) were newly diagnosed with HZ (ICD-9-CM code 053.0) after the RA identification. As the control group, patients with RA without HZ were matched for age, gender and RA disease duration at the time of HZ infection with the RA-HZ case group at a ratio of 4:1, and a total of 1100 control subjects were selected. OUTCOME MEASURES: We estimated ORs using conditional logistic regression to investigate the risk and severity of HZ among patients with RA receiving different immunosuppressive medications. RESULTS: Exposure to corticosteroids (≥10 mg/day adjusted OR (aOR)=2.30, 95% CI 1.25 to 4.22, p=0.01), anti-tumour necrosis factor biologicals (aOR=2.07, 95% CI 1.34 to 3.19, p=0.001) and conventional synthetic disease-modifying anti-rheumatic drugs (methotrexate (aOR=1.98, 95% CI 1.43 to 2.76, p<0.001) and hydroxychloroquine (aOR=1.95, 95% CI 1.39 to 2.73, p<0.001)) was associated with an increased HZ risk in patients with RA. The association between the use of corticosteroids and HZ risk was dose-dependent (p(trend)<0.001). Time-to-HZ diagnosis among patients with RA receiving biological medications was significantly shorter than that in patients not receiving biological medications. A higher proportion of severe HZ and ophthalmic involvement was found in patients with RA receiving biologicals. CONCLUSIONS: There was an increased risk of HZ in patients with RA taking specific immunosuppressive medication. Biologicals used were associated with severe HZ occurrence. Therefore, it is important to closely monitor and prevent severe HZ complications during specific immunosuppressive therapy.
27440135 Investigation of the genetic overlap between rheumatoid arthritis and psoriatic arthritis 2017 May OBJECTIVES: Several rheumatoid arthritis (RA) susceptibility loci have also been found to be associated with psoriatic arthritis (PsA), demonstrating that there is a degree of genetic overlap between various autoimmune diseases. We sought to investigate whether single nucleotide polymorphisms (SNPs) mapping to previously reported RA and/or PsA susceptibility loci, including PLCL2, CCL21, REL, STAT4, CD226, PTPN22, and TYK2, are associated with risk for the two diseases in a genetically homogeneous Greek population. METHOD: This study included 392 RA patients, 126 PsA patients, and 521 healthy age- and sex-matched controls from Greece. Genotyping of the SNPs was performed with Taqman primer/probe sets. Bioinformatic analysis was performed using BlastP, PyMOL, and Maestro and Desmond. RESULTS: A significant association was detected between the GC genotype of rs34536443 (TYK2) in both the PsA and RA cohorts. The C allele of this SNP was associated with PsA only. Evidence for association with PsA was also found for the GG genotype and G allele of the rs10181656 SNP of STAT4. The TC genotype of the rs763361 SNP of CD226 was associated with PsA only. CONCLUSIONS: Genetic overlap between PsA and RA was detected for the rs34536443 SNP of the TYK2 gene within a Greek population. An association of STAT4 (rs10181656) with PsA was confirmed whereas CD226 (rs763361) was associated with PsA but not with RA, in contrast to previous reports. The different findings of this study compared to previous ones highlights the importance of comparative studies that include various ethnic or racial populations.
28097508 Preparation and evaluation of biopolymeric nanoparticles as drug delivery system in effect 2017 Mar PURPOSE: The study purposes to evaluate nanocrystalline biopolymeric nanoparticles encapsulating methotrexate and dexamethasone with high biocompatibility, enhanced therapeutic efficacy and reduced toxicity. METHODS: Chitosan nanoparticles were prepared by ionic gelation, and Methotrexate (MTX) and Dexamethasone (DEX) were loaded during the preparation and screened for their in vitro efficacy in HEK and RAW264.7 cells, ex vivo and in vivo efficacy. RESULTS: FTIR confirmed the involvement of phosphoric group of sTPP with amine groups of chitosan and also role of hydrogen bonding involved in the preparation of MTXCHNP and DEXCHNP. Controlled release patterns coupled with diffusion of drug were observed in two different buffers (PBS) at pH 7.4 and pH 5.8. The IC50 for MTXCHNP for HEK was 26.1 μg/ml and 7.7 μg/ml for RAW 264.7 cells. In DEXCHNP, the IC50 was 20.12 μg/ml for HEK and 7.37 μg/ml for RAW264.7 cells. Enhanced uptake of FITC-CHNP by RAW cells indicated internalization of nanoparticles by phagocytosis. The enhanced release of drug at lower pH justified increased cytotoxicity. Negligible ex-vivo hemolysis indicated the higher biocompatibility of the nanoparticles. (99m)Tc-CHNP exhibited maximum absorption in blood circulation in 3 h, followed by hepatic metabolism and renal clearance. Higher in-vivo anti-arthritic activity and antioxidant activity was observed post-intraperitoneal (i.p.) injections by both MTXCHNP and DEXCHNP when compared to MTX (0.75 mg/Kg by i.p. route) and DEX (0.2 mg/Kg/i.p./daily) per se. CONCLUSION: The nanocrystalline biopolymeric nanoparticles were stable, biocompatible and have potential to be administered through i.p. route with minimal toxicity and high efficacy.
27554682 Semaphorins 4A and 4D in chronic inflammatory diseases. 2017 Feb Long-term inflammatory processes directed at a particular endogenous or exogenous antigen, or sometimes of unknown etiology, form the pathogenetic basis for many debilitating conditions, such as cardiovascular, pulmonary, autoimmune, neurologic diseases, and cancer. Recent discoveries of neuroimmune semaphorins 4A and 4D (Sema4A and Sema4D, respectively) expression and function in the immune system and their key regulatory roles in fine tuning of inflammatory processes made them the molecules of interest for a potential immunotherapy. In this short review, we discuss the current knowledge in the Sema4A and Sema4D actions in chronic inflammation underlying the outlined above diseases.
27859024 Medical cannabis: Another piece in the mosaic of autoimmunity? 2017 Feb Legalization of cannabis' medicinal use is rapidly increasing worldwide, raising the need to evaluate medical implications of cannabis. Currently, evidence supports cannabis and its active ingredients as immune-modulating agents, affecting T-cells, B-cells, monocytes, and microglia cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. Due to the supporting evidence of cannabinoids as an immune-modulating agent, research focusing on cannabinoids and autoimmunity has emerged. Several clinical trials in multiple sclerosis, inflammatory bowel disease, and fibromyalgia suggest cannabis' effectiveness as an immune-modulator. However, contradicting results and lack of large-scale clinical trials obscure these results. Although lacking clinical research, in vitro and in vivo experiments in rheumatoid arthritis, diabetes type 1, and systemic sclerosis demonstrate a correlation between disease activity and cannabinoids.
28782180 Down-regulation of miR-10a-5p in synoviocytes contributes to TBX5-controlled joint inflamm 2018 Jan MicroRNAs are considered to play critical roles in the pathogenesis of human inflammatory arthritis, including rheumatoid arthritis (RA). The purpose of this study was to determine the relationship between miR-10a-5p and TBX5 in synoviocytes and evaluate their contribution to joint inflammation. The expression of miR-10a-5p and TBX5 in the synovium of RA and human synovial sarcoma cell line SW982 stimulated by IL-1β was determined by RT-qPCR and Western blotting. The direct interaction between miR-10a-5p and TBX5 3'UTR was determined by dual-luciferase reporter assay in HeLa cells. Mimics and inhibitors of miR-10a-5p were transfected into SW982 cells. TBX5 was overexpressed by plasmid transfection or knocked down by RNAi. Proinflammatory cytokines and TLR3 and MMP13 expressions were determined by RT-qPCR and Western blotting. Down-regulated expression of miR-10a-5p and up-regulation of TBX5 in human patients with RA were found compared to patients with OA. IL-1β could reduce miR-10a-5p and increase TBX5 expression in SW982 cells in vitro. The direct target relationship between miR-10a-5p and 3'UTR of TBX5 was confirmed by luciferase reporter assay. Alterations of miR-10-5p after transfection with its mimic and inhibitor caused the related depression and re-expression of TBX5 and inflammatory factors in SW982 cells. Overexpression of TBX5 after pCMV3-TBX5 plasmid transfection significantly promoted the production of TLR3, MMP13 and various inflammatory cytokines, while this effect was rescued after knocking down of TBX5 with its specific siRNA. We conclude that miR-10a-5p in a relation with TBX5 regulates joint inflammation in arthritis, which would serve as a diagnostic and therapeutic target for RA treatment.
28958658 A Minimum Ten Years of Follow-Up of Alumina Head on Delta Liner Total Hip Arthroplasty. 2018 Feb BACKGROUND: In the early days when delta ceramics were developed, there was a period of using delta ceramic liner and alumina ceramic head. Therefore, the purpose of this study is to investigate the clinical and radiological outcomes of total hip arthroplasty using delta ceramic liner on alumina ceramic head after a minimum of 10 years of follow-up and to evaluate problems of early delta ceramic liner. METHODS: Alumina on delta cementless total hip arthroplasty was performed in 92 hips (85 patients) from August 2005 to March 2007 at our hospital. Bilateral total hip arthroplasty were performed in 7 patients, 30 patients on the left side and 48 patients on the right side. Preoperative diagnosis was osteonecrosis of the femoral head in 34 hips (37%), degenerative arthritis in 31 hips (33.7%), femur neck fracture in 21 hips (22.8%), and rheumatoid arthritis in 6 hips (6.5%). All surgeries were carried out with anterolateral approach. For the clinical evaluation, Harris hip score (HHS), pain, and range of motion were assessed. Radiographs were reviewed by the authors to search for any signs of osteolysis, loosening of implants, and heterotopic ossification. RESULTS: HHS was compared between preoperative and final follow-ups. The mean HHS improved from preoperative 58.3 points (range 27-76) to 92.7 points (range 78-98) on the final follow-up (P = .02). The mean range of hip motion at the final follow-up was flexion 116.9°, adduction 23.8°, abduction 34.6°, internal rotation 16.3°, and external rotation 39.2°. As for the postoperative pain, 1 patient complained of inguinal pain and 4 patients complained of thigh pain. Because of trauma, 3 cases of dislocation were observed in all cases. There are 3 cases with dislocation and 2 cases were treated with conservative treatment without recurrence, but 1 case was required for surgical treatment due to eccentric rim wear of delta liner. The aseptic loosening of acetabular cup and femoral stem was each 1 hip. CONCLUSION: Alumina head-on-delta liner cementless THA, using a large femoral head 32-36 mm in diameter, demonstrated satisfactory clinical and radiological results in the minimum 10 years of follow-up. Eccentric rim wear can occur even in delta ceramic liners that are known to have high strength, and this can lead to dislocation which can, in turn, increase the possibility of linear fracture.
28845577 The Safety and Immunogenicity of Live Zoster Vaccination in Patients With Rheumatoid Arthr 2017 Oct OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV). METHODS: In this phase II, 14-week, placebo-controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo 2-3 weeks postvaccination. We measured humoral responses (varicella zoster virus [VZV]-specific IgG level as determined by glycoprotein enzyme-linked immunosorbent assay) and cell-mediated responses (VZV-specific T cell enumeration, as determined by enzyme-linked immunospot assay) at baseline and 2 weeks, 6 weeks, and 14 weeks postvaccination. End points included the geometric mean fold rise (GMFR) in VZV-specific IgG levels (primary end point) and T cells (number of spot-forming cells/10(6) peripheral blood mononuclear cells) at 6 weeks postvaccination. RESULTS: One hundred twelve patients were randomized to receive tofacitinib (n = 55) or placebo (n = 57). Six weeks postvaccination, the GMFR in VZV-specific IgG levels was 2.11 in the tofacitinib group and 1.74 in the placebo group, and the VZV-specific T cell GMFR was similar in the tofacitinib group and the placebo group (1.50 and 1.29, respectively). Serious adverse events occurred in 3 patients in the tofacitinib group (5.5%) and 0 patients (0.0%) in the placebo group. One patient, who lacked preexisting VZV immunity, developed cutaneous vaccine dissemination 2 days after starting tofacitinib (16 days postvaccination). This resolved after tofacitinib was discontinued and the patient received antiviral treatment. CONCLUSION: Patients who began treatment with tofacitinib 2-3 weeks after receiving LZV had VZV-specific humoral and cell-mediated immune responses to LZV similar to those in placebo-treated patients. Vaccination appeared to be safe in all of the patients except 1 patient who lacked preexisting VZV immunity.
28749248 Update in perioperative medicine: practice changing evidence published in 2016. 2017 Oct This summary reviews 18 key articles published in 2016 which have significant practice implications for the perioperative medical care of surgical patients. Due to the multi-disciplinary nature of the practice of perioperative medicine, important new evidence is published in journals representing a variety of medical and surgical specialties. Keeping current with the evidence that drives best practice in perioperative medicine is therefore challenging. We set out to identify, critically review, and summarize key evidence which has the most potential for practice change. We integrated the new evidence into the existing body of medical knowledge and identified practical implications for real world patient care. The articles address issues related to anticoagulation, transfusion threshold, immunosuppressive medications, postoperative delirium, myocardial injury after noncardiac surgery, postoperative pain management, perioperative management of antihypertensives, perioperative fasting, and perioperative diabetic control.
28942661 [Etanercept-induced subacute thyroiditis. Case report and literature review]. 2017 Oct 65 years old male patient received 4 mg/day methylprednisolone baseline therapy and 50 mg/week etanercept treatment for 5 years due to rheumatoid arthritis. The patient experienced pain in neck, and developed weakness, fever and dysphagia. He had normal blood count but accelerated erythrocyte sedimentation rate (88 mm/hour), elevated CRP (49.3 mg/l) and hyperthyroidism (TSH 0.006 mIU/l, fT4 27.22 pmol/l, fT3 5.61 pmol/l). The autoimmune origin could be excluded because of normal values of antibodies against thyreoidea peroxidase and TSH receptor. The ultrasound investigation showed focal hypoechogenic structure and low vascularisation. Based on the laboratory and ultrasound results as well as clinical signs etanercept related subacute thyroiditis was supposed. As part of the treatment we interrupted the etanercept treatment and gave 16 mg methylprednisolone for 5 days, then 8 mg for 7 days, after that the patient received the daily 4 mg of methylprednisolone as baseline therapy. After rapid improvement the symptoms got worse again so we repeated the administration of methylprednisolone treatment with a higher dose (16 mg/day for 5 days then 8 mg/day for two months). Thyroid functions and the inflammatory markers got normalized. We conclude the necessity of monitoring the thyroid function during etanercept treatment thus avoiding this rare but serious side effect. Orv Hetil. 2017; 158(39): 1550-1554.
28118538 Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease-M 2017 May OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with limited conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with moderate-to-severe rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, phase IIb trial, patients with RA (n = 289) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg or matching placebo once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. RESULTS: ACR20 response rates at week 12 were 22.0%, 36.8%, 48.3% (P < 0.05), 56.3% (P < 0.01), and 29.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Patients in the peficitinib 100 mg and 150 mg groups achieved a rapid and statistically significant ACR20 response compared with those in the placebo group (P < 0.05), reaching statistical significance by week 2. Overall, the incidence of adverse events (AEs) was similar between patients receiving peficitinib and those receiving placebo. The most common AEs were upper respiratory tract infection (5% [n = 15]), nausea (4% [n = 12]), and urinary tract infection (4% [n = 10]). There was 1 case of herpes zoster in the placebo group, and 1 serious infection (limb abscess) in the peficitinib 25 mg group. There were no incidences of grade 2 or higher neutropenia or lymphopenia. CONCLUSION: In patients with moderate-to-severe RA, orally administered once-daily peficitinib in combination with limited csDMARDs resulted in a dose-dependent ACR20 response rate over 12 weeks with satisfactory tolerability.
28924986 Supplementing electronic health records through sample collection and patient diaries: A s 2018 Feb PURPOSE: To describe a novel observational study that supplemented primary care electronic health record (EHR) data with sample collection and patient diaries. METHODS: The study was set in primary care in England. A list of 3974 potentially eligible patients was compiled using data from the Clinical Practice Research Datalink. Interested general practices opted into the study then confirmed patient suitability and sent out postal invitations. Participants completed a drug-use diary and provided saliva samples to the research team to combine with EHR data. RESULTS: Of 252 practices contacted to participate, 66 (26%) mailed invitations to patients. Of the 3974 potentially eligible patients, 859 (22%) were at participating practices, and 526 (13%) were sent invitations. Of those invited, 117 (22%) consented to participate of whom 86 (74%) completed the study. CONCLUSIONS: We have confirmed the feasibility of supplementing EHR with data collected directly from patients. Although the present study successfully collected essential data from patients, it also underlined the requirement for improved engagement with both patients and general practitioners to support similar studies.
29093159 CNTO6785, a Fully Human Antiinterleukin 17 Monoclonal Antibody, in Patients with Rheumatoi 2018 Jan OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of CNTO6785, a fully human monoclonal antibody that binds to human interleukin 17A, in patients with active rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX) therapy. METHODS: This randomized, double-blind, placebo-controlled, dose-ranging study enrolled patients aged 18 to 80 years (inclusive) with active RA (≥ 6/66 swollen and ≥ 6/68 tender joints) who were refractory to MTX treatment (7.5-25 mg weekly, inclusive). The study duration was 38 weeks, containing a 10-week safety followup. Patients were randomized 1:1:1:1:1 to receive CNTO6785 15, 50, 100, or 200 mg every 4 weeks + MTX or placebo + MTX. The primary endpoint was American College of Rheumatology 20 (ACR20) response at Week 16. RESULTS: There were no significant differences from placebo in the proportion of patients treated with CNTO6785 in the primary endpoint of ACR20 response at Week 16. There were no significant findings in any additional efficacy variables through Week 32. No dose-response relationships or specific patterns were observed in adverse event profiles among CNTO6785 treatment groups. Infections occurred with similar frequency across all groups, and injection site reactions were mild or moderate and did not demonstrate a dose-response relationship. Median serum CNTO6785 concentration increases through Week 38 were about dose-proportional; the incidence of neutralizing antidrug antibodies was 19.4% and was not associated with study drug dose level. CONCLUSION: CNTO6785 was well tolerated, but did not demonstrate clinical efficacy in patients with active RA with inadequate response to MTX.
29173693 Three cases of anti-TNF induced myositis and literature review. 2017 Nov Anti-tumor necrosis factor drugs are frequently preferred in the treatment of rheumatologic diseases and other inflammatory diseases. The development of myositis after using anti-tumor necrosis factor drugs is a rare clinical condition. Here we aimed to report cases who developed myositis after using anti-tumor necrosis factor drugs and review the current literature. We report two cases of rheumatoid arthritis and a case of ankylosing spondylitis developed idiopathic inflammatory myopathy following anti-tumor necrosis factor therapy. In conclusion, myositis could develop during anti-tumor necrosis factor therapy, so these patients should be evaluated carefully initially for myositis and should be closely monitored due to the potential for developing myositis in treatment process.
27893701 The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this und 2017 Jan TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1(-/-) mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.
29216931 VISTA deficiency attenuates antibody-induced arthritis and alters macrophage gene expressi 2017 Dec 8 BACKGROUND: In addition to activated T cells, the immune checkpoint inhibitor "V domain-containing Ig suppressor of T-cell activation" (VISTA) is expressed by myeloid cell types, including macrophages and neutrophils. The importance of VISTA expression by myeloid cells to antibody-induced arthritis and its potential for relevance in human disease was evaluated. METHODS: VISTA was immunolocalized in normal and arthritic human synovial tissue sections and synovial tissue lysates were subjected to western blot analysis. The collagen antibody-induced arthritis model (CAIA) was performed with DBA/1 J mice treated with antibodies against VISTA and with VISTA-deficient mice (V-KO). Total mRNA from arthritic joints, spleens, and cultured macrophages was analyzed with NanoString arrays. Cytokines secreted by splenic inflammatory macrophages were determined. In-vitro chemotaxis and signal transduction assays were performed with cultured macrophages. RESULTS: VISTA protein was localized to synovial membrane cells, neutrophils, and scattered cells in lymphocyte-rich foci and was detected by western blot analysis in normal synovium and synovium from rheumatoid arthritis patients. Deficiency of VISTA or treatment of mice with anti-VISTA monoclonal antibodies attenuated CAIA. Joint damage and MMP-3 expression were significantly reduced in V-KO mice. Surface expression of C5a receptor was reduced on monocytes, neutrophils, and cultured macrophages from V-KO. Upon Fc receptor engagement in vitro, gene expression by V-KO macrophages was altered profoundly compared to WT, including a significant induction of IL-1 receptor antagonist (IL1rn). CONCLUSIONS: VISTA expression supports immune-complex inflammation in CAIA and VISTA is expressed in human synovium. VISTA supports optimal responses to C5a and modulates macrophage responses to immune complexes.
27994091 Rheumatoid arthritis triple therapy compared with etanercept: difference in infectious and 2017 Mar 1 OBJECTIVE: The main aim of this study was to examine the differences between triple therapy (T: SSZ and HCQ added to MTX) and etanercept (E) added to MTX with regard to the infectious and gastrointestinal (GI) adverse events (AEs) reported in The Rheumatoid Arthritis Comparison of Active Therapies Trial. METHODS: The patients were 353 RA MTX incomplete responders who were randomized to T (n = 178) or E (n = 175). Of these, 88 patients were switched to the alternative treatment from the initial treatment (E or T) at 24 weeks per protocol. Infectious and GI serious AEs (SAEs) and non-serious AEs (NAEs) were reported during 48 and 4 weeks after the intervention period. Generalized linear models were used to estimate the incidence rate ratios (IRRs) of AEs between the two therapies. RESULTS: Patients on E therapy were more likely to have infectious NAEs (IRR = 1.56, 95% CI: 1.11, 2.19). There was a greater number of infectious SAEs that occurred when patients received E than T therapy [12 E (6.9%) vs 4 T (2.2%), P = 0.19]. Pneumonia was the most common infectious SAE for both treatments [6 E (3.4%) and 2 T (1.1%)]. Conversely, patients who were on E were less likely to have GI NAEs than those on T therapy (IRR = 0.62, 95% CI: 0.40, 0.94). The most common GI SAE reported was GI haemorrhage, which occurred among three patients on E (1.7%). CONCLUSION: This study provides evidence of different likelihoods of infectious and GI AEs associated with two common, equally effective treatments for RA patients who have had incomplete responses to MTX. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00405275.
29247146 Synoviocytes-derived Interleukin 35 Potentiates B Cell Response in Patients with Osteoarth 2018 Apr OBJECTIVE: Elevated expression of interleukin 35 (IL-35) is associated with autoimmune disease, including rheumatoid arthritis (RA). The present study was undertaken to determine the functional interaction among IL-35, B cells, and stromal cells residing in the synovium of patients with RA and osteoarthritis (OA). METHODS: IL-35 (EBI-3/p35) expression was investigated in RA and OA synovium using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. IL-35 receptor (IL-35R) expression on B cells dissociated from synovium and periphery of patients with RA, OA, and healthy donor controls (HC) was determined by flow cytometry. The degree of B cells activation after IL-4 and/or IL-35 stimulation was measured by flow cytometry and qRT-PCR. Synovial fibroblasts (SF) purified from RA and OA synovium were cocultured with peripheral HC B cells in the presence/absence of tumor necrosis factor-α (TNF-α) and with/without anti-IL-35-blocking antibodies. RESULTS: EBI-3/p35 transcripts were expressed in close proximity to B cells residing in RA and OA synovium. IL-35R subunits, gp130 and IL-27Rα, but not IL-12Rβ2, were expressed in B cells extracted from the synovium and periphery of patients with RA/OA. Notably, RA synovium expressed the highest level of IL-27Rα on their cell surface. IL-35 induced proliferation and IgG production in HC B cells. Cocultures of HC B cells with RASF, but not OASF, exhibited significantly elevated B cells activation. TNF-α-induced, RASF-dependent secretion of IgG in B cells is partly IL-35-dependent. CONCLUSION: To our knowledge, for the first time we demonstrated that synovial/peripheral B cells expressed IL-35R and were responsive to IL-35 stimulation. SF residing in RA synovium can be linked to B cell activation and maintenance in RA synovium through IL-35.
28739353 Incidence of tuberculosis among patients with rheumatoid arthritis using TNF blockers in B 2017 OBJECTIVES: To assess the incidence of tuberculosis and to screen for latent tuberculosis infection among Brazilians with rheumatoid arthritis using biologics in clinical practice. PATIENTS AND METHODS: This cohort study used data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil), from 01/2009 to 05/2013, encompassing 1552 treatments, including 415 with only synthetic disease-modifying anti-rheumatic drugs, 942 synthetic DMARDs combined with anti-tumor necrosis factor (etanercept, infliximab, adalimumab) and 195 synthetic DMARDs combined with other biologics (abatacept, rituximab and tocilizumab). The occurrence of tuberculosis and the drug exposure time were assessed, and screening for tuberculosis was performed. STATISTICAL ANALYSIS: Unpaired t-test and Fisher's two-tailed test; p<0.05. RESULTS: The exposure times were 981 patient-years in the controls, 1744 patient-years in the anti-TNF group (adalimumab=676, infliximab=547 and etanercept=521 patient-years) and 336 patient-years in the other biologics group. The incidence rates of tuberculosis were 1.01/1000 patient-years in the controls and 2.87 patient-years among anti-TNF users (adalimumab=4.43/1000 patient-years; etanercept=1.92/1000 patient-years and infliximab=1.82/1000 patient-years). No cases of tuberculosis occurred in the other biologics group. The mean drug exposure time until the occurrence of tuberculosis was 27(11) months for the anti-TNF group. CONCLUSIONS: The incidence of tuberculosis was higher among users of synthetic DMARDs and anti-TNF than among users of synthetic DMARDs and synthetic DMARDs and non-anti-TNF biologics and also occurred later, suggesting infection during treatment and no screening failure.
29247149 Two-year Efficacy and Safety of Subcutaneous Tocilizumab in Combination with Disease-modif 2018 Apr OBJECTIVE: To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation. RESULTS: The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and ≥ 0.30 decrease from baseline in the Health Assessment Questionnaire-Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (≥ 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed. CONCLUSION: Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated.