Treatment Of RA Patients Research Articles

Efficacy and safety of tetrandrine in treatment of rheumatoid arthritis: a meta-analysis.

To explore the efficacy and safety of tetrandrine in the treatment of rheumatoid arthritis. Randomized controlled studies of tetrandrine in the treatment of rheumatoid arthritis were searched in CNKI, VIP, Wanfang database, SinoMed, PubMed, Springer, Web of Science and Cochrane Central Register of Controlled Trails databases. A meta-analysis was conducted using R 3.5.3 software to evaluate the clinical outcomes, including the total effective rate, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), visual analogue scale (VAS), disease activity score (DAS), tender joint count (TJC), swollen joint count (SJC), and morning stiffness duration, as well as adverse events of rheumatoid arthritis patients. A total of 10 articles were included in the study. The meta-analysis indicated that tetrandrine significantly improved the total effective rate (OR=3.27, 95%CI: 2.01-5.37, P<0.01), ESR (SMD=1.12, 95%CI: 0.06-2.19, P<0.05), CRP (SMD=0.75, 95%CI: 0.28-1.22, P<0.01), VAS (SMD=0.64, 95%CI: 0.29-1.00, P<0.01), TJC (SMD=1.16, 95%CI: 0.58-1.74, P<0.01), SJC (SMD=0.85, 95%CI: 0.40-1.31, P<0.01), and morning stiffness (SMD=1.09, 95%CI: 0.68-1.50, P<0.01). However, no statistical significance was found in RF (SMD=1.70, 95%CI: －1.10-4.51, P>0.05) and DAS (SMD=0.26, 95%CI: －0.59-1.11, P>0.05). The overall incidence of adverse events associated with tetrandrine treatment for rheumatoid arthritis was 20% (95%CI: 12%-27%, I2=60%, P<0.05), with mild severity and favorable outcomes. Tetrandrine is effective in the treatment of RA patients with a mild degree of adverse events.

Trivalent chromium versus baricitinib for rheumatoid arthritis treatment: first phase 2/3 randomized controlled trial, is trivalent chromium the upcoming immune-modulator?

BackgroundRheumatoid arthritis (RA) is a debilitating disease mainly treated by DMARDs. Baricitinib is one of the emerging DMARDs with strong anti-rheumatic effects but has serious side effects. Trivalent chromium (Cr III) is a natural element with anti-inflammatory properties. Trivalent chromium (Cr III) is introduced for the first time to study its effect and safety in treatment of RA patients and compared to those of baricitinib.MethodsThis is a phase 2/3 randomized controlled trial where RA patients were divided in a ratio of 2:1 according to the newly introduced medication either Cr (III) (group A) or baricitinib (group B). Patients attended three visits on day 0, after 3 weeks and 12 weeks, disease activity was scored. Hands ultrasound was done and reassessed. Side effects were monitored throughout the study.ResultsDAS28-CRP improved by 26.9% and 11.8% on third visit for Cr III and baricitinib, respectively (p = 0.001). DAS28-ESR improved by 25.6% and 7.74% on third visit for Cr III and baricitinib, respectively (p = < 0.001). ACR 50 was 18.8% for Cr III and 5.7% for baricitinib on second visit. ACR 70 was 25% for Cr III and 0% for baricitinib on third visit (P = < 0.001). Ultrasound GLOESS, SH, PDUS, joints effusions improved by 38.9%, 38.4%, 56.7% and 74.8% for Cr III, while by 10.5%, 3.75%, 59.6% and worsening of joints effusions happened with baricitinib on third visit. p = 0.022 and 0.002 between groups for GLOESS and SH improvement, respectively.ConclusionsCr III has shown very promising fast clinical and sonographic results in treating RA patients which were surprisingly superior to baricitinib in most aspects. Furthermore, Cr III is potentially safe with evidently fewer side effects than baricitinib and other DMARDs, however, long-term safety is still not established.(IRB No.: 00012098- FWA No.: 00018699, Serial number: 040457) ClinicalTrials.gov ID: NCT05545020.

Intradermal acupuncture in the treatment of rheumatoid arthritis with liver and kidney deficiency syndrome – A sham-controlled, randomized, clinical trial

Background and purposeRheumatoid arthritis (RA) is called “immortal cancer”, and it affects the quality of life, disability rate and even the survival of patients. This study aimed to observe the clinical efficacy, and adverse reactions of intradermal acupuncture (IA) in the treatment of RA patients with liver and kidney deficiency syndrome. Materials and methods132 RA patients were split into an IA group and a sham IA group at a 1:1 ratio. Both groups were assessed before and after the intervention with the assessments: a traditional Chinese medicine (TCM) syndrome evaluation, the Health Assessment Questionnaire (HAQ), the Disease Activity Score 28 (DAS28) and serum C-reactive protein (CRP). ResultsThere was a statistically significant difference in TCM syndrome evaluation, HAQ, DAS28, and CRP between both groups before and after treatment (P < 0.01). The improvement of TCM syndrome evaluation (95% CI [1.14(0.38–1.89)]; P = 0.001), HAQ (95% CI [2.00(1.00–3.00)]; P = 0.003), and DAS28 (95% CI [0.11(0.02–0.20)]; P = 0.021) in the IA group was more obvious than that in the sham IA group (P < 0.05), except for CRP (95% CI [0.50(− 2.09 to 7.08)], P = 0.786). The difference in CRP outcome changes between the two groups was not statistically significant (P > 0.05). Both groups had comparable results in the implementation of RA in the upper and lower extremity acupoints and did not differ due to different sites (IA group: P = 0.852; sham IA group: P = 0.861). The comparison of effective rate of the upper limb as well as that of the lower limb was statistically significant (P = 0.001). Besides, patients reported no adverse effects. ConclusionThe IA intervention was associated with a promising effect on the decrease in RA disease activity and delayed overall disease progression.

Analyzing the risk of osteoporosis and fracture in rheumatoid arthritis patients who have been treated with various biologics.

Rheumatoid arthritis (RA) is a major risk factor for osteoporosis/osteoporotic fractures. We aimed to elucidate the role of treatment choices among osteoporosis/osteoporotic fractures. We utilized the Chang-Gung Research Database to assess the risks of osteoporosis/osteoporotic fractures among independently treated RA patients, using retrospective time-to-event outcomes analysis. A total of 3509 RA patients with a mean of 63.1 ± 8.6 years were analyzed. Among all, 1300 RA patients (37%) were diagnosed with newly diagnosed osteoporosis. The crude incidence of newly diagnosed osteoporosis was the highest among those treated with other conventional disease-modifying anti-rheumatic drugs (cDMARDs; 74.1 events/1000-PYs, 95%CI 66.0-82.3), followed by those with a non-treatment period (68 events/1000-PYs, 95%CI 63.1-72.9), methotrxate (MTX) monotherapy (60.7 events/1000-PYs, 95%CI 41.2-80.3), MTX plus other cDMARDs (51.9 events/1000-PYs, 95%CI 43.4-60.3), and abatacept/rituximab (48.6 events/1000-PYs, 95%CI 14.9-82.3). The lowest crude incidence was found in patients treated with anti-TNFi biologics (40.4 events/1000-PYs, 95%CI 28.6-52.2) and other biologic disease-modifying anti-rheumatic drugs (bDMARDs; 40.1 events/1000-PYs, 95%CI 8.0-72.1). A total of 270 patients (20.8%) suffered from an incident fracture during follow-ups. The crude incidence of fracture was the highest among those treated with abatacept/rituximab (49.0 events/1000-PYs, 95%CI 6.0-91.9), followed by those with non-treatment periods (24.3 events/1000-PYs, 95%CI 19.3-29.4), other cDMARDs (24.2 events/1000-PYs, 95%CI 18.1-30.2), anti-TNFi biologics (20.2 events/1000-PYs, 95%CI 8.8-31.6). Other bDMARDs (13.3 events/1000-PYs, 95%CI 0-39.2), MTX mono (12.5 events/1000-PYs, 95%CI 0.3-24.8), and MTX plus other cDMARDs (11.4 events/1000-PYs, 95%CI 5.4-17.4) were low incidences. The treatment option has emerged as a critical determinant in the context of future osteoporosis and osteoporotic fracture risks among RA. These findings offer a valuable resource for clinicians, empowering them to tailor bespoke treatment strategies for RA patients, thereby mitigating the potential for future osteoporosis and fractures.

The impact of biologic agents on cardiovascular risk factors in patients with rheumatoid arthritis: A meta analysis.

The purpose of the study is to evaluate the effects of biologic therapy on cardiovascular risk factors in rheumatoid arthritis patients to determine its clinical efficacy. Relevant literature was systematically searched in PubMed, Embase, and Cochrane Library databases. Meta-analysis was conducted using standardized mean differences (SMDs) and 95% confidence intervals (CIs) to evaluate cardiovascular risk factors and atherosclerosis. Heterogeneity, sensitivity analysis, and publication bias were assessed. Statistical significance was set at P<0.05. The meta-analysis revealed that biologic treatment in RA patients was associated with decreased high-density lipoprotein cholesterol (HDL-C) levels compared to controls (MD: -0.10, 95% CI: [-0.14, -0.05], P<0.0001). Subgroup analysis based on treatment duration showed heterogeneity and a potential decrease in total cholesterol levels after 12 months of treatment (MD = -0.03, 95% CI [-0.21, -0.15], P = 0.76). Biologic therapy significantly reduced triglyceride levels compared to controls (MD = -0.23, 95% CI [-0.37, -0.09], P = 0.001), as observed in subgroup analysis. Moreover, biologics effectively decreased low-density lipoprotein cholesterol (LDL-C) levels (MD: -0.10, 95% CI: [-0.14, -0.05], P<0.0001). However, biologic treatment was associated with increased inner carotid artery thickness (MD: 0.05, 95% CI: [0.03, 0.07], P<0.0001), indicating potential adverse effects on cardiovascular health. No significant effect on pulse wave velocity (PWV) was observed (MD: -0.23, 95% CI: [-0.80, 0.34], P = 0.43, I2 = 0%, P = 0.55). Biologic agents may improve lipid profiles in RA patients but could also have adverse effects on cardiovascular health. Further research is needed to comprehensively understand the impact of biologic therapy on lipid metabolism and cardiovascular outcomes in RA patients. https://www.crd.york.ac.uk/PROSPERO/, CRD42024504911.

Efficacy of TCM Fumigation Using Dampness-and-cold-dispelling Formula Combined with Methotrexate and Leflunomide Treating Rheumatoid Arthritis with Cold-dampness Bi Syndrome

BackgroundRheumatoid arthritis (RA), a chronic autoimmune disease, has a high incidence and disability rate, causing patients significant discomfort. Although several medicines can be effective, they are also associated with significant adverse effects. In contrast, fumigation as one of the most often used traditional Chinese medicine (TCM) external therapy has shown both efficacy and safety with less side effect. In light of this, we complement western medicine treatment with TCM fumigation therapy to improve patients' clinical efficacy, alleviate symptoms, and improve prognosis. ObjectiveTo investigate the therapeutic effect of TCM fumigation and modern medicine combined therapy in treating RA patients with cold-dampness Bi syndrome. MethodsA single-center, randomized, controlled study was designed. From January 2022 to December 2022, a total of 60 RA patients with cold-dampness Bi syndrome were enrolled in the study. The control group (30 cases) received conventional modern medicine treatment with methotrexate for 4 weeks, while the observation group (30 cases) for 4 weeks received a combination of TCM fumigation treatment and conventional modern medicine. The effects of the two groups were comprehensively compared, including the changes in TCM symptom scores and laboratory indicators, as well as the use of visual analogue scale (VAS) and health status rating scale (HAQ) before and after treatment. ResultsThe total effective rate of the observation group was 93.3%, which was significantly higher than that of the control group, which is 70% (P < 0.05). Before treatment, there were no significant differences in joint functional activity, pain visual analogue scale (VAS), health assessment questionnaire (HAQ-DI) and laboratory indexes between the two groups (P > 0.05). After treatment, each group compared to their initial condition, respectively, showed major improvement of joint functional activity and significantly decreased VAS, HAQ-DI, and RA-related biomarkers (P < 0.05); inter-group comparison of these indicators showed significanty further enhanced effect of TCM fumigation combined therapy on the RA-related biomarkers and joint functional activity of patients (P < 0.05), yet the control group receiving only modern medicine showed better results of the VAS and HAQ-DI . ConclusionThe TCM fumigation combined therapy is effective to treat RA patients with cold-dampness Bi syndrome, and to enhance their life quality, improving the joint function, and reducing inflammation.

Influence of rheumatoid factor on serum drug levels of TNF inhibitors with different structures in rheumatoid arthritis.

Certolizumab pegol (CZP), an Fc-free antibody fragment, has shown stable serum levels and steady efficacy in the treatment of RA patients, irrespective of RF levels at baseline. Here, we examine, in clinical practice, the effect of baseline RF and ACPA levels on serum drug levels of IFX, ADL and CZP an Fc-free antibody fragment. This is a retrospective study performed in real-world patients. We assessed 170 patients with RA: 90 (53%) received IFX, 48 (28%) ADL and 32 (19%) CZP. Demographic and clinical variables, RF and ACPA levels were obtained at the baseline visit (T0), and patients were stratified based on negative, low, medium, or high levels. After 6 months (T6) serum drug levels and anti-drug antibodies (ADAb), were computed. While CZP serum levels did not differ across RF groups at T6, high baseline RF was linked to lower serum drug levels compared to RF negative status in treatment with complete monoclonal antibodies IFX and ADL. No differences in disease activity measured by DAS28 at baseline were observed across RF quartiles in patients treated with IFX or ADL. ADAb was observed in 26 patients with IFX, 3 with ADL and 1 with CZP, following 6 months of treatment. Patients with high baseline RF levels dropped out more frequently by secondary non-response in IFX or ADL than CZP (80% vs. 75% vs. 33%, p=0.002). In this real word data evaluation, CZP serum levels were independent of RF levels in patients however patients with high baseline RF levels who obtained IFX or ADL had lower serum drug levels at 6 months than baseline RF-negative patients. In addition, secondary non-response was more frequent in patients with high RF levels treated with IFX and ADL.

Wangbi granule as a combination therapy to achieve clinical deep remission in rheumatoid arthritis: protocol for a multicenter, triple-blind, randomised, placebo-controlled trial

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that may lead to bone erosion and disability. Although there are many biological therapies in RA treatment nowadays, such as etanercept and tofacitinib, there are still a considerable number of patients who cannot achieve clinical deep remission, which makes patients feel pain and stiffness of joints. As a traditional Chinese medicine preparation, Wangbi granule showed a synergistic role with methotrexate in the treatment of RA patients with “kidney deficiency and dampness” or “stasis blocking channels”. Therefore, it is a promising therapeutic strategy for the clinical deep remission of RA. In this study, Wangbi granule will be used as the test drug. The investigators conduct this study to evaluate the efficacy and safety of Wangbi granule in the treatment of patients who have not achieved deep remission despite the use of methotrexate and tofacitinib.Methods and analysisTwo parallel randomized, triple-blind, placebo-controlled trials will be conducted. In six study centers, 340 eligible RA patients will be recruited and randomly allocated to either the intervention group or the control group (in a 1:1 ratio). They will receive Wangbi granule or Wangbi placebo 12.0 g each time, three times a day for 12 weeks. The primary outcome is the disease activity score derivative for 28 joints (DAS28). Secondary outcomes are patient-reported outcomes, American College of Rheumatology 50% response criteria (ACR50), fatigue scale-14 (FS-14), visual analogue scale for pain (VAS), health assessment questionnaire disability index (HAQ-DI) and biomarkers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).Expected outcomesThe success of this study will provide strong evidence to confirm the efficacy and safety of Wangbi granule in the treatment of RA.Trial registration The trial has been registered in the ClinicalTrials Registry (NCT05540938, Date: 09/15/2022, https://clinicaltrials.gov/ct2/show/NCT05540938)

Echinocystic Acid Ameliorates Arthritis in SKG Mice by Suppressing Th17 Cell Differentiation and Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes Inflammation

Echinocystic acid (EA), a pentacyclic triterpene, exhibits anti-inflammatory, antioxidant, and analgesic activities to counteract pathological effects in various diseases. Here, we aimed to determine the immunomodulatory effect of EA on zymosan-induced arthritis in SKG mice and how it would influence Th17 differentiation and human rheumatoid arthritis fibroblast-like synoviocytes inflammation. Our results showed that EA (10 and 25 mg/kg) attenuated arthritis symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion, and the high levels of proinflammatory cytokines, such as TNF-α, interleukin (IL)-6, and IL-1β in paw tissues, and reduced the number of splenic Th17 cells. Mechanistically, we found that in vitro treatment of EA inhibited both IL-6- and transforming growth factor-β (TGF-β)-induced Th17 cell differentiation by suppressing the phosphorylation of signal transducers and transcriptional activators, especially STAT3. In line with the in vivo result, EA significantly reduced the protein and mRNA expression of IL-6 and IL-1β in human RA-FLA cells, MH7A cells. Furthermore, the production of both cytokines was confirmed with the downregulation of mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB) signaling pathways under the stimulation of TNF-α. In conclusion, these findings revealed that EA was capable of amelioration of arthritic disorders in SKG mice through inhibiting Th17 cell differentiation and synovial fibroblast inflammation, supporting that EA is a promising therapeutic candidate for treating RA patients.

Dysbiotic Oral and Gut Viromes in Untreated and Treated Rheumatoid Arthritis Patients.

ABSTRACTRheumatoid arthritis (RA) is influenced by oral and gut bacteria; however, much less is known about the relationship between oral or gut viromes and RA. Here, we performed whole-oral- and whole-gut-virome analyses based on shotgun sequencing of 497 samples. A comparative analysis of the oral and gut viromes in healthy controls and untreated and treated RA patients was performed, and system interaction networks among viruses, bacteria, and RA-associated clinical indices were constructed to address the potential relationship between the virome and RA by principal-coordinate analysis, distance-based redundancy analysis, permutational multivariate analysis, Spearman correlation coefficient analysis, and random-forest model analysis. The results showed that the viromes could be profiled in dental plaque, saliva, and fecal samples, among which saliva had the highest within-sample diversity. Importantly, significantly different diversities and compositions of the oral (i.e., dental plaque and saliva) viromes were observed not only between RA patients and healthy controls but also between untreated and treated RA patients, yet there were relatively minor differences in the gut viromes. Furthermore, to understand how these viruses affected the bacteriome, a virus-bacterium interaction network was constructed from dental plaque, saliva, and fecal samples of RA patients. Additionally, some RA-associated oral taxa, including Lactococcus phage (vOTU70), Bacteroides vulgatus, Lactococcus lactis, Escherichia coli, and Neisseria elongata, were correlated with the RA-related clinical indices. Whole-virome analysis illustrated the potential role of the oral and gut viromes in affecting our body either directly or via bacteria, which characterized neglected and new candidates contributing to the development of RA.IMPORTANCE Our results demonstrated community variation among dental plaque, saliva, and fecal viromes. In oral and gut samples from untreated and treated RA patients, the perturbance of viral composition and the correlation network of microbes and RA-associated clinical indices might be involved in the pathogenicity of RA. The findings in this study expand the knowledge of the potential role of oral and gut viral communities in the development of RA and may contribute to research on correlations between viruses and other diseases.

The Relationship between Fatty Acids and the Development, Course and Treatment of Rheumatoid Arthritis.

For this systematic review, a search of the relevant literature was conducted in the EMBASE and PubMed databases. We used the following terms: ‘rheumatoid arthritis’ in conjunction with ‘fatty acid’. The following inclusion criteria had to be satisfied for the studies to be included in the analysis: an RCT/observational/cohort study published in English. A total of seventy-one studies were analysed. The presented systematic review of the available data indicates that increased consumption of omega-3 fatty acids (FAs) may have a beneficial effect on human health by decreasing pain and disease activity in patients with RA. The beneficial effect of unsaturated FA on the clinical parameters of RA was demonstrated in all 71 studies analysed. The content of omega-3 FAs in the diet and the consumption of fish, which are their main source, may contribute to a reduced incidence of RA. FAs are an essential component in the synthesis of eicosanoids that exhibit anti-inflammatory properties. Due to the documented positive influence of unsaturated FAs on treatment outcomes, the use of a diet rich in long-chain unsaturated FAs should be the standard of care, along with pharmacotherapy, in the treatment of RA patients. An important element in the control of the treatment process should be the routine assessment of the quality of life of RA patients.

Observation of the curative effect of Guizhi-Shaoyao-Zhimu decoction combined with methotrexate in the treatment of early rheumatoid arthritis based on ultrasonic evaluation: study protocol of a randomized, double-blind, controlled clinical trial

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with the primary clinical symptoms of joint swelling and pain. Early detection of erosion and synovial inflammation at an active stage resulting from RA can prevent damage to the joints and activity restriction. However, there are still many patients who do not respond to these treatments; the development of newer, safer drugs is urgently needed. Compared to Western medicine, Guizhi-Shaoyao-Zhimu decoction has equal or higher efficacy and safety for RA patients. With the widespread use of musculoskeletal ultrasound (MSUS), this technology holds great value for the degree of joint damage in RA patients, guiding the clinical selection of treatments, and assessing of prognosis. Therefore, we designed a double-blinded randomized controlled clinical trial to measure the safety and efficacy of Guizhi-Shaoyao-Zhimu decoction in treating early-stage RA using MSUS.MethodsThis study is a randomized, double-blinded, parallel group, placebo-controlled trial. A total of 152 adult participants with early RA will be enrolled, with balanced treatment allocation (1:1). The experimental intervention will be Guizhi-Shaoyao-Zhimu decoction plus the conventional medicine methotrexate and the control intervention will be placebo plus the conventional drug methotrexate for 3 months. In addition, both groups will receive folic acid during treatment to prevent side effects from methotrexate. The primary outcomes are the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hepatic and renal function, visual analog scale, disease activity score in 28 joints, measurement scale for TCM symptoms, and 7-joint ultrasound score.DiscussionWe designed this double-blinded randomized controlled clinical trial to evaluate the efficacy and safety of Guizhi-Shaoyao-Zhimu decoction in RA patients using MSUS. The results of this trial may provide insights into how to improve the clinical symptoms of RA patients and delay further joint destruction. We hope that this trial may provide preliminary evidence of the efficacy of Guizhi-Shaoyao-Zhimu decoction in treating RA patients and that these results aid researchers, practitioners, and patients alike.AimThe main aim of the study is to clarify the efficacy and safety of Guizhi-Shaoyao-Zhimu decoction in patients with early RA.Trial registrationChinese Clinical Trials Register ChiCTR2000036141. Registered on 21 August 2020 (retroactively registered)

OP0127 CONFOUNDING EFFECTS OF CONTINUED METHOTREXATE IN PLACEBO ARMS (PLC) OF RHEUMATOID ARTHRITIS (RA) CLINICAL TRIALS – A POST-HOC ANALYSIS OF TWO RANDOMIZED CONTROLLED TRIALS (RCTS)

Background:Various hypotheses exist for the explanation of PLC response rates in RA clinical trials. Here we hypothesized that PLC-treated patients who continue to take methotrexate (cMTX) when entering the trial compared to those who have no cMTX would have higher response rates, because of increased adherence to MTX in the trial environment.Objectives:To compare differences in response rates in PLC treated RA patients receiving MTX background therapy to patients receiving PLC without background conventional synthetic (cs)DMARDs in two RCTs.Methods:To investigate the hypothesis we conducted a post-hoc analysis of two RCTs that allowed inclusion of patients with and without cMTX - the GO-AFTER and the SIRROUND-T trials, investigating golimumab and sirukumab, respectively, compared with PLC in patients who had an insufficient response to biological DMARDs.(1,2)All PLC randomized patients of both trials were pooled and included in the analyses; we did not analyse the active treatment groups. Subsequently we stratified the pooled PLC group into patients receiving PLC on top of cMTX and patients receiving PLC without any csDMARD as background therapy. We compared American College of Rheumatology (ACR) 20/50/70% response rates and Clinical Disease Activity Index (CDAI) low disease activity (LDA, i.e. CDAI≤10) responses between the two groups using Fisher’s exact test.Similar to the primary analyses of the individual studies, non-responder imputation (NRI) for state outcomes (ACR responses, CDAI LDA) was applied in patients who initiated any csDMARD after randomization, had MTX or glucocorticoid doses increased during the study or discontinued the study. NRI was also applied for early escape patients receiving active therapy after failing to achieve a ≥20% decrease in joint counts at week (wk) 16 in GO-AFTER and at wk 18 in SIRROUND-T.Results:Of the 398 pooled PLC patients, 285 continued their MTX and 113 had no MTX (or other background csDMARDs). Baseline characteristics were similar (Table 1).Table 1.Baseline characteristicsPlacebo without background csDMARDPlacebo + continued MTXn113285Age (years) *56 (48-64)56 (45-64)Female (%)95 (84.1%)236 (82.8%)Disease duration (years)8.4±5.28.8±7.5ACPA positive (%)88 (77.9%)214 (75.1%)RF positive (%)90 (79.6%)211 (74%)SJC 66 (0-66)15.9±9.916.2±10.8TJC 68 (0-68)29.1±16.826.7±15.7PGA (VAS 0-10)6.8±2.26.5±2.1EGA (VAS 0-10)6.4±1.86.1±1.9Pain (VAS 0-10)7.0±1.96.6±2.1HAQ-DI (0-3)1.6±0.71.6±0.6CRP (mg/dL) *1.2 (0.5-3.5)1.0 (0.4-2.6)CDAI39.4±13.538.5±12.8Concomitant GC intake (%)67 (59.3%)174 (61.1%)Concomitant MTX (%)0 (0%)285 (100%)MTX dosage ≥12.5mg (%)0 (0%)222 (77.9%)MTX dosage &lt;12.5mg (%)0 (0%)63 (22.1%)Data is shown as mean (± standard deviation) or n (%) unless stated otherwise* median (IQR)At wk 16, an ACR20 response was achieved by 72/285 (25.3%) of PLC+cMTX and 14/113 (12.4%) receiving PLC only patients (p=0.005); for ACR50 these numbers were 25/285 (8.4%) vs. 1/113 (0.9%; p=0.003); and for ACR70 they were 8/285 (2.8%) vs. 0/113 (0%; p=0.112). Also, significantly more PLC+cMTX patients achieved a CDAI LDA at wk 16 (25/285, 8.8%) compared to PLC only treated patients (2/113; 1.8%; p=0.013). Results between the two arms were numerically or statistically different already from week 4 (for ACR 20) or week 8 (ACR 50, CDAI LDA) onwards (Figure 1).Figure 1.ACR 20/50/70 and CDAI LDA responses of PLC patients with continued MTX vs. PLC patients without csDMARD background therapy.Conclusion:In patients randomized to placebo therapy, continued MTX background therapy increases clinical responses and achievement of good clinical states. These findings imply that pre-existing and putatively insufficient background therapy should be effectively optimized before enrollment into a clinical trial protocol.

Interleukin-18 in Brazilian Rheumatoid Arthritis Patients: Can Leflunomide Reduce It?

Objectives Rheumatoid arthritis affects about 1% of the world's population. This is a chronic autoimmune disease. It is predominant in females with progressive joint damage. Immune cells are involved, especially Th1/Th17 lymphocytes and their inflammatory cytokines. These proteins have different functions in the immune system, such as IL-16 is a chemotactic factor; IL-18 can activate NFκB transcription producing inflammatory proteins; IL-31 can activate the JAK/STAT pathway which leads to the production of inflammatory factors in chronic diseases; IL-33 promotes IL-16 secretion which causes lymphocyte recruitment, and IL-32 and IL-34 appear to increase TNF secretion by macrophages activation in AR. The aim of this study was to evaluate serum levels of IL-16, IL-18, IL-31, IL-32, IL-33, and IL-34 and compare them with the severity and treatment of RA patients if there are any correlations. Methods A total of 140 RA patients and 40 healthy donors were recruited from the Department of Rheumatology at Hospital das Clínicas from the Federal University of Pernambuco. 60 AR patients were naïve for any treatment. Serum cytokine levels were determined using an ELISA kit. Results Serum IL-16 (p = 0.0491), IL-18 (p < 0.0001), IL-31 (p = 0.0004), and IL-32 (p = 0.0040) levels were significantly increased in RA patients compared with healthy donors. It was observed that patients using leflunomide had the lowest IL-18 levels, close to controls levels (p = 0.0064). Conclusion IL-16, IL-18, IL-31, and IL-32 are increased in the serum of RA patients. IL-18 is at lower levels in those AR who are taking leflunomide as treatment.

Methotrexate in Italian patients wiTh Rheumatoid Arthritis (MITRA study): an observational study about the use of methotrexate in early RA patients and the adherence to the EULAR 2013 recommendations. A project of the Italian Society for Rheumatology.

To assess the delay between the disease onset and the beginning of methotrexate (MTX) treatment in RA patients and to evaluate the Italian rheumatologists' adherence to the EULAR 2013 recommendations. MITRA is an Italian multicentre observational study carried out on DMARD-naïve RA patients recruited in an 18-month period starting from 2015. The data related to the patients' characteristics at baseline will be presented. 332 patients from 13 Italian centres were recruited: the median delay between the onset of symptoms and the beginning of MTX was 197 days (102-431); in 20% of patients a treatment with DMARDs was started within the first 90 days from the onset of symptoms. The clinical target selected was DAS28 remission in 64.2% of cases and low disease activity in 35.8%. Among patients in DAS28 high disease activity, 92.6% received a control visit which was rescheduled within the first 3 months, similarly to those in DAS28 moderate disease activity (91.6%). A DMARD monotherapy was prescribed in 319 patients, while a combined therapy of DMARDs was preferred in 13 cases; 282 patients were treated with MTX. Glucocorticoids were prescribed in 229 patients: the median dosage was of 5 mg (IQR 5-7.5) of prednisone equivalent/day. Diagnostic delay in RA patients continues to be longer than expected. The choice of low disease activity as a target is still very frequent and tight control does not seem to be based on disease activity. This paper offers a realistic and detailed picture of the clinical practice among Italian rheumatologists.

Association of altered folylpolyglutamate synthetase pre-mRNA splicing with methotrexate unresponsiveness in early rheumatoid arthritis

ObjectivesAn efficient pharmacological response to MTX treatment in RA patients relies on the retention and accumulation of intracellular MTX-polyglutamates catalysed by the enzyme folylpolyglutamate synthetase (FPGS). We recently identified a partial retention of FPGS intron 8 (8PR) as a prominent splice variant conferring FPGS dysfunction and decreased MTX polyglutamylation in acute lymphoblastic leukaemia. Here, we explored the association between FPGS 8PR levels and lack of MTX responsiveness in RA patients.MethodsThirty-six patients undergoing MTX treatment were enrolled from the Combinatie behandeling Reumatoide Artritis (COBRA)-light trial. RNA was isolated from blood samples at baseline, 13 weeks and 26 weeks of therapy, from patients in either COBRA-light (n = 21) or COBRA (n = 15) treatment arms. RT-qPCR analysis was used to assess RNA levels of FPGS 8PR over wild-type FPGS (8WT).ResultsIn the COBRA-light treatment arm, higher baseline ratios of 8PR/8WT were significantly associated with higher 44-joint disease activity score (DAS44) at 13 and 26 weeks. Higher baseline ratios of 8PR/8WT also trended towards not obtaining low disease activity (DAS <1.6) and becoming a EULAR non-responder at 13 and 26 weeks. In the COBRA-treatment arm, a significant association was observed between high baseline 8PR/8WT ratios and higher DAS44 score at 26 weeks. Higher 8PR/8WT ratios were associated with non-response at week 26 based on both low disease activity and EULAR criteria.ConclusionThis study is the first to associate alterations in FPGS pre-mRNA splicing levels with reduced responsiveness to MTX treatment in RA patients.Trial registrationISRCTN55552928.

Rheumatological Diseases and Sleep: Somnological Aspects of Diagnostics and Therapy

70 % of patients suffering from rheumatological diseases report poor sleep quality, numerous awakenings at night and non-restorative sleep. More than 20 % of these patients are found to have primary sleep disorders such as obstructive sleep apnoea (OSA) and the restless legs syndrome (RLS). Primary and secondary sleep disorders may increase symptoms associated with rheumatological diseases, e. g. excessive daytime sleepiness, fatigue, depression, pain intensity, and disease activity. Vice versa, pain intensity and inflammatory markers worsen sleep quality. In patients with rheumatic diseases, obesity as well as disease-related skeletal characteristics may be predisposing factors for obstructive sleep apnoea. The restless legs syndrome, which frequently occurs in rheumatological diseases, lowers sleep quality due to a sensory stimulus and periodic leg movements causing sleep fragmentation. Somnological diagnostic investigation consists of sleep-related questionnaires and scales. Objective tests are used to measure reaction time and vigilance. Sleep-related breathing and movement disorders can be identified with screening devices and polygrafic monitoring. A final polysomnografic sleep study is necessary to make the diagnosis and to initiate a specific treatment and follow-up examinations. Sleep disorders associated with rheumatological diseases may be treated with behavioural and drug therapies. Drug therapy is commonly used in the management of insomnia and RLS. Most cases of OSAS can be treated with CPAP or UPS devices. Interdisciplinary cooperation in the fields of somnology and rheumatology may improve treatment in RA patients.

Development of citrullinated-vimentin-specific CAR for targeting Tregs to treat autoimmune rheumatoid arthritis

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by an aberrant inflammation of the synovial membrane that causes irreversible joint and bone damage. Regulatory T cells (Tregs) are defective in RA patients while adoptive transfer of expanded autologous Tregs efficiently reverse disease in collagen-induced arthritis, an animal model of RA. Moreover, providing an antigen (Ag) specificity to Tregs render them more potent to suppress abnormal inflammation by increasing specific activity and promoting selective migration to the Ag-expressing tissue, reducing the risk of pan-immunosuppression in the meantime. These studies strongly suggest that Treg therapy may be effective in the treatment of RA patients by reducing joint inflammation and inducing immune tolerance and may be improved by using Ag-specific Tregs. Therefore, we aimed to engineer Ag-specific Tregs from polyclonal Tregs using a chimeric antigen receptor (CAR) specifically targeting an Ag present in the joint of RA patients. We generated a CAR directed against a post-translationally modified intermediate filament protein, citrullinated vimentin (CV), an Ag found, abundantly and almost exclusively, in the extracellular matrix of the inflamed synovial tissue of the RA patients. CV-specific CAR was transduced into human Tregs that were efficiently activated, expanding and suppressing following CAR-mediated stimulation. Importantly, CV-CAR Tregs were shown to react with CV expressed in RA patient synovial fluid. Studies are underway to demonstrate the functional activity of these CV-CAR Tregs in in vivo mouse models, a validation step in the development of a promising therapeutic tool to treat RA and potentially other autoimmune disorders.

Adipocytokines in Rheumatoid Arthritis: The Hidden Link between Inflammation and Cardiometabolic Comorbidities.

Rheumatoid arthritis is a chronic autoimmune disease affecting typically synovial joints and leading to progressive articular damage, disability, and reduced quality of life. Despite better recent therapeutic strategies improving long-term outcomes, RA is associated with a high rate of comorbidities, infections, malignancies, and cardiovascular disease (CVD). Remarkably, some well-known pathogenic proinflammatory mediators in RA, such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF), may play a pivotal role in the development of CVD. Interestingly, different preclinical and clinical studies have suggested that biologic agents commonly used to treat RA patients may be effective in improving CVD. In this context, the contribution of adipocytokines has been suggested. Adipocytokines are pleiotropic molecules, mainly released by white adipose tissue and immune cells. Adipocytokines modulate the function of different tissues and cells, and in addition to energy homeostasis and metabolism, amplify inflammation, immune response, and tissue damage. Adipocytokines may contribute to the proinflammatory state in RA patients and development of bone damage. Furthermore, they could be associated with the occurrence of CVD. In this study, we reviewed available evidence about adipocytokines in RA, because of their involvement in disease activity, associated CVD, and possible biomarkers of prognosis and treatment outcome and because of their potential as a possible new therapeutic target.

Development of citrullinated-vimentin-specific CAR for targeting Tregs to treat autoimmune rheumatoid arthritis

Abstract Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases that is characterized by an aberrant inflammation of the synovial membrane that causes irreversible joint and bone damage. Regulatory T cells (Tregs) are defective in RA patients while adoptive transfer of expanded autologous Tregs efficiently reversed disease in collagen-induced arthritis (CIA), an animal model of RA. These studies strongly suggest that Treg therapy may be effective in the treatment of RA patients by reducing joint inflammation and inducing immune tolerance. However, clinical treatment with polyclonal Tregs may lead to general immunosuppression. Thus, the development of precise RA Ag-specific Tregs would increase specific activity, promote selective migration to the site of the abnormal inflammation and enhance their function. Thus, we engineered chimeric antigen receptor (CAR)-expressing Tregs specifically targeting an antigen present in the joint of RA patients to induce a localized and effective immunosuppressive response. We developed a single chain Fv directed against a posttranslational modified intermediate filament protein, citrullinated vimentin (CV), an antigen found, almost exclusively, in the extracellular matrix of the synovial tissue of the RA patients and implicated in the pathogenesis of the disease. The scFv was grafted into a functional CAR construct, transduced into human Tregs and shown to react with CV expressed in RA patient synovial fluid and CV-expressing cells. Studies are underway to demonstrate the functional activity of these CAR-expressing Tregs in in vivo mouse models a validation step in the development of a promising therapeutic tool to treat RA and potentially other autoimmune disorders.