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ID PMID Title PublicationDate abstract
26131691 Methotrexate Is a JAK/STAT Pathway Inhibitor. 2015 BACKGROUND: The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. METHODS & FINDINGS: We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. CONCLUSIONS: Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.
27428445 Potentially severe drug-drug interactions among older people and associations in assisted 2016 Sep OBJECTIVE: This study aims to assess potentially severe class D drug-drug interactions (DDDIs) in residents 65 years or older in assisted living facilities with the use of a Swedish and Finnish drug-drug interaction database (SFINX). DESIGN: A cross-sectional study of residents in assisted living facilities in Helsinki, Finland. SETTING: A total of 1327 residents were assessed in this study. Drugs were classified according to the Anatomical Therapeutic Chemical (ATC) classification system and DDDIs were coded according to the SFINX. MAIN OUTCOME MEASURES: Prevalence of DDDIs, associated factors and 3-year mortality among residents. RESULTS: Of the participants (mean age was 82.7 years, 78.3% were females), 5.9% (N = 78) are at risk for DDDIs, with a total of 86 interactions. Participants with DDDIs had been prescribed a higher number of drugs (10.8 (SD 3.8) vs. 7.9 (SD 3.7), p < 0.001). A larger proportion of residents with DDDIs suffered from rheumatoid arthritis or osteoarthritis than those not exposed to DDDIs (24.7% vs. 15.4%, p = 0.030). The most frequent DDDIs were related to the concomitant use of potassium with amiloride (N = 12) or spironolactone (N = 12). Carbamazepine (N = 13) and methotrexate (N = 9) treatments were also frequently linked to DDDIs. During the follow-up, no differences in mortality emerged between the participants exposed to DDDIs and the participants not exposed to DDDIs. CONCLUSIONS: Of the residents in assisted living, 5.9% were exposed to DDDIs associated with the use of a higher number of drugs. Physicians should be trained to find safer alternatives to drugs associated with DDDIs. KEY POINTS   Potentially severe, class D drug-drug interactions (DDDIs) have been defined in the SFINX database as clinically relevant drug interactions that should be avoided.  • Of the residents in assisted living, 5.9% were exposed to DDDIs that were associated with the use of a higher number of drugs.  • The most frequent DDDIs were related to the concomitant use of potassium with amiloride or spironolactone. Carbamazepine and methotrexate were also linked to DDDIs.  • No difference in mortality was observed between residents exposed to DDDIs and residents not exposed to DDDIs.
25036233 Usefulness of tacrolimus for refractory adult-onset still's disease: Report of six cases. 2016 Nov Six patients with refractory adult-onset Still's disease (AOSD) were treated with tacrolimus (TAC). Patient 1 was pregnant, for whom high-dose corticosteroid (CS) monotherapy did not achieve clinical remission, whereas TAC concomitant with CS was successful, and her baby had no apparent abnormalities. Patient 2 had hemophagocytic syndrome (HPS), for whom high-dose CS monotherapy did not achieve clinical remission, whereas TAC improved HPS, and a complete clinical remission was achieved with concomitant administration of TAC and methotrexate (MTX) with CS. Cases 3-5 could not have reduced CS doses due to repeated recurrences and other disease-modifying antirheumatic drugs, including MTX, Cyclosporine A, and tumor necrosis factor alpha inhibitors, did not control disease activity. TAC administration allowed for reduced CS doses. Case 6 experienced adverse effects, and TAC was discontinued due to elevated serum creatinine and potassium levels. TAC was useful for five of six patients, which suggests it as an option for refractory AOSD.
25872649 Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial 2015 Mar 4 BACKGROUND: Osteoarthritis (OA) is the fastest growing cause of disability worldwide. Current treatments for OA are severely limited and a large proportion of people with OA live in constant, debilitating pain. There is therefore an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. In inflammatory arthritides such as rheumatoid arthritis, methotrexate (MTX) is the gold standard treatment for synovitis and has a well-known, acceptable toxicity profile. We propose that using MTX to treat patients with symptomatic knee OA will be a practical and safe treatment to reduce synovitis and, consequently, pain. METHODS/DESIGN: Pain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness (PROMOTE) is an investigator-initiated, multi-centre, randomized, double-blind, pragmatic placebo-controlled trial. A total of 160 participants with symptomatic knee OA will be recruited across primary and secondary care sites in the United Kingdom and randomized on a 1:1 basis to active treatment or placebo, in addition to usual care, for 12 months. As is usual practice for MTX, dosing will be escalated over six weeks to 25 mg (or maximum tolerated dose) weekly for the remainder of the study. The primary endpoint is change in average knee pain during the past week (measured on an 11-point numerical rating scale) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures. A health economics analysis will also be performed. A magnetic resonance imaging substudy will be conducted to provide an explanatory mechanism for associated symptom change by examining whether MTX reduces synovitis and whether this is related to symptom change. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis. DISCUSSION: The PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA. TRIAL REGISTRATION: Current Controlled Trials identifier: ISRCTN77854383 (registered: 25 October 2013).
27604426 Methotrexate-Induced Epithelial-Mesenchymal Transition in the Alveolar Epithelial Cell Lin 2016 Dec PURPOSE: Methotrexate (MTX) therapy of certain cancers and rheumatoid arthritis often induces serious interstitial lung complications including pulmonary fibrosis. In this study, we investigated the epithelial-mesenchymal transition (EMT) induced by MTX and by transforming growth factor (TGF)-β1 in the human alveolar epithelial cell line A549 in order to develop new strategies for the prevention of EMT. METHODS: First, we examined the effect of TGF-β1 and MTX on cell morphology and the expression of EMT-related mRNAs in A549 cells. Then, the effects of SB431542 (SB), a potent inhibitor of TGF-β receptor kinase, and a neutralizing antibody for TGF-β1 on the phenotypic changes of A549 cells induced by TGF-β1 and MTX were examined. RESULTS: After incubation with TGF-β1 and MTX, the mRNA expression of epithelial markers such as cytokeratin 19 was reduced, while that of mesenchymal markers such as α-smooth muscle actin was increased. SB suppressed the development of morphological changes and partially rescued alterations in mRNA expression of EMT markers induced by MTX. In addition, the enhancement of SMAD2 phosphorylation by MTX was also prevented by SB. On the other hand, EMT-related changes induced by MTX were not affected by a neutralizing antibody for TGF-β1. CONCLUSION: We have demonstrated that phenotypic changes of A549 cells induced by MTX are partly mediated by a TGF-β1-related intracellular signaling pathway, although TGF-β1 itself is not directly involved in this process.
26083398 Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviatio 2015 Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 μM) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading to ΔΨm dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.
26280210 Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability 2015 Aug BACKGROUND: Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents. OBJECTIVES: Our objective was to examine the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in RA, SpA, and IBD, and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis. METHODS: We conducted a comprehensive literature search using three databases (PubMed, Web of Science, and the Cochrane library) to identify studies examining the immunogenicity of TNF inhibitors in autoimmune diseases between 1966 and 31 December 2013. Inclusion criteria required that studies be in English, be randomized controlled trials, observational studies, or case reports involving more than five patients, and that the patients be aged 18 years or older. Studies were excluded if they were strictly genetic with no clinical correlate, if the patients had concomitant cancer within 5 years of the study, or if the patients had a renal disease requiring dialysis. Double extraction was followed by a third extraction if needed. Consensus was reached by discussion when disagreements occurred. Random-effect models were generated for the meta-analysis of 68 studies to estimate the odds ratio (OR) of the ADAB effects on TNF inhibitor response. Regression analysis was used to compare among the drugs and diseases. RESULTS: A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5-16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5-32.3) developed ADABs compared with 14.1 % (95 % CI 8.6-22.3) using adalimumab, 6.9 % (95 % CI 3.4-13.5) for certolizumab, 3.8 % (95 % CI 2.1-6.6) for golimumab, and 1.2 % (95 % CI 0.4-3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated OR (with ADABs vs. without) of 0.42 (95 % CI 0.30-0.58); the summary effect for adalimumab yielded an estimated OR (as above) of 0.13 (95 % CI 0.08-0.22); and the OR (as above) for golimumab was 0.42 (95 % CI 0.22-0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when we only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The OR for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21-0.32). CONCLUSION: ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation.
29173689 Esophageal abnormalities in juvenile localized scleroderma: is it associated with other ex 2017 Nov OBJECTIVE: To assess esophageal involvement (EI) in juvenile localized scleroderma (JLS) population and the possible association between this gastrointestinal manifestation and demographic data, clinical features, laboratory exams, treatments and outcomes. METHODS: For a period of 30 years, 5881 patients with rheumatic diseases were followed in our Pediatric Rheumatology Division. EI was defined by the presence of symptoms (solid/liquid dysphagia, heartburn, esophageal regurgitation, nausea/vomiting and epigastralgia) and confirmed by at least one EI exam abnormality: barium contrast radiography, upper gastrointestinal endoscopy and 24-hour esophageal pH-monitoring. RESULTS: JLS was observed in 56/5881 patients (0.9%), mainly linear morphea subtype. EI was observed in 23/56(41%) of JLS patients. Eight(35%) of 23 EI patients with JLS were symptomatic and presented heartburn(5/8), solid and liquid dysphagia(3/8), nausea and epigastralgia(1/8). The frequency of any cumulative extracutaneous manifestations (calcinosis, arthritis/arthralgia, central nervous system, interstitial pneumonitis, mesangial nephritis and/or arrhythmia) was significantly higher in JLS patients with EI compared to those without this complication (56% vs. 24%, p=0.024). No differences were evidenced in demographic data, JLS subtypes and in each extracutaneous manifestation in both groups (p>0.05). The frequency of methotrexate use was significantly higher in JLS patients with EI compared to those without (52% vs. 12%, p=0.002). Autoantibody profile (antinuclear antibodies, anti-SCL-70, rheumatoid factor, anticentromere, anti-cardiolipin, anti-Ro/SSA and anti-La/SSB) was similar in both groups (p>0.05). CONCLUSIONS: Our study demonstrated that EI was frequently observed in JLS patients, mainly in asymptomatic patients with linear subtype. EI occurred in JLS patients with other extracutaneous manifestations and required methotrexate therapy.
28455580 Cardiovascular risk in patients with rheumatoid arthritis. 2017 Jun Substantial epidemiologic data have shown an increased risk of cardiovascular (CV) disease in rheumatoid arthritis (RA) patients. Traditional CV risk factors may partly contribute to CV disease in RA; however, current evidence underlines the important role of inflammation in the pathogenesis of atherosclerosis and amplification of CV risk. Interplays between inflammation and lipid metabolism in the development of atherosclerosis have been established by recent scientific advances. Atherosclerosis is currently viewed as an inflammatory disease, and modifications of lipoproteins during inflammation accelerate atherogenesis. The role of inflammation in the increased CV risk in RA has been further demonstrated by the CV protective effect of methotrexate and TNF antagonists, particularly in patients responding to these treatments. The management of CV risk in RA should include the use of effective disease-modifying anti-rheumatic drugs to control disease activity and the treatment of traditional CV risk factors.
27481831 Possibilities for preventive treatment in rheumatoid arthritis? Lessons from experimental 2017 Feb OBJECTIVE: Current research in rheumatoid arthritis focuses on preclinical disease phases as it is hypothesised that early preclinical treatment might prevent progression to full-blown disease. Since performance of studies in prearthritis phases in humans is challenging, animal models offer an opportunity to evaluate preventive treatments. We performed a systematic literature review and summarised treatment effects during different stages of arthritis development in animal models. METHODS: Eight medical literature databases were systematically searched. Studies were selected if they reported effects of synthetic or biological disease-modifying antirheumatic drugs in animal models of arthritis (collagen-induced arthritis and adjuvant-induced arthritis) on arthritis severity, as measured with arthritis severity scores, paw swelling or paw volume. Quality was assessed using an 11-item checklist. Study characteristics were extracted and effect sizes obtained in high-quality studies were summarised in meta-analyses. Studies were categorised into three groups: prophylactic (prior to generation of autoantibody response), prearthritis (after induction of autoantibody response) and therapeutic intervention (after arthritis development). RESULTS: Out of 1415 screened articles, 22 studies (including n=712 animals) were eligible of good quality and included in meta-analyses. Prophylactic (16 experiments, n=312 animals) and prearthritis treatment (9 experiments, n=156 animals) both were associated with a reduction of arthritis severity (p<0.001 and p=0.005, respectively). Stratified analyses for different antirheumatic drugs initiated in the prearthritis phase suggested higher efficacy of methotrexate than of anti-tumour necrosis factor. CONCLUSIONS: Data of experimental studies in animal models of arthritis suggest that prophylactic and prearthritis treatment strategies are effective and hint at differences in efficacy between antirheumatic drugs.
27503624 cDNA phage display for the discovery of theranostic autoantibodies in rheumatoid arthritis 2017 Feb Rheumatoid arthritis (RA) is the world's most common autoimmune disease mainly characterized by a chronic inflammation of multiple synovial joints. Rheumatologists now have a whole range of treatment options including glucocorticoids (GCs), classical synthetic and biological disease-modifying antirheumatic drugs (cs- and bDMARDS), resulting in a tremendous improvement in treatment outcomes for RA patients over the last two decades. Despite this progress, the choice of treatment regimen to achieve stable remission at the individual patient level still largely depends on trial and error. In this review, the need for novel theranostic markers that can predict a patient's response to methotrexate, the standard first-line csDMARD treatment, is discussed. Like in many autoimmune diseases, the majority of RA patients form a whole range of autoantibodies. We aim to find novel theranostic autoantibody markers using serological antigen selection, a high-throughput technique that uses cDNA phage display to identify novel antigen targets. We have constructed a barcoded cDNA phage display library from the synovial tissue of three RA patients by fusing cDNA products to the filamentous phage minor coat protein VI. This library contains a large proportion of full-length genes and gene fragments that are cloned in frame with the phage gene VI. By screening this library for antibody reactivity in serum samples of patients from the CareRA trial, which compared different intensive treatment strategies based on csDMARDs and a step-down GC schedule, our cDNA phage display library has great potential for the discovery of novel theranostic autoantibody biomarkers.
29033202 [Pyopneumothorax in rheumatoid arthritis]. 2017 Nov INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the joints but which frequently includes extra articular effects, including pulmonary nodules, which grow faster under immunosuppressive treatment. CASE REPORT: A 74 years old man, with mild asbestosis, underwent treatment with methotrexate then leflunomide (LEF) for seropositive RA. In February 2014, during monitoring of his asbestosis, chest CT scan showed the appearance of thick-walled cavitating lung nodules, with a central and sub pleural distribution. The patient was asymptomatic. Bronchoalveolar lavage excluded infection and tumor. LEF was stopped but in May 2014, the patient was admitted with respiratory infection and a pyopneumothorax which required surgical management. The postoperative course was complicated with a persistent pneumothorax. CONCLUSIONS: We describe a case of RA complicated by a pyopneumothorax after treatment with LEF. The risk of this complication could be reduced by regular chest imaging.
28571554 Methotrexate in the Treatment of Psoriasis and Rheumatoid Arthritis: Mechanistic Insights, 2017 Our review is focused on the use of methotrexate in drug therapy of two autoimmune diseases, psoriasis and rheumatoid arthritis (RA). The article describes the pathogenesis of psoriasis and RA, the role of methotrexate in the treatment of these diseases with more focused review on the mechanism behind the clinical benefits of methotrexate therapy. Methotrexate due to its cytotoxic, anti-inflammatory and immune modulatory activities provides clinical benefits in the therapy of the selected diseases. This review also gives a panorama of the problems associated with the use of methotrexate in the selected diseases and the guidelines provided by FDA for its safe use. The novel colloidal drug delivery systems of methotrexate, with particular emphasis on advantages offered by liposomal formulation, niosomal gel, hydrogel, albumin conjugates, nanoparticles and nano structured lipid carriers in psoriasis and RA are also reviewed. It seemed that the use of newer colloidal carriers with improved skin permeability by minimizing its systemic availability will be a useful strategy to reduce the toxic effects of the drug in psoriatic patients. In rheumatoid arthritis patients, the development of newer therapeutic strategies using appropriate targeting ligands that specifically deliver the drug to the inflamed joint space will help to overcome its toxic effects by minimizing the systemic exposure.
27992285 Are gene polymorphisms related to treatment outcomes of methotrexate in patients with rheu 2017 Jan AIM: Identifying the predictors of responsiveness and adverse events in methotrexate (MTX) treated patients with rheumatoid arthritis (RA) has been the focus of most concern, but still without consistent consensus. METHODS: PubMed and OVID EMBASE were searched to collect relevant studies that addressed correlations between gene polymorphisms and efficacy and/or toxicity in MTX-treated RA patients. Allelic, recessive, dominant and over-dominant model were applied. RESULTS: A total of 68 studies were included. For associations with efficacy, AMPD1 34C>T polymorphism was related to responsiveness in dominant model (odds ratio [OR]: 1.77; 95% CI: 1.19-2.63) and over-dominant model (OR: 1.59; 95% CI: 1.04-2.45). ATIC T675C polymorphism had association with responsiveness in recessive model (OR: 2.54; 95% CI: 1.23-5.26). For associations with toxicity, polymorphisms in TYMS 1494 del6 and FPGS rs10106 were correlated to absenting overall adverse events in recessive model (OR: 0.68; 95% CI: 0.49-0.95) and dominant model (OR: 0.54; 95% CI: 0.35-0.83) respectively while MTHFR C677T was associated with presenting overall adverse events in allelic model (OR: 1.29; 95% CI: 1.02-1.63), recessive model (OR: 1.38; 95% CI: 1.00-1.89) and dominant model (OR: 1.41; 95% CI: 1.02-1.94). CONCLUSION: Polymorphisms in AMPD1 34C>T and ATIC T675C predict responsiveness. The absence of TYMS 1494 del6 and FPGS rs10106 and presence of MTHFR C677T predict adverse events in RA patients treated with MTX. Moreover, variations of the associations were found between Caucasians and non-Caucasians.
28544525 Lack of association between MTHFR A1298C polymorphism and outcome of methotrexate treatmen 2017 May OBJECTIVES: The aim of this study was to evaluate the association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphism A1298C and methotrexate (MTX) outcome in rheumatoid arthritis (RA) patients. METHODS: We conducted a meta-analysis of the relevant published literature through to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effect models. RESULTS: A total of 1325 cases (10 studies) of MTX efficacy and 2777 cases (18 studies) of MTX toxicity in RA patients were analyzed. Pooled results showed that MTHFR gene A1298C polymorphism was not significantly related to MTX toxicity or efficacy in RA patients. However, subgroup analysis indicated a significant association between MTHFR gene A1298C polymorphism and decreased MTX efficacy in the South Asian population (CCvs. CA + AA: OR = 0.45, 95% CI = 0.23-0.89, P = 0.021). Also, MTHFR gene A1298C polymorphism in the partial folate supplementation group showed a relationship with decreased MTX efficacy (CCvs. CA + AA: OR = 0.43, 95% CI = 0.20-0.92, P = 0.029) and toxicity (CCvs. CA + AA: OR = 0.40, 95% CI = 0.17-0.96, P = 0.04; CCvs. AA: OR = 0.38, 95% CI = 0.16-0.94, P = 0.035). CONCLUSIONS: Overall, our meta-analysis suggested no significant effect of MTHFR gene A1298C polymorphism on MTX outcome in RA patients. However, due to several limitations of our meta-analysis, the results should be interpreted cautiously and require further confirmation using high-quality studies.
27733490 Therapeutic management of patients with rheumatoid arthritis and associated interstitial l 2017 Jan Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that can present different extrarticular manifestations involving heart, lungs and kidneys. In recent years there has been a growing awareness of the central role played by the lungs in the onset and progression of RA. In particular interstitial lung disease (ILD) is a common pulmonary manifestation that may be related to the inflammatory process itself, infectious complications and to the treatments used. Management of patients with ILD/RA is still a challenge for clinicians, both synthetic [mainly methotrexate (MTX), leflunomide] and biologic immunosuppressors [mainly anti-tumor necrosis factor (TNF)α] have in fact been related to the onset or worsening of lung diseases with conflicting data. Here we report the case of a 61-year-old male patient with severely active early RA, previously treated with MTX, who developed subacute ILD, along with a review of ILD/RA topic. Tocilizumab (humanized monoclonal antibody against the interleukin-6 receptor) was introduced on the basis of its effectiveness in RA without concomitant MTX and the ability to overcome the profibrotic effects of interleukin (IL)-6. After 3 months of treatment the clinical condition of the patient strongly improved until it reached low disease activity. He no longer complained of cough and dyspnea and bilateral basal crackles were no more present. Considering its distinctive features, tocilizumab, in such a challenging clinical condition, appears to be a safe and effective therapy, thus it enables RA remission without deteriorating ILD, at 1-year follow up, as confirmed by ultrasonography of the affected joints and chest high-resolution computed tomography (HRCT).
28388359 Crocin reduces the inflammation response in rheumatoid arthritis. 2017 May This study is to determine the role and mechanism of crocin in rheumatoid arthritis (RA). Totally 60 Wistar SD rats were randomly divided into control group, RA model group, methotrexate group, crocin high dose, middle dose, and low dose groups. The paw swelling degree, arthritis score, thymus and spleen index, the mRNA and protein levels of iNOS, and the serum content of TNF-α, IL-1β, and IL-6 were evaluated. Crocin treatment significantly alleviated the paw swelling of RA rats. The arthritis score in crocin treatment groups was significantly lower than that in RA model group. Additionally, the thymus index, but not the spleen index, declined remarkably in crocin treatment groups than in RA model group. Besides, crocin administration significantly reduced the iNOS production and the serum content of TNF-α, IL-1β, and IL-6. Crocin may exert potent anti-RA effects through inhibiting cytokine.
29141688 Chinese Registry of rheumatoid arthritis (CREDIT): II. prevalence and risk factors of maj 2017 Nov 15 BACKGROUND: Rheumatoid arthritis patients are at higher risk of developing comorbidities. The main objective of this study was to evaluate the prevalence of major comorbidities in Chinese rheumatoid arthritis patients. We also aimed to identify factors associated with these comorbidities. METHODS: Baseline demographic, clinical characteristics and comorbidity data from RA patients enrolled in the Chinese Registry of rhEumatoiD arthrITis (CREDIT) from Nov 2016 to August 2017 were presented and compared with those from five other registries across the world. Possible factors related to three major comorbidities (cardiovascular disease, fragility fracture and malignancy) were identified using multivariate logistic regression analyses. RESULTS: A total of 13,210 RA patients were included (80.6% female, mean age 52.9 years and median RA duration 4.0 years). Baseline prevalence rates of major comorbidities were calculated: CVD, 2.2% (95% CI 2.0-2.5%); fragility fracture, 1.7% (95% CI 1.5-1.9%); malignancy, 0.6% (95% CI 0.5-0.7%); overall major comorbidities, 4.2% (95% CI 3.9-4.6%). Advanced age was associated with all comorbidities. Male gender and disease duration were positively related to CVD. Female sex and longer disease duration were potential risk factors for fragility fractures. Ever use of methotrexate (MTX) was negatively related to baseline comorbidities. CONCLUSIONS: Patients with rheumatoid arthritis in China have similar prevalence of comorbidities with other Asian countries. Advanced age and long disease duration are possible risk factors for comorbidities. On the contrary, MTX may protect RA patients from several major comorbidities, supporting its central role in the management of rheumatoid arthritis.
28585060 Rheumatoid arthritis-related interstitial lung disease (RA-ILD): methotrexate and the seve 2017 Jul Interstitial lung disease (ILD) is a severe rheumatoid arthritis (RA) manifestation. The worst survival has been associated with usual interstitial pneumonia (UIP) definitive pattern in high-resolution chest tomography (HRCT) scans. Moreover, the use of methotrexate in RA-ILD is controversial. Our aim was to evaluate prognostic factors including methotrexate in an RA-ILD cohort and their association with survival. RA-ILD patients referred for medical evaluation and treatment at a single center were included. At the baseline, pulmonary function tests were carried out and a HRCT was obtained. A radiologist evaluated the ILD tomographic pattern and the extent of lung disease. Patients were considered as receiving methotrexate therapy if this drug was specifically prescribed for the treatment of RA-ILD at the beginning of follow up. Seventy-eight patients were included. UIP definite pattern in HRCT was not associated to worse survival. Variables associated with mortality reflected the severity of lung disease. Treatment with methotrexate was associated with survival (HR 0.13, 95% CI 0.02-0.64); older patients had worse prognosis (HR 1.04, 95% CI 1.003-1.09). After adjusting for confounding variables, methotrexate was strongly associated with survival. Methotrexate treatment during follow up was associated with survival. The severity of lung disease and not the tomographic pattern is associated with mortality; older patients had worse prognosis.
28732547 Crescentic glomerular nephritis associated with rheumatoid arthritis: a case report. 2017 Jul 21 BACKGROUND: Rheumatoid arthritis is a systemic disorder where clinically significant renal involvement is relatively common. However, crescentic glomerular nephritis is a rarely described entity among the rheumatoid nephropathies. We report a case of a patient with rheumatoid arthritis presenting with antineutrophil cytoplasmic antibody-negative crescentic glomerular nephritis. CASE PRESENTATION: A 54-year-old Sri Lankan woman who had recently been diagnosed with rheumatoid arthritis was being treated with methotrexate 10 mg weekly and infrequent nonsteroidal anti-inflammatory drugs. She presented to our hospital with worsening generalized body swelling and oliguria of 1 month's duration. Her physical examination revealed that she had bilateral pitting leg edema and periorbital edema. She was not pale or icteric. She had evidence of mild synovitis of the small joints of the hand bilaterally with no deformities. No evidence of systemic vasculitis was seen. Her blood pressure was 170/100 mmHg, and her jugular venous pressure was elevated to 7 cm with an undisplaced cardiac apex. Her urine full report revealed 2+ proteinuria with active sediment (dysmorphic red blood cells [17%] and granular casts). Her 24-hour urinary protein excretion was 2 g. Her serum creatinine level was 388 μmol/L. Abdominal ultrasound revealed normal-sized kidneys with acute parenchymal changes and mild ascites. Her renal biopsy showed renal parenchyma containing 20 glomeruli showing diffuse proliferative glomerular nephritis, with 14 of 20 glomeruli showing cellular crescents, and the result of Congo red staining was negative. Her rheumatoid factor was positive with a high titer (120 IU/ml), but results for antinuclear antibody, double-stranded deoxyribonucleic acid, and antineutrophil cytoplasmic antibody (perinuclear and cytoplasmic) were negative. Antistreptolysin O titer <200 U/ml and cryoglobulins were not detected. The results of her hepatitis serology, retroviral screening, and malignancy screening were negative. Her erythrocyte sedimentation rate was 110 mm in the first hour, and her C-reactive protein level was 45 mg/dl. Her liver profile showed hypoalbuminemia of 28 g/dl. She was treated with immunomodulators and had a good recovery of her renal function. CONCLUSIONS: This case illustrates a rare presentation of antineutrophil cytoplasmic antibody-negative crescentic glomerular nephritis in a patient with rheumatoid arthritis, awareness of which would facilitate early appropriate investigations and treatment.