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ID PMID Title PublicationDate abstract
33337815 Efficacy, Safety, and Immunogenicity of Biosimilar Etanercept (Enerceptan) Versus Its Orig 2021 Sep 1 BACKGROUND: Enerceptan (EtaBS) has been developed as a proposed biosimilar of etanercept. METHODS: This randomized, multicenter, evaluator-blinded, noninferiority study conducted in Argentina included adults with active, moderate, and severe rheumatoid arthritis with inadequate response to methotrexate. Subjects were randomly assigned to 32 weeks treatment with EtaBS (n = 99) or etanercept (n = 51) at a weekly 50-mg dose administered subcutaneously. Patients were categorized according to prior use of biologic disease-modifying antirheumatic drugs and concomitant use of steroids. The primary efficacy endpoint was ACR20 response rate at week 32. Safety, immunogenicity, and steady-state concentration of both drugs were evaluated. The noninferiority margin for ACR20 was estimated at 12%. RESULTS: In the per-protocol population, 85 subjects (92.4%) treated with EtaBS and 44 subjects (93.6%) treated with etanercept achieved ACR20 (difference, -1.2%; 95% confidence interval, -10.1% to 7.6%). Frequent adverse drug reactions occurred in 34.3% and 38% of subjects treated with EtaBS and etanercept, respectively. The most common reaction was upper respiratory tract infection. Six and 3 serious adverse events occurred in 4 and 3 subjects treated with EtaBS and etanercept, respectively. Injection site reactions occurred in 67.7% and 66.0% of subjects treated with EtaBS and etanercept, respectively. Two subjects treated with EtaBS and 1 subject treated with etanercept developed antibodies by week 32. CONCLUSIONS: Efficacy outcomes for EtaBS were noninferior to original etanercept in patients with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate. Safety and immunogenicity results were comparable between the two. This study is a major step toward improving access to biologics in Latin America.
34304373 Filgotinib in Rheumatoid Arthritis: A Profile of Its Use. 2021 Aug Filgotinib (Jyseleca(®)), an oral Janus kinase (JAK) inhibitor, is approved as monotherapy or in combination with methotrexate to treat moderate to severe active rheumatoid arthritis (RA) in adults who have an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). In phase 3 trials, once-daily filgotinib was generally well tolerated and associated with an improvement in RA signs and symptoms as well as physical function in patients with an inadequate response to ongoing methotrexate, an inadequate response to ongoing conventional synthetic DMARDs plus an inadequate response or intolerance to prior biologic DMARDs, or limited or no prior exposure to methotrexate. In addition, filgotinib was noninferior to adalimumab in terms of low disease activity response rate (DAS28-CRP ≤ 3.2) in patients with an inadequate response to methotrexate. Filgotinib also appeared to inhibit the radiographic progression of joint damage and led to low disease activity or disease remission (DAS28-CRP < 2.6). Filgotinib showed sustained efficacy, and the safety profile of filgotinib longer term was similar to that in the phase 2 and 3 trials.
33040843 Suppressive effect of vitamin K2 against mitogen-activated peripheral blood mononuclear ce 2021 Jan OBJECTIVE: To investigate the immunosuppressive effect of vitamin K2 against mitogen-activated peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients. MATERIALS AND METHODS: Concanavalin A-stimulated PBMC culture procedure was used to evaluate the pharmacodynamics of vitamin K2 in vitro. Methotrexate was set up as the positive control. The proliferation of PBMCs was detected by MTT assay. Relationship between IC(50) values of drugs on PBMC proliferation and patient-related factors including laboratory data was analyzed by nonparametric Spearman correlation test. RESULTS: Vitamin K2 inhibited the proliferation of mitogen-activated PBMCs of RA patients with an IC(50) value of 3,288.47 ± 4,910.02 ng/mL (mean ± SD). There was a significant correlation between IC(50) values of vitamin K2 and patient-related factors of RA patients (p < 0.05), such as C-reactive protein (CRP), rheumatoid factor, anti-cyclic citrullinated peptide antibody (ACPA), matrix metalloproteinase-3, Pre-DAS-28 (CRP), and ∆DAS-28 (CRP). It would be possible to predict the pharmacodynamics of vitamin K2 in RA patients according to the above factors. Methotrexate inhibited the proliferation of mitogen-activated PBMCs of RA patients with a IC(50) value of 22.83 ± 12.47 ng/mL (mean ± SD). IC(50) values of methotrexate only showed significant correlation with ACPA (p = 0.0158, r = 0.6905), which suggests that ACPA might be a suitable predictor of the pharmacodynamics of methotrexate. CONCLUSION: The above information suggests that vitamin K2 could provide a benefit for the treatment of RA patients via its immunosuppressive function.
33626293 Guizhi-Shaoyao-Zhimu decoction attenuates bone erosion in rats that have collagen-induced 2021 Dec CONTEXT: Guizhi-Shaoyao-Zhimu decoction (GSZD) is commonly used to treat rheumatoid arthritis (RA), but its mechanism is unclear. OBJECTIVE: To investigate the effect of GSZD on bone erosion in type II collagen (CII)-induced arthritis (CIA) in rats and to identify the underlying mechanism. MATERIALS AND METHODS: The CIA model was prepared in male Wistar rats by two subcutaneous injections of CII, 1 mg/mL. Fifty CIA rats were randomized equally into the control group given saline daily, the positive group given saline daily and methotrexate 0.75 mg/kg once a week, and three GSZD-treated groups gavaged daily with 800, 1600 and 3200 mg/kg of GSZD for 21 days. GSZD effects were assessed by paw volume, arthritic severity index and histopathology. Cytokine levels were determined by ELISA. The effects of GSZD on RAW264.7 cells were evaluated by receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption assay. Expression of IκB-α and p65 was measured by Western blotting. Major components of GSZD were identified by HPLC. RESULTS: Arthritis index score, paw volume and bone destruction score showed that GSZD improved inflammatory symptoms and reduced joint tissue erosion (p < 0.01). GSZD decreased RANKL, and the number of osteoclasts (OCs) in joint tissues (p < 0.01) and increased osteoprotegerin levels (p < 0.01). GSZD inhibited RANKL-induced RAW264.7 differentiation and reduced bone resorption by OCs. GSZD upregulated IκB (p < 0.01) and p65 (p < 0.01) in the cytoplasm and downregulated p65 (p < 0.01) in the cell nucleus. CONCLUSIONS: Guizhi-Shaoyao-Zhimu decoction has an anti-RA effect, suggesting its possible use as a supplement and alternative drug therapy for RA.
33205906 Etanercept or Methotrexate Withdrawal in Rheumatoid Arthritis Patients in Sustained Remiss 2021 May OBJECTIVE: Patients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination. METHODS: Of the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24-week open-label period. These 253 patients then entered a 48-week, double-blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease-worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run-in period. The primary end point was the proportion of patients in whom SDAI-defined remission was maintained without disease-worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease-worsening, and the proportion of patients in whom SDAI-defined remission was recaptured after initiation of rescue therapy. RESULTS: Baseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI-defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI-defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease-worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI-defined remission was recaptured in 70-80% in each treatment group. No new safety signals were reported. CONCLUSION: The efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI-defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision-making when withdrawal of therapy is being considered to reduce treatment burden in patients with well-controlled RA.
33572002 Total Flavonoids of Bidens pilosa Ameliorates Bone Destruction in Collagen-Induced Arthrit 2021 Jun Rheumatoid arthritis is a chronic autoimmune disease characterized by the infiltration of synovial inflammatory cells and progressive joint destruction. Total flavonoids of Bidens pilosa have been used against inflammation in rheumatoid arthritis, but its role in bone destruction remains to be explored. The aim of this paper was to study whether total flavonoids of B. pilosa relieve the severity of collagen-induced arthritis in rats, particularly whether it regulates the production of proinflammatory cytokines and the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin signaling pathway. In this research, a collagen-induced disease model was induced in adult rats by subcutaneous injection of collagen II. Total flavonoids of B. pilosa at different doses (40, 80, and 160 mg/kg/d) were administered intragastrically, while methotrexate (1 mg/kg/w) was injected intraperitoneally as a positive control. Paw swelling, arthritis score, and body weight were assessed and evaluated. The severity of joint damage was determined using X-ray and confirmed by histopathology. The expression levels of receptor activator of nuclear factor-κB ligand, osteoprotegerin, IL-1β, IL-17, and TNF in the serum and tissue were assayed using ELISA and immunohistochemistry. We found that total flavonoids of B. pilosa attenuated collagen-induced arthritis at the macroscopic level, and total flavonoids of B. pilosa-treated rats showed reduced paw swelling, arthritis scores, and X-ray appearance of collagen-induced arthritis in addition to improved histopathological results. These findings were consistent with reduced serum and tissue receptor activator of nuclear factor-κB ligand, TNF, IL-1β, and IL-17 levels but increased osteoprotegerin levels. Our data suggest that total flavonoids of B. pilosa attenuate collagen-induced arthritis by suppressing the receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB/osteoprotegerin pathway and the subsequent production of proinflammatory cytokines. In addition, total flavonoids of B. pilosa may be a promising therapeutic candidate for the management of rheumatoid arthritis.
34674083 Seroconversion of rheumatoid arthritis patients after yellow fever vaccination. 2022 Mar Vaccination is a current strategy used to prevent infections in patients with immune-mediated rheumatic diseases. However, the use of live-attenuated vaccines prepared from living microorganisms in these patients should be avoided due to the risk of acquiring infections. The present study aimed to investigate the effect of the yellow fever (YF) vaccine (a live-attenuated vaccine) in 12 patients with rheumatoid arthritis (RA). The sample comprised 12 patients (9 females and 3 males; mean age 52.2 ± 6.5 years) with RA, who inadvertently received fractionated 17D yellow fever vaccination during an outbreak of this disease. In this cohort, 10 were administered leflunomide; 7 were administered methotrexate; 6 were administered prednisone (median dose of 5.0 mg/day); 6 took biologic drugs; and 1 took tofacitinib. All but one patient (used rituximab, prednisone, and methotrexate) seroconverted. None of them developed clinical signs of infection after the procedure. The fractionated dose of the YF vaccine is effective and safe in the observed sample. Key Points • Patients with autoimmune inflammatory rheumatic diseases (AIIRD) are at a high risk of acquiring infections • The fractionated dose of the YF vaccine is effective and safe in the observed sample • Vaccination against YF should be avoided in patients with AIIRD under immunosuppression owing to the risks of inducing YF infection.
33914203 Iguratimod combination therapy compared with methotrexate monotherapy for the treatment of 2021 Oct OBJECTIVE: We estimated the relative efficacy and safety of iguratimod combination therapy compared with methotrexate monotherapy for the treatment of rheumatoid arthritis. METHOD: We identified parallel randomized controlled trials from the Cochrane Central Register of Controlled Trials in The Cochrane Library (CENTRAL), MEDLINE, Embase, and other databases and trial registries for January April 2020. Independent assessment of the risk of bias and grading of the certainty of evidence was performed for the selected trials. We operated RevMan 5 software to compute the meta-analysis. We applied the random-effects model. The statistical methods applied were the Mantel-Haenszel method and the inverse-variance method for dichotomous and continuous outcomes, respectively. RESULTS: We included 12 trials involving 1095 participants. Based on our result, patients on iguratimod combination are likely to have 3.53 (95% CI 2.22 to 5.60, moderate-certainty), 3.24, and 2.73 times higher odds for attaining American College of Rheumatology criteria (ACR) 20, 50, and 70, respectively, than methotrexate monotherapy. Disease state measured using DAS28 score (MD -0.71 score, 95% CI -1.03 to -0.39, very low certainty) and functional ability indicated by HAQ (Health Assessment Questionnaire) (MD -0.23, 95% CI -0.34 to -0.11, very low certainty) may also be better. The combination therapy also produced better results for C-reactive protein, erythrocyte sedimentation rate, pain intensity, and patient's and physician's global assessment of disease state. Incidence of adverse events were similar between the groups (OR 1.30, 95% CI 0.92 to 1.83, moderate-certainty). CONCLUSION: Iguratimod combined with methotrexate may be considered a promising alternative for treating RA. Key Points • Iguratimod combination therapy produced better results in all the efficacy outcomes than methotrexate monotherapy. • Iguratimod combination therapy may be as safe as methotrexate monotherapy. • We recommend future clinical trials of iguratimod combination therapy in RA with iguratimod combined with DMARDs other than methotrexate and conducted in diverse population.
34365877 Emerging protein kinase inhibitors for the treatment of rheumatoid arthritis. 2021 Sep INTRODUCTION: Protein tyrosine kinase inhibitors are emergent drugs in the treatment of rheumatoid arthritis (RA); they block the signal transduction in immune cells preventing the production and release of pro-inflammatory cytokines. AREAS COVERED: The current research aims to review the role of Janus, Bruton's and spleen kinase inhibitors for the treatment of RA. Mechanism of action, rationale for usage, and the main efficacy and safety outcomes in phase II and III clinical trials are described. EXPERT OPINION: In RA, the development of Bruton kinase inhibitors was interrupted because they failed to demonstrate superiority versus placebo. The spleen kinase inhibitors had their development deprioritized because their risk/benefit profile was unfavorable compared to janus kinase inhibitors (JAKi). JAKi proved to be effective in treatment naïve patients and in those with previous failure to methotrexate and/or biological therapy. There still remain important points about JAKi that need more studies: the clinical importance of JAKi selectivity should be further evaluated in head-to-head trials and the safety profile of JAKi, mainly regarding the risk of malignancy and thromboembolic events, must be analyzed in long-term real-life studies.
34537057 HLA-DRB1 risk alleles for RA are associated with differential clinical responsiveness to a 2021 Sep 18 BACKGROUND: Certain risk alleles associated with autoantibody-positive rheumatoid arthritis (RA) have been linked to poorer prognoses. In patients with autoantibody-positive RA, abatacept shows differential efficacy to tumor necrosis factor inhibitors. Our aim was to investigate the relationship between clinical response to abatacept and to adalimumab and presence of risk alleles encoding human leukocyte antigen (HLA)-DRB1 shared epitope (SE) in RA. METHODS: In this head-to-head study, biologic-naïve adults with early (≤ 12 months), moderate-to-severe RA and inadequate response to methotrexate (MTX-IR), autoantibody-positive for both anti-cyclic citrullinated peptide 2 and rheumatoid factor, were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly or subcutaneous adalimumab 40 mg every 2 weeks for 24 weeks with stable, weekly oral MTX. An open-label period to 48 weeks followed, during which adalimumab-treated patients were switched to abatacept. Patients were genotyped for HLA-DRB1 alleles and classified as SE-positive (≥ 1 SE allele) or SE-negative (no SE alleles). Efficacy was assessed at weeks 24 and 48. RESULTS: Forty patients each received abatacept (9 SE-negative, 30 SE-positive, one unknown) or adalimumab (9 SE-negative, 31 SE-positive). Mean age and disease duration were 46.0 years and 5.5 months, respectively. At week 24, a greater percentage of abatacept patients achieved 50% improvement in ACR criteria (ACR50) compared with adalimumab patients (73% vs 45%, respectively) and estimate of difference (95% confidence interval [CI]), 28 (5, 48). In SE-positive patients, ACR50 estimate of difference (95% CI) was 32 (7, 55). During the open-label period, responses were sustained in the abatacept non-switch group and showed trends toward further improvement in the adalimumab-to-abatacept switch group at week 48, in both the overall and the SE-positive subpopulation. No new safety signals were identified. CONCLUSIONS: In MTX-IR patients with early, autoantibody-positive RA, abatacept resulted in numerically higher efficacy responses versus adalimumab after 24 weeks, with more pronounced treatment differences in SE-positive patients. After 48 weeks, responses were sustained in patients who continued abatacept while those who switched to abatacept showed further clinical improvement, overall, and in SE-positive patients. This supports co-stimulation blockade as an effective treatment strategy for patients with early, autoantibody-positive RA, particularly among SE-positive patients. TRIAL REGISTRATION: NIH US National Library of Medicine, NCT02557100 . Registered on September 23, 2015.
33242532 RNA interference-mediated suppression of TNF-α converting enzyme as an alternative anti-T 2021 Feb 10 Excessive tumor necrosis factor-α (TNF-α) is associated with the pathogenesis of rheumatoid arthritis (RA). Approximately 90% of patients with RA, who have inadequate response to methotrexate, follow anti-TNF-α therapy as the first-line immuno-treatment. However, ineffective long-term anti-TNF-α antibody cycling for 40% of non-responders to anti-TNF-α antibodies is costly and associated with various side effects, which needs alternative mechanism of action therapies. In the present study, a novel strategy to down-regulate TNF-α level was developed by using an alternative method of suppressing TNF-α converting enzyme (TACE), a transmembrane enzyme involved in cleaving and releasing bioactive soluble TNF-α. TACE suppression can be an effective remedy to block the production of soluble TNF-α, leading to an increased sensitivity to anti-TNF-α non-responders. A disease site-targeted RNA interference system was developed by forming non-viral complex between shRNA against TACE (shTACE) and bone resorption site-specific peptide carrier composed of aspartate repeating and arginine repeating sequences. The shTACE/peptide carrier complex alleviated arthritic symptoms in collagen induced arthritis (CIA) models by demonstrating enhanced anti-inflammatory and anti-osteoclastogenic effects. Similar results were obtained with human primary synovial cells and osteoclast precursor isolated from tissues and synovial fluids of RA patients. Taken together, the shTACE/targeting peptide complex provides a strong potential as an alternative anti-TNF-α therapeutic for RA treatment.
34867944 Methotrexate Treatment of Newly Diagnosed RA Patients Is Associated With DNA Methylation D 2021 BACKGROUND: Methotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX. We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4(+) T cells before and after MTX treatment of RA patients. DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing. RESULTS: We found that MTX treatment significantly influenced DNA methylation levels at multiple CpG sites in both cell populations. Interestingly, we identified differentially methylated sites annotated to two genes; TRIM15 and SORC2, previously reported to predict treatment outcome in RA patients when measured in bulk T cells. Furthermore, several of the genes, including STAT3, annotated to the significant CpG sites are relevant for RA susceptibility or the action of MTX. CONCLUSION: We detected CpG sites that were associated with MTX treatment in CD4(+) naïve and memory T cells isolated from RA patients. Several of these sites overlap genetic regions previously associated with RA risk and MTX treatment outcome.
34521462 The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual " 2021 Sep 14 BACKGROUND: There is a need for biomarker to identify patients "at risk" for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers. METHODS: Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. RESULTS: HnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP-2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. The citrullinated/native index of autoantibodies against hnRNP-DL (CN(DL)-Index) was identified as a new value for an "individual window of treatment success" in early RA and for the detection of RF IgM/α-CCP-2 seronegative RA patients (24-46%). Negative CN(DL)-index was found in SLE patients, risk-RA and early RA cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CN(DL)-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients. CONCLUSION: CN(DL)-index defines people at risk to develop RA and the "window of treatment success" thereby closing the sensitivity gap in RA.
33682353 Sustained Remission in Patients With Rheumatoid Arthritis Receiving Triple Therapy Compare 2021 Jul OBJECTIVE: To compare the real-life effectiveness of biologic therapy (a biologic disease-modifying antirheumatic drug plus methotrexate [MTX]) versus triple therapy (MTX plus sulfasalazine plus hydroxychloroquine/chloroquine) for sustained remission of rheumatoid arthritis (RA). METHODS: RA patients who were registered in the nationwide Swedish Rheumatology Quality Register between 2000 and 2012 and were receiving biologic or triple therapy as a first treatment strategy after MTX monotherapy were included. Sustained remission was defined as a Disease Activity Score in 28 joints (DAS28) of <2.6 for ≥6 months (short-term sustained remission) or for ≥24 months (long-term sustained remission). Treatment groups were compared during treatment, at 1 year, and at 2 years for 1) all patients starting therapy and 2) patients continuing to receive therapy, using propensity score-adjusted regression analyses. In addition, survival analyses were used to compare treatment groups at any time during follow-up irrespective of therapy retention. RESULTS: A total of 1,502 patients were included (1,155 receiving biologic therapy and 347 receiving triple therapy). For patients starting therapy, the adjusted odds ratios (ORs) of achieving short-term and long-term remission, respectively, at 1 year after start of biologic therapy versus triple therapy were 1.79 (95% confidence interval [95% CI] 1.18-2.71) and 1.86 (95% CI 1.00-3.48). At 2 years, the ORs were 1.92 (95% CI 1.21-3.06) and 1.62 (95% CI 0.94-2.79), respectively. For patients continuing to receive therapy, corresponding results at 1 year were 1.12 (95% CI 0.72-1.75) and 1.1 (95% CI 0.59-2.16); at 2 years, 0.85 (95% CI 0.49-1.47) and 0.76 (95% CI 0.41-1.39). Hazard ratios for short-term and long-term sustained remission at any time during follow-up were 1.15 (95% CI 0.91-1.46) and 1.09 (95% CI 0.77-1.54), respectively. CONCLUSION: Among patients starting biologic or triple therapy, biologic therapy was more effective for remaining on therapy and achieving sustained remission. However, similar probabilities were found for achieving sustained remission among patients remaining on therapy and at any time during follow-up irrespective of therapy retention. Although the likelihood of reaching sustained remission is higher with biologic therapy, for certain RA patients triple therapy may still be an alternative to biologic therapy without hampering future chances of obtaining sustained remission.
34782180 Systematic review of imaging tests to predict the development of rheumatoid arthritis in p 2022 Feb OBJECTIVE: To estimate and compare the diagnostic accuracy of magnetic resonance imaging (MRI) and ultrasound, for the prediction of rheumatoid arthritis (RA) in unclassified arthritis (UA). METHODS: MEDLINE, Embase and BIOSIS were searched from 1987 to May 2019. Studies evaluating any imaging test in participants with UA were eligible. Reference standards were RA classification criteria or methotrexate initiation. Two authors independently extracted data and assessed validity using QUADAS-2. Sensitivities and specificities were calculated for each imaging characteristic and joint area. Summary estimates with 95% confidence intervals (CI) were estimated where possible. RESULTS: Nineteen studies were included; 13 evaluated MRI (n=1,143; 454 with RA) and 6 evaluated ultrasound (n=531; 205 with RA). Studies were limited by unclear recruitment procedures, inclusion of patients with RA at baseline, differential verification, lack of blinding and consensus grading. Study heterogeneity largely precluded meta-analysis, however summary sensitivity and specificity for MRI synovitis in at least one joint were 93% (95% CI 88%, 96%) and 25% (95% CI 13%, 41%) (3 studies). Specificities may be higher for other MRI characteristics but data are limited. Ultrasound results were difficult to synthesise due to different diagnostic thresholds and reference standards. CONCLUSION: The evidence for MRI or ultrasound as single tests for predicting RA in people with UA is heterogeneous and of variable methodological quality. Larger studies using consensus grading and consistently defined RA diagnosis are needed to identify whether combinations of imaging characteristics, either alone or in combination with other clinical findings, can better predict RA in this population.
33413588 Connective tissue remodelling is differently modulated by tocilizumab versus methotrexate 2021 Jan 7 OBJECTIVE: Associations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo. METHODS: Tissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5-20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman's correlation and logistic regression adjusted for age, gender, BMI and disease duration. RESULTS: C1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01). CONCLUSION: Patients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00109408 . Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.
34273810 Rheumatoid arthritis treatment using hydroxychloroquine and methotrexate co-loaded nanomic 2021 Oct Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1% of the world population. It is a long-lasting autoimmune disease, which mainly affects the joints causing inflammation and swelling of the synovial joint. RA has a significant impact on the ability to perform daily activities including simple work and household chores. Nonetheless, due to the long periods of pain and the continuous use of anti-inflammatory drugs, RA can debilitate the quality of life and increases mortality. Current therapeutic approaches to treat RA aim to achieve prolonged activity and early and persistent remission of the disease, with the gradual adoption of different drugs available. In this study, we developed a novel hydroxychloroquine and methotrexate co-loaded Pluronic® F-127 nanomicelle and evaluated its therapeutic effects against RA. Our results showed that drug-loaded nanomicelles were capable of modulating the inflammatory process of RA and reducing osteoclastogenesis, edema, and cell migration to the joint. Overall, compared to the free drugs, the drug-loaded nanomicelles showed a 2-fold higher therapeutic effect.
33444321 Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and 2021 Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.
34425026 Sinomenine increases adenosine A(2A) receptor and inhibits NF-κB to inhibit arthritis in 2021 Dec Sinomenine (SIN) is a clinical drug for treating rheumatoid arthritis (RA) in China. Our previous study found SIN inhibited inflammation via alpha7 nicotinic acetylcholine receptor (α7nAChR) in macrophages in vitro. Adenosine receptor A(2A) has anti-inflammatory and immunosuppressive function. However, the mechanisms of SIN acting on α7nAChR and the effect on adenosine A(2A) receptor (A(2A) R) in RA are not clear. In the present study, the effects of SIN on adjuvant-induced-arthritis (AIA) rats in vivo and on fibroblast-like synoviocytes (FLSs) in vitro were investigated. Indomethacin (Indo) and methotrexate (MTX), the clinical anti-arthritis drugs, were used as controls. Nicotine (Nic), a specific agonist of α7nAChR, was used as a control for targeting α7nAChR. Alpha-bungarotoxin (α-BTX), the antagonist of α7nAChR or small interference RNA (siRNA) was used to block or knock down α7nAChR. Results showed that SIN decreased arthritis index, hind paw volume, erythrocyte sedimentation (ESR) and serum TNF-α in AIA rats, and α-BTX attenuated the earlier-mentioned effects of SIN and Nic, but not Indo and MTX. The expressions of A(2A) R in synovium declined in AIA rats, but remarkably increased after the intervention of SIN. The expression of A(2A) R decreased by LPS or TNF-α, but increased by SIN; cAMP also increased by SIN in FLSs in vitro. SIN inhibited the expression of MCP-1, IL-6, and vascular endothelial growth factor in LPS-induced FLSs. SIN inhibited the activation of NF-κB. Meanwhile, α-BTX or α7nAChR siRNA blocked the earlier-mentioned effects of SIN in FLSs. Results suggested the expressions of A(2A) R in synovium and FLSs are negatively correlated with the arthritis progression of AIA rats and the activation of FLSs. SIN increases A(2A) R and inhibits the activation of NF-κB pathway via α7nAChR in AIA rats and FLSs.
32970188 Comparative study of the efficacy and safety of tofacitinib, baricitinib, upadacitinib, an 2021 Nov An assessment of the relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) was performed in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA). We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) so as to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and MTX in DMARD-naïve RA patients. Four RCTs comprising 2185 patients met the inclusion criteria. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of achieving the American College of Rheumatology 20% (ACR20) response rate, followed by baricitinib 4 mg, tofacitinib 5 mg, filgotinib 200 mg, and MTX. Tofacitinib, baricitinib, upadacitinib, and filgotinib treatments achieved significantly higher ACR50 and ACR70 responses compared to MTX. Tofacitinib 5 mg had the highest probability of achieving the ACR50 and ACR70 response rates, followed by upadacitinib 15 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX. The safety analysis based on serious adverse events, adverse events (AEs), and withdrawals due to AEs revealed no statistically significant differences between the respective intervention groups. In conclusion, tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for DMARD-naïve RA patients, suggesting a difference in efficacy and safety among the different JAK inhibitors.