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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
24533552 A case of bilateral rheumatoid pleuritis successfully treated with tocilizumab. 2014 Nov The patient was a 77-year-old woman diagnosed as having rheumatoid arthritis (RA) in 1973. She was initiated on infliximab therapy in addition to methotrexate administration in 2009. The therapeutic response decreased after the fifth dose of infliximab, and the patient developed rheumatoid pleuritis due to increased RA disease activity. The therapy was switched from infliximab to tocilizumab, which resulted in amelioration of the arthralgias well as pleuritis. Our results suggest that tocilizumab is an effective treatment alternative for the treatment of rheumatoid pleuritis.
24053746 Idiopathic membranous nephropathy preceding the onset of rheumatoid arthritis: a case repo 2013 Sep INTRODUCTION: Membranous nephropathy (MN) in the context of rheumatoid arthritis (RA), is often an iatrogenic complication due to the nephrotoxic effects of antirheumatic drugs. Rare cases of non-iatrogenic association between these two diseases were reported in the literature. CASE REPORT: A 30-year-old female patient presented in September 2005 with nephrotic syndrome. Renal biopsy showed features consistent with MN. Search for etiology was negative, particularly lupus serology which remained negative throughout the course of her illness. Accordingly, she was diagnosed as a case of idiopathic MN. Initially, she was treated with angiotensin converting enzyme inhibitors and angiotensin receptor blockers which maintained her protein excretion below nephrotic range for two years. Her nephrotic syndrome then relapsed and was treated with steroids and chlorambucil, according to the Ponticelli protocol. A few months later, she presented with early morning joint stiffness, polyarthritis involving the small joints of the hands, and strongly positive rheumatoid factor, fulfilling the diagnostic criteria of rheumatoid arthritis (RA). Her serum creatinine remained normal and a second renal biopsy revealed the same features of MN. Her RA was treated with pulsed methylprednisolone followed by oral steroids and methotrexate resulting in remission of the joints disease and the nephrotic syndrome. Remission was maintained for the last two years up to the time of this report. CONCLUSION: We hereby report a case of secondary membranous nephropathy that preceded the onset of rheumatoid arthritis by three years.
24533548 Presence of ultrasound subclinical synovitis and increment of serum vascular endothelial g 2014 Jul A 63-year-old male Japanese rheumatoid arthritis (RA) patient, in whom treatment with infliximab and methotrexate (MTX) had once led to drug-free remission, experienced a disease flare in July 2010. He was retreated with a combination of adalimumab and MTX, and clinical remission was achieved in 3 months. In contrast, power Doppler signals by ultrasonography with increased serum vascular endothelial growth factor still remained after he achieved sustained clinical remission, whereas no radiographic progression has been found.
24032610 RAPID3, an index of only 3 patient self-report core data set measures, but not ESR, recogn 2013 OBJECTIVE: To perform a longitudinal cohort study concerning the capacity of prospectively-collected erythrocyte sedimentation rates (ESR) and scores for physical function, pain, patient global estimate, and routine assessment of patient index data (RAPID3) on a multidimensional health assessment questionnaire (MDHAQ), to recognize incomplete versus adequate responses to methotrexate in rheumatoid arthritis (RA) in one usual care setting, prior to description of RAPID3. METHODS: All patients were seen in one academic setting, in which MDHAQ scores were collected in all patients at all visits in the infrastructure of care. ESR was collected in all RA patients. All 93 RA patients in whom methotrexate was initiated between 1996 and 2001 with available 5-year follow-up were analyzed. "Incomplete response" was defined as initiation of subsequent biological therapy and "adequate response" as no biological therapy over 5 years. Measures were analyzed at the baseline methotrexate visit and at a subsequent visit: in 30 "incomplete responders" when biological therapy was prescribed; and in 63 "adequate responders 2.6 years after methotrexate initiation (mean interval to biological therapy in "incomplete responders"). RESULTS: ESR fell similarly by 33% to 36% in both groups. MDHAQ scores fell by 56% to 79% over 2.6 years in adequate responders but increased by 0% to 31% in incomplete responders. Median RAPID3 fell from 10.6 to 3.6 (low severity=3.1 to 6, remission≤3) in adequate responders and rose from 14.9 to 16.2 (high severity>12) in incomplete responders. CONCLUSION: RAPID3, but not ESR, recognizes incomplete versus adequate methotrexate responses in usual clinical care, and may be useful in busy usual care settings.
24701712 [Disease modifying antirheumatic drugs]. 2014 Mar 12 The natural history of rheumatoid arthritis, previously burdened with high morbidity, has been strongly modified by appropriate treatment. Early diagnosis and treatment, and follow-up by a specialist, with the aim to achieve remission or low disease activity, are essential for the functional outcome of patients. Disease-modifying anti-rheumatic drugs include "conventional" treatments like methotrexate, biologic therapies such as TNF-inhibitors, abatacept, tocilizumab and rituximab, and targeted synthetic therapies such as tofacitinib (a JAK kinase inhibitor). New treatments currently under study should allow rheumatologists to successfully treat even more patients than nowadays.
24624921 Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrex 2014 Mar Rheumatoid arthritis (RA) is a complex, systemic autoimmune disease characterized by chronic inflammation of multiple peripheral joints, which leads to serious destruction of cartilage and bone, progressive deformity and severe disability. Methotrexate (MTX) is one of the first-line drugs commonly used in RA therapy owing to its excellent long-term efficacy and cheapness. However, the efficacy and toxicity of MTX treatment have significant interpatient variability. Genetic factors contribute to this variability. In this review, we have summarized and updated the progress of RA response to MTX treatment since 2009 by focusing on the fields of pharmacogenetics and pharmacogenomics. Identification of genetic factors involved in MTX treatment response will increase the understanding of RA pathology and the development of new personalized treatments.
23711386 MDR-ABC transporters: biomarkers in rheumatoid arthritis. 2013 Sep MDR-ABC transporters are widely expressed in cell types relevant to pathogenesis of rheumatoid arthritis. Many reports demonstrate the interaction of small molecule drugs with MDR-ABC transporters. Cell-based assays for disease relevant cell types can be easily gated and could reveal specific drug targets and may increase significance and utilisation of data in clinical practice. Many commonly used DMARDs (e.g. methotrexate, sulfasalazine, leflunomide/teriflunomide, hydroxychloroquine) are ABCG2 substrates. Consequently, the activity of this transporter in patients should be determined to understand the disposition and pharmacokinetics of the therapy. In addition, MDR-ABC transporters transport a variety of endobiotics that play important roles in cell proliferation, cell migration, angiogenesis and inflammation. Therefore, MDR-ABC transporters are important biomarkers in rheumatoid arthritis.
23437156 Performance of the 2010 classification criteria for rheumatoid arthritis: a systematic lit 2013 OBJECTIVES: To evaluate the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria for rheumatoid arthritis (RA) with a systematic literature review and a meta-analysis. METHODS: PubMed, Embase, Cochrane Library and the abstracts of the ACR and EULAR meetings (2010-2012) were searched for original articles or abstracts with the following inclusion criteria: 1) recent onset arthritis, with at least one swollen joint and no alternative diagnosis; 2) the ACR/EULAR 2010 criteria as index test; 3) the prescription of methotrexate (MTX) or disease modifying antirheumatic drugs (DMARDs) at any time during follow-up as reference standard. Data were pooled using the bivariate model. Three meta-analyses were performed with MTX (primary analysis), DMARDs or their combination (secondary analyses) as reference standard. Heterogeneity was formally tested and explored performing an influence analysis. RESULTS: The search identified 1,277 references. Six full papers and 4 abstracts met the inclusion criteria. With MTX as reference standard, sensitivity (95% confidence interval, CI) was 0.80 (0.74,0.85), specificity 0.61 (0.56,0.67), positive likelihood ratio (LR) 2.11 (1.92,2.32), negative LR 0.31 (0.25,0.38) and the diagnostic odds ratio (DOR) was 6.74 (5.49,8.28). Using DMARDs as reference standard, sensitivity was 0.73 (0.64,0.80), specificity was 0.74 (0.68,0.79), LR+2.85 (2.53,3.22), LR- 0.35 (0.27,0.45) and DOR 8.03 (6.4,10.09). Using the combination of MTX and DMARDs as reference standard, intermediate results were obtained. The influence analysis detected one potentially influential study. However, its exclusion from the meta-analysis did not have a clinically relevant impact on the results. CONCLUSIONS: The new classification criteria have good sensitivity, lower specificity and an overall moderate diagnostic accuracy. These results confirm that the criteria have classificative and not diagnostic function.
24893961 A hyaluronic acid-methotrexate conjugate for targeted therapy of rheumatoid arthritis. 2014 Jul 21 In an effort to improve the therapeutic efficacy of methotrexate (MTX), we prepared the hyaluronic acid-MTX conjugate for targeted therapy of rheumatoid arthritis (RA). Owing to the pH-sensitive nature of the conjugate, MTX was rapidly released under the mildly acidic conditions, similar to the environment of inflamed synovial tissue in RA.
25365085 An evidence-based approach to laboratory tests in usual care of patients with rheumatoid a 2014 Sep Laboratory tests often are regarded as the most important information in clinical care by patients and doctors, and dominate clinical decisions in many chronic diseases such as diabetes and hyperlipidemia. Most patients with rheumatoid arthritis (RA) have a positive test for rheumatoid factor or anti-cyclic citrullinated peptide antibodies (ACPA), or an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). However, about a third of RA patients, have negative tests for rheumatoid factor or ACPA, and more than 40% have a normal ESR or CRP at presentation ('false-negative' results). Furthermore, many normal people have a positive test for rheumatoid factor or ACPA but do not have RA, even among those with extensive musculoskeletal pain ('false-positive' results). Abnormal laboratory tests are the most significant predictor of high levels of radiographic progression, and therefore regarded as indicators of 'poor prognosis RA'. By contrast, laboratory tests are far less predictive of severe long-term outcomes such as work disability and premature mortality than functional difficulties reported on a patient questionnaire. A patient questionnaire score is abnormal in 89% of RA patients at presentation, and therefore more useful than ESR or CRP to document subsequent clinical improvement or deterioration. In clinical practice, patient questionnaire scores and RAPID3, an index of physical function, pain, and patient global estimate of status, identify incomplete responses to methotrexate more effectively than ESR. Improved understanding of the limitations of laboratory tests in diagnosis and management of individual patients with RA (and all rheumatic diseases) could improve patient care and outcomes.
24863583 High serum level of haptoglobin is associated with the response of 12 weeks methotrexate 2016 May BACKGROUND: We previously found, using microarray, haptoglobin (HP) expression signal was 5.1-fold increased in peripheral blood mononuclear cells (PBMCs) from methotrexate (MTX)-resistant rheumatoid arthritis (RA) patients. OBJECTIVES: To investigate whether serum levels of HP are associated with the response of 12 weeks MTX therapy in recent-onset RA patients. METHODS: Sixty-nine active RA patients with recent onset (< 24 months) were treated with MTX. Clinical variables, levels of HP messenger RNA (mRNA) in PBMCs and HP serum levels were tested at week 0 and week 12. RESULTS: After 12 weeks of MTX treatment, 34.7% of RA patients were categorized as responders according to European League Against Rheumatism (EULAR) response criteria (Week 12 Disease Activity Score of 28 joints [DAS-28] ≤ 3.2 and decrease > 1.2) and all others (65.2%) were defined as non-responders. The baseline HP mRNA in PBMCs from non-responders is significantly higher than those in responders (P < 0.05). Similar to mRNA expression, non-responders showed significantly elevated serum HP levels at baseline (369.9 ± 159.8 mg/dL) compared to those in responders (255.3 ± 143.9 mg/dL) (P = 0.01). Serum HP levels were decreased significantly from 255.3 ± 143.9 mg/dL at baseline to 186.4 ± 108.5 mg/dL at week 12 (P = 0.04) in responders, but remained at high levels in non-responders. CONCLUSIONS: High serum levels of HP at baseline are associated with inadequate response of 12 weeks MTX treatment in recent-onset RA patients. Further replication studies in larger samples are needed to validate HP as a potential predictive biomarker for response to MTX therapy in RA.
23553540 Effectiveness of golimumab in clinical management of patients with rheumatoid arthritis. 2013 Mar BACKGROUND AND OBJECTIVES: Limited data are available regarding the use of golimumab (100 mg) every 4 weeks, with or without methotrexate (MTX). The aim of this retrospective analysis was to evaluate the effectiveness and safety of golimumab following usual clinical practice in Japanese patients with rheumatoid arthritis (RA) according to the recommendations given in the Japanese package insert. PATIENTS AND METHODS: Japanese RA patients with moderate-to-high disease activity, according to the 28-joint disease activity score based on C-reactive protein (DAS28-CRP) criteria, despite treatment with MTX or another biological agent, were enrolled. Patients were assigned to 50 mg golimumab plus MTX or 100 mg golimumab monotherapy every 4 weeks for 24 weeks. All patients were given MTX if it was not contraindicated. The primary endpoint was the proportion of patients achieving clinical remission (defined as a DAS28-CRP <2.3 or a simplified disease activity index [SDAI] score <3.3) at 24 weeks. RESULTS: Most patients received combined 50 mg golimumab plus MTX (41/43). In these patients, the primary endpoint, clinical remission, was attained in 83 % of patients according to DAS28-CRP criteria (p < 0.001) and 69 % according to SDAI criteria (p < 0.001) by week 24. Adverse events were reported in 11.6 % of patients receiving golimumab. CONCLUSIONS: Golimumab (50 mg) plus MTX effectively reduced the signs and symptoms of RA and was generally well tolerated in patients with an inadequate response to MTX and other biological agents.
24386983 CD8-positive T-cell lymphoproliferative disorder associated with Epstein-Barr virus-infect 2016 We report a 48-year-old female who developed lymphoproliferative disorder (LPD) during treatment of rheumatoid arthritis (RA) with methotrexate (MTX). She presented with multiple tumors in the cervical lymph nodes (LNs), multiple lung shadows and round shadows in both kidneys with pancytopenia and a high CRP level. The LN showed CD8-positive T-cell LPD associated with Epstein-Barr (EB) virus-infected B-cells. Clonality assays for immunoglobulin (Ig) heavy chain and T-cell receptor gamma (TCRγ) were negative. The cessation of MTX without chemotherapy resulted in the complete disappearance of the tumors and abnormal clinical features. We compared this case with previously published ones and discuss the pathological findings, presuming that the proliferation of CD8 T-cells was a reactive manifestation to reactivated EB virus-infected B-cells.
25536484 Rheumatoid arthritis in 2014: Exciting times for RA research. 2015 Feb 2014 saw the emergence of a novel rheumatoid arthritis therapy to rival methotrexate, as well as advances in our understanding of mouse T.cell biology and of the cross-talk between the nervous system and the immune system. How will these advances affect the future of rheumatoid arthritis research and therapy?
22450926 Genetic polymorphisms in key methotrexate pathway genes are associated with response to tr 2013 Jun We investigated the effect of single-nucleotide polymorphisms (SNPs) spanning 10 methotrexate (MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1 (RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient cohort. Tagging SNPs were selected and genotyping was performed in 309 patients with predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were detected with efficacy (P-trend 0.05) including four SNPs in the ATIC gene (rs12995526, rs3821353, rs7563206 and rs16853834), six SNPs in the SLC19A1 gene region (rs11702425, rs2838956, rs7499, rs2274808, rs9977268 and rs7279445) and a single SNP within the GGH gene (rs12681874). Five SNPs were significantly associated with adverse events; three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline significance in the FPGS gene. The results suggest that genetic variations in several key MTX pathway genes may influence response to MTX in the RA patients. Further studies will be required to validate these findings and if confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA.
24249328 Does tocilizumab contribute to elevation of rheumatoid factor and induction of paradoxical 2014 Feb A 56-year-old woman, treated with tocilizumab (TCZ) for 8 months for severe rheumatoid arthritis (RA), was admitted to the hospital due to the swelling and tenderness of parotid glands. The patient was diagnosed with seropositive erosive RA in 1988, and treated with different disease modifying antirheumatic drugs (DMARDs) that were used together with a low dosage of glucocorticoides, followed by biologic therapy with infliximab and adalimumab which also proved to be inefficient. The patient had an excellent initial response on TCZ therapy. After 8 months, she was presented with an extreme enlargement of parotid glands. Bacterial, viral, and granulomatous diseases were excluded. A spectrum of autoantibodies including anti-Ro and anti-La showed normal values, expect for slightly elevated anti-cyclic citrullinated peptide (anti-CCP) and extreme elevation of the rheumatoid factor (RF) to 10,100 IU/ml. The biopsy of salivary glands was done and histological specimen showed limphoplasmocytic syaloadenitis. Tocilizumab therapy was stopped and the dosage of glucocorticoids and methotrexate (MTX) was raised. After 6 weeks, the patient was in better condition with slightly lower levels of RF (9,010 IU/ml). We hypothesise that in this patient, TCZ stimulated RF hyper production which can induce a paradoxical secondary syaloadenitis in RA.
25026799 [Cardiovascular diseases in patients with rheumatoid arthritis during long-term methotrexa 2014 AIM: To compare the prevalence of risk factors, clinical and subclinical manifestations of cardiovascular diseases (CVD) and their complications in methotrexate (MT)-treated and untreated patients with rheumatoid arthritis. SUBJECTS AND METHODS: The investigation enrolled 193 patients (168 women and 25 men) less than 60 years of age (mean age 49 [44; 53] years) with RA. The patients were divided into 2 groups: 1) 69 patients who received MT in a dose of 15.1 [10.2; 21] mg/week for at least 12 months (mean disease duration 25 [18; 48] months); 2) 124 patients who did not take MT. The patient groups were matched for age, gender, disease duration, RA activity, and the rate of rheumatoid factor (RF) seropositivity and extraarticular manifestations. RESULTS: Dyslipidemia was significantly less frequently identified in MT-treated patients (35/69 or 51%) than in MT-untreated ones (85/124 or 69%; p = 0.01). The serum from the patients treated with MT exhibited higher high-density lipoprotein cholesterol concentrations ((1.8 [0.9; 2.0] mmol/l) than in those untreated with MT (1.2 [1.0; 1.6] mmol/l; p = 0,047). In Group 1, hypertension (49%) and diabetes mellitus (3%) were slightly rare than in Group 2 (62 and 13%, respectively; p > 0.05). Carotid atherosclerotic plaques were found in 19 and 16% and intima-media thickness (IMT) enlargement was seen in 53 and 56% of the patients in Groups 1 and 2, respectively. Silent myocardial ischemia was diagnosed in every 10 patients; heart disease (exertional angina, myocardial infarction) was in every 5 patients in both groups. Aortocoronary bypass surgery was performed in 2 (3%) patients from those who received MT and had experienced MI and in one (1.6%) patient from the MT-untreated group. CONCLUSION: Long-term MT therapy was associated with the lower rate of dyslipidemia, but it failed to affect the incidence of CVD in patients with RA.
23907586 Cost-effectiveness of biological therapy compared with methotrexate in the treatment for r 2013 Dec The objectives of the study are to develop a cost-effectiveness model comparing biological therapy (BT) with methotrexate (MTX) alone, in the treatment for rheumatoid arthritis (RA), combining clinical and quality-of-life data from international trials with local costs and local epidemiological data. We designed a six-month cycle Markov model with five functional states, based on Health Assessment Questionnaire, with patients initiating treatment in any of the predefined states, based on a sample of 150 local RA patients. Simulations ran for 10 and 20 years, and for the whole life span. Utilities, in quality-adjusted life years (QALY), were taken from international literature. Discount rate was 3 % for costs and utilities. We calculated direct and indirect costs using a combination of international and local data. Results are presented as incremental cost-effectiveness ratios (ICER). ICERs in euros per QALY were 143,072 for 10 years; 139,332 for 20 years; and 137,712 for the whole life span. Total costs with MTX were lower than with BT, despite higher out of pocket, productivity, and complication costs. Under conventional thresholds, and for the "average" RA patient, BT would not be cost-effective in Colombia. BT compared to MTX provides more QALYs, but at a high cost. When ICERs were estimated for Colombia, BT would not be cost-effective. We propose different thresholds for different conditions, perhaps prioritizing chronic diseases that lead to disability.
25198168 Aseptic meningitis occurring during anti-TNF-alpha therapy in rheumatoid arthritis and ank 2014 Sep OBJECTIVES: Aseptic meningitis is a rare and aggressive complication of rheumatoid arthritis (RA), usually histologically characterised by rheumatoid nodules and lymphocytic aggregates in leptomeninges. The aim of this study was to describe the clinical onset and evolution of aseptic meningitis occurring during anti-TNF-alpha (TNF-α) therapy. METHODS: we retrospectively analysed the clinical records of patients with RA or ankylosing apondylitis (AS) treated by TNF-α drugs in the last 10 years. RESULTS: Four out of 718 patients, treated with TNF-α, developed meningitis after a mean of 5 years (SD: 3.7) of TNF-α exposure (0.55%). Three subjects were affected by long-standing RA (median: 11 years, IQR:8.5-25), one patient by active AS of 8 years' duration. RA patients were treated with etanercept (2 cases) and infliximab (1 case), in association with methotrexate and prednisone. The AS patient was treated with adalimumab. Neurological onset was focal epilepsy (3 cases) and dysarthria (1 case). RM showed leptomeningeal enhancement of basal nuclei (1 case) or fronto-parietal zone (3 cases), associated in one patient with cerebritis. Bacterial, viral or parasitic infections were excluded. One patient underwent cerebral biopsy showing T and B lymphocytes' aggregates. All patients discontinued TNF-α drugs and were treated with high dose of steroids, added to methotrexate in two cases. Neurological symptoms resolved without residuals, and meningeal enhancement showed resolution with high latency. CONCLUSIONS: Meningeal inflammation is a rare manifestation occurring in long-standing RA and AS in clinical remission. TNF-α therapy did not prevent this extra-articular complication.
21931346 MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid 2013 Apr Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83-1.32) and OR=0.81 (95% CI 0.53-1.24), respectively; toxicity: OR=1.38 (95% CI 0.90-2.12) and OR=1.19 (95% CI 0.80-1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.