Treatment Of Active Rheumatoid Arthritis Research Articles

Comparative efficacy of five approved Janus kinase inhibitors as monotherapy and combination therapy in patients with moderate-to-severe active rheumatoid arthritis: a systematic review and network meta-analysis of randomized controlled trials.

The European League of Rheumatology(EULAR)guidelines recommend Janus kinase (JAK) inhibitors for patients with moderate to severe rheumatoid arthritis (RA) who are insensitive or under-responsive to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). But there was no recommendation for which one was preferred in five currently approved JAK inhibitors. The objective of this network meta-analysis study was to evaluate the efficacy of five JAK inhibitors as monotherapy and combination therapy in patients with moderate-to-severe active rheumatoid arthritis. The randomized controlled trials (RCTs) of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy or combined with csDMARD in the treatment of active RA were searched in database of PubMed, Embase, Web of Science and Cochrane Library, up to December 2023. The control group included placebo or csDMARD. Outcome indicators included American College of Rheumatology 20% response (ACR20), ACR50, ACR70 and the percentage of patients achieving 28-joint disease activity score using C-reactive protein (DAS28(CRP))<2.6at 12 weeks and 24 weeks. The statistical analysis was performed by Stata14 and RevMan5.4. Data processing, network evidence plots, surface under the cumulative ranking curve (SUCRA) ranking, league plots and funnel plots were generated. Risk ratio (RR) and 95% confidence interval (95%CI) as effect sizes to analyze the statistics. This study included thirty-six RCTs with 16,713 patients. All JAK inhibitors were more effective than placebo in ACR20 (RRs ranging between 1.74 and 3.08), ACR50 (RRs ranging between 2.02 and 7.47), ACR70 (RRs ranging between 2.68 and 18.13), DAS28(CRP) < 2.6 (RRs ranging between 2.70 and 7.09) at 12 weeks. Upadacitinib 30mg and upadacitinib 15mg showed relatively good efficacy according to their relative SUCRA ranking. All JAK inhibitors were more effective than csDMARD or placebo in ACR20 (RRs ranging between 1.16 and 1.86), ACR50 (RRs ranging between 1.69 and 2.84), ACR70 (RRs ranging between 1.50 and 4.47), DAS28(CRP) < 2.6 (RRs ranging between 2.28 and 7.56) at 24 weeks. Upadacitinib 15mg + csDMARD and baricitinib 4mg + csDMARD showed relatively good efficacy according to their relative SUCRA ranking. The safety analysis results such as serious infection, malignancy, major adverse cardiovascular event (MACE), and venous thromboembolic events (VTE) showed no statistical difference. This NMA study indicated that all JAK inhibitors performed better than placebo. Based on the results of this study, upadacitinib 30mg, upadacitinib 15mg, upadacitinib 15mg + csDMARD and baricitinib 4mg + csDMARD were recommended treatment options with relatively good efficacy and safety. However, attention should be paid to monitoring the occurrence of adverse events in high-risk RA patients with medication. Combination therapy with csDMARD might be more suitable for the maintenance of long-term efficacy. However, in clinical practice, it is still necessary to select the appropriate therapeutic regimen based on the actual clinical situation.

A multi-center, open-label, randomized study to explore efficacy and safety of baricitinib in active primary Sjogren’s syndrome patients

BackgroundPrimary Sjogren’s syndrome (pSS) is a systemic autoimmune disease involving multiple organ systems. The Janus kinase/signal transduction and activator of transcription (JAK/STAT) signaling pathway is a key pathway involving the pathogenesis of pSS. Baricitinib, a selective JAK1 and JAK2 inhibitor, has been approved for treatment of active rheumatoid arthritis and reported in treatment of some other autoimmune diseases including systemic lupus erythematosus. We have found that baricitinib might be effective and safe in pSS in a pilot study. However, there is no published clinical evidence of baricitinib in pSS. Hence, we conducted this randomized study to further explore the efficacy and safety of baricitinib in pSS.MethodsThis is a multi-center, prospective, open-label, randomized study to compare the efficacy of baricitinib + hydroxychloroquine (HCQ) with HCQ alone in pSS patients. We plan to involve 87 active pSS patients with European League Against Rheumatism pSS disease activity index (ESSDAI) ≥ 5 from eight different tertiary centers in China. Patients will be randomized (2:1) to receive baricitinib 4 mg per day + HCQ 400 mg per day or HCQ 400 mg per day alone. We will switch HCQ to baricitinib + HCQ if the patient in the latter group has no ESSDAI response at week 12. The final evaluation will be at week 24. The primary endpoint is the percentage of ESSDAI response, or minimal clinically important improvement (MCII), which was defined as an improvement of ESSDAI at least three points at week 12. The secondary endpoints include EULAR pSS patient-reported index (ESSPRI) response, change of Physician’s Global Assessment (PGA) score, serological activity parameters, salivary gland function test, and focus score on labial salivary gland biopsy.DiscussionThis is the first randomized controlled study to evaluate the clinical efficacy and safety of baricitinib in pSS. We hope that the result of this study can provide more reliable evidence of the efficacy and safety of baricitinib in pSS.Trial registrationClinicalTrials.gov NCT05016297. Registered on 19 Aug 2021.

Rheumatoid arthritis patients initiating rituximab with low number of previous bDMARDs failures may effectively reduce rituximab dose and experience fewer serious adverse events than patients on full dose: a 5-year cohort study

BackgroundRituximab is used for the treatment of active rheumatoid arthritis. In the present study, we examined the long-term flare risk and safety of reduced doses of rituximab.Patients-methodsThis was a prospective, observational, single-center study of patients starting rituximab on standard dose (SD). Patients were switched to low dose (LD) (1 g every 6 months), based on the treating rheumatologist’s decision after having achieved sustained clinical responses, while the rest of the patients continued on standard dose (SD). During a 60-month period, we assessed (Kaplan–Meier survival analysis) the relapse rate (increase ≥ 1.2 in DAS28-ESR for ≥ 6 months) and discontinuations due to treatment failure in the low dose group, and we compared the incidence of serious adverse events (SAEs) between LD and SD groups.ResultsOut of 361 patients [females 83.4%, mean age 61.9 (10.6) years, seropositive 50.3%, median total comorbidities count 4], 81 patients (22.4%) entered LD in a median time of 24 months (95% CI 18–30 months). Seropositivity (OR 1.823), more than 2 previous bDMARDs failures (OR 0.428), and DAS28 < 4.88 at 6 months (OR 2.329) predicted the odds of entering LD (p < 0.05 for all). During 60 months of follow-up, only 7.5% of patients on LD relapsed. Patients on LD had significantly less SAEs and all-cause hospitalizations as compared to the SD group (p < 0.05 for all). Linear regression analysis showed that previous hospitalization while on bDMARDs (p < 0.0001), use of prednisolone > 5 mg/day while on rituximab (p < 0.0001), and a history of ≥ 2 previous csDMARDs (p = 0.041) predicted the risk of SAEs.ConclusionIn a cohort of patients with established RA and significant comorbidities who taper rituximab after substantial initial disease activity improvement, a low rate of relapses and lower risk of SAEs compared to SD were recorded. Seropositivity, a lower number of previous bDMARDs use, and lower DAS28 at 6 months predicted the probability of entering the LD regimen.

Is Janus Kinase Inhibition the Future of the Management of Rheumatoid Arthritis-associated Interstitial Lung Disease?

Interstitial lung disease is a leading complication of rheumatoid arthritis (RA). However, no drugs are yet available to treat these pulmonary and articular diseases together, although several agents show promise. Janus kinase inhibitors have found increasing favour among rheumatologists in the treatment of active RA because they can rapidly reduce articular disease activity and because they have a simple oral dosing regime and good patient acceptability. There are many plausible reasons to believe that Janus kinase inhibitors may delay the onset and improve the outcomes of RA-associated interstitial lung disease, in tandem with their beneficial articular effects. This editorial describes the rationale for exploring this possibility further.

Efficacy and Safety of Azathioprine during Remission of Immune-Mediated Thrombotic Thrombocytopenic Purpura

▪IntroductionAcquired immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy caused by the development of anti-ADAMTS13 autoantibodies. Up to 50% of patients surviving an acute iTTP event experience one or more relapses. Recent guidelines suggest treatment with rituximab in clinical remission in iTTP patients with low ADAMTS13 activity to prevent acute iTTP relapses. A 10% of cases who do not respond to rituximab or develop allergic reactions requiring therapy discontinuation have been reported. In these patients, azathioprine might be an alternative treatment to prevent acute iTTP relapses. The aim of this study was to assess the efficacy and safety of azathioprine treatment in iTTP patients in clinical remission.MethodsWe designed a retrospective cohort study including all iTTP patients treated with azathioprine during clinical remission, enrolled in the Milan TTP Registry between May 2003 and October 2020 and followed for at least six months.The efficacy of azathioprine was assessed in patients with at least four weeks of treatment. The primary outcome was clinical relapse during azathioprine treatment. The secondary outcomes were the partial and complete responses of ADAMTS13 (an ADAMTS13 activity increase above 20% and 45%, respectively) in patients with ADAMTS13 activity below 20% before azathioprine start. ADAMTS13 relapse (an ADAMTS13 activity decrease below 20%) in patients with a prior ADAMTS13 response was also assessed.As for the safety analysis, adverse events (AEs), associated or not with treatment discontinuation, were retrieved from clinical charts of all patients.Lastly, we assessed the association between variables such as sex, age, and concomitant autoimmune diseases, and ADAMTS13 response, using logistic regression models.ResultsWe enrolled 43 patients with iTTP treated with azathioprine during clinical remission (Table 1). Forty-two percent of the patients had at least one concomitant autoimmune disease. The median exposure to azathioprine was 16 months (interquartile range [IQR] 8-49 months), the median dosage 1.3 mg/kg/day (IQR 0.9-1.6 mg/kg/day).Thirty-five cases were available for the primary outcome analysis (Table 2). Seven patients relapsed after a median time of 14 months after azathioprine start (IQR 8-58 months). The cumulative incidence of clinical relapse during azathioprine treatment was 10% at 1 year (95% Confidence Interval [CI] 0-21%), 22% at 2 years (95% CI 6-38%).Twenty-one cases were available for the secondary outcomes analysis. An ADAMTS13 partial response occurred in 10 patients (48%), after a median time of 3 months (IQR 3-9 months) after azathioprine start and lasted for a median time of 40 months (IQR 16-56 months). An ADAMTS13 complete response was achieved in 33% of patients, after a median time of 8 months (IQR 3-16 months) after azathioprine start and lasted for a median time of 16 months (IQR 0-53 months). Of the 10 responders, 3 (30%) had a subsequent ADAMTS13 relapse at 22, 24 and 37 months after azathioprine start.Adverse events were observed in 30% of patients, after a median time of 50 days after azathioprine start (IQR 26-331 days). Liver and pancreas alterations with increased levels of ALT, AST, GGT, ALP and lipase were the most frequent, followed by nausea and leukopenia (Table 3). In one patient, acute myeloid leukemia was diagnosed 6 months after azathioprine start. Fifteen percent of the patients had to stop the treatment due to AEs.No demographic or anamnestic variables were associated with ADAMTS13 response to azathioprine.ConclusionsForty-eight percent of patients attained an ADAMTS13 activity above 20%, with a durable response lasting more than 3 years, while adverse events were generally mild in nature. Azathioprine could be a valid and safe alternative in case of ineligibility or failure to respond to rituximab. [Display omitted] DisclosuresMancini: Instrumentation Laboratory, Sanofi: Honoraria. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. OffLabel Disclosure:Azathioprine. It is an immunosuppressive drug used for the prevention of rejection in renal homotransplantation and for treatment of active rheumatoid arthritis.

Lymphocyte modulation by tofacitinib in patients with rheumatoid arthritis.

Tofacitinib is an oral small molecule targeting the intracellular Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100nM tofacitinib for 20h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme-linked immunosorbent assay (ELISA) analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] and T [interferon (IFN)-γ, IL-17 or TNF-α] cells in the short term, while a significant reduction of IL-17 and IL-6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.

Efficacy and safety of jakinibs in rheumatoid arthritis: a systematic review and meta-analysis.

To assess the efficacy and safety of jakinibs for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response or intolerance to conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). A systematic search was conducted in PubMed, Embase, and the Cochrane Library. Randomized placebo-controlled trials (RCTs) of jakinibs in RA patients were eligible. The effective outcome was RA improvement to reach an American College of Rheumatology 20%/50%/70% (ACR20/50/70) response rate at weeks 12 and 24 after treatment. The safety outcomes included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events, infections, and serious infections. Twenty-eight randomized, double-blind, controlled trials including 14,500 patients were included. At both weeks 12 and 24, the pooled analysis suggested effective treatment with jakinibs, represented as an increased clinical response of ACR20, ACR50, and ACR70. Subgroup analysis based on different types of jakinibs demonstrated that only peficitinib treatment had no impact on the clinical response of ACR50 or ACR70 at week 12. Jakinibs were associated with an increased incidence of infections at week 12 and TEAEs and infections at week 24. No increase in the risk of SAEs, discontinuations due to adverse events, or serious infections was observed in comparisons between treatment with jakinibs and treatment with placebo in these patients. Jakinibs are efficacious and well tolerated in RA patients up to 24 weeks, although they are associated with an increased risk of infectious complications. Key Points • ACR20/50/70 in patients treated with jakinibs was significantly higher than those in patients treated with placebo. • No difference in ACR50/70 was observed in patients with RA treated with peficitinib and placebo. • Jakinibs are beneficial and well tolerated in RA treatment.

Cost-Effectiveness of Repository Corticotropin Injection versus Standard of Care for the Treatment of Active Rheumatoid Arthritis.

IntroductionPatients with active rheumatoid arthritis (RA) often have inadequately controlled symptoms and are unable to achieve remission or low disease activity despite aggressive treatment. This results in irreversible joint damage, adversely affecting patients’ physical and social functioning. The objective was to estimate the cost-effectiveness of repository corticotropin injection (RCI) versus standard of care (SoC) in patients with active RA from the United States (US) payer and societal perspectives over two to three years.MethodsAn individual-level microsimulation was developed to generate individual trajectories for patients with RA, using data from a published Phase 4 trial of RCI. These trajectories report a patient’s disease pathway and associated cost and quality-of-life outcomes. The incremental cost-effectiveness ratio (ICER) of RCI versus SoC was assessed using the literature-derived direct medical and indirect costs, and quality-adjusted life-years (QALY) derived from a Phase 4 trial of RCI. The uncertainty in base case estimates of the parameters was evaluated in the sensitivity analysis.ResultsOver two years, RCI has an incremental QALY gain of 1.591 and incremental cost of $183,965 and $117,443 from payer and societal perspective, respectively, resulting in an ICER of $115,629/QALY and $73,817/QALY compared to SoC. Over three years, RCI has an incremental QALY gain of 2.336 and incremental cost of $202,315 and $104,506 from payer and societal perspective, respectively, resulting in an ICER of $86,607/QALY and $44,737/QALY compared to SoC. Results from the probabilistic sensitivity analysis are consistent with those of the base case model.ConclusionRCI is a cost-effective strategy for patients with persistently active RA who are previously treated with disease-modifying anti-rheumatic drugs and corticosteroids compared to SoC over two to three years from the payer and societal perspectives at a US willingness-to-pay threshold of $150,000/QALY. Further, the economic benefit of RCI is realized with improvement in a patient’s clinical and health outcomes.

Clinical pharmacology of filgotinib in the treatment of rheumatoid arthritis: current insights

ABSTRACT Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose natural course has been deeply modified thanks to the development of new therapeutic approaches. The Janus kinase inhibitors (Jakinibs) represent the newest class of drugs introduced for treating RA. Among these, Filgotinib (FIL) has been developed as Janus kinase1 (JAK1) selective inhibitor, specifically targeting key pro-inflammatory mediators in RA pathogenesis. Areas covered This narrative review provides an overview on FIL as new therapeutic approach for RA, with focus on its pharmacological properties, clinical efficacy, and safety profile. The following electronic databases were adopted for the study search: PubMed, Google Scholar, ClinicalTrials.gov and archive from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Expert opinion The phase II and phase III randomized controlled trials (RCTs) performed so far and their long-term extensions showed a comparable clinical efficacy of FIL to biologic treatments, with an acceptable safety profile. Thanks to these data, FIL was approved in Europe and Japan for the treatment of active RA, increasing the spectrum of therapeutic approaches and improving the possibility of a more tailored therapeutic strategy. Real-life data and head-to-head clinical trials will be needed to confirm its efficacy and safety.

Randomised study of PF-06410293, an adalimumab (ADL) biosimilar, compared with reference ADL for the treatment of active rheumatoid arthritis: results from weeks 26–52, including a treatment switch from reference ADL to PF-06410293

ObjectiveTo investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar adalimumab (ADL) PF-06410293 (ADL-PF; adalimumab-afzb) versus EU-sourced reference ADL (ADL-EU) in patients with active rheumatoid arthritis (RA) on longer-term treatment...

Systemic pharmacological investigation of the Feng Shi Gu Tong capsule in the treatment of rheumatoid arthritis.

Feng Shi Gu Tong (FSGT) capsule is a commonly used Chinese Traditional Patent Medicine in clinical practice, which has been proven to be effective for the treatment of active rheumatoid arthritis (RA). However, due to its complex composition, the precise molecular mechanism of the FSGT capsule in the treatment of RA is still indistinct. Therefore, the method of systemic pharmacology was used to obtain candidate compounds through absorption, distribution, metabolism, elimination (ADME) parameters, and supplementation of references. Network construction and analysis were also included to reveal the potential mechanism of FSGT capsule in treating RA. A total of 119 compounds were obtained in FSGT capsule, and a total of 107 compounds with targets were included in the study. These compounds acted on 267 targets in total. In addition, there were 317 targets related to RA disease. All constructed networks included four major networks and four minor networks. In addition, the clusters of RA disease protein-protein interaction (PPI) network and FSGT capsule-RA disease targets network revealed that the biological process involved in these clusters including immune response and apoptosis, etc. The pathways enriched by the direct targets of FSGT capsule acted on RA also highly overlapped with the pathways enriched by the RA PPI network, such as the TNF signaling pathway. Our research has managed to predict and explain the pharmacological effects and the molecular mechanisms of the FSGT capsule in RA, and provided a realistic exploration method for studying the potentially active ingredients of traditional Chinese medicines simultaneously.

62] The mystery of gross haematuria in a patient on leflunomide: A case report and literature review

ObjectiveTo report a case of gross haematuria in a patient on leflunomide. In 1998, the USA Food and Drug Administration approved leflunomide for the treatment of active rheumatoid arthritis. Leflunomide is classified as a disease-modifying anti-rheumatic drug (DMARD), which has immunomodulatory, anti-inflammatory, analgesics, and antipyretic effects.

Add-on Clarithromycin and Tacrolimus Treatment for Rheumatoid Arthritis

A 67-year-old woman suffering from rheumatoid arthritis (RA) presented with gradual exacerbation of arthralgia and/or articular swellings. She was diagnosed with RA at 62 years of age and successfully treated using methotrexate (MTX) in combination with loxonin (LOX). Three months after this treatment, cytopenia occurred as a side effect of MTX; therefore, MTX was stopped. Thereafter, RA had been largely controlled using salazosulfapyridine in combination with prednisolone and LOX for almost 4 years. On this visit, because RA became worse, clarithromycin (CAM) was added in expectation of its anti-inflammatory effects on RA. CAM treatment was effective for RA, to a certain extent; however, the RA activity was not sufficiently suppressed. In order to suppress the RA activity further, tacrolimus (TAC), an armament in the treatment for active RA in Japan, was added. Three months after initiating TAC treatment, the RA activity was considerably suppressed. This case shows that physicians should consider add-on CAM and TAC treatment when existing ant-rheumatic agents show little effects on RA.

Treatment of active rheumatoid arthritis: comparison of patients younger vs older than 75 years (CORPUS cohort)

ABSTRACTObjectives: Little information is available on the characteristics of elderly patients starting TNFα antagonist treatment for rheumatoid arthritis (RA). The objective of this work was to compare prescription patterns in RA patients younger vs. older than 75 years.Methods: Biologic-naive patients with active RA (DAS28 > 3.2) despite first-line therapy were included between 2007 and 2009 in the prospective, multicentre, longitudinal, observational, population-based CORPUS-RA cohort. TNFα antagonist users were defined as having received at least one TNFα antagonist during the first study year. The groups < 75 years and ≥ 75 years were compared regarding comorbidities, inflammation (CRP and ESR), disease activity (DAS28), disability (HAQ-DI), number of physician visits, and treatment. To verify the impact of the cut off, we also compared patients aged 70 years or more to patients younger than 70 years.Results: Of 543 RA patients, 382 had complete one-year follow-up data, including 114 TNFα antagonist users, 3 (6%) among the 49 patients aged 75 years or over and 111 (32%) of the 333 patients younger than 75 years (p < 0.01). Disease activity in the two age groups was similar at inclusion and after one year. Comorbidities and a history of auto-immunity were more common in the older group. Compared to their younger counterparts, the older patients received glucocorticoids more often (p = 0.003) and synthetic disease-modifying anti-rheumatic drugs less often (p = 0.01).Conclusion: TNFα antagonists are used less often and glucocorticoids more often in elderly patients with active RA compared to their younger counterparts. The fact that this study was performed in 2007–9 is a limitation in terms of relevance to today’s patients and further studies should be conducted in new cohorts of active RA.

A comparative clinical study of PF-06410293, a candidate adalimumab biosimilar, and adalimumab reference product (Humira\xae) in the treatment of active rheumatoid arthritis

BackgroundThis double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10–25 mg/week). We report results for the first 26 weeks of treatment.MethodsPatients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (−12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28–4(CRP)], European League Against Rheumatism (EULAR) response, DAS28–4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26.ResultsPatients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28–4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was −2.98% and corresponding CIs—95% CI (−10.38%, 4.44%) and 90% CI (−9.25%, 3.28%)—were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU).ConclusionsThe study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX.Trial registrationClinicalTrials.gov Identifier: NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29. Start date: October 27, 2014.

Comparison of the impact of Tripterygium wilfordii Hook F and Methotrexate treatment on radiological progression in active rheumatoid arthritis: 2-year follow\xa0up of a randomized, non-blinded, controlled study

BackgroundTripterygium wilfordii Hook F (TwHF) alone or in combination with methotrexate (MTX) has been shown to be more effective than MTX monotherapy in controlling the manifestations in subjects with disease-modifying antirheumatic drug (DMARD)-naïve active rheumatoid arthritis (RA) over a 6-month period. The long-term impact of these therapies on disease activity and radiographic progression in RA has not been examined.MethodsPatients with DMARD-naïve RA enrolled in the “Comparison of Tripterygium wilfordii Hook F with methotrexate in the Treatment of Active Rheumatoid Arthritis” (TRIFRA) study were randomly allocated into three arms with TwHF or MTX or the two in combination. Clinical indexes and radiographic data at baseline and year 2 was collected and compared using an intent-to-treat (ITT) and a per-protocol (PP) analysis. Two radiologists blinded to the treatment scored the images independently.ResultsOf 207 subjects 109 completed the 2-year follow up. The number of subjects withdrawing from the study and the number adhering to the initial regimens were similar among the three groups (p > = 0.05). In the ITT analysis, proportions of patients reaching American College of Rheumatology 50% (ACR50) response criteria were 46.4%, 58.0% and 50.7% in the MTX, TwHF and MTX + TwHF groups (TwHF vs MTX monotherapy, p = 0.004). Similar patterns were found in ACR20, ACR70, Clinical Disease Activity Index good responses, European League Against Rheumatism good response, remission rate and low disease activity rate at year 2. The results of the PP analysis agreed with those in the ITT analysis. The changes in total Sharp scores and joint erosion and joint space narrowing during the 2 years were associated with changes in disease activity measured by the 28-joint count Disease Activity Score and were comparable among the three groups (p > 0.05). Adverse events were similar in the three treatment groups.ConclusionsDuring the 2-year therapy period, TwHF monotherapy was not inferior to MTX monotherapy in controlling disease activity and retarding radiological progression in patients with active RA.Trial registrationThis is a follow-up study. Original trial registration: ClinicalTrials.gov, NCT01613079. Registered on 4 June 2012.

Tofacitinib in the treatment of active rheumatoid arthritis in adults.

Tofacitinib, a pan Janus kinase inhibitor, has been investigated as monotherapy in patients naive to methotrexate and in methotrexate incomplete responders and in combination with disease-modifying antirheumatic drugs in antirheumatic drug incomplete responders and TNF inhibitor failures in the Phase II and III programs. The clinical trial program demonstrated efficacy and a reasonable safety profile in these disease populations that has led to the approval of tofacitinib 5mg twice daily orally in many countries. The pharmacology, chemistry, pharmacokinetics, pharmacodynamics, efficacy and safety in the Phase II and III clinical trials, safety in the long-term extension studies and postmarketing safety reports are the focus of this review.

Effect of Artemisia annua extract on treating active rheumatoid arthritis: A randomized controlled trial.

To investigate the effect and safety of the complementary use of the extract of Artemisia annua L. (EAA) on treating active rheumatoid arthritis (RA). A randomized controlled clinical trial was performed. All the 159 participates with active RA were randomly assigned to the control group (80 cases) and EAA group (79 cases) using concealed random allocation method. In the control group, patients were medicated with leflflunomide and methotrexate for 48 weeks; and patients in the EAA group were administrated with leflflunomide, methotrexate plus EAA (30 g/d). At the time points of 0, 12, 24 and 48 weeks, the clinical outcome measures, including objective pain score, tenderness score, number of painful joints, number of swollen joints, health assessment questionnaire (HAQ) score for quality of life, levels of serum rheumatoid factor (RF), anti-cyclic citrullinated protein antibodies (CCP-Ab), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), visual analogue score for pain (VAS), and the overall effificacy were detected and recorded. The objective pain score, number of painful joints and ESR at 12 weeks, tenderness score and HAQ at 24 weeks, and the tenderness score, number of painfull joints, number of swollen joints, HAQ, CRP, RF and CCP-Ab at 48 weeks were signifificantly improved in the EAA group compared with the control group (P<0.01 or P<0.05). At 24 and 48 weeks, the overall effificacy of the EAA group was signifificantly higher than the control group (P<0.01). There were signifificantly higher withdrawal rate of corticosteroids within 12 weeks post-treatment and lower incidence rate of adverse effects in the EAA group compared with the control group (P<0.01 or P<0.05). EAA plus methotrexate and leflflunomide were more effective and safer than the routine use of methotrexate and leflflunomide in the treatment of active RA.

Plasmapheresis therapy in combination with TNF-α inhibitor and DMARDs: A multitarget method for the treatment of rheumatoid arthritis

Objective: To evaluate the effects of a multitarget method involving plasmapheresis therapy combined with tumor necrosis factor (TNF)-α inhibitor and disease-modifying antirheumatic drugs (DMARDs) on disease activity parameters in the treatment of active rheumatoid arthritis (RA).Methods: Sixty-five patients with active RA were divided into two groups according to the treatment administered: the plasmapheresis combination therapy group (Plasmapheresis combination group; 38 cases), in which patients received plasmapheresis therapy along with a TNF-α inhibitor (recombinant human tumor necrosis factor-Fc; rhTNFR:Fc; Etanercept biosimilars) and DMARDs, and a TNF-α inhibitor therapy group (biological agent group; 27 cases), in which patients received a TNF-α inhibitor and DMARDs. Clinical parameters were measured before and at 4 and 24 weeks after treatment.Results: ACR20, ACR50, and ACR70 responses at week 4 were achieved in 84.2%, 78.9%, and 60.5% of the patients in the plasmapheresis combination group, respectively, and 74.1%, 55.6%, and 29.6% of the patients in the biological agent group, respectively. The ACR50 and ACR70 response rates were superior in the former than the latter group (p < 0.05). Similar patterns of statistical significance were observed for ACR20, ACR50, and ACR70 responses at week 24 after the treatment. ACR50 responses were achieved in 84.2% patients and ACR70 responses were achieved in 76.3% patients in the plasmapheresis combination group, and these proportions were better than those in the biological agent group (p < 0.05).Conclusions: The multitarget method combining plasmapheresis, TNF-α inhibitor, and DMARDs for RA therapy was superior to the combination of TNF-α inhibitor for reducing disease activity parameters in patients with active RA.

Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial

Tumour necrosis factor (TNF) inhibition and B-cell depletion are highly effective treatments for active rheumatoid arthritis, but so far no randomised controlled trials have directly compared their safety, efficacy, and cost-effectiveness. This study was done to test the hypothesis that using rituximab would be clinically non-inferior and cheaper compared with TNF inhibitor treatment in biological-treatment naive patients with rheumatoid arthritis. This open-label, randomised controlled, non-inferiority trial enrolled patients with active, seropositive rheumatoid arthritis and an inadequate response to synthetic disease modifying anti-rheumatic drugs (DMARDs) from 35 rheumatology departments in the UK. Patients were randomly assigned 1:1 to the rituximab or TNF inhibitor groups with minimisation to account for methotrexate intolerance using a web-based randomisation system. Patients were given intravenous rituximab 1 g on days 1 and 15, and after 26 weeks if they responded to treatment but had persistent disease activity (28 joint count disease activity score [DAS28-ESR] >3.2; rituximab group) or a TNF inhibitor-adalimumab (40 mg subcutaneously every other week) or etanercept (50 mg per week subcutaneously) according to the patient's and rheumatologist's choice (TNF inhibitor group). Patients could switch treatment in the case of drug-related toxic effects or absence or loss of response. The primary outcome measure was the change in DAS28-ESR between 0 and 12 months in the per-protocol population of patients who were assigned to treatment and remained in follow-up to 1 year. We assessed safety in all patients who received at least one dose of study drug. We also assessed the cost-effectiveness of each strategy. The non-inferiority margin was specified as 0.6 DAS28-ESR units. This study is registered with ClinicalTrials.gov, number NCT01021735. Between April 6, 2009, and Nov 11, 2013, 295 patients were randomly assigned and given either rituximab (n=144) or TNF inhibitor (n=151) treatment. After 12 months, the change in DAS28-ESR for patients assigned to rituximab was -2.6 (SD 1.4) and TNF inhibitor was -2.4 (SD 1.5), with a difference within the prespecified non-inferiority margin of -0.19 (95% CI -0.51 to 0.13; p=0.24). The health-related costs associated with the rituximab strategy were lower than the TNF inhibitor strategy (£9,405 vs £11,523 per patient, p<0.0001). 137 (95%) of 144 patients in the rituximab group and 143 (95%) of 151 patients in the TNF inhibitor group had adverse events. 37 serious adverse events occurred in patients receiving rituximab compared with 26 in patients receiving TNF inhibitors, of which 27 were deemed to be possibly, probably, or definitely related to the treatment (15 vs 12, p=0.5462). One patient in each group died during the study. Initial treatment with rituximab is non-inferior to initial TNF inhibitor treatment in patients seropositive for rheumatoid arthritis and naive to treatment with biologicals, and is cost saving over 12 months. Arthritis Research UK, Roche.