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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
31617429 Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity i 2020 Feb OBJECTIVE: The objective was to explore the association of methylene tetrahydrofolate reductase (MTHFR) C667T and A1298C and reduced folate carrier 1 (RFC-1) A80G single nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) and efficacy and toxicity of methotrexate (MTX) treatment in Chinese Han patients in Henan, China. METHODS: Two hundred ninety-six patients with RA were enrolled (cases) and 120 healthy individuals served as controls. The genotypes of MTHFR C667T and A1298C SNP and RFC-1 A80G SNP were detected by restriction fragment length polymorphism-PCR and compared between cases and controls. We analyzed correlations of clinical effect, toxicity, and SNPs after 6 months of MTX treatment. RESULTS: We detected no significant differences in MTHFR C677T and A1298C and RFC-1 A80G SNPs between cases and controls. The RFC-1 A80G SNP differed between RA patients with good and poor efficacy after 6 months of MTX, and was an independent factor of MTX efficacy. The MTHFR C677T SNP was differently distributed in the adverse drug reaction (ADR) and non-ADR groups and was an independent factor of MTX toxicity. CONCLUSIONS: In Chinese Han patients with RA, the MTHFR C667T SNP may correlate with MTX toxicity, whereas the RFC-1 A80G SNP may correlate with MTX efficacy rather than toxicity.
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.
31820195 Influence of treatments on cell adhesion molecules in patients with systemic lupus erythem 2020 Apr BACKGROUND: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases characterized by changes in cell adhesion molecules (CAMs). OBJECTIVE: To review the influence of the main drugs used in the treatment of SLE and RA on CAM levels. METHODS: A bibliographic search was performed using electronic databases. The research included human studies, in vivo or in vitro, with an experimental or observational design, and with no limit of publication date or number of subjects. Animal studies and non-standard treatments were not considered. RESULTS: We included 21 studies, 3 on SLE and 18 on RA with monotherapy or combined trials. The most used drugs were cyclophosphamide (CY, in 2 studies) and methylprednisolone pulse (pMP, n = 2) in SLE; and methotrexate (MTX, n = 9) and infliximab (IFX, n = 4) in RA. In addition, the most frequently examined CAMs to predict response to treatment were vascular cell adhesion molecule-1 (VCAM-1, n = 2) in SLE, and intercellular adhesion molecule-1 (ICAM-1, n = 12), VCAM-1 (n = 12), and E-selectin (n = 14) in RA. After treatment, CAM levels were decreased in SLE and RA patients with active disease. CONCLUSIONS: It is concluded that the CAM biomarkers may reflect disease activity and the response to treatment in SLE and RA patients.
32112341 A case of esophageal cancer complicated with methotrexate-related lymphoproliferative diso 2020 Aug A 69-year-old woman had been undergoing treatment with methotrexate for rheumatoid arthritis for 9 years. Because fever and right hypochondriac pain continued, she visited the nearby hospital. The enlargement of intraabdominal multiple lymph nodes was detected through abdominal computed tomography. Esophagogastroduodenoscopy showed a depressed lesion in the lower intrathoracic esophagus, and squamous cell carcinoma was diagnosed by a biopsy. Positron emission tomography-computed tomography showed a highly abnormal accumulation of lymph nodes, mainly in the upper abdomen, and some lymph nodes around the aorta. Suspecting methotrexate-lymphoproliferative disorder, we discontinued the oral administration of methotrexate. Multiple lymphadenopathy reduced by the withdrawal of the oral administration of methotrexate. We operated for esophageal cancer, and she was discharged on the 17th postoperative day. The postoperative pathological result showed moderately differentiated squamous cell carcinoma. Metastasis to the lymph nodes around the esophagus was observed, and the patient was diagnosed with T1b (SM3), N2 M0, Stage II cancer. Immunostaining showed enlarged lymph nodes composed of CD20-positive cells and with cells positive for EBV-encoded small RNA in situ hybridization. This case shows that patients with rheumatoid arthritis who are being administered methotrexate may have enlarged lymph nodes due to methotrexate-lymphoproliferative disorder.
31791581 Theacrine alleviates chronic inflammation by enhancing TGF-β-mediated shifts via TGF-β/S 2020 Feb 12 Rheumatoid arthritis is a chronic and systemic autoimmune disease, which affects approximately 1% of the adult population worldwide. The present study investigated the therapeutic effect of theacrine (TC) on arthritis and its mechanisms in Freund's incomplete adjuvant (FIA)-induced SD rats. Rats were randomly divided into 5 groups: i) healthy control; ii) model; iii) positive control with methotrexate (MTX); iv) treatment with 12.5 mg/kg TC; and v) treatment with 25.0 mg/kg TC. The apparent scores, including changes in body weights, degree of paw swelling and arthritis indicators, were analyzed to evaluate the anti-chronic inflammatory effect of TC. The levels of interleukin (IL)-6 and transforming growth factor-β (TGF-β) in serum were measured by enzyme-linked immunosorbent assay. The protein and RNA expression levels of the critical factors in rats were measured to elucidate the mechanisms responsible for chronic inflammation and to verify molecular indexes of chronic inflammatory conditions. TC notably suppressed the severity of FIA-induced rat by attenuating the apparent scores, animal weight and inflammatory indexes in the 25 mg/kg TC group compared with the FIA rat model. Furthermore, TC significantly decreased the levels of IL-6 and increased the levels of TGF-β. Histopathological examinations indicated that TC rescued the synovial hyperplasia and inflammatory cell infiltration in joint tissues. In addition, TC enhanced TGF-β-mediated shifts in inflammatory marker expression in joint tissue. Overall, the present study demonstrated that TC exerted a superior anti-arthritic effect via the suppression of IL-6 and the activation of TGF-β by the TGF-β/SMAD pathway.
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.
32241795 Two-year cost-effectiveness of different COBRA-like intensive remission induction schemes 2020 May OBJECTIVES: To evaluate the cost-effectiveness of treat-to-target strategies among recently diagnosed patients with rheumatoid arthritis (RA) using methotrexate (MTX) and a step-down glucocorticoid (GC) scheme (COBRA Slim) compared with (1) this combination with either sulphasalazine (COBRA Classic) or leflunomide (COBRA Avant-Garde) in high-risk patients and (2) MTX without GCs (Tight-Step-Up, TSU) in low-risk patients. METHODS: The incremental cost-utility was calculated from a healthcare perspective in the intention-to-treat population (n=379) of the 2-year open-label pragmatic randomised controlled Care in early RA trial. Healthcare costs were collected prospectively through electronic trial records. Quality-adjusted life years (QALYs) were estimated using mapping algorithms for EuroQoL-5 Dimension. Multiple imputation was used to handle missing data and bootstrapping to calculate CIs. Robustness was tested with biological disease-modifying antirheumatic drugs at biosimilar prices. RESULTS: In the high-risk group, Classic (∆k€1.464, 95% CI -0.198 to 3.127) and Avant-Garde (∆k€0.636, 95% CI -0.987 to 2.258) were more expensive compared with Slim and QALYs were slightly worse for Classic (∆-0.002, 95% CI -0.086 to 0.082) and Avant-Garde (∆-0.009, 95% CI -0.102 to 0.084). This resulted in the domination of Classic and Avant-Garde by Slim. In the low-risk group, Slim was cheaper (∆k€-0.617, 95% CI -2.799 to 1.566) and QALYs were higher (∆0.141, 95% CI 0.008 to 0.274) compared with TSU, indicating Slim dominated. Results were robust against the price of biosimilars. CONCLUSIONS: The combination of MTX with a GC bridging scheme is less expensive with comparable health utility than more intensive step-down combination strategies or a conventional step-up approach 2 years after initial treatment. TRIAL REGISTRATION NUMBER: NCT01172639.
31998962 Is background methotrexate advantageous in extending TNF inhibitor drug survival in elderl 2020 Sep 1 OBJECTIVE: To evaluate drug survival with monotherapy compared with combination therapy with MTX in RA older adults. METHODS: Patients from the British Society for Rheumatology Biologics Register, a prospective observational cohort, who were biologic naïve and commencing their first TNF inhibitors (TNFi) were included. The cohort was stratified according to age: <75 and ≥75. Cox-proportional hazards models compared the risk of TNFi discontinuation from (i) any-cause, (ii) inefficacy and (iii) adverse events, between patients prescribed TNFi-monotherapy compared with TNFi MTX combination. RESULTS: The analysis included 15 700 patients. Ninety-five percent were <75 years old. Comorbidity burden and disease activity were higher in the ≥75 cohort. Fifty-two percent of patients discontinued TNFi therapy during the follow-up period. Persistence with therapy was higher in the <75 cohort. Patients receiving TNFi monotherapy were more likely to discontinue compared with patients receiving concomitant MTX [hazard rate 1.12 (1.06-1.18) P <0.001]. This finding only held true in patients <75 [hazard rate (HR) 1.11 (1.05-1.17) vs ≥75 [HR 1.13 (0.90-1.41)]. Examining TNFi discontinuation by cause revealed patients ≥75 receiving TNFi monotherapy were less likely to discontinue TNFi due to inefficacy [HR 0.66 (0.43-0.99) P=0.04] and more likely to discontinue therapy from adverse events [HR 1.41(1.02-1.96) P =0.04]. These results were supported by the multivariate adjustment in complete case and imputed analyses. CONCLUSION: TNFi monotherapy is associated with increased treatment failure. In older adults, the disadvantage of TNFi monotherapy on drug survival is no longer seen. Patients ≥75 have fewer discontinuations due to inefficacy than adverse events compared with younger patients. This likely reflects greater disposition to toxicity but perhaps also a decline in immunogenicity associated with immunosenescence.
32478474 Tofacitinib in the treatment of Indian patients with rheumatoid arthritis: A post hoc anal 2020 Jul OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized tofacitinib efficacy/safety in Indian vs rest of the world (ROW; excluding India) RA patients. METHODS: Efficacy data were pooled for disease-modified antirheumatic drug (DMARD) inadequate responders from Phase (P)3 studies. For Indian patients, ORAL Solo and ORAL Scan; ROW (excluding India), these studies plus ORAL Step, ORAL Sync, and ORAL Standard. Safety data also included ORAL Start (P3; methotrexate-naïve) and ORAL Sequel (long-term extension [LTE] study; data cut-off March 2017) for Indian patients, and these studies plus A3921041 (LTE study; Japanese study) for ROW. Efficacy outcomes at months 3/6: American College of Rheumatology (ACR)20/50/70; Disease Activity Score in 28 joints, erythrocyte sedimentation rate remission/low disease activity; change from baseline in Health Assessment Questionnaire-Disability Index. Incidence rates (IRs; patients with events/100 patient-years) for adverse events of special interest (AESIs) were assessed throughout. Descriptive data underwent no formal comparison. RESULTS: One-hundred-and-ninety-seven Indian and 3879 ROW patients were included. Compared with ROW patients, Indian patients were younger, had lower body mass index, shorter RA duration, and higher baseline disease activity; most Indian patients were non-smokers and all were biologic DMARD (bDMARD)-naïve. Month 3 ACR20 rates with tofacitinib 5 mg twice daily/10 mg twice daily/placebo were 67.4%/82.1%/40.9% (India) and 59.0%/66.1%/28.2% (ROW), and month 6 rates were 76.2%/92.1%/88.9% (India) and 69.0%/74.2%/66.5% (ROW). Month 3/6 improvements in other outcomes were generally numerically greater with tofacitinib vs placebo, and similar in both populations. Compared with ROW, Indian patients had numerically fewer AEs/serious AEs, and similar IRs for discontinuations due to AEs and AESIs, except that tuberculosis (TB) IR was higher in Indian (IR = 1.21; 95% CI 0.49, 2.49) vs ROW patients (IR = 0.17; 95% CI 0.11, 0.25). CONCLUSIONS: Tofacitinib efficacy/safety were similar in both populations, except TB IR, which was higher in Indian patients but in line with those in bDMARD-treated RA patients from high-risk countries (IR = 0.00-2.56; TB IR >0.05 [World Health Organization]). Limitations included the small Indian population and baseline differences between populations.
32811536 Assessment of the association of baseline anti-CarbV and anti-MCV antibodies with response 2020 Aug 18 BACKGROUND: The development of autoantibodies in patients with rheumatoid arthritis (RA) has potential as a marker of treatment response. This analysis assessed the association of an autoantibody response to carbamylated vimentin (anti-CarbV) and to vimentin modified by citrullination (anti-MCV) with response to treatment and structural damage progression in the phase III study RA-BEGIN. METHODS: Data from patients in the modified intent-to-treat population of RA-BEGIN were included for analysis; these patients received methotrexate (MTX), baricitinib 4 mg once daily, or baricitinib plus MTX during the 52-week study period. Endpoints analyzed were clinical response to treatment, assessed using change from baseline (CFB) in Simplified Disease Activity Index (SDAI) and Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP), and structural damage progression, assessed using CFB greater than the smallest detectable change in the van der Heijde-modified Total Sharp Score. The anti-CarbV and anti-MCV isotypes assessed were immunoglobulin (Ig) A, IgG, and IgM. Multivariable mixed-effect models for repeated measures (MMRMs) were used for the longitudinal analysis of treatment response, and multivariable logistic regression models were used for the analysis of structural damage progression at week 52. RESULTS: Analysis of the association between autoantibodies and treatment response showed that high titers of anti-CarbV (IgA and IgG) were associated with a greater clinical response as measured by SDAI and DAS28-hsCRP. Anti-CarbV IgA and IgG, but not IgM, demonstrated an association after adjustment for other factors included in the MMRMs. High titers of anti-CarbV IgM were associated with a poor response to MTX monotherapy, whereas a nonsignificant trend toward a better response to baricitinib and baricitinib plus MTX was observed. There was no association between anti-MCV antibodies and treatment response. High titers of anti-CarbV IgA were associated with a greater probability of radiographic progression, but no association between anti-MCV antibodies and radiographic progression was observed. CONCLUSIONS: High titers of anti-CarbV IgA and IgG isotypes, but not anti-MCV isotypes, may be useful prognostic biomarkers for identifying the likelihood of the response to treatment and structural damage progression in patients with RA.
32371387 Implication of baseline levels and early changes of C-reactive protein for subsequent clin 2020 Jul BACKGROUND: Rheumatoid arthritis (RA) is characterised by clinical joint swelling and elevation of acute phase reactant levels, typically measured by the C-reactive protein (CRP). Clinical and inflammatory responses are usually concordant, except for inhibition of IL-6, which often disproportionally reduces the CRP due to direct inhibition of its hepatic production. We investigated whether pre-treatment CRP is a useful marker that can guide a preferential treatment choice towards IL-6 inhibition. METHODS: Data of 1126 treatment courses with tocilizumab (TCZ; early RA), 250 courses of rituximab (RTX; established RA) and 249 courses of methotrexate (MTX; established RA) were analysed. We compared clinical disease activity index (CDAI) values and change along 24 weeks' follow-up to CRP values at baseline or its early change. We validated the results using data from a separate TCZ trial in early RA. RESULTS: CRP levels in the TCZ group on average dropped by 74% within 4 weeks. Patients who attained CDAI remission at 24 weeks on TCZ had the highest baseline CRP levels while patients in high disease activity had the lowest; this association was reverse in the RTX and MTX groups. TCZ patients who achieved remission at 24 weeks showed the largest reductions of CRP levels by week 4 compared with those reaching higher disease activity states. Early CRP non-response was indicative of a risk of not achieving clinical treatment goals (p=0.038). CONCLUSION: Baseline CRP appears to have a positive association with reaching the therapeutic target on TCZ treatment, but is a negative predictor for RTX and MTX. Patients on TCZ without an early CRP response have a lower chance of achieving remission. CRP and its early course may inform, to some extent, the estimation of potential therapeutic success in patients with RA.
32378457 Heart Failure Risk Associated With Rheumatoid Arthritis-Related Chronic Inflammation. 2020 May 18 Background Inflammation may contribute to incident heart failure (HF). Rheumatoid arthritis (RA), a prototypic inflammatory condition, may serve as a model for understanding inflammation-related HF risk. Methods and Results Using the Vanderbilt University Medical Center electronic health record, we retrospectively identified 9889 patients with RA and 9889 control patients without autoimmune disease matched for age, sex, and race. Prevalent HF at entry into the electronic health record or preceding RA diagnosis was excluded. Incident HF was ascertained using International Classification of Diseases, Ninth Revision (ICD-9), codes and medications. Over 177 566 person-years of follow-up, patients with RA were at 21% greater risk of HF (95% CI, 3-42%) independent of traditional cardiovascular risk factors. Among patients with RA, higher CRP (C-reactive protein) was associated with greater HF risk (P<0.001), while the anti-inflammatory drug methotrexate was associated with ≈25% lower HF risk (P=0.021). In a second cohort (n=115) of prospectively enrolled patients with and without RA, we performed proteomics and cardiac magnetic resonance imaging to discover circulating markers of inflammation associated with cardiac structure and function. Artemin levels were higher in patients with RA compared with controls (P=0.009), and higher artemin levels were associated with worse ventricular end-systolic elastance and ventricular-vascular coupling ratio (P=0.044 and P=0.031, respectively). Conclusions RA, a prototypic chronic inflammatory condition, is associated with increased risk of HF. Among patients with RA, higher levels of CRP were associated with greater HF risk, while methotrexate was associated with lower risk.
32448869 Analysis of association of ADORA(2)A and ADORA(3) polymorphisms genotypes/haplotypes with 2020 Dec Adenosine receptors ADORA(2)A and ADORA(3) are part of the adenosine-mediated antiinflammatory pathway and are overexpressed in patients with Rheumatoid arthritis (RA). Methotrexate (MTX) antiinflammatory effects are partially mediated via increased release of adenosine into extracellular space. Polymorphisms in ADORA(2)A and ADORA(3) genes may have an impact on the efficacy and toxicity of MTX in RA patients. The study included 127 RA patients. Treatment efficacy was estimated using the changes in Disease activity score (DAS28) after 6 months of MTX monotherapy, according to EULAR response criteria. Patients with good and moderate response were classified as "responders", and with a poor response as "nonresponders". Adverse effects were collected during the follow-up period. Genotyping for polymorphisms within ADORA(2)A gene (rs2298383, rs2236624, rs5751876, rs17004921) and ADORA(3) gene (rs2298191, rs1544223, rs3393) was performed using the KASPar assays. Among patients 112 (88.19%) were responders (18.8% good, 81.2% moderate). We observed no association between analyzed genotypes or alleles and MTX response by EULAR criteria but carriers of ADORA(2)A rs17004921 T allele (CT + TT) had a higher DAS28 decrease after 6 months of treatment than patients with CC genotype (p = 0.013). Adverse effects were reported in 31 patients (24.41%). Bone erosions were present in 82 (64.6%) patients. Haplotype block was observed among all 3 analyzed polymorphisms within ADORA(3) gene and TAA haplotype was associated with bone erosions (29% vs 15.6%, p = 0.023) and hepatotoxicity (51.3% vs 21.6%, p = 0.013). According to our study, ADORA(3) TAA haplotype may be associated with bone erosions and hepatotoxicity in RA patients treated with MTX.
33076964 TREAT Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid arthritis 2020 Oct 16 BACKGROUND: We present a study protocol for a randomized, double-blind, placebo-controlled trial that investigates the hypothesis if intervention in the symptomatic phase preceding clinical arthritis (clinically suspect arthralgia (CSA)) is effective in preventing progression from subclinical inflammation to clinically apparent persistent arthritis. Currently, rheumatoid arthritis (RA) can be recognized and diagnosed when arthritis (joint swelling) has become detectable at physical examination. Importantly, at this time, the immune processes have already matured, chronicity is established, and patients require long-standing treatment with disease-modifying anti-rheumatic drugs. The TREAT EARLIER trial studies the hypothesis that intervention in the symptomatic phase preceding clinical arthritis is more often successful in permanent disease modification because of less matured underlying disease processes. METHODS: A two-level definition to identify patients that are prone to develop RA is used. First, patients should have CSA and recent-onset arthralgia (< 1 year) that is suspect to progress to RA according to the expertise of the treating rheumatologist. Second, patients need to have subclinical inflammation of the hand or foot joints at 1.5 T MRI. The trial aims to recruit 230 participants from secondary care hospital settings across the south-west region of The Netherlands. Intervention will be randomly assigned and includes a single-dose of intramuscular 120 mg methylprednisolon followed by methotrexate (increasing dose to 25 mg/week orally) or placebo (both; injection and tablets) over the course of 1 year. Thereafter, participants are followed for another year. The primary endpoint is the development of clinically detectable arthritis, either fulfilling the 2010 criteria for RA or unclassified clinical arthritis of ≥ 2 joints, which persists for at least 2 weeks. DMARD-free status is a co-primary endpoint. The patient-reported outcomes functioning, along with workability and symptoms, are key secondary endpoints. Participants, caregivers (including those assessing the endpoints), and scientific staff are all blinded to the group assignment. DISCUSSION: This proof-of-concept study is the logical consequence of pre-work on the identification of patients with CSA with MRI-detected subclinical joint inflammation. It will test the hypothesis whether intervention in patients in this early phase with the cornerstone treatment of classified RA (methotrexate) hampers the development of persistent RA and reduce the disease burden of RA. TRIAL REGISTRATION: Dutch Trial Register NL4599 (NTR4853). Registered on 20 October 2014.
32304147 Association between SLCO1A2 genetic variation and methotrexate toxicity in human rheumatoi 2020 Aug Methotrexate (MTX), one of the important disease-modifying anti-rheumatic drugs, is the first-line drug for rheumatoid arthritis (RA) treatment. However, its adverse drug effects (ADEs) often lead to the abortion of MTX therapy. Human organic anion-transporting polypeptide 1A2 (OATP1A2, also referred as OATP-A or OATP1) encoded by SLCO1A2 gene is an important isoform of the solute carrier transporter (SLC) family. It is known to participate in the cellular uptake of MTX. In our previous study, we identified four OATP1A2 natural variants (E184K, D185N, T259P, and D288N) with impaired MTX uptake activity. This study aimed to evaluate the association of the SLCO1A2 genetic variations encoding these OATP1A2 variants and MTX-related toxicity in RA patients. A total of 60 RA patients were genotyped for these four polymorphisms (G550A, G553A, A775C, and G862A). The association between SLCO1A2 genetic variations and MTX toxicity was analyzed by binary logistic regression analysis. Single nucleotide polymorphisms (SNPs) analysis revealed that A775C and G862A SNPs were not detected in RA patients enrolled in this study, and the presence of 550AA genotype was associated with a high risk of MTX ADEs. Haplotype analysis revealed that H3 (H3 = AG) showed a high risk of MTX ADEs. Furthermore, there was a significant association of 550AA genotype and impaired MTX disposition, which might be the cause of the increased incidence of MTX ADEs in RA patients. Therefore, genetic variations in SLCO1A2 gene are risk factors for MTX toxicity and its information contributes to the prediction of MTX-related toxicity in RA treatment.
32343882 Association of High Serum Interleukin-6 Levels With Severe Progression of Rheumatoid Arthr 2020 Sep OBJECTIVE: The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL-6 levels are predictive of sarilumab treatment responses in 2 phase III studies. METHODS: Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression. RESULTS: In MONARCH, patients with high baseline IL-6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL-6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL-6 levels. In MOBILITY, compared to patients with low IL-6 levels (n = 397), patients with high IL-6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL-6 and C-reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles. CONCLUSION: IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses.
32514854 [Biological therapy after COVID-19 infection : No reactivation of a COVID-19 infection wi 2020 Aug A case with rheumatoid arthritis and insufficient compensation under disease-modifying combined long-term therapy with methotrexate and leflunomide is reported. After recovery from a COVID-19 infection, a tumor necrosis factor (TNF) inhibitor therapy was initiated. Until now no reactivation of the COVID-19 infection with positive SARS-CoV‑2 antibody status has occurred.
32483919 Comparison of the efficacy and safety of tofacitinib and peficitinib in patients with acti 2020 Jul OBJECTIVES: The relative efficacy and safety of tofacitinib and peficitinib were assessed in patients with rheumatoid arthritis (RA) with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). METHOD: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and peficitinib in combination with DMARDs in patients with an inadequate response to DMARDs. RESULTS: Nine RCTs, including 3836 patients, met the inclusion criteria. Fifteen pairwise comparisons were performed, including six direct comparisons of seven interventions. Tofacitinib 10 mg+methotrexate (MTX) and peficitinib 150 mg+MTX were among the most effective treatments for patients with active RA with an inadequate DMARD response. The efficacy of tofacitinib 10 mg+MTX, peficitinib 150 mg+MTX or tofacitinib 5 mg+MTX tended to be higher than that of adalimumab+MTX. The ranking probability based on the surface under the cumulative ranking curve indicated that tofacitinib 10 mg+MTX had the greatest probability of being the best treatment to achieve the American College of Rheumatology 20 response rate, followed by peficitinib 150 mg+MTX, tofacitinib 5 mg+MTX, adalimumab+MTX, peficitinib 100 mg+MTX, and placebo+MTX. No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib+MTX, peficitinib+MTX, adalimumab+MTX, or placebo+MTX. CONCLUSIONS: In patients with RA with an inadequate response to DMARDs, tofacitinib 10 mg+MTX and peficitinib 150 mg+MTX were the most efficacious interventions and were not associated with a significant risk of serious adverse events.
33259474 Perturbation of the human gastrointestinal tract microbial ecosystem by oral drugs to trea 2020 BACKGROUND: Oral drugs can have side effects such as diarrhea that indicate the perturbation of the gut microbial community. To further understand the dynamics of perturbation, we have assessed the strain relatedness of samples from previously published data sets from pre and post bowel evacuation, episodes of diarrhea, and administration of oral drugs to treat diabetes and rheumatoid arthritis. METHODS: We analyzed a total of published five data sets using our strain-tracking tool called Window-based Single Nucleotide Variant (SNV) Similarity (WSS) to identify related strains from the same individual. RESULTS: Strain-tracking analysis using the first data set from 8 individuals pre and 21-50 days post iso-osmotic bowel wash revealed almost all microbial strains were related in an individual between pre and post samples. Similarly, in a second study, strain-tracking analysis of 4 individuals pre and post sporadic diarrhea revealed the majority of strains were related over time (up to 44 weeks). In contrast, the analysis of a third data set from 22 individuals pre and post 3-day exposure of oral metformin revealed that no individuals had a related strain. In a fourth study, the data set taken at 2 and 4 months from 38 individuals on placebo or metformin revealed individual specific sharing of pre and post strains. Finally, the data set from 18 individuals with rheumatoid arthritis given disease-modifying antirheumatic drugs methotrexate or glycosides of the traditional Chinese medicinal component Tripterygium wilfordii showed individual specific sharing of pre and post strains up to 16 months. CONCLUSION: Oral drugs used to treat chronic disease can result in individual specific microbial strain change for the majority of species. Since the gut community provides essential functions for the host, our study supports personalized monitoring to assess the status of the dominant microbial strains after initiation of oral drugs to treat chronic disease.
30938551 Clinical features and human T-cell leukemia virus type-1 (HTLV-1) proviral load in HTLV-1- 2020 May Objective: Recently, Human T-cell leukemia virus type-1 proviral load (HTLV-1 PVL) has been evaluated as an important predictor of adult T-cell leukemia/lymphoma (ATL) in HTLV-1 carriers. We aimed to evaluate whether HTLV-1 PVL is also important for the development of ATL among HTLV-1-positive patients with rheumatoid arthritis (RA).Methods: We established a cohort of 82 HTLV-1-positive RA patients between 2017 and 2018. Of those, 27 (32.9%) were treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) with/without methotrexate. We measured HTLV-1 PVL in peripheral blood mononuclear cells (PBMCs) at study entry and compared the value by clinical status and treatment options.Results: The median PVL for all was 9.6 copies per 1000 PBMCs without sex difference (male 17.2 and female 8.6; p = .24). The median PVL was significantly higher for patient's comorbid bronchiectasis, malignancies, and opportunistic infectious diseases, compared with patients without comorbidity. There were no significant differences in PVL levels among types of bDMARDs, although the level was tended to be higher for patients treated with JAK inhibitor.Conclusions: HTLV-1 seropositive RA patients comorbid for any diseases having higher HTLV-1 PVLs will be a higher risk for developing ATL. Careful follow-up of these patients is necessary to detect ATL development.