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33780033 Effects of vitamin K(2) combined with methotrexate against mitogen-activated peripheral bl 2021 Oct BACKGROUND: Methotrexate (MTX) is used as anchor drug for patients with early and established rheumatoid arthritis (RA). Vitamin K(2) administration was also reported to be associated with decreased disease activity in RA. OBJECTIVES: Immunosuppressive pharmacodynamics of vitamin K(2) combined with MTX was investigated. METHODS: Mitogen-activated peripheral blood mononuclear cells (PBMCs) were used to evaluate immunosuppressive pharmacodynamics of drugs in vitro. RESULTS: Vitamin K(2) alone dose-dependently suppressed T cell mitogen-activated proliferation of PBMCs of both healthy subjects and RA patients. 446.5 and 2232.5 ng/mL vitamin K(2) significantly decreased the IC(50) values of MTX on the proliferation of PBMCs of RA patients, with little influences on the pharmacodynamics of MTX in the healthy PBMCs. 4465 ng/mL vitamin K(2) potentiated the pharmacodynamics of MTX in both RA patients and healthy PBMCs. The additional effects of vitamin K(2) to potentiate the suppressive effects of MTX seemed not to be related to the regulation of CD4(+) CD25(+) T cells or CD4(+) CD25(+) Foxp3(+) Treg cells. MTX alone at 100 ng/mL significantly decreased the percentage of CD4(+) T cells in PBMCs of healthy subjects (p < 0.001) with a slight influence in that of RA patients (not significant) and the combination did not show synergistic inhibitory effect. Vitamin K(2) alone tended to suppress the secretion of IL-17, IFN-γ, and TNF-α from the activated PBMCs of RA patients with smaller influences on the cytokine productions from healthy PBMCs. These additional effects of vitamin K(2) were also observed in combination with MTX. CONCLUSION: The above information may partially elucidate the potentiation effects of vitamin K(2) on the immunosuppressive efficacy of MTX.
33060309 Benefits of Methotrexate Use on Cardiovascular Disease Risk Among Rheumatoid Arthritis Pat 2021 Jun OBJECTIVE: Methotrexate (MTX) has been associated with reduced risk for cardiovascular disease (CVD) events among patients with rheumatoid arthritis (RA) not exposed to biologic disease-modifying antirheumatic drugs (bDMARDs). The effect of concomitant MTX on CVD risk among RA patients initiating bDMARDs remains unknown. METHODS: A retrospective cohort study was conducted to assess the effect of MTX on CVD risk using 2006-2015 Medicare claims data for patients with RA initiating bDMARD. The main exposure was current use of MTX, updated in a time-varying fashion. The primary outcome was a composite of incident myocardial infarction (MI), stroke, and fatal CVD. Secondary outcomes were each event that comprised the primary outcome. Incidence rates (IR) and 95% CI were calculated using Poisson regression. Associations between MTX and risk of CVD were assessed using Cox regression. RESULTS: A total of 88,255 bDMARD initiations and 1861 CVD events were included in this study. Mean age was 64.6 (12.3) years, 84.0% were female, and 68.2% were non-Hispanic White. The crude IRs (95% CI) for CVD were 17.9 (16.9-18.8) and 12.1 (11.1-13.2) per 1000 patient-years among MTX unexposed and exposed, respectively. The multivariable adjusted HR (95% CI) for CVD events associated with MTX was 0.76 (0.68-0.85). Multivariable adjusted HRs were 0.78 (0.66-0.91), 0.74 (0.62-0.88), 0.77 (0.68-0.86), and 0.82 (0.73-0.93) for MI, stroke, MI or stroke, and a composite CVD outcome, respectively. Results were robust in sensitivity and subgroup analyses. CONCLUSION: Among patients with RA receiving biologics, concomitant MTX use was associated with a 24% lower risk for CVD events.
33043757 Cost-effectiveness analysis of tofacitinib compared with adalimumab and etanercept in the 2021 Aug BACKGROUND AND OBJECTIVE: This study aimed to evaluate the cost-utility of Tofacitinib (TFC) in patients with severe rheumatoid arthritis (RA) who had not responded well to methotrexate from the Iranian payer's perspective. METHODS: An individual microsimulation Markov model was developed to compare TFC with etanercept (ETN) and Adalimumab (ADA) over a life-time horizon. Treatment efficacy was estimated based on the American College of Rheumatology (ACR) response improvement criteria in 6 months. Changes in the Health Assessment Questionnaire (HAQ) scores were mapped onto utility values to calculate outcomes in terms of QALYs. Direct medical costs were taken from national databases. Uncertainty in model parameters was evaluated by sensitivity analyses. RESULTS: This study demonstrated that TFC was cost-effective in both scenarios. Although TFC was associated with lower QALYs than ETN (6.664 versus 6.876), it was also associated with lower costs over a life-time horizon ($42,565.04 versus $58,696.29). Additionally, TFC was found to be the dominant strategy with a lower cost ($50,299.91 versus $51,550.29) and higher QALYs gained (6.900 versus 6.687) compared to ADA. CONCLUSION: TFC was found to be cost-effective in patients with severe RA who do not respond well to methotrexate compared to ADA, ETN in Iran.
33132219 Circulating Fibroblast Growth Factor-21 Levels in Rheumatoid Arthritis: Associations With 2021 Apr OBJECTIVE: This study evaluated associations between fibroblast growth factor (FGF)-21, an adipokine associated with metabolic stress, and adverse longitudinal changes in body composition and physical functioning in patients with rheumatoid arthritis (RA). METHODS: At baseline and follow-up, patients with RA aged 18-70 years completed whole-body dual-energy X-ray absorptiometry and peripheral quantitative computed tomography to quantify lean mass, fat mass, and muscle density. Dynamometry assessed muscle strength at the hand and knee, and physical functioning was measured with the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). FGF-21 and inflammatory cytokines were measured at baseline. Linear and logistic regression analyses assessed associations between FGF-21 levels and both body composition and physical functioning over time. RESULTS: There were 113 patients with RA enrolled, and 84 (74%) returned for follow-up at a median of 2.68 years. At baseline, FGF-21 was associated with age, smoking, methotrexate use, adiposity, and inflammatory cytokines: tumor necrosis factor receptor type I, YKL-40, vascular endothelial growth factor (VEGF), and resistin. The highest FGF-21 quartile was associated with worse SPPB and HAQ. Higher baseline FGF-21 levels (per 1 SD) were associated with worsening in muscle density and area Z-scores (β -0.06, 95% CI -0.12 to 0.008, P = 0.08; and β -0.05, 95% CI -0.10 to 0.006, P = 0.08, respectively) and a greater probability of a clinically meaningful worsening of HAQ (OR 2.37, 95% CI 1.21-4.64, P = 0.01). The fourth FGF-21 quartile was associated with worsening of SPPB (β -0.57, 95% CI -1.04 to -0.09, P = 0.02). CONCLUSION: FGF-21 levels are associated with obesity and inflammatory cytokines, and with worsening in physical functioning in RA. These data support the hypothesis that FGF-21 can identify patients at risk of functional decline.
34302046 AHR-dependent genes and response to MTX therapy in rheumatoid arthritis patients. 2021 Oct Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis. Nevertheless, MTX resistance is quite a common issue in clinical practice. There are some premises that aryl hydrocarbon receptor (AhR) gene battery may take part in MTX metabolism. In the present retrospective study, we analyzed genes expression of AHR genes battery associated with MTX metabolism in whole blood of RA patients with good and poor response to MTX treatment. Additionally, sequencing, genotyping and bioinformatics analysis of AHR repressor gene (AHRR) c.565C > G (rs2292596) and c.1933G > C (rs34453673) have been performed. Theoretically, both changes may have an impact on H3K36me3 and H3K27me3. Evolutionary analysis revealed that rs2292596 may be possibly damaging. Allele G in rs2292596 and DAS28 seems to be associated with a higher risk of poor response to MTX treatment in RA. RA patients with poor response to MTX treatment revealed upregulated AhR and SLC19A1 mRNA level. Treatment with IL-6 inhibitor may be helpful to overcome the low-dose MTX resistance. Analysis of gene expression revealed possible another cause of poor response to MTX treatment which is different from that observed in the case of acute lymphoblastic leukemia.
34448148 Filgotinib for Moderate to Severe Rheumatoid Arthritis: An Evidence Review Group Perspecti 2021 Dec The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Gilead) of filgotinib (Jyseleca(TM)), as part of the single technology appraisal process, to submit evidence for its clinical and cost effectiveness for the treatment of patients with moderate to severe rheumatoid arthritis (RA). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee. The evidence for filgotinib was based on two good-quality international randomised controlled trials. In FINCH 1, filgotinib was compared with placebo, and in FINCH 2, filgotinib was compared with adalimumab and placebo. As there was no head-to-head evidence with most active comparators, the company performed two separate network meta-analyses (NMAs), one for the conventional disease-modifying antirheumatic drugs-inadequate response population and one for the biological disease-modifying antirheumatic drugs-inadequate response population. The outcomes analysed were American College of Rheumatology response criteria at weeks 12 and 24, and European League Against Rheumatism response criteria at 24 weeks. The statistical methods used to perform the NMAs were valid and were in line with previous NICE appraisals. Results of the NMAs are confidential and cannot be reported here, but they were uncertain due to heterogeneity of the included studies. The economic analysis of the patient population with moderate RA suffered from limited evidence on the progression from moderate to severe health states. For the moderate RA population, the final analyses comparing filgotinib, with or without methotrexate, against standard of care resulted in incremental cost-effectiveness ratios of around £20,000 per quality-adjusted life-year gained in the company's and ERG's base-case and scenario analyses. NICE recommended filgotinib in combination with methotrexate or as monotherapy when methotrexate is contraindicated, or if people cannot tolerate it, for patients with moderate RA whose disease had responded inadequately to two or more conventional disease-modifying antirheumatic drugs (DMARDs). For the severe RA population, in view of the higher or similar net health benefits that filgotinib provided versus its comparators, NICE recommended filgotinib with or without methotrexate for patients whose disease had responded inadequately to two or more conventional DMARDs, who had been treated with one or more biological DMARDs, if rituximab was not an option, or after treatment with rituximab.
33483918 Factors predicting addition of disease-modifying antirheumatic drugs after initial methotr 2021 Jul INTRODUCTION: We investigated factors predicting the addition of disease-modifying antirheumatic drugs (DMARDs) after an initial methotrexate (MTX) monotherapy in rheumatoid arthritis (RA) patients to support an early decision on the DMARDs addition. METHODS: This retrospective cohort study included 311 patients who were diagnosed with RA and started on MTX monotherapy at Showa University Hospital, Japan. The outcome was addition of DMARDs after an initial MTX monotherapy at 6 months. Baseline patient characteristics were compared between the DMARDs addition and MTX monotherapy continuation groups, and significant independent predictive factors for the addition of DMARDs were selected using multivariate analysis. RESULTS: The median age of patients was 62 years (range 24-90), 170 patients (73%) were women, the median swollen 28-joint count (SJC28) was 3 (0-28), and the median tender 28-joint count (TJC28) was 5 (0-28). DMARDs were added in 65 (27.9%) patients. In the univariate analysis, higher TJC28 and SJC28, concomitant use of nonsteroidal anti-inflammatory drugs, and intra-articular glucocorticoid (GC) injection history were significantly associated with the DMARDs addition. In the multivariate analysis, by adding covariates to the variables identified in the univariate analysis, SJC28 (odds ratio [OR] 1.390 per 5 joints increase; 95% confidence interval [CI], 1.036-1.866) and intra-articular GC injection history (OR 3.678; 95% CI, 1.170-11.557) were independent predictors of DMARDs addition. CONCLUSION: A higher SJC28 and intra-articular GC injection history may be useful predictors of DMARDs addition after the initial MTX monotherapy. We expect that using these predictors will enable an earlier shift to a more aggressive treatment. Key Points ・We performed a retrospective cohort study with the addition of DMARDs as the outcome in patients with RA who were started on MTX monotherapy. ・A higher SJC28 (OR 1.390; 95% CI, 1.036-1.866) and an intra-articular GC injection history (OR 3.678; 95% CI, 1.170-11.557) may be useful predictors for the addition of DMARDs of initiating MTX monotherapy at 6 months. ・The use of such indicators may support an early decision on the addition of DMARDs after the initial MTX monotherapy.
34334357 Heterogeneity in Patient Characteristics and Differences in Treatment Across 4 Canadian Rh 2022 Jan OBJECTIVE: To compare clinical characteristics and treatment of patients with rheumatoid arthritis (RA) across 4 Canadian cohorts. METHODS: The 4 longitudinal cohorts included the following: the Canadian Early Arthritis Cohort (CATCH; n = 2878), Ontario Best Practices Research Initiative (OBRI; n = 3734), RHUMADATA (Quebec, n = 2890), and the Rheum4U Precision Health Registry (Calgary, Alberta, n = 709). Data were from cohort inception (range 1998-2016) to 2020. Clinical characteristics and drug treatments were summarized descriptively. RESULTS: In total, 10,211 patients with RA were included. The percentage of patients who entered the cohort with early RA (2 yrs of disease at enrollment) ranged from 29% (Rheum4U) to 100% (CATCH). Mean age (55 yrs), sex (74% female), and seropositivity (69%) were similar between cohorts. At the time of initial disease-modifying antirheumatic drug (DMARD) use, median Disease Activity Score in 28 joints (DAS28) varied, ranging from 2.99 (Rheum4U) to 5.19 (CATCH), but were more similar at the time of the first DMARD switch (range 3.57-5.03), first biologic (bDMARD) or targeted synthetic DMARD (tsDMARD) use (range 4.01-4.67), and second bDMARD or tsDMARD (range 3.71-4.39). The initial DMARD was most commonly methotrexate, either in monotherapy (32%, range 18-40%) or dual therapy (34%, range 29-42%). The first DMARD switch was to another DMARD monotherapy in 20% (range 10-32%), dual therapy in 49% (range 39-56%), and bDMARD or tsDMARD in 24% (range 15-28%). The first bDMARD was an anti-tumor necrosis factor in 79% (range 78-82%). CONCLUSION: Canadian RA cohorts demonstrate some heterogeneity in treatment, which could reflect differences in inclusion criteria, calendar year, or regional differences. This project is a first step toward conducting harmonized analyses across Canadian RA cohorts.
33510353 Network theoretic analysis of JAK/STAT pathway and extrapolation to drugs and viruses incl 2021 Jan 28 Whenever some phenomenon can be represented as a graph or a network it seems pertinent to explore how much the mathematical properties of that network impact the phenomenon. In this study we explore the same philosophy in the context of immunology. Our objective was to assess the correlation of "size" (number of edges and minimum vertex cover) of the JAK/STAT network with treatment effect in rheumatoid arthritis (RA), phenotype of viral infection and effect of immunosuppressive agents on a system infected with the coronavirus. We extracted the JAK/STAT pathway from Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04630). The effects of the following drugs, and their combinations, commonly used in RA were tested: methotrexate, prednisolone, rituximab, tocilizumab, tofacitinib and baricitinib. Following viral systems were also tested for their ability to evade the JAK/STAT pathway: Measles, Influenza A, West Nile virus, Japanese B virus, Yellow Fever virus, respiratory syncytial virus, Kaposi's sarcoma virus, Hepatitis B and C virus, cytomegalovirus, Hendra and Nipah virus and Coronavirus. Good correlation of edges and minimum vertex cover with clinical efficacy were observed (for edge, rho =  - 0.815, R(2) = 0.676, p = 0.007, for vertex cover rho =  - 0.793, R(2) = 0.635, p = 0.011). In the viral systems both edges and vertex cover were associated with acuteness of viral infections. In the JAK/STAT system already infected with coronavirus, maximum reduction in size was achieved with baricitinib. To conclude, algebraic and combinatorial invariant of a network may explain its biological behaviour. At least theoretically, baricitinib may be an attractive target for treatment of coronavirus infection.
33860755 Comparison of the efficacy and safety of tofacitinib and mavrilimumab in patients with act 2021 Aug OBJECTIVES: The relative efficacy and safety of tofacitinib and mavrilimumab were assessed in patients with rheumatoid arthritis (RA) presenting an inadequate response to disease-modifying antirheumatic drugs (DMARDs). MATERIALS AND METHODS: We performed a Bayesian network meta-analysis combining direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and mavrilimumab combined with DMARDs in patients with an inadequate response to DMARDs. RESULTS: In total, 8 RCTs with 2,965 patients met inclusion criteria. 21 pairwise comparisons were performed, including 12 direct comparisons of 7 interventions. In patients with active RA and an inadequate DMARD response, mavrilimumab 150 mg+methotrexate (MTX) and mavrilimumab 100 mg+MTX were the most effective treatments. Compared with placebo+MTX, all tofacitinib and mavrilimumab doses, except mavrilimumab 50 mg+MTX, achieved significant ACR20 responses. The ranking probability based on the surface under the cumulative ranking curve indicated that mavrilimumab 150 mg+MTX had the highest probability for best treatment outcome in terms of the ACR20 response rate, followed by mavrilimumab 100 mg+MTX, tofacitinib 10 mg+MTX, tofacitinib 5 mg+MTX, mavrilimumab 30 mg+MTX, mavrilimumab 50 mg+MTX, and placebo+MTX. No significant differences were noted in the incidence of serious adverse events (SAEs) after tofacitinib+MTX, mavrilimumab+MTX, or placebo+MTX. CONCLUSION: In patients with RA showing inadequate DMARD response, mavrilimumab 150 mg+MTX and mavrilimumab 100 mg+MTX, followed by tofacitinib 10 mg+MTX and tofacitinib 5 mg+MTX, were the most efficacious interventions and were not associated with a significant risk of SAEs.
32573414 The effect of methotrexate on neutrophil reactive oxygen species and CD177 expression in r 2021 May OBJECTIVES: Neutrophils are found in abundance in the synovial fluid of patients with rheumatoid arthritis (RA), where they are activated and show high reactive oxygen species (ROS) production. However, there is limited data on circulating neutrophils in peripheral blood of patients with RA in terms of ROS production, expression of activation markers and the effect of treatment with methotrexate (MTX) on ROS. METHODS: This single-centre prospective study recruited patients of RA classified as per the 2010 ACR/EULAR criteria. In the cross-sectional arm, we included three groups, treatment-naïve RA (naïve-RA), MTX-treated RA (MTX-RA) and healthy controls, and compared ROS production and surface markers of neutrophil activation. In the longitudinal arm, we studied the change in neutrophil ROS production after 8 weeks of MTX treatment in naïve-RA patients. Neutrophil ROS production was measured by flow cytometry using dihydrorhodamine-123 (DHR) and by chemiluminescence using luminol. Surface expression of CD177, CD11b and CD64 was measured by flow cytometry. RESULTS: This study included 103 patients (50 naïve-RA, 53 MTX-RA) and 20 controls. Both naïve-RA and MTX-RA patients showed higher ROS production than healthy controls in unstimulated neutrophils in the DHR assay (p<0.001 and p=0.004). MTX-RA patients showed significantly lower ROS production than naive-RA, in both unstimulated (p=0.004) and PMA-stimulated neutrophils in the DHR assay (p=0.03). On longitudinal follow-up of 24 naïve-RA patients, there was a significant reduction of neutrophil ROS production (by 55% from baseline) (p<0.001) after 8 weeks of MTX. Neutrophil CD177 expression was higher in both naïve-RA and MTX-RA (trend) than controls (p=0.001 and p=0.09). MTX-RA neutrophils showed lower expression of CD177 than naïve-RA (p=0.01). CD11b expression was higher in MTX-RA compared to controls (p=0.01). CONCLUSIONS: Circulating neutrophils in RA showed higher ROS production and higher expression of CD177 and CD11b compared to controls. MTX treatment was associated with a reduction in ROS production and CD177 expression, which may be one of the mechanisms by which MTX works in RA.
32985955 Immunoglobulin D-kappa multiple myeloma in a patient with rheumatoid arthritis: a case rep 2021 Jan A 77-year-old Japanese woman with a 21-year history of seropositive, erosive rheumatoid arthritis (RA) and a 10-year history of methotrexate (MTX) therapy was admitted with malaise and mild consciousness disturbance. Laboratory data showed hypercalcemia, acute kidney injury, normocytic anaemia, and thrombocytopenia. As we first assumed drug-induced toxicity by MTX and eldecalcitol, both were discontinued and leucovorin rescue therapy and calcitonin were administered. However, her condition continued to worsen. Serum protein electrophoresis showed only a small M-peak, immunoelectrophoresis of both the serum and urine demonstrated Bence-Jones kappa (κ) type monoclonal protein without immunoglobulin heavy chain, and bone marrow examination revealed proliferation of plasma cells. We diagnosed her with Bence-Jones κ type multiple myeloma (MM) and transferred her to the department of haematology of a higher order medical institution. Conclusively, the diagnosis of immunoglobulin (Ig) D-κ type MM, a rare variant of this disorder, was determined in accordance with serum immunofixation. Several previous studies have suggested that pre-existing RA is a risk factor for MM. Although IgD MM is characterised by its clinical severity and poor prognosis compared to other subtypes, it is often misdiagnosed or mistaken as light chain type MM, as in the present case, because of the low level of IgD M-protein, resulting in delayed diagnosis. Physicians must take MM into consideration as a differential diagnosis when inactive RA patients present with inexplicable elevated calcium, renal failure, anaemia, and bone lesion symptoms and should be aware of IgD MM to establish the correct diagnosis promptly.
32075475 A phase 2a, randomized, double-blind, placebo-controlled trial of the efficacy and safety 2021 Jan OBJECTIVES: Many patients with rheumatoid arthritis (RA) are not able to achieve long-term disease remission. This phase 2a study (NCT02884635) evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of the novel, oral, gonadotropin-releasing hormone antagonist, ASP1707, in combination with methotrexate (MTX) for treatment of RA. METHODS: Postmenopausal women with RA who had been receiving MTX for ≥90 days were randomized to ASP1707 30 mg twice daily or placebo for 12 weeks. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Secondary endpoints included: ACR20, ACR50, and ACR70 response rates; disease activity score (DAS)28-CRP; DAS28-ESR; Tender or Swollen Joint Counts; and remission rates. RESULTS: Of 105 patients screened, 72 were randomized to ASP1707 30 mg twice daily (n = 37) or placebo (n = 35). ASP1707 did not improve ACR20, ACR50, or ACR70 response rates at any time point and did not improve any secondary efficacy endpoint. Plasma luteinizing hormone (LH) concentration decreased >90% in >90% of patients receiving ASP1707, with a rapid decrease to <1 IU/L at week 1 that remained stable throughout the treatment. CONCLUSION: In the current study, ASP1707 did not demonstrate a clinical benefit.
33958440 Tofacitinib versus tocilizumab in the treatment of biological-naïve or previous biologica 2021 May OBJECTIVES: To compare effectiveness between tofacitinib and tocilizumab treatments for biological disease-modifying antirheumatic drug (bDMARD)-naïve patients or previous bDMARD-failure patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX). METHODS: We used two ongoing real-world registries of patients with RA who had first started tofacitinib or tocilizumab between August 2013 and February 2019 at our institutions. Clinical disease activity index (CDAI)-based improvements at 12 months were used for comparisons between tofacitinib and tocilizumab treatments, separately for bDMARD-naïve and previous bDMARD-failure patients. RESULTS: A total of 464 patients with RA with high or moderate CDAI were enrolled (247 with tofacitinib and 217 with tocilizumab). After adjustments for treatment-selection bias by propensity score matching, we showed that tofacitinib was more likely to induce and maintain ≥85% improvement in CDAI (CDAI85), CDAI70 and remission at 12 months compared with tocilizumab in bDMARD-naïve patients. After adjusting for concurrent use of MTX and prednisolone, the ORs of tofacitinib versus tocilizumab were 3.88 (95% CI 1.87 to 8.03) for CDAI85, 2.89 (95% CI 1.43 to 5.84) for CDAI70 and 3.31 (95% CI 1.69 to 6.48) for remission. These effects were not observed in bDMARD-failure patients. In tofacitinib treatment for bDMARD-failure patients, the number of previously failed bDMARD classes was not associated with CDAI-based improvements. The rate of overall adverse events was similar between both treatments. Similar ORs were obtained from patients adjusted by inverse probability of treatment weighting. CONCLUSIONS: Compared with tocilizumab, tofacitinib can induce greater improvements during the first 12-month treatment in bDMARD-naïve patients, but this difference was not observed in previous bDMARD-failure patients.
33325280 Tapering and discontinuation of oral glucocorticoids without deterioration of disease stat 2021 Jul OBJECTIVE: To retrospectively evaluate whether oral glucocorticoid (GC) administration can be tapered or discontinued over a 2-year observation period in patients with rheumatoid arthritis (RA) undergoing a stable oral GC treatment, without deterioration in the disease status. METHODS: Methotrexate (MTX) and prednisolone (PSL) dosages were increased and decreased, respectively, to the maximum extent possible. Concomitant biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) were used as required. Changes in PSL and MTX use and disease status were evaluated at baseline (BL), year-1, and year-2. RESULTS: Thirty-six patients were enrolled (median age, 65.4 years; disease duration, 7.1 years). The proportion of patients using PSL decreased over 2 years (100-13.9%, p < .0001). While no change was observed in the proportion of patients using MTX, the average administered dose increased at year-1 (p = .06). Moreover, b/tsDMARDs were administered in nine patients (two in year-1, seven in year-2). The Clinical Disease Activity Index remission rate increased from 25.0% to 38.9%. Serious adverse events were identified in two patients. CONCLUSIONS: Oral GC administration was discontinued without deterioration in the rheumatoid arthritis disease control.
33806304 Effect of Anti-Rheumatic Treatment on the Periodontal Condition of Rheumatoid Arthritis Pa 2021 Mar 4 Periodontitis, a bacterial-induced infection of the supporting soft and hard tissues of the teeth (the periodontium), is common in patients with rheumatoid arthritis (RA). As RA and periodontitis underlie common inflammatory pathways, targeting the progression of RA might mediate both periodontitis and RA. On the other hand, patients with RA on immunosuppressive medication have an increased risk of infection. Therefore, the objective of this longitudinal observation study was to assess the effect of methotrexate (MTX) and anti-tumor necrosis factor-α (anti-TNF, etanercept) treatment on the periodontal condition of RA patients. Overall, 14 dentate treatment-naive RA patients starting with MTX and 12 dentate RA patients starting with anti-TNF therapy in addition to MTX were included. Follow-up was scheduled matching the routine protocol for the respective treatments. Prior to the anti-rheumatic treatment with MTX or the anti-TNF therapy in addition to MTX, and during follow-up, i.e., 2 months for MTX, and 3 and 6 months for the anti-TNF therapy in addition to MTX, the periodontal inflamed surface area (PISA) was measured. The efficacy of the anti-rheumatic treatment was assessed by determining the change in RA disease activity (DAS28-ESR). Furthermore, the erythrocyte sedimentation rates were determined and the levels of C-reactive protein, IgM-rheumatoid factor, anti-cyclic citrullinated protein antibodies, and antibodies to the periodontal pathogen Porphyromonas gingivalis, were measured. Subgingival sampling and microbiological characterization of the subgingival microflora was done at baseline. MTX or anti-TNF treatment did not result in an improvement of the periodontal condition, while both treatments significantly improved DAS28 scores (both p < 0.01), and reduced C-reactive protein levels and erythrocyte sedimentation rates (both p < 0.05). It is concluded that anti-rheumatic treatment (MTX and anti-TNF) has negligible influence on the periodontal condition of RA patients.
33572934 Folinate Supplementation Ameliorates Methotrexate Induced Mitochondrial Formate Depletion 2021 Jan 29 (1) Background: Antifolate methotrexate (MTX) is the most common disease-modifying antirheumatic drug (DMARD) for treating human rheumatoid arthritis (RA). The mitochondrial-produced formate is essential for folate-mediated one carbon (1C) metabolism. The impacts of MTX on formate homeostasis in unknown, and rigorously controlled kinetic studies can greatly help in this regard. (2) Methods: Combining animal model (8-week old female C57BL/6JNarl mice, n = 18), cell models, stable isotopic tracer studies with gas chromatography/mass spectrometry (GC/MS) platforms, we systematically investigated how MTX interferes with the partitioning of mitochondrial and cytosolic formate metabolism. (3) Results: MTX significantly reduced de novo deoxythymidylate (dTMP) and methionine biosyntheses from mitochondrial-derived formate in cells, mouse liver, and bone marrow, supporting our postulation that MTX depletes mitochondrial 1C supply. Furthermore, MTX inhibited formate generation from mitochondria glycine cleavage system (GCS) both in vitro and in vivo. Folinate selectively rescued 1C metabolic pathways in a tissue-, cellular compartment-, and pathway-specific manner: folinate effectively reversed the inhibition of mitochondrial formate-dependent 1C metabolism in mouse bone marrow (dTMP, methionine, and GCS) and cells (dTMP and GCS) but not methionine synthesis in liver/liver-derived cells. Folinate failed to fully recover hepatic mitochondrial-formate utilization for methionine synthesis, suggesting that the efficacy of clinical folinate rescue in MTX therapy on hepatic methionine metabolism is poor. (4) Conclusion: Conducting studies in mouse and cell models, we demonstrate novel findings that MTX specifically depletes mitochondrial 1C supply that can be ameliorated by folinate supplementation except for hepatic transmethylation. These results imply that clinical use of low-dose MTX may particularly impede 1C metabolism via depletion of mitochondrial formate. The MTX induced systematic and tissue-specific formate depletion needs to be addressed more carefully, and the efficacy of folinate with respect to protecting against such depletion deserves to be evaluated in medical practice.
33269654 Methotrexate-associated lymphoproliferative disorder with histopathological features of hi 2021 Jan An 84-year-old Japanese woman suffering from rheumatoid arthritis (RA), who had been treated with methotrexate (MTX) for 15 years, was admitted to our hospital for generalised lymphadenopathy, thrombocytopenia, anaemia, elevated aminotransferases, and elevated CRP levels. Pathological findings of cervical lymph node biopsy were compatible with histiocytic necrotising lymphadenitis (HNL). Small lymphocytes positive for Epstein-Barr virus (EBV)-encoded small RNA were detected in the tissue. We suspected a MTX-associated lymphoproliferative disorder (MTX-LPD), withdrew MTX and administered leucovorin (folic acid). The patient's symptoms gradually resolved following discontinuation of MTX. We considered that this patient developed HNL as an MTX-LPD when EBV was reactivated. This is the first case of HNL associated with MTX treatment for RA, which we report here along with clinical course.
34198264 miR-let-7c-5p and miR-149-5p inhibit proinflammatory cytokine production in osteoarthritis 2021 Jul 1 Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common types of arthritis. Both are characterized by the infiltration of a number of proinflammatory cytokines into the joint microenvironment. miRNAs play critical roles in the disease processes of arthritic disorders. However, little is known about the effects of miRNAs on critical inflammatory cytokine production with OA and RA progression. Here, we found higher levels of proinflammatory cytokines including interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in human OA and RA synovial fibroblasts (SFs) compared with normal SFs. Searches of open-source microRNA (miRNA) software determined that miR-let-7c-5p and miR-149-5p interfere with IL-1β, IL-6 and TNF-α transcription; levels of all three proinflammatory cytokines were lower in human OA and RA patients compared with normal controls. Anti-inflammatory agents dexamethasone, celecoxib and indomethacin reduced proinflammatory cytokine production by promoting the expression of miR-let-7c-5p and miR-149-5p. Similarly, ibuprofen and methotrexate also enhanced miR-let-7c-5p and miR-149-5p expression in human SFs. The evidence suggests that increasing miR-let-7c-5p and miR-149-5p expression is a novel strategy for OA and RA.
33237533 Rapid Onset of Efficacy of Baricitinib in Chinese Patients with Moderate to Severe Rheumat 2021 Jan INTRODUCTION: Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with rheumatoid arthritis (RA). This report aims to analyze the onset time of baricitinib in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate. METHODS: This post hoc analysis evaluated clinical improvements of Chinese patients treated with baricitinib 4 mg once daily compared with placebo, based on data from a phase 3 study RA-BALANCE. Efficacy measures including American College of Rheumatology 20% (ACR20) response, ACR core set values, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28) using high-sensitivity C-reactive protein (hsCRP), DAS28-erythrocyte sedimentation rate, Simplified Disease Activity Index, Clinical Disease Activity Index, DAS28-hsCRP ≤ 3.2 response (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 (except for FACIT-F evaluated every 4 weeks). A logistic regression model and an analysis of covariance model were used to analyze treatment comparisons of categorical and continuous measures, respectively. RESULTS: Statistically significant (p ≤ 0.05) improvements were observed as early as week 1 or 2 for the baricitinib group compared to placebo in almost all main efficacy measures. For other outcomes including 66 swollen joint count, 68 tender joint count, FACIT-F, and DAS28-hsCRP ≤ 3.2 response rate, differences were evident (p ≤ 0.05) by week 4 in the baricitinib group compared with placebo. Significant improvements in all efficacy measures were sustained through 24 weeks. CONCLUSIONS: Baricitinib demonstrated a rapid onset of efficacy on ACR20 response, ACR core set values, disease activity, and patient-reported outcome improvements in Chinese patients from RA-BALANCE. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02265705.