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ID PMID Title PublicationDate abstract
35653787 Plumbagin relieves rheumatoid arthritis through nuclear factor kappa-B (NF-κB) pathway. 2022 May This study aimed to explore the effects of plumbagin on rheumatoid arthritis (RA) and its mechanism. The RA cell model was simulated following the treatment of interleukin-1β (IL-1β). After the treatment of various concentrations of plumbagin, the impact of plumbagin on the cell viability was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The collagen-induced arthritis (CIA) model was established using the solution of bovine type II collagen. Hematoxylin-eosin staining was used to observe the changes of ankle joint tissue, while enzyme-linked immunosorbent assay and western blot were applied to detect the level of inflammatory cytokines. Plumbagin inhibited the viability of human fibroblast-like synoviocytes (HFLS) at the concentration of 1 ~ 3.5 μM. The inhibitory effect of 1 μM plumbagin on cell proliferation was similar to that of methotrexate, the drug used as the positive control. Plumbagin downregulated the levels of inflammatory cytokines and matrix metalloproteinases (MMPs) in IL-1β-treated HFLS, and suppressed the activation of IκB and nuclear factor kappa-B (NF-κB) as well as the entry of p65 into the nucleus. It was also demonstrated in animal experiments that plumbagin inhibited the activation of NF-κB pathway, down-regulated the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and MMPs, and alleviated joint damage in CIA-modeled mice. Collectively speaking, plumbagin might down-regulate the levels of inflammatory cytokines and MMPs through inhibiting the activation of the NF-κB pathway, thereby attenuating RA-induced damage to cells and joints.Abbreviations: CIA: Collagen-induced arthritis; ELISA: Enzyme-linked immuno sorbent assay; HFLS: Human fibroblast-like synoviocytes; IL-6: Interleukin-6; IL-1β: Interleukin-1β; NF-κB: nuclear factor kappa-B; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MMPs: Matrix metalloproteinase; OD: Optical density; RA: Rheumatoid arthritis; SDS: Sodium dodecyl sulfate; SD: Standard deviation; TNF-α: Tumor necrosis factor-α; PVDF: Polyvinylidene fluoride.
35330353 Comparison of Adalimumab to Other Targeted Therapies in Rheumatoid Arthritis: Results from 2022 Feb 25 Few studies compared adalimumab to other targeted therapies in head-to-head randomized clinical trials (RCTs) for rheumatoid arthritis (RA), but multiple comparisons are not available. This Bayesian Network Meta-Analysis evaluated which targeted therapy is more likely to achieve ACR50 response with good safety at 24 weeks of treatment in RA. A systematic literature review was conducted for head-to-head phase 3 RCTs that compared adalimumab to other targeted therapies in combination with methotrexate (MTX) or as monotherapy to treat RA patients, and searched through MEDLINE, EMBASE, Cochrane Library and Clinicaltrial.gov. The outcomes of interest were ACR50 response and withdrawals due to adverse events at 24 weeks. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses, using a random effect model. Sixteen studies were included in the analysis. The most favorable SUCRA for the ACR50 response rate at 24 weeks of treatment in combination with MTX was ranked by upadacitinib, followed by baricitinib, tofacitinib and filgotinib. As monotherapy, the highest probability was ranked by tocilizumab followed by sarilumab. No significant differences in safety profile among treatment options were found. Jak-inhibitors in combination with MTX and interleukin-6 antagonism as monotherapy showed the highest probability to achieve ACR50 response after 24 weeks of treatment. None of assessed targeted therapies were associated to risk of withdrawal due to adverse events. Key messages: Direct and indirect comparison between adalimumab and other targeted therapies demonstrated some differences in terms of efficacy that may help to drive RA treatment. Jak-inhibitors and interleukine-6 antagonists ranked as first in the probability to achieve ACR50 response after 24 weeks of treatment in combination with methotrexate or monotherapy, respectively.
35464950 The Potential of Gut Microbiota Metabolic Capability to Detect Drug Response in Rheumatoid 2022 Gut microbiota plays an essential role in the development of rheumatoid arthritis (RA) and affects drug responses. However, the underlying mechanism remains elusive and urgent to elucidate to explore the pathology and clinical treatment of RA. Therefore, we selected methotrexate (MTX) as an example of RA drugs to explore the interactions between the gut microbiota and drug responses and obtain an in-depth understanding of their correlation from the perspective of the metabolic capability of gut microbiota on drug metabolism. We identified 2,654 proteins and the corresponding genes involved in MTX metabolism and then profiled their abundances in the gut microbiome datasets of four cohorts. We found that the gut microbiota harbored various genes involved in MTX metabolism in healthy individuals and RA patients. Interestingly, the number of genes involved in MTX metabolism was not significantly different between response (R) and non-response (NR) groups to MTX, but the gene composition in the microbial communities significantly differed between these two groups. Particularly, several models were built based on clinical information, as well as data on the gene, taxonomical, and functional biomarkers by using the random forest algorithm and then validated. Our findings provide bases for clinical management not only of RA but also other gut microbiome-related diseases. First, it suggests that the potential metabolic capability of gut microbiota on drug metabolism is important because they affect drug efficiency; as such, clinical treatment strategies should incorporate the gene compositions of gut microbial communities, in particular genes involved in drug metabolism. Second, a suitable model can be developed to determine hosts' responses to drugs before clinical treatment.
35348759 Impact of Janus Kinase Inhibitors on Antibody Response to 13-Valent Pneumococcal Conjugate 2022 Mar 26 OBJECTIVE: To evaluate the antibody response to 13-valent pneumococcal conjugate vaccine (PCV13) in patients with rheumatoid arthritis (RA) receiving Janus kinase inhibitors (JAKIs). METHODS: Fifty-three patients receiving methotrexate (MTX) (n = 10), JAKI (n = 20), or MTX + JAKI (n = 23) were vaccinated with PCV13. Serum concentrations of IgG antibodies to 13 pneumococcal serotype capsular polysaccharides were quantified before and 4-6 weeks after vaccination. Positive antibody response was defined as a two-fold or more increase in IgG concentrations from pre-vaccination levels. RESULTS: After vaccination, IgG concentrations significantly increased in all treatment groups (p <0.001), but fold increases (post-vaccination to pre-vaccination ratios) were different among treatment groups (9.30 for MTX, 6.36 for JAKI, and 3.46 for combination therapy). Positive antibody response rates were comparable between the MTX group (90%) and the JAKI group (95%), but lower in the MTX + JAKI group (52.2%). In multivariable logistic regression analysis, the combination therapy was the only factor associated with reduced antibody response to PCV13. No severe adverse events were observed in any treatment group. CONCLUSION: Although JAKIs do not impair PCV13 immunogenicity in RA patients, the combination of MTX with JAKI can reduce the antibody response in this patient population.
35636524 Discovery and pre-clinical characterization of a selective PI3Kδ inhibitor, LL-00071210 i 2022 May 27 PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC(50) values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kβ as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.
35078225 Rates and predictors of methotrexate-related adverse events in patients with early rheumat 2022 Jan 25 OBJECTIVES: To estimate prevalence rates and identify baseline predictors of adverse events (AEs) over the first year of treatment in patients with rheumatoid arthritis (RA) starting methotrexate (MTX). METHODS: Data came from the UK Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of patients with RA starting MTX. This analysis included patients aged ≥ 18 years with physician diagnosed RA and symptom duration ≤ two years, who were commencing MTX for the first time. AEs were recorded by interviewing patients at six- and twelve-month follow-up visits. The period prevalence rates of AEs are reported for 0-6 months, 6-12 months, and 0-12 months of follow-up. The associations between baseline characteristics and AEs were assessed using multivariable logistic regression. RESULTS: A total of 1069 patients were included in the analysis. Overall, 77.5% experienced at least one AE. The most commonly reported AEs were: gastrointestinal (42.0%), neurological (28.6%), mucocutaneous (26.0%), pulmonary (20.9%), elevated alanine transaminase (18.0%) and haematologic AEs (5.6%).Factors associated with increased odds of AEs were: women vs men (gastrointestinal, mucocutaneous, neurological), and alcohol consumption (nausea, alopecia, mucocutaneous). Older age, higher estimated Glomerular Filtration Rate (eGFR), and alcohol consumption were associated with less reporting of haematologic AEs. CONCLUSIONS: AEs were common among patients over the first year of MTX, although most were not serious. Knowledge of the rates and factors associated with AEs occurrence are valuable when communicating risks prior to commencing MTX. This can help patients make informed decisions whether to start MTX, potentially increasing adherence to treatment.
35094058 Machine Learning using Genetic and Clinical Data Identifies a Signature that Robustly Pred 2022 Jan 30 OBJECTIVE: To develop a hypothesis-free model that best predicts response to methotrexate (MTX) drug in rheumatoid arthritis (RA) patients utilizing biologically meaningful genetic feature selection of potentially functional single nucleotide polymorphisms (pfSNPs) through robust machine learning (ML) feature selection methods. METHODS: MTX-treated RA patients with known response were divided in a 4:1 ratio into training and test sets. From the patients' exomes, potential features for classifier prediction were identified from pfSNPs and non-genetic factors through ML using recursive feature elimination with cross-validation incorporating Random Forest Classifier. Feature selection was repeated on random subsets of the training cohort, and consensus features were assembled into the final feature set. This feature set was evaluated for predictive potential using six ML classifiers, first by cross-validation within the training set, and finally by analyzing its performance with the unseen test set. RESULTS: The final feature set contains 56 pfSNPs and five non-genetic factors. The majority of these pfSNPs are located in pathways related to RA pathogenesis or methotrexate action and are predicted to modulate gene expression. When used for training in six ML classifiers, performance was good in both the training set (AUC : 0·855-0·916, sensitivity : 0·715-0·892 and specificity : 0·733-0·862) in the unseen test set (AUC : 0·751-0·826, sensitivity: 0·581-0·839 and specificity: 0·641-0·923). CONCLUSION: Sensitive and specific predictors of MTX response in RA patients were identified in this study through a novel strategy combining biologically meaningful and machine learning feature selection and training. These predictors may facilitate better treatment decision-making in RA management.
35377422 Humoral response to Coronavirus Disease-19 vaccines is dependent on dosage and timing of r 2022 Apr 4 OBJECTIVES: Humoral response to vaccines in rheumatoid arthritis (RA) patients treated with rituximab (RTX) in standard dosages (≥1000mg) is decreased. Ultralow dosages (500 or 200 mg) may have better response. Also, timing after latest RTX infusion may be an important variable. We aimed to investigate the influence of RTX dosage and timing on response to COVID-19 vaccination in RA patients. METHODS: A single-centre observational study (n = 196) investigated the humoral response, measured by total Ig anti-COVID-19 assay (positive response ≥1.1), 2-6 weeks after complete COVID-19 vaccination. A multivariable logistic regression model was built to study the effect of RTX dosage and time between latest rituximab and vaccination on response, adjusting for age and methotrexate use. RESULTS: After two-dose vaccination, the response rate was significantly better for patients receiving 200 mg (n = 31, 45%) rituximab compared with 1000 mg (n = 98, 26%; OR 3.07, 95% CI 1.14-8.27,) and for each additional month between latest rituximab and vaccination (OR 1.67, 1.39-2.01). CONCLUSION: Both increased time between latest rituximab infusion and complete vaccination and 200 mg as latest dose were associated with a better response to COVID-19 vaccination and should be considered when trying to increase vaccine response after rituximab in RA patients. TRIAL REGISTRATION: Netherlands Trial Register, https://www.trialregister.nl/, NL9342.
35410410 Clinical characteristics and variants that predict prognosis of difficult-to-treat rheumat 2022 Apr 11 Factors influencing prognosis after administration of the last biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) to patients with difficult-to-treat rheumatoid arthritis (D2T_RA) were evaluated in a clinical setting. RA patients who met the EULAR definition of D2T_RA were recruited. These patients were grouped according to success/failure. Success was defined as sustained within light disease activity or discontinued after clinical remission, and all of the following were met, including glucocorticoid (GCS) < 7.5 mg/day, no rapid radiographic progression, and improved quality of life from the beginning of the b/tsDMARD (baseline). Failure was defined as any other condition from success. The primary endpoint of the study was success or failure at 12 months after baseline. Factors influencing success/failure were statistically evaluated. A total of 71 D2T_RA patients were selected, 22 were in the success group and 49 in the failure group. For patients taking GCS and methotrexate (MTX) ≤ 8.6 mg/week, only one was included in the success group and the other 24 were included in the failure group (p < 0.001). Of the 18 patients without GCS and with MTX ≥ 8.7 mg, 12 patients whose 28-joint disease activity score ≤ 1.90 at 3 months or ≤ 2.54 at 6 months were in the success group (p < 0.01). D2T_RA patients with GCS or MTX ≤ 8.6 mg at baseline are considered to be at high risk of repeat D2T_RA. Patients with no GCS and MTX ≥ 8.7 mg are more likely to withdraw from D2T_RA if their disease activity is tightly controlled.
35218177 Factors influencing methotrexate and methotrexate polyglutamate in patients with rheumatoi 2022 Feb 24 Low dose methotrexate (MTX) is commonly used in the treatment of rheumatoid arthritis. The clinical effect is mediated by its metabolite, methotrexate polyglutamate (MTX-PGn). The drug exhibits high interindividual pharmacokinetic variability and the optimal MTX dose is different among individuals. Thus, several MTX population pharmacokinetic (PopPK) models were developed to characterize factors affecting MTX pharmacokinetic variability. This review summarizes significant predictors for MTX pharmacokinetics and identifies knowledge gaps to be further examined. A total of 359 articles were identified from a systematic search of four databases: PubMed, Science Direct, and CINAHL Complete. Of these eight studies were included. Most studies investigated influential factors on MTX pharmacokinetics, but information on MTX-PGn is limited, with only one study performing a parent-metabolite (MTX-PG3) model. MTX pharmacokinetics was described using a two-compartment model with first-order elimination in most studies, with the MTX clearance ranging from 6.94 to 12.39 L/h. Significant predictors influencing MTX clearance included weight, creatinine clearance, sex, OATP1B3 polymorphism, and MTX multiple dosing. While body mass index and red blood cell counts were significant predictors for MTX-PG3 clearance. Providing that MTX-PGn plays a crucial role in clinical effect, further studies should determine other factors affecting MTX-PGn as well as its relationship with clinical response.
35031905 Na-AIP-1 secreted by human hookworms suppresses collagen-induced arthritis. 2022 Apr Proteins from helminths have been posed as new immunomodulatory agents with exciting potential in the treatment of immune-mediated diseases including rheumatoid arthritis (RA). In this study we assess the effects of a helminthic excretory/secretory (ES) protein Na-AIP-1 as monotherapy and in combination with methotrexate (MTX) in the well-described collagen-induced arthritis (CIA) model of RA. CIA was induced in DBA/1 J mice which were treated after the onset of arthritis with Na-AIP-1 monotherapy, MTX or Na-AIP-1 + MTX. The clinical scores for weight, arthritis and paw width were recorded along with joint histology as outcome measures. For the clinical parameters of weight, paw score and paw width, none of the Na-AIP-1 monotherapy, MTX therapy or Na-AIP-1 + MTX combination therapy groups displayed any significant difference when compared to the arthritis control. However, a significant reduction in histological score was identified after both monotherapy (Na-AIP-1: 0.83 ± 0.24 vs Arthritis control: 5.58 ± 1.49, p = 0.0277) and combination therapy (Na-AIP-1 + MTX: 0.55 ± 0.28 vs Arthritis control: 5.58 ± 1.49, p = 0.0233) when compared to arthritis control. Furthermore, Na-AIP-1 as both monotherapy (Na-AIP-1: 0.83 ± 0.24 vs MTX: 5.73 ± 1.82 p = 0.0261) and combination therapy (Na-AIP-1 + MTX: 0.55 ± 0.28 vs MTX: 5.73 ± 1.82, p = 0.0221) also significantly reduced histological score when compared to MTX monotherapy. Na-AIP-1 significantly reduced joint pathology in CIA. The hookworm protein Na-AIP-1 seems to be effective in the treatment of RA as monotherapy and when dosed together with MTX, constituting a potential new candidate for drug development. Research should focus on elucidating the mechanism of Na-AIP-1 action as a means to identify novel targets for therapeutics and to further our current understanding of immunobiology in RA.
35562091 Metabolomics and molecular docking-directed antiarthritic study of the ethyl acetate extra 2022 Aug 10 ETHNOPHARMACOLOGICAL RELEVANCE: Celastrus orbiculatus Thunb., an important folk medicine, has long been used for the treatment of rheumatoid arthritis and its ethyl acetate extract (COE) has been reported to possess anticancer, antiinflammation and antiarthritic effects. However, the therapeutic effect and mechanism of COE treatment in rheumatoid arthritis has been rarely studied especially from the perspective of metabolomics. AIM OF STUDY: To reveal the therapeutic effects of COE on adjuvant-induced arthritis (AIA) rats through histopathological analysis, non-targeted metabolomics, and molecular docking study. MATERIALS AND METHODS: Forty-three Wistar rats were randomly divided into normal group, AIA model group, methotrexate group, and COE groups (80 mg/kg, 160 mg/kg and 320 mg/kg of ethyl acetate extract). Paw swelling and arthritis score were monitored through the experiment. Serum levels of tumor necrosis factor α (TNF-α) and nitric oxide were determined and histopathological evaluation was performed. Furthermore, Ultra-high performance liquid chromatography-linear trap quadrupole-Orbitrap-based metabolomics was employed to characterize metabolic changes of AIA rats after COE treatment and molecular docking was performed to predict the potential phytochemicals of COE against TNF-α. RESULTS: COE at three dosages could significantly relieve paw swelling and reduce arthritis scores of AIA rat. Histopathological analysis revealed remarkable decrease in synovial inflammation and bone erosion after COE treatment, especially at middle and high dosage. Additionally, COE down-regulated serum levels of TNF-α and nitric oxide. Serum metabolomics showed that 22 potential biomarkers for the COE treatment of AIA rats were identified, which were closely related to fatty acid metabolism, glycerophospholipid catabolism, and tryptophan metabolism. The molecular docking models predicted that olean-type triterpenes in COE may contribute most to therapeutic effects of rheumatoid arthritis through targeting TNF-α. CONCLUSIONS: COE could significantly relieve the arthritic symptoms in AIA rats and the ultra-high performance liquid chromatography-mass spectrometry based metabolomics proved to be an efficient method to characterize subtle metabolic changes of AIA rats after COE treatment.
35586477 Is Pharmacogenetic Panel Testing Applicable to Low-Dose Methotrexate in Rheumatoid Arthrit 2022 PURPOSE: Pharmacogenetic (PGx) panel testing could help to determine the heritable component of a rheumatoid arthritis (RA) patient's susceptibility for therapy failure and/or adverse drug reactions (ADRs) from methotrexate (MTX). Considering the literature mentioning the potential applicability of PGx panel testing within MTX regimens, we discuss the case of a patient who was treated with MTX, suffered from ADRs, and obtained a reactive PGx panel testing. GENOTYPING: We used a commercial PGx panel test involving the ABC-transporters P-glycoprotein (P-gp; gene: ABCB1), and breast cancer resistance protein (BCRP; gene: ABCG2), the solute carriers reduced folate carrier 1 (RFC1; gene: SLC19A1), and organic anion transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1), and the enzymes inosine triphosphatase (ITPA), and glutathione transferase P1 (GSTP1). In addition, we genotyped the patient for the enzymes 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICAR)/inosine monophosphate (IMP) cyclohydrolase (gene name: ATIC), gamma-glutamyl hydrolase (gene name: GGH) and methylenetetrahydrofolate reductase (gene name: MTHFR). RESULTS: The PGx profile of the patient revealed genetic variants in SLC19A1, ABCB1, and MTHFR, which may explain the ADRs experienced during the treatment with MTX and a potentially lower efficacy of MTX. Based on our interpretation of the PGx profile, we recommended the patient to avoid MTX in the future. CONCLUSION: The MTX pathway is complex, which makes the interpretation of genetic variants affecting metabolism challenging. A reactive PGx panel test was applicable to explain ADRs experienced during MTX treatment for a patient with RA. However, the clinical utility of PGx-guided MTX treatment in a primary care setting is still limited. In order to base a recommendation for MTX on PGx data, we need genome-wide association studies, large prospective multicenter studies and PGx studies, which analyze different multi-gene haplotypes and gene-drug-drug interactions for MTX.
35437350 Associations Between Genetic Polymorphisms Within Transporter Genes and Clinical Response 2022 PURPOSE: To investigate the associations between genetic polymorphisms within transporter genes and clinical response to methotrexate (MTX) in Chinese rheumatoid arthritis (RA) patients. PATIENTS AND METHODS: A total of 100 RA patients receiving MTX were prospectively followed up for approximately 3 months to determine the clinical response based on several criteria, including European League Against Rheumatism (EULAR) good and moderate response, disease activity score in 28 joint counts - erythrocyte sedimentation rate (DAS28-ESR) low disease activity (LDA), change in DAS28-ESR (ΔDAS28-ESR) and ΔDAS28-ESR >0.6. Fifty-four single nucleotide polymorphisms (SNPs) within seven transporter genes, including SLC19A1, ABCB1, ABCC1~4 and ABCG2, were genotyped. RESULTS: Multivariable analysis revealed that SLC19A1 rs12659 and rs3788200, ABCC2 rs3740066, rs4148396 and rs717620 were significantly associated with EULAR good and moderate response, and ABCC2 rs3740066 and rs717620 were significantly associated with DAS28-ESR LDA, and ABCB1 rs1128503, rs4148737 and ABCC3 rs2277624, rs4148416 were significantly associated with ΔDAS28-ESR. Moreover, 12 genetic polymorphisms were found to be significantly associated with ΔDAS28-ESR >0.6. With adjustment for corresponding confounders, SLC19A1 TGAA haplotype consisting of rs1051266, rs1131596, rs12659 and rs3788200 was significantly associated with EULAR good and moderate response and ΔDAS28-ESR >0.6 compared with the most common haplotype CAGG. The ABCC2 haplotype TTT composed of rs717620, rs4148396 and rs3740066 was significantly associated with EULAR good and moderate response and ΔDAS28-ESR >0.6 compared with the most common haplotype CCC. CONCLUSION: Our results highlight the potential of genetic polymorphisms within transporter genes, particularly SLC19A1 and ABCC2, as predictors of clinical response to MTX in Chinese RA patients.
35142908 Relative remission rates of Janus kinase inhibitors in comparison with adalimumab in patie 2022 Feb 10 OBJECTIVES: The relative remission rates of tofacitinib, baricitinib, upadacitinib, and filgotinib compared with those of adalimumab were assessed in patients with rheumatoid arthritis (RA) who responded poorly to methotrexate (MTX). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the Disease Activity Score in 28 joints with C‑reactive protein (DAS28-CRP), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and the Boolean remission of tofacitinib, baricitinib, upadacitinib, filgotinib, and adalimumab in RA patients with inadequate responses to MTX. RESULTS: Four RCTs, comprising 3507 patients, met the inclusion criteria. The filgotinib 200 mg + MTX and upadacitinib 15 mg + MTX groups showed a significantly higher DAS28-CRP < 2.6 than adalimumab 40 mg + MTX. Upadacitinib 15 mg + MTX showed a significantly higher CDAI (≤ 2.8) than adalimumab 40 mg + MTX (odds ratio [OR]: 1.62; 95% credible interval [CrI]: 1.16-2.29). The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg + MTX had the highest probability of being the best treatment as it achieved a CDAI ≤ 2.8, followed by filgotinib 200 mg + MTX, baricitinib 4 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab 40 mg + MTX. The Boolean remission showed the same distribution pattern as that of the CDAI ≤ 2.8. Upadacitinib 15 mg + MTX showed a significantly higher SDAI ≤ 3.3 than adalimumab 40 mg + MTX (OR: 1.62; 95% CrI: 1.16-2.28). SUCRA ranking based on SDAI ≤ 3.3 indicated that upadacitinib 15 mg + MTX had the highest probability of being the best treatment for achieving an SDAI ≤ 3.3, followed by baricitinib 4 mg + MTX, filgotinib 200 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab 40 mg + MTX. CONCLUSIONS: In RA patients with an inadequate response to MTX, remission rates with JAK inhibitors were significantly higher; there is evidence for differences in efficacy regarding remission among the different JAK inhibitors.
35650059 [A patient with rheumatoid arthritis who developed liver cirrhosis after increased soft dr 2022 A Japanese woman in her 80s with rheumatoid arthritis (RA) was admitted for weakness, edema, and ascites. She was obese (148 cm in height, 60 kg in weight) and had a high gamma-glutamyltransferase level according to her laboratory findings before treatment. She had received methotrexate (MTX) at a dose of 6 mg/week for 1 year and 9 months. She had consumed large amounts of soft drinks (about 110 g of sugar/day) for a long time, but during the course of treatment for RA, she began drinking even more (170 g/day). Her condition improved with the discontinuation of MTX, adequate nutrition, and administration of diuretics. We diagnosed her with liver cirrhosis caused by both drug-induced hepatic injury due to MTX and by exacerbation of non-alcoholic steatohepatitis due to excessive sugar intake.
35306206 Possible association of methotrexate use with osteonecrosis of the jaw: Systematic review. 2022 Mar 16 The aim was to search systematically, evaluate, and then summarize scientific literature about possible methotrexate-associated osteonecrosis of the jaw (ONJ), its signs and symptoms, diagnosis, treatment, and prognosis in adults. After registration at PROSPERO this systematic review was conducted and reported according to the PRISMA checklist. The following databases were systematically searched: MEDLINE, EBSCO, The Cochrane Central Register of Controlled Trials (Central), SCIndex, Scopus, Google Scholar and Registry of clinical studies with human participants. In total 9 studies with 14 patients were included in the review. All cases of ONJ associated with methotrexate were described in patients suffering from Rheumatoid arthritis (RA), and only about 40% of them were taking other concomitant medication described to be associated with ONJ (bisphosphonates). Both sexes were equally affected, and the patients were rather old (over 60 years if age), already taking methotrexate for more than 12 years on average. Antibiotics were ineffective in the treatment of ONJ; after stopping methotrexate, all lesions healed after several months on average; however, half of the cases required covering of the exposed bone with mucosal flap. Recurrence of the methotrexate-associated ONJ was not observed for at least two years after the lesions were healed. Methotrexate-associated ONJ is serious clinical condition that may occur in patients with RA, but given the small number of cases we have found in the literature, direct involvement of methotrexate in the development of ONJ remains elusive.
35640491 Nanoparticulate DNA scavenger loading methotrexate targets articular inflammation to enhan 2022 May 24 Abnormal high cell-free DNA (cfDNA) activates toll-like receptor 9 (TLR9) in immune cell's endosome to produce inflammatory cytokines that aggravate rheumatoid arthritis (RA). Previously, we successfully developed cationic nanoparticles (cNPs) relieving symptoms of RA rats by scavenging cfDNA, but the strong positive charges of cNPs may cause systemic toxicity during circulation via intravenous injection. Herein, we design cNP-pp-PEG to shield the nanoparticles with MMP2-sensitive peptide (pp) linked PEG, the cations are exposed only when PEG is removed by MMP2, which is enriched in the inflamed articular cavity. Taking advantage of the self-assembled cNP-pp-PEG, hydrophobic methotrexate (MTX) is loaded into its core through hydrophobicity interaction, obtaining MTX@cNP-pp-PEG. The engineered reagents exhibit lower toxicity, longer retention time and higher accumulation in inflamed joints comparing to its counterpart MTX@cNP-pp due to the hidden cationic charges. Moreover, the anti-inflamed activity of MTX strengthens the therapeutic efficiency of cNPs. The dual roles of cNPs as therapeutic agent and MTX carrier significantly enhance the therapeutic efficacy and extended administration interval to 4 days. This research addresses the issues of targeting inflamed joints, reducing the systemic toxicities of both cNPs and MTX, and extending administration interval, demonstrating an upgraded strategy for DNA scavenger application.
35267027 Post hoc Analysis of Clinical Characteristics of Patients with Radiographic Progression in 2022 Mar 10 OBJECTIVE: To determine efficacy of peficitinib in reducing joint damage, and predictive factors affecting treatment response in Japanese patients with rheumatoid arthritis (RA). METHODS: This post hoc analysis used data from a placebo-controlled, phase 3 trial (RAJ4) of peficitinib in patients with RA and inadequate response to methotrexate. Erosion and joint space narrowing (JSN) was assessed at baseline and at Week 28/early termination (ET) of treatment using the van der Heijde-modified Sharp method. Univariate logistic regression analysis of change from baseline in modified total Sharp score identified predictive factors with significant treatment interaction; the effects of these factors on treatment response were further evaluated using a multivariate model. RESULTS: The analyses included 481 patients. For most joint groups, peficitinib demonstrated reduced change from baseline at Week 28/ET in erosion and JSN scores versus placebo; a numerically greater effect was observed with peficitinib 150mg versus 100mg. Baseline C-reactive protein (CRP) and prednisolone dose were identified as clinically significant negative predictive factors: treatment effect decreased as CRP or prednisolone dose increased, for both peficitinib doses. CONCLUSIONS: : Peficitinib 100mg and 150mg reduced joint damage versus placebo, across almost all joint groups. Higher baseline CRP and/or prednisolone dose were associated with reduced peficitinib efficacy. CLINICALTRIALS.GOV IDENTIFIER: : NCT02305849.
35220965 Incidence and predictors of fragility fracture in postmenopausal rheumatoid arthritis pati 2022 Feb 28 BACKGROUND: Although many studies have reported the predictors of fractures in patients with rheumatoid arthritis (RA) who are not receiving anti-osteoporotic treatments or who are receiving unspecified treatments, studies focusing on the predictors of fracture in patients with RA who are currently being treated with oral bisphosphonates (BP) are quite scarce. This study aims to investigate the incidence and predictors of fragility fracture in postmenopausal patients with RA receiving oral BP. METHODS: This retrospective longitudinal observational study comprised 98 postmenopausal RA patients receiving oral BP for a minimum of 6 months between April 2015 and December 2020. The cumulative incidence of fragility fractures including vertebral and nonvertebral fractures was investigated using the Kaplan-Meier method. Cox proportional hazards analysis was used to analyze baseline predictors of future fragility fractures. To determine a cutoff value of continuous predictors, the receiver-operating characteristic curve was applied. RESULTS: Twenty patients developed fractures during the study period, with a cumulative incidence of 6.1% at 12 months, 10.5% at a median follow-up of 28 months, and 14.4% at 36 months. Multivariable Cox hazards analysis showed a history of prior vertebral fracture (hazard ratio [HR] 6.26, 95% confidence interval [CI] 1.99‒19.68, P = 0.001) and dose of methotrexate (HR 0.87, 95% CI 0.76‒0.99, P = 0.041) to be independent predictors. The cutoff value for methotrexate dose was 4 mg/week. CONCLUSIONS: We found a cumulative incidence of any fractures of 10.5% at 28 months in patients with RA currently being treated with oral BP. A history of prior vertebral fractures and methotrexate dose were positive and negative predictors for fractures, respectively. Practitioners should consider selecting another anti-osteoporotic drug in patients with RA who remain at risk despite receiving oral BP.