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ID PMID Title PublicationDate abstract
32539813 Drug retention of 7 biologics and tofacitinib in biologics-naïve and biologics-switched p 2020 Jun 15 BACKGROUND: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of 7 biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib (TOF), one of the janus kinase inhibitors, in bDMARDs-naïve and bDMARDs-switched patients with rheumatoid arthritis (RA). METHODS: This study assessed 3897 patients and 4415 treatment courses with bDMARDs and TOF from 2001 to 2019 (2737 bDMARDs-naïve courses and 1678 bDMARDs-switched courses [59.5% of switched courses were their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate 4.3; concomitant prednisolone [PSL] dose 6.1 mg/day [usage 42.4%], and methotrexate [MTX] dose 8.5 mg/week [usage 60.9%]). Treatment courses included abatacept (ABT; n = 663), adalimumab (ADA; n = 536), certolizumab pegol (CZP; n = 226), etanercept (ETN; n = 856), golimumab (GLM; n = 458), infliximab (IFX; n = 724), tocilizumab (TCZ; n = 851), and TOF (n = 101/only bDMARDs-switched cases). Drug discontinuation reasons (categorized into lack of effectiveness, toxic adverse events, non-toxic reasons, or remission) and rates were estimated at 36 months using Gray's test and statistically evaluated after adjusted by potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX usage, starting date, and number of switched bDMARDs) using the Fine-Gray model. RESULTS: Cumulative incidence of drug discontinuation for each reason was as follows: lack of effectiveness in the bDMARDs-naïve group (from 13.7% [ABT] to 26.9% [CZP]; P < 0.001 between agents) and the bDMARDs-switched group (from 18.9% [TCZ] to 46.1% [CZP]; P < 0.001 between agents); toxic adverse events in the bDMARDs-naïve group (from 4.6% [ABT] to 11.2% [ETN]; P < 0.001 between agents) and the bDMARDs-switched group (from 5.0% [ETN] to 15.7% [TOF]; P = 0.004 between agents); and remission in the bDMARDs-naïve group (from 2.9% [ETN] to 10.0% [IFX]; P < 0.001 between agents) and the bDMARDs-switched group (from 1.1% [CZP] to 3.3% [GLM]; P = 0.9 between agents). CONCLUSIONS: Remarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.
32275944 Regulatory T cells in patients with early untreated rheumatoid arthritis: Phenotypic chang 2020 Jul Rheumatoid arthritis (RA) is frequent systemic autoimmune disease characterized by excessive activation of collagen-specific T helper cells, and elevated level of autoantibodies in the serum. Development of RA is associated with defect in compartment of regulatory CD4+Foxp3+ T cells (Treg), but data concerning suppressive potential of Treg population in RA patients are contradictory and depend on the stage of disease. In this study we aimed to characterize abundance and phenotypic markers of CD4+Foxp3+ Treg in peripheral blood of healthy donors compared to untreated early RA patients to find potential correlations with the disease activity, antibody level, and absolute numbers and proportion of different subpopulations of T cells. Moreover, we assessed the influence of methotrexate (MT) treatment on percentage and absolute numbers of CD4+Foxp3+ Treg from the peripheral blood of untreated early RA patients. We demonstrate that increase and phenotypic changes in Treg population correlate well with response to MT. Analysis of the cohorts of matched RA patients (n = 45) and healthy controls (n = 20) revealed that patients with untreated early RA demonstrate substantial decrease in blood Treg percentage and absolute number, as well as low level of activated Treg surface markers in comparison to healthy control. The defect in Treg compartment negatively correlates with both RA activity and antibody level. MT treatment of patients with early untreated RA increases both proportion and absolute number of Treg with high level of activation markers, suggesting an increase of their functional capacity. Here we speculate the role of Tregs as specific cellular marker of successful RA treatment.
31390271 Discontinuation of concomitant methotrexate in Japanese patients with rheumatoid arthritis 2020 May Objectives: To evaluate the efficacy and safety of methotrexate (MTX) discontinuation in Japanese rheumatoid arthritis (RA) patients with sustained low disease activity undergoing combination therapy with tocilizumab (TCZ) plus MTX.Methods: This multicenter, open-label, uncontrolled, prospective study included RA patients maintaining low disease activity (Clinical Disease Activity Index (CDAI) ≤10) for ≥12 weeks with TCZ plus MTX. Methotrexate was discontinued following 12 weeks of biweekly administration while continuing TCZ therapy. The primary endpoint was the proportion of patients maintaining low disease activity with no flare at week 36.Results: A total of 49 patients completed 36 weeks of therapy. The proportion of patients maintaining low disease activity at week 36 was 75.5%. The lower limit of the 95% confidence interval exceeded the assumed threshold response rate of 60%, demonstrating the clinical feasibility of MTX discontinuation. The prevalence of gastroesophageal reflux disease, defined as a Frequency Scale for Symptoms of Gastroesophageal reflux disease score ≥8, significantly decreased from week 0 to 12 (27.1-18.4%; p= .025).Conclusion: Discontinuation of concomitant MTX is clinically feasible for maintaining low disease activity, and may be beneficial from the perspective of reducing gastrointestinal symptoms in Japanese RA patients treated with TCZ. Trial registration number: UMIN000021247.
32209540 Immunosuppression and the risk of readmission and mortality in patients with rheumatoid ar 2020 May OBJECTIVES: The impact of immunosuppression on postoperative outcomes has primarily been studied in patients undergoing joint replacement surgery. We aimed to evaluate the impact of biologics and glucocorticoids on outcomes after other major surgeries. METHODS: This retrospective cohort study used Medicare data 2006-2015 to identified adults with rheumatoid arthritis undergoing hip fracture repair, abdominopelvic surgery (cholecystectomy, hysterectomy, hernia, appendectomy, colectomy) or cardiac surgery (coronary artery bypass graft, mitral/aortic valve). Logistic regression with propensity-score-based inverse probability weighting compared 90-day mortality and 30-day readmission in patients receiving methotrexate (without a biologic or targeted synthetic disease-modifying antirheumatic drug (tsDMARD)), a tumour necrosis factor inhibitor (TNFi) or a non-TNFi biologic/tsDMARD <8 weeks before surgery. Similar analyses evaluated associations between glucocorticoids and outcomes. RESULTS: We identified 10 777 eligible surgeries: 3585 hip fracture, 5025 abdominopelvic and 2167 cardiac surgeries. Compared with patients receiving methotrexate, there was no increase in the risk of 90-day mortality or 30-day readmission among patients receiving a TNFi (mortality adjusted OR (aOR) 0.83 (0.67 to 1.02), readmission aOR 0.86 (0.75 to 0.993)) or non-TNFi biologic/tsDMARD (mortality aOR 0.78 (0.49 to 1.22), readmission aOR 1.02 (0.78 to 1.33)). Analyses stratified by surgery category were similar. Risk of mortality and readmission was higher with 5-10 mg/day of glucocorticoids (mortality aOR 1.41 (1.08 to 1.82), readmission aOR 1.26 (1.05 to 1.52)) or >10 mg/day (mortality aOR 1.64 (1.02 to 2.64), readmission aOR 1.60 (1.15 to 2.24)) versus no glucocorticoids, although results varied when stratifying by surgery category. CONCLUSIONS: Recent biologic or tsDMARD use was not associated with a greater risk of mortality or readmission after hip fracture, abdominopelvic or cardiac surgery compared with methotrexate. Higher dose glucocorticoids were associated with greater risk.
32471854 Earlier is better when treating rheumatoid arthritis: but can we detect a window of opport 2020 May OBJECTIVES: The window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic ('curved') decline in the chance to achieve the outcome sustained drug-free remission (sDFR) over time, after which achieving sDFR is not possible anymore, or by a more gradual linear decline approaching zero chance to achieve sDFR. METHODS: Patients with RA (symptom duration <2 years) were included from two randomised trials: BehandelStrategieën (BeSt), n=508 and Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED), n=479. Cox-regression was performed to assess the shape of the association between symptom duration and sDFR (Disease Activity Score<1.6, no disease-modifying anti-rheumatic drugs for ≥1 year) for patients starting slow-acting monotherapy (IMPROVED, BeSt) or fast-acting combination therapy (BeSt). Likelihood ratio tests were used to compare the fit of linear and non-linear models in both databases separately. Predictions from the best fitting models were used to assess whether the absolute risk to achieve sDFR approaches zero with increasing symptom duration. RESULTS: In BeSt and IMPROVED, 54/226 and 110/421 patients achieved sDFR with fast-acting treatment, and 53/243 (BeSt) with slow-acting treatment. Non-linear models did not fit better than linear models (fast-acting treatment BeSt p=0.743, IMPROVED p=0.337; slow-acting treatment BeSt p=0.609). After slow-acting monotherapy, linear models declined steeper. None of the models approached zero chance to achieve sDFR over time. CONCLUSIONS: The chance to achieve sDFR decreased gradually over time, and decreased fastest in patients starting slow-acting monotherapy. In both treatment groups, we found no evidence for a WOO within 2 years symptom duration.
33191277 Relationship Between Depression and Disease Activity in United States Veterans With Early 2021 Jun OBJECTIVE: Depression is common in patients with rheumatoid arthritis (RA), exacerbates disease activity, and may decrease response to first-line disease-modifying antirheumatic drugs. This study aimed to determine if depression affects disease activity among veterans with early RA prescribed methotrexate (MTX). METHODS: Participants included veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry with early RA (onset < 2 yrs) prescribed MTX. Depression was assessed at enrollment using the International Classification of Diseases, 9th revision codes (296.2-296.39, 300.4, 311). Disease activity was measured using the Disease Activity Score in 28 joints (DAS28) and other core measures of RA disease activity. Propensity score weights were used to adjust depressed (n = 48) and nondepressed (n = 220) patients on baseline confounders within imputed datasets. Weighted estimating equations were used to assess standardized mean differences in disease activity between depressed and nondepressed patients at 6-month, 1-year, and 2-year follow-ups. RESULTS: The analytic sample was composed of 268 veterans with early RA prescribed MTX who were predominantly male (n = 239, 89.2%) and older (62.7 yrs, SD 10.6) than patients with RA in the general population. Adjusted estimates indicated that depression was associated with significantly higher DAS28 at 6 months (β 0.35, 95% CI 0.01-0.68) but not at the 1- or 2-year follow-up. Also, depression was associated with significantly worse pain at 6 months (β 0.39, 95% CI 0.04-0.73) and 1 year (β 0.40, 95% CI 0.04-0.75). CONCLUSION: In early RA, depression is associated with greater short-term disease activity during MTX treatment, as well as more persistent and severe pain.
33087159 ASP5094, a humanized monoclonal antibody against integrin alpha-9, did not show efficacy i 2020 Oct 21 BACKGROUND: Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune condition characterized by joint synovial inflammation. Current treatments include methotrexate (MTX), biologic agents, and Janus kinase (JAK) inhibitors. However, these agents are not efficacious in all patients and there are concerns regarding side effects and risk of infection as these treatments target immune-related pathways. Overexpression and activation of integrin alpha-9 (α9) on fibroblast-like synoviocytes are associated with RA disease onset and exacerbation. The humanized immunoglobulin G1 monoclonal antibody ASP5094 was designed to inhibit human α9 and is currently under investigation for the treatment of RA. METHODS: This phase 2a, multicenter, randomized, placebo-controlled, double-blind, parallel-group study (NCT03257852) evaluated the efficacy, safety, and biological activity of intravenous ASP5094 10 mg/kg in patients with moderate to severe RA that was refractory to MTX. Patients received ASP5094 or placebo every 4 weeks for a total of three administrations. Both treatment groups used concomitant MTX. The primary efficacy endpoint was the proportion of patients who responded per American College of Rheumatology 50% improvement using C-reactive protein (ACR50-CRP) after 12 weeks of treatment. Biological activity of ASP5094 was assessed via pharmacokinetics and pharmacodynamics of known downstream effectors of α9. Safety was also assessed. RESULTS: Sixty-six patients were enrolled and randomized to placebo (n = 33) or ASP5094 (n = 33). In the primary efficacy analysis, ACR50-CRP response rates were 6.3% and 18.2% at week 12 in the ASP5094 and placebo groups, respectively; a difference of - 11.9, which was not significant (2-sided P value = 0.258). No trends in ACR50 response rates were observed in subgroups based on demographics or baseline disease characteristics, and no significant differences between placebo and ASP5094 were identified in secondary efficacy or pharmacodynamic endpoints, despite achievement of target serum concentrations of ASP5094. Most treatment-emergent adverse events were mild to moderate in severity, and ASP5094 was considered safe and well tolerated overall. CONCLUSION: Although no notable safety signals were observed in this study, ASP5094 was not efficacious in patients with moderate to severe RA with an inadequate response to MTX. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03257852 . Registered on 22 Aug. 2017.
32105179 Treatment Patterns and Costs in Biologic DMARD-Naive Patients with Rheumatoid Arthritis In 2020 Mar BACKGROUND: Etanercept (ETN) and adalimumab (ADA) are tumor necrosis factor inhibitors indicated for treatment of moderate to severe rheumatoid arthritis (RA) and are used as monotherapy or in combination with conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX). Data on treatment patterns and costs of ETN and ADA as monotherapies or in combination therapy with MTX are lacking in biologic DMARD (bDMARD)-naive patients with RA. OBJECTIVE: To evaluate treatment patterns and costs of ETN and ADA monotherapy and combination therapy in bDMARD-naive patients with RA. METHODS: Data from adult bDMARD-naive patients with RA were evaluated according to index therapy (ADA or ETN as monotherapy or combination therapy with MTX) in a retrospective cohort study using the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental Databases from January 1, 2010, to June 30, 2017. Participants were bDMARD-naive for ≥ 12 months before initial ETN or ADA pharmacy claim (index date) and had continuous enrollment for ≥ 12 months pre-index and 24 months post-index. Combination therapy cohorts had an MTX claim within 30 days of the index date. Outcomes included persistence (no treatment changes or gap [≥ 60 days]); modifications to index therapy (discontinuation or switching without prior gap, restarting as switch or restart after gap, or MTX initiation/discontinuation); and mean total bDMARD costs for 2 years post-index. RESULTS: Patients on ETN monotherapy (n = 2,064) had higher persistence (26.8% vs. 21.1%, respectively; P < 0.001) on index treatment and received treatment for a longer duration (mean 375.9 days vs. 339.7 days, respectively; P < 0.001) than those on ADA monotherapy (n = 1,528). Regimen changes were more common in patients on ADA monotherapy than patients on ETN monotherapy (38.0% vs. 33.4%, respectively; P = 0.004). More patients on ADA monotherapy added MTX than those on ETN (17.5% vs. 12.6%, respectively; P < 0.001). Overall, 790 patients receiving index monotherapy had a regimen change following a gap (≥ 60 days), with a similar proportion between cohorts. Among these patients, 13.8% restarted index therapy, and 7.9% switched from index therapy. Significantly more patients receiving ETN monotherapy restarted their index regimen after a gap than those receiving ADA monotherapy (14.9% vs. 12.2%, respectively; P = 0.023). The proportion of patients persistent on combination therapy was similar between the ETN and ADA combination therapy cohorts (21.9% vs. 22.2%, respectively; P = 0.818). Treatment pattern rates were similar regardless of index combination therapy. Overall, costs for ADA were consistently higher within the index regimen throughout the follow-up period irrespective of MTX. CONCLUSIONS: ETN monotherapy as first-line treatment was associated with higher persistence, lower rate of MTX supplementation, and lower bDMARD costs than ADA monotherapy. ETN monotherapy may represent a less costly option for achieving treatment targets in bDMARD-naive patients with RA. DISCLOSURES: This study was sponsored by Amgen. Tkacz, Henderson DeYoung, and Wilson are employees of IBM Watson Health, which received funding from Amgen for this study. Collier and Oko-osi are employees and shareholders of Amgen. Gharaibeh was an employee of Amgen at the time of study execution and manuscript drafting. Data pertaining to this study were presented in a poster at AMCP Nexus 2018; October 25-28, 2018; Orlando, FL.
32033937 Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature res 2020 Jun OBJECTIVES: To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA). METHODS: A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019. RESULTS: 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products. CONCLUSION: This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation.
32448834 Progressive Multifocal Leukoencephalopathy during Tocilizumab Treatment for Rheumatoid Art 2020 Aug 15 A 61-year-old woman was diagnosed with rheumatoid arthritis 12 years ago and received multiple treatment regimens before achieving symptomatic stability with methotrexate plus tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, about 2 years prior to the current presentation. Sixteen months after tocilizumab initiation, she exhibited dysarthria and disorientation; five months later, she was hospitalized with movement difficulties. Her neurological symptoms deteriorated thereafter, accompanied by enlarged cerebral white matter lesions on magnetic resonance imaging. A biopsy of the right frontal lesion confirmed progressive multifocal leukoencephalopathy (PML). While several therapeutic monoclonal antibodies have been linked to PML, this is the first case associated with tocilizumab.
32506853 "Wang-Bi tablet, a patented Chinese medicine, maintains the balance of Th1/Th2 in mice wit 2020 Jun OBJECTIVE: To investigate the pharmacological mechanism of Wang-Bi tablets (WBTs), a Chinese patented medicine, in rheumatoid arthritis (RA) using mice with collagen-induced arthritis (CIA). METHODS: A mouse model of CIA was induced using bovine type Ⅱ collagen. WBT treatment was administered and efficacy was evaluated. The levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), and interleukin-4 (IL-4) were examined using an enzyme-linked immunosorbent assay, and the proportions of Th1 and Th2 were detected using flow cytometry. T-bet and GATA-binding protein 3 (GATA3) expression were demonstrated using Western blot analysis. RESULTS: Paw swelling and the arthritis index decreased significantly following WBT treatment. Histopathological analysis revealed markedly alleviated damage to synovium tissue in the WBT and methotrexate treatment groups. WBT regulated the production of IFN-γ, IL-2, and IL-4 and modulated Th1 and Th2 cell populations, which might have been induced by the attenuation of Th1 and Th2 cell differentiation through a decrease in the expression of T-bet and an increase in the expression of GATA3 in the synovial tissue in CIA mice. CONCLUSION: These results indicate that WBT may produce a therapeutic effect on CIA through maintaining the balance of Th1/Th2 cells, which could result in a decrease in the autoinflammatory disorder observed in RA.
31781849 Comparison of the efficacy and safety of tofacitinib and filgotinib in patients with activ 2020 Aug OBJECTIVE: We compared the efficacy and safety of tofacitinib and filgotinib in patients with rheumatoid arthritis (RA) showing inadequate response to conventional synthetic (cs) or biologic (b) disease-modifying anti-rheumatic drugs (DMARDs). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and filgotinib in combination with methotrexate (MTX) in patients with RA exhibiting inadequate cs- or bDMARD response. RESULTS: Nine RCTs consisting of 5466 patients met the inclusion criteria. We obtained 15 pairwise comparisons, including 11 direct comparisons from 6 interventions. Tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX were among the most effective treatments for active RA showing an inadequate cs- or bDMARD response, followed by tofacitinib 5 mg + MTX, filgotinib 100 mg + MTX, and adalimumab + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX showed the highest probability of being the best treatment options in terms of ACR20 response rate (SUCRA = 0.898, 0.782), followed by tofacitinib 5 mg + MTX (SUCRA = 0.602), filgotinib 100 mg + MTX (SUCRA = 0.359), adalimumab + MTX (SUCRA = 0.358), and placebo + MTX (SUCRA = 0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib + MTX, filgotinib + MTX, adalimumab + MTX, or placebo + MTX. CONCLUSION: In patients with RA exhibiting an inadequate response to cs- or bDMARDs, tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX were the most efficacious interventions and risks of serious adverse events did not differ between tofacitinib and filgotinib groups.
32907617 Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients wit 2020 Sep 9 BACKGROUND: Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. METHODS: Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. RESULTS: Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was - 0.28 (- 0.40, - 0.16; nominal p <  0.0001) and - 0.42 (- 0.54, - 0.31; nominal p <  0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was - 0.13 (- 0.22, - 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. CONCLUSIONS: In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. TRIAL REGISTRATION: ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.
32452344 Baricitinib in patients with rheumatoid arthritis with inadequate response to methotrexate 2020 Jul OBJECTIVES: This study evaluated the efficacy and safety of baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) therapy. METHODS: In this phase 3, double-blind, 52-week, placebo-controlled study, 290 patients with moderately to severely active RA and inadequate response to MTX were randomly assigned 1:1 to placebo or baricitinib 4-mg once daily, stratified by country (China, Brazil, Argentina) and presence of joint erosions. Primary endpoint measures included American College of Rheumatology 20% response (ACR20) at week 12. Secondary endpoints included changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Disease Activity Score for 28-joint counts (DAS28)-high-sensitivity C-reactive protein (hsCRP), Simplified Disease Activity Index (SDAI) score ≤3.3, mean duration of morning joint stiffness, severity of morning joint stiffness numeric rating scale (NRS 0-10), worst tiredness NRS, and worst joint pain NRS at week 12. RESULTS: Most patients (approximately 80%) were from China. More patients achieved ACR20 response at week 12 with baricitinib than with placebo (58.6% vs. 28.3%; p<0.001). Statistically significant improvements were also seen in HAQ-DI, DAS28-hsCRP, morning joint stiffness, worst tiredness, and worst joint pain in the baricitinib group compared to placebo at week 12. Through week 24, rates of treatment-emergent adverse events, including infections, were higher for baricitinib compared to placebo, while serious adverse event rates were similar between baricitinib and placebo. CONCLUSIONS: In patients with RA who had an inadequate response to MTX, baricitinib was associated with significant clinical improvements as compared with placebo.
32415503 Molecular mechanism of action and pharmacokinetic properties of methotrexate. 2020 Jun Since its discovery in 1945, methotrexate has become a standard therapy for number of diseases, including oncological, inflammatory and pulmonary ones. Major physiological interactions of methotrexate include folate pathway, adenosine, prostaglandins, leukotrienes and cytokines. Methotrexate is used in treatment of pulmonary sarcoidosis as a second line therapy and is drug of choice in patients who are not candidates for corticosteroid therapy, with recommended starting weekly dose of 5-15 mg. Number of studies dealt with methotrexate use in rheumatoid arthritis and oncological patients. Authors are conducting research on oral methotrexate use and pharmacokinetics in chronic sarcoidosis patients and have performed literature research to better understand molecular mechanisms of methotrexate action as well as high level pharmacokinetic considerations. Polyglutamation of methotrexate affects its pharmacokinetic and pharmacodynamic properties and prolongs its effect. Bile excretion plays significant role due to extensive enterohepatic recirculation, although majority of methotrexate is excreted through urine. Better understanding of its pharmacokinetic properties in sarcoidosis patients warrant optimizing therapy when corticosteroids are contraindicated in these patients.
32019572 Thrombotic microangiopathy and liver toxicity due to a combination therapy of leflunomide 2020 Feb 5 BACKGROUND: Treatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy. CASE PRESENTATION: A 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 μg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found. For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered. CONCLUSIONS: Under a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity.
32417912 Circulating CD19+CD24hiCD38hi regulatory B cells as biomarkers of response to methotrexate 2020 Oct 1 OBJECTIVE: The protagonism of regulatory B cells seems to vary along the course of the disease in murine models of inflammatory conditions. Decreased numbers of circulating regulatory CD19+CD24hiCD38hi transitional (cTr) B cells have been described in patients with long-standing RA, thus our objective was to examine the frequency and evolution of cTr B cells in the peripheral blood of early RA (ERA) patients. METHODS: Freshly isolated peripheral blood mononuclear cells from 48 steroid- and DMARD-naïve ERA patients with a disease duration of <24 weeks and 48 healthy controls (HCs) were examined by flow cytometry. Co-cultures of isolated memory B cells were established with autologous T cells in the absence or presence of Tr B cells. RESULTS: As compared with HCs, ERA patients demonstrated an increased frequency of cTr B cells. cTr B cells of ERA patients and HCs displayed an anti-inflammatory cytokine profile and were able to downregulate T cell IFN-γ and IL-21 production, together with ACPA secretion in autologous B/T cell co-cultures. Basal frequencies of cTr B cells above the median value observed in HCs were associated with a good EULAR response to MTX at 12 months [relative risk 2.91 (95% CI 1.37, 6.47)]. A significant reduction of cTr B cells was observed 12 months after initiating MTX, when the cTr B cell frequency was no longer elevated but decreased, and this was independent of the degree of clinical response or the intake of prednisone. CONCLUSION: An increased frequency of regulatory cTr B cells is apparent in untreated ERA and the baseline cTr B cell frequency is associated with the clinical response to MTX at 12 months.
31814481 Successful cessation of tumor necrosis factor inhibitor treatment in rheumatoid arthritis 2020 Nov Objectives: To investigate the prevalence and the consequence of tumor necrosis factor inhibitor (TNFi) cessation after clinical improvement in rheumatoid arthritis (RA) patients in clinical practice and predictors of flare after TNFi cessation.Methods: We retrospectively assessed the prevalence of TNFi cessation after achieving sustained improvement, disease flare and joint damage progression after TNFi cessation in consecutive RA patients who started TNFi due to insufficient response to methotrexate were studied. Predictors for flare after TNFi cessation were investigated using Cox regression analysis.Results: In 135 patients who started TNFi with methotrexate, 95 stopped TNFi after sustained improvement and continued methotrexate thereafter. Over 1 year, 33 patients had a flare and 26 restarted TNFi therapy. In 78 patients whose radiographs adequate for evaluation were available, 73 did not exhibit joint damage progression. Female gender, smoking, the interval from starting methotrexate to starting TNFi of more than 9 months and glucocorticoid use at starting TNFi were independently associated with shorter time to flare.Conclusion: Sixty-five percent of patients were successfully discontinued TNFi over 1 year. Radiographic joint damage progression was rare. Early intervention with TNF inhibitor may contribute to successful TNF inhibitor cessation in patients with insufficient response to methotrexate.Key messageSuccessful TNF inhibitor cessation is achievable in two-third of RA patients after achieving sustained remission.Female gender and smoking may predispose to flare after TNF inhibitor cessation.Early intervention with TNF inhibitor may contribute to successful TNF inhibitor cessation.
32048083 Re-establishment of efficacy of tofacitinib, an oral JAK inhibitor, after temporary discon 2020 Jul INTRODUCTION/OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post-hoc analysis evaluated the effect of temporary discontinuation and reinitiation of tofacitinib on disease control in patients with RA in the vaccine sub-study of the long-term extension (LTE) study ORAL Sequel (NCT00413699). METHODS: The sub-study of ORAL Sequel was a randomized, parallel-group, open-label study. Patients who received tofacitinib 10 mg twice daily for ≥ 3 months in ORAL Sequel were randomized to receive continuous (tofacitinib monotherapy/with methotrexate) or interrupted (tofacitinib withdrawn for 2 weeks post-randomization then reinitiated as monotherapy/with methotrexate) treatment. Efficacy assessments included ACR20/50/70 response rates, change from baseline (∆) in C-reactive protein (CRP), Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4 [ESR]), Clinical Disease Activity Index (CDAI), Patient Global Assessment of arthritis (PtGA), Pain (Visual Analog Scale [VAS]), and Physician Global Assessment of arthritis (PGA). Safety was assessed throughout. RESULTS: The sub-study included 99 patients each in the continuous and interrupted treatment groups. ACR20/50 response rates, ∆CRP, ∆HAQ-DI (day 15), ∆DAS28-4 (ESR), ∆CDAI, ∆PtGA, ∆Pain (VAS), and ∆PGA were significantly worse in interrupted vs continuous patients during dose interruption, but were generally similar to pre-interruption/continuous treatment levels 28 days post-reinitiation. A numerically higher proportion of interrupted patients reported adverse events (49.5%) vs continuous patients (35.4%). CONCLUSIONS: Tofacitinib efficacy can be re-established after temporary withdrawal and reinitiation. The safety profile of patients who temporarily discontinued tofacitinib in the sub-study was consistent with previous tofacitinib LTE studies over 9 years. CLINICAL TRIAL REGISTRATION NUMBER: NCT00413699 Key Points • In this sub-study of the long-term extension (LTE) study, ORAL Sequel, the efficacy of tofacitinib was re-established after temporary withdrawal (2 weeks) and reinitation of treatment in patients with RA. • Patients with RA who temporarily discontinued tofacitinib had similar safety events to those reported in previous LTE studies. • The results of this sub-study were consistent with a post-hoc analysis of pooled data from two LTE studies, ORAL Sequel and A3921041, which assessed the efficacy of tofacitinib following a treatment discontinuation period of 14-30 days.
32055928 Relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, and filgotinib in 2020 Oct OBJECTIVE: The relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to adalimumab were assessed in rheumatoid arthritis (RA) patients with inadequate responses 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 efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and adalimumab in RA patients with inadequate responses to MTX. RESULTS: Four RCTs comprising 5451 patients met the inclusion criteria. Baricitinib 4 mg + MTX and upadacitinib 15 mg + MTX showed a significantly higher American College of Rheumatology 20% (ACR20) response rate than adalimumab 40 mg + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4 mg + MTX had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by upadacitinib 15 mg + MTX, tofacitinib 5 mg + MTX, filgotinib 200 mg + MTX, filgotinib 100 mg + MTX, adalimumab 40 mg + MTX, and placebo + MTX. Upadacitinib 15 mg + MTX and baricitinib 4 mg + MTX showed significantly higher ACR50 and ACR70 response rates than adalimumab 40 mg + MTX. For herpes zoster infection, the ranking probability based on SUCRA indicated that placebo + MTX was likely to be the safest treatment, followed by filgotinib 200 mg + MTX, filgotinib 100 mg + MTX, adalimumab 40 mg + MTX, tofacitinib 5 mg + MTX, upadacitinib 15 mg + MTX, and baricitinib 4 mg + MTX. No statistically significant differences were found between the intervention groups in terms of safety. CONCLUSION: In RA patients with an inadequate response to MTX, baricitinib 4 mg + MTX and upadacitinib 15 mg + MTX showed the highest ACR response rates, suggesting a difference in efficacy among the different JAK inhibitors.