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ID PMID Title PublicationDate abstract
32662413 ICHIBAN, a non-interventional study evaluating tocilizumab long-term effectiveness and saf 2021 Mar OBJECTIVES: We aimed to measure long-term effectiveness and safety of tocilizumab in patients with rheumatoid arthritis in daily German practice. METHODS: ICHIBAN was a prospective, multi-centre, non-interventional study (ML22928) that enrolled adult patients with active moderate to severe rheumatoid arthritis. Patients were to be treated according to tocilizumab label and observed for up to two years. Effectiveness outcomes included DAS28-ESR remission, EULAR response, CDAI and HAQ. RESULTS: Overall, 3164 patients received at least one dose of tocilizumab. Patient mean age was 55.5±13.1 years (74.8% female). At baseline, 72.1% of patients had at least one comorbidity. Approximately 50.9% of patients received concomitant csDMARDs, mostly methotrexate, and 80.7% received concomitant glucocorticoids (GCs). In patients receiving GCs at baseline, the mean dose decreased from 9.32±16.36 mg/d to 4.60±4.48 mg/d at week 104. In the effectiveness population with no prior TCZ (n=2902), 61.4% of patients achieved the primary outcome, DAS28-ESR remission. Improvements were seen as early as week 4. At week 104, 77.9% of patients had DAS28-ESR low disease activity, 89.6% achieved good or moderate EULAR response, and 29.5% achieved a CDAI-based remission. Effectiveness outcomes were similar in all previous therapy subgroups. The incidence of serious infections was similar to the rates in former studies involving tocilizumab. Patients receiving GC at baseline experienced slightly higher rates of treatment-related serious adverse events, mainly infections. No new safety signals were observed. CONCLUSIONS: Long-term effectiveness and safety in ICHIBAN were in line with previously reported tocilizumab efficacy and safety studies.
34778939 Pregnancy outcomes in patients with rheumatoid arthritis who discontinue methotrexate trea 2022 Mar INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) develops at reproductive age. Methotrexate (MTX), the anchor drug for RA treatment, is contraindicated during pregnancy. We investigated pregnancy outcomes in RA patients in whom MTX was withdrawn. METHOD: Pregnancy outcomes, RA treatment, and infertility factors were examined in patients with RA who discontinued MTX prior to attempting conception. The Mann-Whitney U test and Fisher's exact test were used to evaluate differences between the groups. RESULTS: Of the 52 patients enrolled in this study, 33 gave birth after discontinuing MTX and 19 did not. The age at MTX discontinuation was significantly different between the childbirth and non-childbirth groups (p = 0.0258). The use of non-steroidal anti-inflammatory drugs (NSAIDs) and salazosulfapyridine was significantly different between the groups (p = 0.0079 and p = 0.0438, respectively). Patients whose time from MTX discontinuation to pregnancy was longer than 12 months had a longer previous MTX administration period (p = 0.0182) and were older at the time of pregnancy (p = 0.0128) than those whose was shorter. CONCLUSIONS: The results suggest that to ensure successful childbirth in women with RA, the decision to conceive should be made at the youngest possible age, NSAIDs should not be used, and a shorter duration of MTX treatment should be considered before pregnancy. Nevertheless, additional studies with larger sample sizes are warranted to analyse the effects of other factors on pregnancies in patients with RA. KEY POINTS: • Patients with RA who plan to conceive must discontinue MTX therapy. • To achieve successful pregnancy outcomes, female patients with RA should become pregnant when they are young, discontinue NSAIDs prior to conception, and shorten their durations of MTX therapy before attempting pregnancy.
33840694 Immune Reconstitution Inflammatory Syndrome-like Condition Associated with Pneumocystis ji 2021 Oct 1 A 94-year-old woman with rheumatoid arthritis who had been treated with low-dose methotrexate was referred to our hospital because of a 3-day history of a fever and pancytopenia. With a diagnosis of febrile neutropenia of unknown origin, empirical antibiotic treatment and folinic acid therapy were initiated. Despite a recovery from pancytopenia, the high fever remained, and dyspnea developed. She was clinically diagnosed with Pneumocystis jirovecii pneumonia (PCP) and successfully treated with trimethoprim/sulfamethoxazole and adjunctive corticosteroid therapy. Folinic acid treatment effectively brought about rapid immune recovery but might have led to a clinical manifestation of PCP resembling immune reconstruction inflammatory syndrome.
33397481 Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthr 2021 Jan 4 Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.
33124557 Systematic analysis of the molecular mechanisms of methotrexate therapy for rheumatoid art 2021 Jul OBJECTIVES: The purpose of this study was to determine the expression of related genes in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), to identify hub genes, and to systematically analyse the functions, pathways, and networks of these genes. METHODS: The PubMed identifiers (PMIDs) of relevant publications were obtained from the PubMed database, and gene data were extracted from these documents using the text mining software PubTator. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to obtain enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway information. In addition, the STRING database was used to construct a protein-protein interaction (PPI) network. Genes with which at least 10 other genes interacted were identified as hub genes. RESULTS: A total of 216 genes were identified as being associated with treatment efficacy for MTX, of which 14 pathways exhibited significant correlation (p<0.05, FDR<0.05). In addition, the constructed MTX treatment-related network consisted of 267 interactions. Fourteen genes were found to interact with at least 10 other genes (p<0.05, FDR<0.05) and identified as hub genes in the PPI network. These genes were JAK1, MAPK1, JUN, AKT1, MAPK14, MAPK8, FGB, FN1, ALB, B2M, IL2RB, GGH, IL2RA, and TP53. CONCLUSIONS: This study will assist in elucidating the molecular mechanisms associated with the treatment efficacy of MTX for RA and provide a scientific rationale for guiding patient medication. However, the relationship between particular genes and the efficacy of MTX treatment for RA patients requires additional investigation.
34489924 A Cross-Sectional and Longitudinal Study to Define Alarmins and A-SAA Variants as Companio 2021 Nowadays, in the study of rheumatoid arthritis (RA), more and more interest is directed towards an earlier effective therapeutic intervention and the determination of companion markers for predicting response to therapy with the goal to prevent progressive joint damage, deformities, and functional disability. With the present work, we aimed at quantifying in a cohort of early RA (ERA) patients naïve to DMARD therapy, proteins whose increase was previously found associated with RA: serum amyloid A (A-SAA) and alarmins. Five A-SAA variants (SAA1α, SAA1β, SAA1γ, SAA2α, and SAA2β) but also S100A8 and S100A9 proteins were simultaneously quantified in plasma applying a method based on single targeted bottom-up proteomics LC-MS/MS. First, we compared their expression between ERA (n = 100) and healthy subjects (n = 100), then we focused on their trend by monitoring ERA patients naïve to DMARD treatment, 1 year after starting therapy. Only SAA1α and SAA2α levels were increased in ERA patients, and SAA2α appears to mostly mediate the pathological role of A-SAA. Levels of these variants, together with SAA1β, only decreased under biologic DMARD treatment but not under methotrexate monotherapy. This study highlights the importance to better understand the modulation of expression of these variants in ERA in order to subsequently better characterize their biological function. On the other hand, alarmin expression increased in ERA compared to controls but remained elevated after 12 months of methotrexate or biologic treatment. The work overcomes the concept of considering these proteins as biomarkers for diagnosis, demonstrating that SAA1α, SAA1β, and SAA2α variants but also S100A8 and S100A9 do not respond to all early treatment in ERA and should be rather considered as companion markers useful to improve the follow-up of treatment response and remission state. Moreover, it suggests that earlier use of biologics in addition to methotrexate may be worth considering.
34804067 The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Bi 2021 The identification of "trained immunity/tolerance" in myeloid cells has changed our perception of the performance of monocytes and macrophages during inflammatory and immune responses. Pemetrexed (PMX) and methotrexate (MTX) are blockers of the one-carbon metabolism (OCM) and commonly used therapeutic agents in cancer and rheumatoid arthritis (RA). We have previously showed that MTX promotes trained immunity in human macrophages. In the present manuscript, we have assessed the anti-inflammatory effects of PMX and MTX and found that OCM blockers alter the functional and gene expression profile of human macrophages and that OCM blockade reprograms macrophages towards a state of lipopolysaccharide (LPS) tolerance at the signaling and functional levels. Moreover, OCM blockade reduced macrophage LPS responsiveness by impairing the expression of membrane-bound and soluble CD14 (sCD14). The therapeutic relevance of these results was later confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. As a whole, our results demonstrate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance and positions sCD14 as a valuable tool to predict MTX response in RA patients.
32167789 Usefulness of daily folic acid supplementation during methotrexate treatment of Japanese p 2021 Jan OBJECTIVES: We investigated the effect of daily folic acid supplementation on methotrexate (MTX) toxicity and efficacy in Japanese patients with rheumatoid arthritis (RA). METHODS: We followed 19 patients treated with MTX who switched from taking weekly 5 mg folic acid supplementation (weekly regimen) to 1.25 mg daily (daily regimen). White blood cell (WBC) and platelet (PLT) counts, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were collected for 24 weeks following the change. RESULTS: We observed no significant changes in WBC or PLT counts. AST and ALT levels, which had exceeded the upper limits of their normal ranges at the beginning of the study, were improved significantly at weeks 4 and 8, no subsequent deterioration in liver function was found. Further, no significant changes in ESR and CRP levels were observed. CONCLUSION: Our data indicate that supplementing 1.25 mg of folic acid daily rather than 5 mg weekly reduces toxicity caused by MTX without affecting its efficacy.
34721377 Sustained Drug Treatment Alters the Gut Microbiota in Rheumatoid Arthritis. 2021 Several studies have investigated the causative role of the microbiome in the development of rheumatoid arthritis (RA), but changes in the gut microbiome in RA patients during drug treatment have been less well studied. Here, we tracked the longitudinal changes in gut bacteria in 22 RA patients who were randomized into two groups and treated with Huayu-Qiangshen-Tongbi formula (HQT) plus methotrexate (MTX) or leflunomide (LEF) plus MTX. There were differences in the gut microbiome between untreated (at baseline) RA patients and healthy controls, with 37 species being more abundant in the RA patients and 21 species (including Clostridium celatum) being less abundant. Regarding the functional analysis, vitamin K2 biosynthesis was associated with RA-enriched bacteria. Additionally, in RA patients, alterations in gut microbial species appeared to be associated with RA-related clinical indicators through changing various gut microbiome functional pathways. The clinical efficacy of the two treatments was further observed to be similar, but the response trends of RA-related clinical indices in the two treatment groups differed. For example, HQT treatment affected the erythrocyte sedimentation rate (ESR), while LEF treatment affected the C-reactive protein (CRP) level. Further, 11 species and 9 metabolic pathways significantly changed over time in the HQT group (including C. celatum, which increased), while only 4 species and 2 metabolic pathways significantly changed over time in the LEF group. In summary, we studied the alterations in the gut microbiome of RA patients being treated with HQT or LEF. The results provide useful information on the role of the gut microbiota in the pathogenesis of RA, and they also provide potentially effective directions for developing new RA treatments.
33773207 The AMPK modulator metformin as adjunct to methotrexate in patients with rheumatoid arthri 2021 Jun BACKGROUND: Metformin (MET) may exert anti-rheumatic effects and reduce cartilage degradation through its immunomodulatory and anti-inflammatory actions. METHODS: This was a double-blind placebo-controlled study, 120 adult patients with active rheumatoid arthritis (RA) were randomized to receive MET (1000 mg) or placebo daily with methotrexate (MTX, 7.5 mg/week) for 12 weeks. American College of Rheumatology (ACR)20, ACR50, and ACR70 response rates, Disease Activity Score in 28 joints (DAS-28), and drug safety were the efficacy endpoints. Serum levels of TNF-α, IL-1β, IL-6, IL-10, IL-17A, NF-κB, TGG-β1, MDA together with gene expression of AMPK and IGF-IR were assessed before and after the therapy. RESULTS: A total of 80.8% of the patients in the MET group, compared with 54.7% in placebo group, met the criteria of ACR20 response after 12 weeks (P = 0.001). Statistically significant enhancements in the DAS28-3 (CRP) were observed after 4 and 8 weeks for the MET group compared with placebo and were sustained after 12 weeks. MET group showed statistically significant increase in percentage of patients achieving DAS remission after 12 weeks (P = 0.015). Significant improvements in ACR50, ACR70, Health Assessment Questionnaire Disability Index (HAQ-DI), and DAS28-3 (CRP) were also reported. MET was well-tolerated, and no serious adverse effects were reported in both groups. Furthermore, the MET group was superior in improving the measured parameters compared to the placebo. CONCLUSIONS: MET improved the anti-rheumatic effect of MTX; suggesting it to be a beneficial adjuvant in patients with RA. Trial registration ID: NCT04068246.
34491649 [Effect of Bo's abdominal acupuncture as adjunctive therapy on rheumatoid arthritis and ES 2021 Sep 12 OBJECTIVE: To explore the therapeutic effect on rheumatoid arthritis treated with Bo's abdominal acupuncture for "guiding qi to the source" plus "opening four gates on the abdomen" and the relevant effect mechanism. METHODS: A total of 104 patients with rheumatoid arthritis were randomized into and an observation group (52 cases, 1 case dropped off) and a control group (52 cases, 3 cases dropped off). In the control group, methotrexate tablets were prescribed for oral administration, 5 mg each time, once a week. In the observation group, on the base of the treatment as the control group, Bo's abdominal acupuncture was combined. The acupoints included Zhongwan (CV 12), Xiawan (CV 10), Guanyuan (CV 4), Qihai (CV 6), Huaroumen (ST 24), Wailing (ST 26), etc. The treatment was given once every two days, 3 times weekly. Totally 12 weeks were required in the two groups. Before and after treatment, the score of TCM symptoms (including joint pain, the range of motion, joint swelling and morning stiffness), and the levels of erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) and C-reactive protein (CRP) were observed and the clinical therapeutic effect was assessed in the two groups. RESULTS: After treatment, the total effective rate was 88.2% (45/51) in the observation group, higher than 73.5% (36/49) in the control group (P<0.05). The score of each TCM symptom and the total scores after treatment were all lower than those before treatment in the two groups (P<0.05), and these scores in the observation group were lower than the control group (P<0.05). After treatment, the levels of ESR, RF and CRP were all lower than those before treatment in the two groups (P<0.05), while the levels of those indexes in the observation group were lower than the control group (P<0.05). CONCLUSION: Bo's abdominal acupuncture for "guiding qi to the source" plus "opening four gates on the abdomen" as the adjunctive therapy effectively relieves the clinical symptoms in the patients with rheumatoid arthritis, which is related to the reduction of ESR, RF and CRP in mechanism.
34050794 Therapeutic education improves rheumatoid arthritis patients' knowledge about methotrexate 2021 Nov To assess, by means of a questionnaire, the effectiveness of a therapeutic education session on rheumatoid arthritis patients' knowledge about methotrexate. Retrospective study of data collected in routine care. STROBE guidelines were used. Rheumatoid arthritis patients treated with methotrexate had a therapeutic education session conducted by a rheumatology nurse at time 0 and 6 months after. They completed a questionnaire to assess their knowledge about methotrexate before the first therapeutic education session and 6 and 12 months after. A score from 0 to 100 was calculated based on 20 questions. A total of 66 patients were enrolled (50 women), with a mean age of 57 years, median disease duration of 4 years, and methotrexate treatment duration of 2 years. The knowledge score improved 6 months after the first therapeutic education session and was unchanged at 12 months. Significant improvement was observed in knowledge about the need for contraception, the contraindication of trimethoprim, the maximum dose not to be exceeded, reduction in alcohol consumption, and the value of combining folic acid with methotrexate. Knowledge about the risk of hypersensitivity pneumonitis did not improve. Skills related to the need for and timing of laboratory testing and contraception were evaluated using two role-playing situations. None of the skills improved. A therapeutic education session improves patients' knowledge about methotrexate at 6 months.
33200208 Peripheral blood mononuclear cells are hypomethylated in active rheumatoid arthritis and m 2021 Apr 6 OBJECTIVE: Epigenetic modifications are dynamic and influence cellular disease activity. The aim of this study was to investigate global DNA methylation in peripheral blood mononuclear cells (PBMCs) of RA patients to clarify whether global DNA methylation pattern testing might be useful in monitoring disease activity as well as the response to therapeutics. METHODS: Flow cytometric measurement of 5-methyl-cytosine (5'-mC) was established using the cell line U937. In the subsequent prospective study, 62 blood samples were investigated, including 17 healthy donors and 45 RA patients at baseline and after 3 months of treatment with methotrexate, the IL-6 receptor inhibitor sarilumab, and Janus kinase inhibitors. Methylation status was assessed with an anti-5'-mC antibody and analysed in PBMCs and CD4+, CD8+, CD14+ and CD19+ subsets. Signal intensities of 5'-mC were correlated with 28-joint DASs with ESR and CRP (DAS28-ESR and DAS28-CRP). RESULTS: Compared with healthy individuals, PBMCs of RA patients showed a significant global DNA hypomethylation. Signal intensities of 5'-mC correlated with transcription levels of DNMT1, DNMT3B and MTR genes involved in methylation processes. Using flow cytometry, significant good correlations and linear regression values were achieved in RA patients between global methylation levels and DAS28-ESR values for PBMCs (r = -0.55, P = 0.002), lymphocytes (r = -0.57, P = 0.001), CD4+ (r = -0.57, P = 0.001), CD8+ (r = -0.54, P = 0.001), CD14+ (r = -0.49, P = 0.008) and CD19+ (r = -0.52, P = 0.004) cells. CONCLUSIONS: The degree of global DNA methylation was found to be associated with disease activity. Based on this novel approach, the degree of global methylation is a promising biomarker for therapy monitoring and the prediction of therapy outcome in inflammatory diseases.
34248117 Immune Reconstitution Inflammatory Syndrome Associated with Pneumocystis jirovecii Pneumon 2022 Jan 15 A 68-year-old woman presenting with rheumatoid arthritis was admitted due to pancytopenia caused by methotrexate. Pneumocystis jirovecii pneumonia was diagnosed based on the abnormal shadows observed on chest computed tomography, the presence of serum β-D-glucan, and positive P. jirovecii-DNA results in a sputum analysis. Subsequently, after treatment with leucovorin and trimethoprim-sulfamethoxazole, lung consolidation was found to be aggravated, along with a rapidly increasing leukocyte count. In addition, cytomegalovirus colitis was diagnosed. Both conditions were associated with immune reconstitution inflammatory syndrome caused by recovery from leukopenia. The patient was successfully treated with intravenous methylprednisolone pulse therapy and ganciclovir.
34870735 Usefulness of noninvasive diagnostic procedures for assessment of methotrexate hepatotoxic 2022 Apr Methotrexate (MTX) is recommended as a first-line treatment for rheumatoid arthritis (RA). There are no strict guidelines regarding monitoring for liver damage in RA patients. This study aimed to evaluate noninvasive diagnostic procedures in assessing liver fibrosis in RA patients. Ninety-six RA patients were recruited for this study. The procollagen III N-terminal peptide (PIIINP) serum level was measured in all patients. The Enhanced Liver Fibrosis score (ELF-1) was calculated for 82 patients. Transient elastography (TE) was performed in 91 patients, those examined were divided into two groups: a study and control group, comprising patients with and without risk factors for liver fibrosis, respectively. The TE result correlated only with the body mass index-BMI (p < 0.05); there was no correlation with the cumulative MTX dose (p = 0.33). The TE result was significantly higher in those with risk factors for liver fibrosis than in those without risk factors (TE result >  = 7.1 kPa 28/42 vs 13/41, HR = 2.103, Mann-Whitney U test, approximately 0.02). There was a positive correlation between the PIIINP level and body weight (p = 0.028), cumulative MTX dose (p = 0.007), RA activity (p = 0.028) and diabetes mellitus (DM) (p = 0.001). There was a positive correlation between the ELF-1 score and age (p < 0.001), cumulative MTX dose (p = 0.007) and RA activity (p < 0.001). The PIIINP level and ELF-1 score are not organ specific, and readings may vary depending on RA activity. TE is organ specific and can be performed by a skilled ultrasonographer might be useful to assess actual liver condition.
34153036 Rheumatoid arthritis serotype and synthetic disease-modifying anti-rheumatic drugs in pati 2021 Patients with rheumatoid arthritis (RA) experience a higher prevalence of periodontitis. This study aimed to examine the variation of periodontitis experienced with different serotypes suffered by RA patients and to examine the relationship between the different medications taken for RA that may influence this relationship. Two hundred and sixty RA and control participants underwent standardized periodontal examinations. Medical, serological and radiological (Sharp/van der Heijde) records were assessed. Functional status was assessed using the administered Health Assessment Questionnaire. Moreover, disease parameters, including disease activity (DAS28-ESR) and anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) seropositivity were evaluated. Periodontitis was higher in RA (71.54%) compared with controls (54.62%). The stage of periodontitis experienced by ACPA-positive participants were higher than APCA-negative participants. The probing pocket depth and recession experienced by RF-positive participants were higher than those who were RF-negative. RA participants on methotrexate had lower clinical attachment loss and lower periodontal probing depth compared with participants on a combination methotrexate and other disease-modifying antirheumatic drugs. Participants taking corticosteroids had lower gingival index scores. The association between seropositivity and the type of medications taken with periodontal health parameters in this group of patients suggests that both seropositivity and medications taken are important modifiers in the relationship between periodontitis and RA.
34721412 Molecular Changes in the Adipose Tissue Induced by Rheumatoid Arthritis: Effects of Diseas 2021 Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.
34006152 Methotrexate and cardiovascular risk in rheumatic diseases:A comprehensive review. 2021 Sep Introduction: Management of inflammatory rheumatic diseases has evolved based on improved treatment strategies and better management of comorbidities, specifically cardiovascular risk. Methotrexate is one of the first-line treatments in the management of inflammatory rheumatic diseases, but its cardiovascular effects are poorly understood. The purpose of this review is to assess the cardiovascular impact of methotrexate in inflammatory rheumatic disease.Areas covered: Current knowledge about the mechanism of action of methotrexate on cardiovascular tissue is presented. A review of the literature in the Medline, Cochrane and Embase databases was performed. Current data about the cardiovascular effects of methotrexate in rheumatoid arthritis, psoriatic arthritis, and psoriasis are presented.Expert opinion: Mechanism of action of methotrexate is based on the antagonism of purines. It reduces systemic inflammation and oxidative stress and improves the major cardiovascular risk factors. Methotrexate improves cardiovascular risk in rheumatoid arthritis, psoriasis and psoriatic arthritis, but the mechanisms involved are partially identified. Data are controversial regarding its effects on endothelial function and atherosclerosis. Conversely, in the general population and in patients with HIV infection, methotrexate does not modify cardiovascular outcomes. Thus, methotrexate only improves cardiovascular risk by reducing systemic inflammation, and should not be used to prevent cardiovascular events.
34432365 Assessing methotrexate intolerance and its prevalence in rheumatoid arthritis: Development 2021 Oct OBJECTIVE: Methotrexate (MTX) intolerance refers to unpleasant symptoms that accompany use of MTX. Although a validated questionnaire on MTX intolerance exists for children with juvenile idiopathic arthritis, it is lacking for adult rheumatoid arthritis (RA) patients. METHODS: A 10-item questionnaire called Methotrexate Intolerance and Severity assessment in Adults (MISA) was developed to assess MTX intolerance. On receiver operating characteristic analysis, its predictive ability was compared to Methotrexate Intolerance Severity Score (MISS), a validated questionnaire for children. Subsequently, prevalence and associations of intolerance were assessed in 414 RA patients. After 1 year, discontinuation of MTX was compared between patients with and without MTX intolerance. RESULTS: MISA score had a good predictive ability (area under the curve [AUC] of 0.904), with sensitivity and specificity of 91.4% and 84.3% (cut-off ≥1) to correctly classify MTX intolerance and was better than MISS score (AUC of 0.823). Among 414 RA patients, 159 (38.4%) had MTX intolerance, with common symptoms being nausea, lethargy, irritability and loss of appetite. On multivariable analysis, age (odds ratio 0.972) and body mass index (odds ratio 1.061) were significant predictors of MTX intolerance. At 1 year, a higher proportion of patients with intolerance than without intolerance had discontinued MTX (odds ratio 2.4, P = 0.02). To classify severity of intolerance, another score, MISA-cross-product, was developed and validated, with an AUC of 0.899. CONCLUSIONS: The newly developed MISA questionnaire and score had good predictive ability to diagnose MTX intolerance. Intolerance to MTX was common, being found in one-third of RA patients. Patients with intolerance were twice more likely to discontinue MTX at 1 year.
33592662 [EBV-positive MTX-associated lymphoproliferative disorder and Ig M myeloma in rheumatoid a 2021 Feb HISTORY: An 80-year-old female patient arrived with a pronounced lymphadenopathy and weight loss. 6 years ago she had been diagnosed with rheumatoid arthritis. At the time of arrival, she was administered Methotrexate (MTX) 10 mg/week. FINDINGS AND DIAGNOSIS: By lymph node biopsy, a clonal population of both EBV-positive B and T cells was seen. Newly occurring anemia (Hb 10 g/dl), monoclonal gammopathy of the Ig M isotype and detection of 40 % EBV-positive plasma cells in the bone marrow were consistent with the diagnosis of Ig M myeloma. We interpret these findings as a biclonal Epstein Barr Virus-positive Methotrexate-associated lymphoproliferative disorder (MTX-LPD). TREATMENT AND COURSE: The clinical condition improved immediately after MTX discontinuation. In the follow-up after 4 months, the gamma globulin concentration in serum was significantly reduced (from 51.1 to 34.7 %) and a renewed immune electrophoresis of the serum was without evidence of monoclonal gammopathy. CONCLUSION: Based on this case, the association of RA with lymphoproliferative disorders can be confirmed - here as an association of RA with biclonal MTX-LPD or multiple myeloma. Therapy with MTX and reactivation of EBV infection are important influencing factors.