Browse

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

ID PMID Title PublicationDate abstract
32905192 Impact of tumor necrosis factor inhibitors and methotrexate on diabetes mellitus among pat 2020 BACKGROUND: To determine whether initiation of a tumor necrosis factor inhibitor (TNFi) or methotrexate improves hemoglobin A1c in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS) who also have diabetes mellitus (DM). METHODS: A retrospective cohort study was conducted in Optum's de-identified Clinformatics® Data Mart Database, an administrative claims database, using data from 2000 to 2014. Patients with PsA, RA, or AS, with DM (defined by ICD-9-CM codes) and/or HbA1c ≥7%, who newly initiated either a TNFi, MTX, or metformin (positive control) were identified. The change in HbA1c after drug initiation was calculated. Statistical differences in the change in HbA1c between drugs were assessed using the Wilcoxon rank sum test and linear regression models adjusting for potential confounders. RESULTS: Among 10,389 drug initiations in 9541 patients with PsA, RA, or AS, and available HbA1c values, HbA1c was ≥7 at baseline in 254 (35%) TNFi initiations, 361(37%) MTX initiations, and 2144 (50%) metformin initiations. Median HbA1c change was - 0.35 (IQR -1.10, 0.30) after TNFi initiation, - 0.40 (IQR -1.20, 0.30) after MTX initiation, and - 0.80 (IQR -1.60, - 0.10) after metformin initiation. In adjusted analyses, TNFi initiators had less of a decrease in HbA1c compared to MTX initiators (β 0.22, 95% CI: 0.004, 0.43), p = 0.046. Metformin initiators had a significantly greater decrease in HbA1c than MTX, β - 0.38 (95% CI: - 0.52, - 0.23), p < 0.001. Glucocorticoid use was not accounted for in the models. CONCLUSION: HbA1c decreased with TNFi initiation or MTX initiation. Reductions in HbA1c after initiation of a TNFi or MTX are about half (~ 0.4 units) the decrease observed after initiation of metformin.
32426102 Are gene polymorphisms related to adverse events of methotrexate in patients with rheumato 2020 AIMS: We performed an updated meta-analysis to verify correlations between gene polymorphisms and adverse events in methotrexate (MTX)-treated rheumatoid arthritis (RA) patients. Then, we conducted a retrospective cohort study of Han Chinese in China. METHODS: Relevant studies were collected from the PubMed database and the EMBASE database until December 2017. Pre-allele, dominant, recessive, codominant, and homozygotic models were applied. In addition, a retrospective cohort study enrolling 162 RA patients treated with MTX was conducted. Single nucleotide polymorphism (SNP) genotyping was analyzed by PCR and product sequencing. RESULTS: A total of 39 studies were included in 20 meta-analyses; meta-analysis showed a significant association between MTX-related toxicity and 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T(rs1801133) polymorphism in East Asian RA patients, and significant associations were observed between MTX-related toxicity and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) 347C>G (rs2372536), reduced folate carrier 1 (RFC-1) 80G>A (rs1051266), and adenosine triphosphate-binding cassette B1 (ABCB1) 3435C>T(rs1045642) polymorphisms in European RA patients but not in East Asian RA patients. Moreover, in our retrospective cohort study, ATIC 347C>G(rs2372536) and ABCB1 3435C>T(rs1045642) polymorphisms were not associated with MTX-related toxicity. However, a significant association was observed between MTX-related toxicity and RFC-1 80G>A (rs1051266) polymorphism in Chinese Han RA patients. CONCLUSION: Evidence-based results suggest that the MTHFR 677C>T(rs1801133), ATIC 347C>G(rs2372536), RFC-1 80G>A (rs1051266), ABCB1 3435C>T(rs1045642) polymorphisms are associated with MTX-related toxicity. Larger and more stringent study designs may provide more accurate findings for the effects of these SNPs on MTX-related toxicity, and larger sample-size studies of the Chinese Han population should be conducted for further validation.
33376379 Methotrexate (MTX) Plus Hydroxychloroquine versus MTX Plus Leflunomide in Patients with MT 2020 PURPOSE: To compare the efficacy, safety, and cost-effectiveness of methotrexate (MTX) plus hydroxychloroquine (HCQ) vs MTX plus leflunomide (LEF) in established rheumatoid arthritis (RA) with inadequate response to MTX monotherapy in a real-world Chinese cohort. PATIENTS AND METHODS: A prospective RA cohort (n=549) was screened with eligible patients who had inadequate response (disease activity score in 28 joints using erythrocyte sedimentation rate, DAS28-ESR>3.2) to initial MTX monotherapy and subsequently received either MTX+HCQ or MTX+LEF. Propensity score matching (PSM) was applied to adjust the possible baseline confounders between two groups. The primary outcome was the proportion of patients achieving first remission (DAS28-ESR<2.6) during follow-up by log rank test. Secondary outcomes were changes of DAS28, glucocorticoids (GCs) exposure, safety, cost-effectiveness, sustained remission, and low disease activity (LDA) rate after 24-month follow-up. RESULTS: Overall, 222 eligible patients were subjected to the aforementioned two treatment protocols (MTX+HCQ, n=102; MTX+LEF, n=120). After PSM adjustment, 97 patients in each group were analyzed. A higher remission rate was observed in the MTX+HCQ group than in the MTX+LEF group (70.1% vs 56.7%, P=0.048). The median time to remission was 11 and 16 months in the two groups, respectively. At the endpoint, more patients achieved remission (46.8% vs 32.5%, P=0.063) and maintained sustained LDA in the HCQ group (53.2% vs 38.6%, P=0.062) and also more patients withdrew GCs in this group (32% vs 16.7%, P=0.053) than those in the LEF group. Safety profiles were non-alarming, with no significant difference between the two groups. The incremental cost-effectiveness ratio yielded by MTX+HCQ over MTX+LEF was $1,111.8 per quality-adjusted life-year (QALY), within the cost-effective threshold set as the per capita gross domestic product (GDP) of China. CONCLUSION: The MTX+HCQ combination was seemingly superior to MTX+LEF in a real-world cohort of Chinese RA patients with inadequate response to methotrexate monotherapy in respect of the efficacy and cost-effectiveness.
32993083 Clinical and Laboratory Associations with Methotrexate Metabolism Gene Polymorphisms in Rh 2020 Sep 26 Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that causes loss of joint function and significantly reduces quality of life. Plasma metabolite concentrations of disease-modifying anti-rheumatic drugs (DMARDs) can influence treatment efficacy and toxicity. This study explored the relationship between DMARD-metabolising gene variants and plasma metabolite levels in RA patients. DMARD metabolite concentrations were determined by tandem mass-spectrometry in plasma samples from 100 RA patients with actively flaring disease collected at two intervals. Taqman probes were used to discriminate single-nucleotide polymorphism (SNP) genotypes in cohort genomic DNA: rs246240 (ABCC1), rs1476413 (MTHFR), rs2231142 (ABCG2), rs3740065 (ABCC2), rs4149081 (SLCO1B1), rs4846051 (MTHFR), rs10280623 (ABCB1), rs16853826 (ATIC), rs17421511 (MTHFR) and rs717620 (ABCC2). Mean plasma concentrations of methotrexate (MTX) and MTX-7-OH metabolites were higher (p < 0.05) at baseline in rs4149081 GA genotype patients. Patients with rs1476413 SNP TT or CT alleles have significantly higher (p < 0.001) plasma poly-glutamate metabolites at both study time points and correspondingly elevated disease activity scores. Patients with the rs17421511 SNP AA allele reported significantly lower pain scores (p < 0.05) at both study intervals. Genotyping strategies could help prioritise treatments to RA patients most likely to gain clinical benefit whilst minimizing toxicity.
32922141 Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and 2020 Sep Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is accompanied by progressive joint damage and disability. The intolerability of conventional antirheumatic drugs by some patients necessitates the search for effective antirheumatic agents having better tolerability. In the current work, we aimed to investigate the efficacy of cinnamaldehyde, tadalafil, and aliskiren as potential antirheumatic candidates and to explore their modulatory effects on joint destruction, inflammatory response, and intracellular signaling. Arthritis was induced in female Wistar rats by complete Freund's adjuvant (CFA) 0.4 ml s.c. on days 1, 4, and 7. Treated groups received their respective drugs, starting from day 13, daily for 3 weeks. Methotrexate and prednisolone were the standard antirheumatic drugs, while cinnamaldehyde, tadalafil, and aliskiren were the test agents. Treatment with cinnamaldehyde, tadalafil, or aliskiren reduced serum levels of rheumatoid factor, and pro-inflammatory cytokines; tumor necrosis factor-alpha and interleukin-6 (IL-6), along with elevated level of IL-10 which is an anti-inflammatory cytokine. Besides, cartilage and bone destruction biomarkers; matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear factor-kappa B ligand (RANKL); were significantly reduced after treatment with the test agents, which was further confirmed by histopathological investigation. The elevated protein expressions of phosphorylated-Janus kinase 2 (p-JAK2), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), and inducible nitric oxide synthase (iNOS) in articular tissue were markedly attenuated after treatment with cinnamaldehyde, tadalafil, or aliskiren, while that of endothelial nitric oxide synthase (eNOS) was greatly enhanced. In addition, oxidative stress and inflammatory markers such as malondialdehyde, nitric oxide, and myeloperoxidase were reduced in joint tissue after treatment with the test agents, while glutathione content was elevated. Furthermore, the renin inhibitor aliskiren produced effects close to those of the normal and methotrexate, the gold standard antirheumatic drug, in most of the measured parameters. Collectively, these findings led to the assumption that the downregulation of IL-6/JAK2/STAT3 signaling by cinnamaldehyde, tadalafil, and aliskiren could alleviate joint destruction by MMP-3 and RANKL, reduce iNOS, and enhance eNOS expressions. Moreover, aliskiren could be a promising therapeutic agent for RA, because of its ability to normalize most of the measured parameters after CFA-induced arthritis.
33321888 Identification of Metabolic Biomarkers in Relation to Methotrexate Response in Early Rheum 2020 Dec 10 This study aimed to identify baseline metabolic biomarkers for response to methotrexate (MTX) therapy in rheumatoid arthritis (RA) using an untargeted method. In total, 82 baseline plasma samples (41 insufficient responders and 41 sufficient responders to MTX) were selected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, trial number: ISRCTN26791028) based on patients' EULAR response at 3 months. Metabolites were assessed using high-performance liquid chromatography-quadrupole time of flight mass spectrometry. Differences in metabolite concentrations between insufficient and sufficient responders were assessed using partial least square regression discriminant analysis (PLS-DA) and Welch's t-test. The predictive performance of the most significant findings was assessed in a receiver operating characteristic plot with area under the curve (AUC), sensitivity and specificity. Finally, overrepresentation analysis was performed to assess if the best discriminating metabolites were enriched in specific metabolic events. Baseline concentrations of homocystine, taurine, adenosine triphosphate, guanosine diphosphate and uric acid were significantly lower in plasma of insufficient responders versus sufficient responders, while glycolytic intermediates 1,3-/2,3-diphosphoglyceric acid, glycerol-3-phosphate and phosphoenolpyruvate were significantly higher in insufficient responders. Homocystine, glycerol-3-phosphate and 1,3-/2,3-diphosphoglyceric acid were independent predictors and together showed a high AUC of 0.81 (95% CI: 0.72-0.91) for the prediction of insufficient response, with corresponding sensitivity of 0.78 and specificity of 0.76. The Warburg effect, glycolysis and amino acid metabolism were identified as underlying metabolic events playing a role in clinical response to MTX in early RA. New metabolites and potential underlying metabolic events correlating with MTX response in early RA were identified, which warrant validation in external cohorts.
31955346 Successful treatment of methotrexate-associated classical Hodgkin lymphoma with brentuxima 2020 May Methotrexate (MTX)-associated classical Hodgkin lymphoma (CHL) is unlikely to regress following discontinuation of MTX, and its treatment usually requires chemotherapy. Standard chemotherapy for CHL is the ABVD regimen, which contains pneumotoxic bleomycin. This can be problematic in MTX-CHL patients suffering from an autoimmune disease (AID), such as rheumatoid arthritis (RA), as they frequently have pulmonary complications. However, brentuximab vedotin (BV)-containing chemotherapy without bleomycin (A + AVD regimen) was recently reported to show favorable efficacy for CHL, and could therefore be beneficial in MTX-CHL. We treated three cases of MTX-CHL using the A + AVD regimen. All were female and had received MTX for more than 15 years. Underlying AIDs in these patients were RA in two patients, and overlap syndrome with systemic lupus erythematosus and dermatomyositis in one patient. The A + AVD regimen resulted in a complete response in all patients. Peripheral neuropathy developed in two patients, necessitating reduction of the BV dose. All three patients experienced hematological toxicity necessitating dose reduction; however, no severe adverse effects, including infection or pulmonary complication, were documented. RA was well-controlled without additional immunosuppressants. The A + AVD regimen is a promising chemotherapy for MTX-CHL with favorable efficacy and tolerable toxicity profiles.
31489783 Risk of cutaneous herpes zoster in patients with spondyloarthritis treated with convention 2020 Feb OBJECTIVES: To investigate the risk of cutaneous herpes zoster (HZ) in spondyloarthritis (SpA) compared with that in rheumatoid arthritis (RA), and in disease-modifying antirheumatic drugs (DMARDs) used in SpA. METHOD: A total of 727 patients with an expert diagnosis of SpA were identified retrospectively from four rheumatology centers in Hong Kong. Electronic medical records from 1995 to 2018 were reviewed for incidence of cutaneous HZ and demographic data including age, sex, comorbidities, smoking and drinking status. DMARDs used included sulphasalazine, methotrexate, leflunomide, steroids, etanercept, infliximab, adalimumab, golimumab, secukinumab and ustekinumab. Cox regression models were used to evaluate hazard ratios (HRs) of different DMARDs in patients with SpA. Propensity score was used for matching and comparison with 857 patients with RA. RESULTS: There were 23 cases of cutaneous HZ in patients with SpA and 59 cases in patients with RA. Among patients with SpA, 7 cases of cutaneous HZ may be attributed to sulfasalazine treatment, 7 to methotrexate, 2 to leflunomide, 2 to infliximab, 1 to etanercept, 2 to adalimumab, and 1 to secukinumab. Risks of cutaneous HZ were the same in SpA (stratified HR 0.97; 95% CI 0.58; 1.61; P = .89) and RA. Methotrexate (adjusted HR 3.47; 95% CI 1.25; 9.63; P = .02) and infliximab (adjusted HR 10.67; 95% CI 1.37; 82.88; P = .02) were found to be associated with HZ after adjustments for traditional risk factors. CONCLUSION: Risk of cutaneous HZ in SpA was not lower than in RA. Methotrexate and infliximab were associated with cutaneous HZ in SpA.
33280773 54-Year-Old Man With Cough, Chest Pain, and Dyspnea on Exertion. 2020 Dec A 54-year-old man presented with 6 months' history of dry cough and dyspnea on exertion. He also reported intermittent joint pain and orthopnea. He denied fevers, chills, and rashes. His medical history was significant for rheumatoid arthritis, for which he was taking 20 mg of prednisone daily. He had not been receiving adalimumab or methotrexate for several months. He never smoked and drank alcohol occasionally. Family history was significant for rheumatoid arthritis.
33123205 Upadacitinib versus placebo or adalimumab with background methotrexate in patients with rh 2020 BACKGROUND: In the randomized, phase III, global SELECT-COMPARE study, upadacitinib 15 mg demonstrated efficacy at week 12 versus placebo and adalimumab with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX, which was maintained over 48 weeks. This post hoc analysis of SELECT-COMPARE reports the efficacy and safety of upadacitinib in Central and Eastern European (CEE) patients. METHODS: Patients were randomized 2:2:1 to upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week, and continued MTX. Efficacy and safety were assessed through 48 weeks. Primary endpoints were the achievement of ≥20% improvement in American College of Rheumatology response criteria and Disease Activity Score in 28 joints with C-reactive protein <2.6 responses at week 12 for upadacitinib versus placebo. No statistical comparisons were conducted. RESULTS: A total of 596 patients from 12 CEE countries were randomized. At week 12, a numerically greater proportion of patients receiving upadacitinib versus placebo or adalimumab achieved ≥20% improvement in American College of Rheumatology response criteria (72% versus 33% and 59%), Disease Activity Score in 28 joints with C-reactive protein <2.6 (26% versus 4% and 11%), low disease activity and remission, and improved physical function, with results maintained over 48 weeks. Upadacitinib treatment numerically inhibited structural progression versus placebo at week 26. Serious infection and herpes zoster rates were numerically higher with upadacitinib versus adalimumab (2.7 versus 1.7 and 2.3 versus 1.1 events/100 patient-years, respectively) over 48 weeks. CONCLUSION: Consistent with the global population of patients with rheumatoid arthritis and an inadequate response to MTX, in CEE patients, upadacitinib 15 mg demonstrated clinical and functional improvements versus placebo and adalimumab, radiographic improvements versus placebo, and reasonable safety, over 48 weeks.
31643544 Methotrexate. 2012 Methotrexate is an antineoplastic and immunosuppressive agent widely used in the therapy of leukemia, lymphoma, solid tumors, psoriasis and rheumatoid arthritis. When given in high intravenous doses, methotrexate can cause acute elevations in serum enzymes, and long term methotrexate therapy has been associated with frequent but mild elevations in serum liver enzymes and, more importantly, with development of chronic liver injury, progressive fibrosis, cirrhosis and portal hypertension.
32598111 2020 Mar Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that primarily affects the joints of the body. Characterized by acute and chronic inflammation of the synovium, or soft tissue surrounding the joints, patients are subject to severe pain, stiffness, and fatigue, all of which can affect a patient’s ability to perform activities of daily living and overall health-related quality of life (HRQoL). Prolonged inflammation may lead to damage and destruction of the joints through erosion of the cartilage and bone and, consequently, disability and premature mortality. Other areas of the body may be affected as well, including the eyes, lungs, heart, or skin. It is estimated that about 1% of Canadians have the disease. Upadacitinib is a Janus kinase (JAK) inhibitor. JAK mediates the effects of cytokines and their production, thus JAK inhibitors may have more of a global effect on various cytokine production than do biologics, which tend to target specific cytokines. Upadacitinib is the third JAK inhibitor approved in Canada, the first being tofacitinib, followed by baricitinib, both of which were previously reviewed and issued recommendations by the CADTH Canadian Drug Expert Committee. The systematic review protocol for the current review was established before the granting of Notice of Compliance from Health Canada for upadacitinib. The objective is to perform a systematic review of the beneficial and harmful effects of upadacitinib 15 mg extended-release tablets for once daily administration for the treatment of moderate to severe RA in adult patients who have responded inadequately to, or who are intolerant to, one or more disease-modifying antirheumatic drugs (DMARDs). Upadacitinib may be used as monotherapy or in combination with methotrexate or other conventional synthetic DMARDs (csDMARDs).
31963908 Safety of Abatacept in Italian Patients with Rheumatoid Arthritis and Interstitial Lung Di 2020 Jan 19 BACKGROUND: Treatment of rheumatoid arthritis (RA)-related interstitial lung disease (ILD) is challenging, and many conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) have been associated with ILD development or progression. The aim of this multicentric retrospective study was to analyze the evolution of ILD in Italian RA-ILD patients treated with abatacept (ABA). METHODS: All RA-ILD patients treated with ABA for at least six months were retrospectively evaluated. Serology, previous and concurrent therapies, chest high-resolution computer tomography (HRCT), forced vital capacity (FVC), and lung diffusion of carbon monoxide (CO, DLCO) were collected. RESULTS: Forty-four patients were included; HRCT, FVC, and DLCO were analyzed at baseline, at one year, and at the end of follow-up. A remission or a low disease activity of RA was reached in 41/44 patients. Overall, FVC and DLCO remained stable or increased in 86.1% and 91.7% of patients, respectively, while HRCT was stable or improved in 81.4% of them. Previous and concurrent treatments, in particular, methotrexate, serology, age, sex, joint and lung disease duration were not associated with the outcome at univariate analysis. CONCLUSION: The management of RA-ILD patients remains a critical unmet medical need. Waiting for prospective controlled studies, ABA has shown a good safety profile in our cohort of Italian RA-ILD patients.
33447265 Methotrexate at middle and high accumulative doses might be associated with lower risk of 2020 BACKGROUND: We investigated whether taking methotrexate (MTX) is associated with a lower risk of new-onset cancers in patients with rheumatoid arthritis (RA). METHODS: We conducted a 12-year retrospective cohort study from a population-based National Health Insurance Research Database in Taiwan. A total of 21,699 patients with newly diagnosed RA were enrolled during 2000-2009. The overall cancer rate was compared between 10,352 new users of MTX and 11,347 non-users. We used the WHO Defined Daily Dose (DDD) as a tool to assess drug exposure. Cox proportional hazard regression models were used to estimate the hazard ratio (HR) of disease after controlling for demographics and other comorbidities. RESULTS: After adjusting for age, sex, cancer-related comorbidities, and RA-combined medication, the HR of cancer risk was 0.87 (95% CI = 0.74-1.02) for the MTX user group compared with the MTX non-user group. The cumulative incidence of cancer in the MTX non-user group was significantly higher than that of the MTX user group (log-rank test p < 0.001). In the low accumulative dose group [cumulative dose <1125 mg, cumulative defined daily dose (cDDD) <450], the HR of cancer risk for MTX users was 1.20 (95% CI = 1.01-1.42) compared with the MTX-non-user group. However, the adjusted HR of cancer risk was reduced to 0.66 (95% CI = 0.49-0.87) in MTX middle-dose users (cumulative dose 1125-2250 mg, cDDD: 450-899) and 0.33 (95% CI = 0.23-0.48) for the MTX high-dose group (cumulative dose ⩾2250 mg, cDDD ⩾900), respectively (p for trend < 0.0001). CONCLUSION: MTX at middle and high accumulative doses might be associated with lower risk of new-onset cancers in patients with RA.
32336980 Traditional Chinese medicine Biqi capsule compared with leflunomide in combination with me 2020 BACKGROUND: Biqi capsule is a traditional Chinese medicine widely used as a complementary and alternative treatment for rheumatoid arthritis (RA). The objective is to understand the efficacy, safety and mechanism of Biqi combined with methotrexate (MTX) in RA. METHODS: We present a randomized, controlled pilot trial on Biqi combined with MTX against patients with active RA. Seventy patients were randomized 1:1 to receive Biqi + MTX or Leflunomide (LEF) + MTX for 24 weeks, and were assessed at baseline, 4, 12 and 24 weeks. Serum and urine samples were collected for metabolomics. RESULTS: Overall, 81.2% patients in Biqi group achieved ACR20 at 24 weeks. No statistically significant differences were observed in primary or secondary outcomes between the two groups. A better safety profile was observed for Biqi with significantly fewer adverse effects reported (11.4%) compared to LEF group (40%, P < 0.05). Comparison between treatment responders and non-responders indicated a unique urine metabolic profile of enriched fatty acids and decreased acylcarnitines associated with Biqi responders, indicating a restored energy homeostasis in response to Biqi. The gene targets of these metabolites were significantly enriched in interleukin-4 and interleukin-13 pathways, implying that Biqi could ameliorate Th2-derived inflammatory response. Multivariate network analysis indicated that patient morning stiffness and SJC were key factors associated with metabolomics in Biqi-treated patients, whereas CRP was the main factor in LEF group. Therefore, Biqi and LEF likely work by influencing different patient clinical parameters. CONCLUSIONS: Our study suggests that Biqi capsule can be a promising alternative option in combination with MTX for RA treatment, and demonstrates the capability of using metabolomics to interrogate mechanism of action for traditional Chinese medicine.Trial registration This trial is registered with ChiCTR, No. ChiCTR-IPR-16009029. Registered August 15, 2016. http://www.chictr.org.cn/showprojen.aspx?proj=15034.
33134809 Incidence, predictive factors and severity of methotrexate-related liver injury in rheumat 2020 OBJECTIVES: The aims were to determine the incidence rate, predictive factors and severity of liver injury that develops during MTX treatment for RA and to evaluate the role of pretreatment hepatic fat deposition. METHODS: We used an ongoing real-life registry containing RA patients who had started MTX between August 2007 and April 2018 at participating institutions. The liver-to-spleen attenuation ratio on CT scans at enrolment was used to evaluate pretreatment fat deposition quantitatively. Patients were followed until persistent transaminitis developed or until the end of the study. Liver biopsy was performed for patients who presented with persistent transaminitis. RESULTS: We followed 289 new MTX users without pretreatment elevations of transaminases (mean follow-up time, 58.3 months). Hepatic fat deposition was detected in half of the patients at enrolment. During follow-up, persistent transaminitis occurred at a crude incidence rate of 3.13 per 100 person-years, and the cumulative incidence at 5 years was estimated to be 13%. A multivariate Fine-Gray regression analysis showed that the most important predictive factors were pre-existing moderate to severe fat deposition (adjusted hazard ratio, 7.69; 95% CI: 3.10, 19.10) and obesity (adjusted hazard ratio, 2.68; 95% CI: 1.37, 5.25). Non-alcoholic steatohepatitis (NASH) was the most predominant pattern in liver biopsy samples. Hepatic fibrosis was found in 90% of samples, but most cases were not advanced. CONCLUSION: Aggravation of underlying fatty liver to NASH with fibrosis seems to be an important mechanism of liver injury that occurs in MTX-treated RA patients.
32218732 Synergistic Effects of Erzhi Pill Combined With Methotrexate on Osteoblasts Mediated via t 2020 Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by chronic synovitis, bone erosion, and bone loss. Erzhi Pill (EZP), a classic Chinese patent medicine, is often used to treat osteoporosis and shows a capacity for bone metabolism regulation. Methotrexate (MTX), an essential drug for RA treatment, has been reported to inhibit generalized bone loss in RA patients. However, the combined therapeutic effects and mechanism of EZP and MTX in RA have not been fully elucidated. The aim of this study was to investigate the synergistic effect of EZP and MTX on RA and to explore the underlying mechanism through network pharmacological prediction and experimental verification. Chemical compounds of EZP, human target proteins of EZP and MTX, and RA-related human genes were identified in the Encyclopedia of Traditional Chinese Medicine database, PubChem database, and NCBI database, respectively. The molecular network of EZP and MTX in RA was generated and analyzed with Ingenuity Pathway Analysis software according to the datasets. Then, MTX monotherapy, EZP monotherapy, and combined MTX and EZP therapy were administered to collagen-induced arthritis rats, followed by assessment of pathological score, bone damage, bone alkaline phosphatases (BALP), and tartrate-resistant acid phosphatase (TRACP), and of gene levels related to the Wnt1/LRP5/β-catenin pathway according to network pharmacological analysis. Finally, serum samples from MTX-, EZP- and MTX+EZP-treated rats were used to treat the rat osteoblast (OB)-like UMR-106 cell line to evaluate gene levels related to Wnt1/LRP5/β-catenin. Network pharmacological analysis showed that the Wnt/β-catenin signaling pathway was the top signaling pathway shared among MTX, EZP, and RA. The results from in vivo experiments indicated that EZP combined with MTX reduced arthritis severity, alleviated ankle bone damage, increased BALP and decreased TRACP serum levels, and regulated the mRNA expression of Wnt1, LRP5, β-catenin, Runx2, BALP, and BGP in the ankles. In vitro experiments showed that EZP combined with MTX could also improve the expression of genes related to the Wnt1/LRP5/β-catenin pathway. This study demonstrated that EZP in combination with MTX played a synergistic role in regulating OBs in RA, which was connected to the modulatory effect of EZP and MTX on the Wnt1/LRP5/β-catenin signaling pathway.
33363853 Intraoral localized methotrexate-associated lymphoproliferative disorders concurrent with 2020 Dec Intraoral localized methotrexate-associated lymphoproliferative disorders can cause antiresorptive agent-related osteonecrosis of the jaw associated with infection due to its immunological abnormalities and ulcer formation.
32607016 A Case of Rhupus with Rowell Syndrome. 2020 We report a case of 30-year-old female who presented initially with hair loss, photosensitive malar rash, morning stiffness and synovitis. She was diagnosed with Rhupus syndrome based on clinical and laboratory findings. Few months after starting hydroxychloroquine, esomeprazole and azathioprine, and failing methotrexate (because of erosive pill-induced esophagitis), she presented with generalized maculopapular dusky reddish rash in her body, back and extremities. Her anti-double stranded-DNA, anti-nuclear antibody, anti-Ro/SSA and anti-La/SSB were positive. Anti-cyclic citrullinated peptide antibody was moderately positive. She had low complements: C3 and C4. Herpes simplex IgM and mycoplasma tested negative. Skin biopsy from right arm showed evidence of erythema multiform. She met the criteria for the diagnosis of Rowell syndrome. We managed her with hydroxychloroquine, prednisolone, mycophenolate mofetil and topical agents and discontinued esomeprazole. We also review the management of Rowell syndrome in the literature.
32926395 Validation of a Prognostic Multivariable Prediction Model for Insufficient Clinical Respon 2020 Dec INTRODUCTION: Methotrexate (MTX) constitutes the first-line therapy in rheumatoid arthritis (RA), yet approximately 30% of the patients do not benefit from MTX. Recently, we reported a prognostic multivariable prediction model for insufficient clinical response to MTX at 3 months of treatment in the treatment in the Rotterdam Early Arthritis Cohort (tREACH), including baseline predictors: Disease activity score 28 (DAS28), Health Assessment Questionnaire (HAQ), erythrocyte folate, single-nucleotide polymorphisms (SNPs; ABCB1, ABCC3), smoking, and BMI. The purpose of the current study was (1) to externally validate the model and (2) to enhance the model's clinical applicability. METHODS: Erythrocyte folate and SNPs were assessed in 91 early disease-modifying antirheumatic drug (DMARD)-naïve RA patients starting MTX in the external validation cohort (U-Act-Early). Insufficient response (DAS28 > 3.2) was determined after 3 months and non-response after 6 months of therapy. The previously developed prediction model was considered successfully validated in the U-Act-Early (validation cohort) if the area under the curve (AUC) of the receiver operating characteristic (ROC) was not significantly lower than in the tREACH (derivation cohort). RESULTS: The AUCs in U-Act-Early at three and 6 months were 0.75 (95% CI 0.64-0.85) and 0.71 (95% CI 0.60-0.82) respectively, similar to the tREACH. Baseline DAS28 > 5.1 and HAQ > 0.6 were the strongest predictors. The model was simplified by excluding the SNPs, while still classifying 73% correctly. Furthermore, interaction terms between BMI and HAQ and BMI and erythrocyte folate significantly improved the model increasing correct classification to 75%. Results were successfully implemented in Evidencio online platform assisting clinicians in shared decision-making to intensify treatment when appropriate. CONCLUSIONS: We successfully externally validated our recently reported prediction model for MTX non-response and enhanced its clinical application thus enabling its evaluation in a clinical trial. TRIAL REGISTRATION: The U-Act-Early is registered at ClinicalTrials.gov. number: NCT01034137. tREACH is registered retrospectively at ISRCTN registry, number: ISRCTN26791028 at 23 August 2007.