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ID PMID Title PublicationDate abstract
29578394 Comparative efficacy and safety of TNF-inhibitor plus methotrexate versus oral triple ther 2018 Jun AIMS: The study aimed to assess the efficacy and safety of tumor necrosis factor inhibitor (TNFI) with methotrexate (MTX) vs. oral triple therapy in patients with active rheumatoid arthritis (RA), showing inadequate response to MTX. MATERIALS AND METHODS: We performed a meta-analysis of three randomized controlled trials (RCTs) (913 MTX-resistant RA patients) to examine the relative efficacy and safety of TNFI+MTX compared to triple therapy (hydroxychloroquine, sulfasalazine, MTX) in patients with RA responding inadequately to MTX. RESULTS: The American College of Rheumatology's 70% improvement (ACR70) response rate was significantly higher for TNFI+MTX-treated patients than for triple therapy-treated controls (RR 1.549, 95% confidence interval (CI) 1.087 - 2.207, p = 0.016). However, the ACR20 and ACR50 response rates did not differ between the TNFI+MTX group and the triple therapy group. The total Sharp score was significantly lower in TNFI+MTX-treated patients than in triple therapy-treated controls (SMD -0.173, 95% CI -0.301 to -0.045, p = 0.008). There was no significant difference related to the number of patients with serious adverse events between the TNFI+MTX group and the triple therapy group (RR 1.033, 95% CI 0.710 - 1.504, p = 0.864); however, TNFI+MTX resulted in higher infection rates than triple therapy (RR 1.513, 95% CI 1.149 - 1.992, p = 0.004). CONCLUSION: TNFI+MTX was found to be more effective than triple therapy in active RA patients inadequately responsive to MTX, but it is associated with a higher risk of infection.
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29119481 Prevalence of rheumatoid cachexia assessed by bioelectrical impedance vector analysis and 2018 Mar Rheumatoid arthritis (RA) patients frequently have changes in their body composition, with a decrease in muscle mass and an increase in fat mass, a syndrome that is termed rheumatoid cachexia (RC). The prevalence of this nutritional alteration is not well known; there is as yet no consensus, seeing as it depends on the methods, techniques, and cutoff points that are used for its diagnosis. The main aim of this study was to identify RC through assessment by bioelectrical impedance vector analysis (BIVA) and its association with metabolic causes, physical function, and the main disease status, among others. The prevalence of RC was identified in those subjects who fell outside the right lower quadrant of the reference curve of RXc graph of BIVA. Clinical, anthropometric, biochemical and physical activity, emotional status, and diet markers were also evaluated. Ninety-four patients were included (92.55% women). The prevalence of RC assessed by BIVA was 21.28%. BIVA-cachexia patients had a lesser value of handgrip strength vs. patients without BIVA-cachexia 10.2 kg (7.2-13.4) vs. 14.7 kg (9.6-19), p = 0.0062. Disability and folic acid with methotrexate consumption are related to BIVA-cachexia ((OR 4.69, 95% CI 1.33, 16.54, p = 0.016) and (OR 0.19, 95%CI 0.058, 0.651, p = 0.008), respectively). BIVA could represent a valuable tool to assess presence of RC. It is important that RA patients have physical therapy to improve their nutritional status.
29546668 Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti- 2018 Sep As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Pfizer) of tofacitinib (TOF; Xeljanz(®)) to submit evidence of the drug's clinical and cost-effectiveness in the treatment of rheumatoid arthritis (RA) after the failure of conventional disease-modifying antirheumatic drugs (cDMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost-effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for TOF is based predominantly on four randomised controlled trials (RCTs) comparing the efficacy of TOF against placebo. Three RCTs investigated TOF in combination with methotrexate (MTX), and one RCT investigated TOF monotherapy. All four RCTs compared TOF with placebo plus cDMARDs, one RCT also included adalimumab as a comparator. The study population in the four RCTs comprised patients who were MTX inadequate responders or cDMARD inadequate responders (cDMARD-IR). The company performed network meta-analyses (NMA) to assess the relative efficacy of TOF compared with biologic DMARDs (bDMARDs) in patients who were cDMARD-IR or bDMARD-IR with moderate-to-severe RA for European League Against Rheumatism (EULAR) response and change in the Health Assessment Questionnaire Disability Index at 6 months. The company's NMA concluded that TOF had comparable efficacy to bDMARDs currently recommended by NICE. The company submitted a de novo model that assessed the cost-effectiveness of TOF versus its comparators in six different populations: (1) cDMARD-IR with severe RA; (2) cDMARD-IR with severe RA for whom MTX is contraindicated or not tolerated; (3) bDMARD-IR; (4) bDMARD-IR for whom rituximab (RTX) is contraindicated or not tolerated; (5) bDMARD-IR for whom MTX is contraindicated or not tolerated; and, (6) cDMARD-IR with moderate RA. According to the company's economic analyses, in cDMARD-IR with severe RA, TOF plus MTX dominates or extendedly dominates most comparators, whilst TOF monotherapy is slightly less effective and less expensive than its comparators, with the cost saved per quality-adjusted life year (QALY) lost always higher than £50,000. In bDMARD-IR with severe RA, RTX plus MTX dominated TOF plus MTX, but in patients for whom RTX was not an option, TOF plus MTX dominated all comparators included in the analysis (four comparators recommended by NICE were not included). In cDMARD-IR with moderate RA, the cost per QALY for TOF in combination with MTX or as monotherapy compared with a sequence of cDMARDs was estimated to be greater than £50,000/QALY. The ERG identified a number of limitations in the company's analyses, including use of a fixed-effects model in the NMA and the use of treatment sequences in the cost-effectiveness model which did not reflect NICE recommendations. These limitations were addressed partly by the company during the clarification round and partly by the ERG. The exploratory analyses undertaken by the ERG resulted in similar conclusions: (1) TOF plus MTX was dominated by RTX plus MTX; (2) TOF in combination with MTX or as monotherapy dominates or extendedly dominates some of its comparators in cDMARD-IR and bDMARD-IR with severe RA for whom RTX plus MTX was not an option; and (3) in cDMARD-IR with moderate RA, the cost per QALY of TOF in combination with MTX or as a monotherapy versus cDMARDs was in excess of £47,000. The NICE Appraisal Committee consequently recommended TOF plus MTX as an option for patients whose disease has responded inadequately to intensive therapy with a combination of cDMARDs only if (1) disease is severe [a Disease Activity Score (DAS28) of more than 5.1] and (2) the company provides TOF with the discount agreed in the Patient Access Scheme (PAS). TOF plus MTX is also recommended as an option for adults whose disease has responded inadequately to, or who cannot have, other DMARDs, including at least one bDMARD, only if (1) disease is severe, (2) they cannot have RTX, and (3) the company provides TOF with the discount agreed in the PAS. For patients who are intolerant of MTX, or where MTX is contraindicated, TOF monotherapy is recommended where TOF plus MTX would be recommended.
29882210 Sarilumab for Previously-Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Revi 2018 Dec As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Sanofi Genzyme) of sarilumab (SAR; Kevzara(®)) to submit evidence of its clinical effectiveness and cost-effectiveness for previously treated moderate or severe rheumatoid arthritis (RA). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical effectiveness and cost-effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for SAR was based predominantly on five randomised controlled trials comparing the efficacy of SAR against adalimumab, tocilizumab or placebo. The clinical effectiveness review identified no head-to-head evidence on the efficacy of SAR against all the comparators within the scope. Therefore, the company performed three network meta-analyses (NMAs) in two different populations: two in patients who had had an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARDs) (one for combination therapies and one for monotherapies) and the other one in patients who had had an inadequate response to tumour necrosis factor inhibitors (TNFis). The company's NMAs concluded that SAR in combination with cDMARDs or as monotherapy has a statistically superior efficacy to cDMARDs and a comparable efficacy to most biologic disease-modifying antirheumatic drugs (bDMARDs) in both populations. The company submitted a Markov model that assessed the cost-effectiveness of SAR from the perspective of the National Health Service (NHS) and Personal Social Services in seven different populations: (1) patients with severe RA who have had an inadequate response to cDMARDs (cDMARD-IR); (2) cDMARD-IR patients with severe RA for whom methotrexate (MTX) is contraindicated or not tolerated; (3) patients with severe RA who have had an inadequate response to a TNFi (TNFi-IR); (4) TNFi-IR patients with severe RA for whom rituximab (RTX) is not an option; (5) TNFi-IR patients with severe RA for whom MTX is contraindicated or not tolerated; (6) TNFi-IR patients after RTX; and (7) cDMARD-IR patients with moderate RA whose 28-joint Disease Activity Score (DAS28) is between 4.0 and 5.1. The company's economic evaluation resulted in incremental cost-effectiveness ratios (ICERs) lower than £20,000 per quality-adjusted life year (QALY) gained for SAR in combination with MTX or as monotherapy versus its comparators when the comparators were less effective, and it resulted in cost savings higher than £60,000 per QALY lost when SAR was less effective, except in TNFi-IR patients who are RTX eligible (where the ICER for SAR + MTX compared with RTX + MTX was £130,691 per QALY gained) and in patients with moderate RA and a DAS28 of > 4.0 (where the ICER of SAR + MTX compared with MTX was £38,254 per QALY gained). Following a critique of the model, the ERG undertook exploratory analyses after applying two changes to the company's model: (1) use of a latent class approach to model Health Assessment Questionnaire Disability Index (HAQ-DI) progression for patients on cDMARDs; and (2) amendment of the company's modelling of patient progression from moderate to severe RA. The ICERs estimated by the ERG's exploratory analyses for SAR + MTX increased to £171,466 per QALY gained when compared with RTX + MTX in TNFi-IR patients who are RTX eligible, and to £63,438 per QALY gained when compared with MTX in patients with moderate RA and a DAS28 of > 4.0. The Appraisal Committee concluded that SAR in combination with MTX or as monotherapy is a cost-effective use of NHS resources in the considered populations, except in TNFi-IR patients who are RTX eligible and in patients with moderate RA and a DAS28 of > 4.0.
29736870 Can we predict thrombotic tendency in rheumatoid arthritis? A thromboelastographic analysi 2018 Sep The higher incidence of arterial and venous events is well established in patients with rheumatoid arthritis (RA). Our aim here was to investigate whether there is a prothrombotic state in RA patients by using rotational thromboelastometry (ROTEM) method and to demonstrate whether the disease variables play a role in this process. A total of 85 patients who met the 2010 RA classification criteria were consecutively included in the study. The patients with RA who have been using antiaggregant, anticoagulant, or nonsteroidal anti-inflammatory drugs (NSAIDs) and had a history of arterial or venous thromboembolism were excluded from the study. Their complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, D-dimer, and lipid profiles were measured, DAS-28 disease activation scores were calculated, and simultaneous ROTEM analysis was performed to determine the predisposition to thrombosis. Of the ROTEM parameters, clotting time (CT, seconds (s)), clot formation time (CFT, s), and maximum clot firmness (MCF) were evaluated. Having a shorter CT and/or CFT in intrinsic (I) or extrinsic (E) pathway and/or a longer MCF compared to the healthy controls was considered as "predisposition to hypercoagulability". The mean age of the 85 RA patients were 54.12 ± 13 years, and 77.6% of the patients were female (n = 66). Of the patients, 52.9% (n = 45) were using methotrexate (MTX) ± hydroxychloroquine (HCQ) ± corticosteroid (CS), while 43.5% (n = 37) were using anti-tumor necrosis factor (TNF) ± MTX. Active steroid usage was ongoing in 64.7% of the patients (n = 55). When evaluated according to DAS-28, in those with higher disease activity, a shorter I-CFT and greater I-MCF were determined (p = 0.020 and p = 0.033, respectively). In those with higher disease activity based on the correlation analysis, I-CFT and E-CFT were shorter and I-MCF and E-MCF were longer, indicating a higher predisposition to thrombosis. Using linear regression, variables with a major effect on ROTEM parameters were identified as DAS-28, CRP, and platelet count. As the first study in the literature, we identified that disease activation is the most important risk factor for prothrombotic state in RA patients irrespective of the drugs used. ROTEM can be used in clinical practice to predict thrombotic events in RA patients.
30187188 Co-Delivery of Teriflunomide and Methotrexate from Hydroxyapatite Nanoparticles for the Tr 2018 Sep 5 PURPOSE: The present investigation was aimed at developing Teriflunomide (TEF) and Methotrexate (MTX) loaded hydroxyapatite nanoparticles and increasing tolerability towards combination therapy against rheumatoid arthritis by reducing hepatotoxicity. METHODS: Drug-loaded HAp-NPs were synthesized by wet-chemical precipitation method and optimized by Box-Behnken experimental design. The developed NPs were subjected to in vitro and in vivo characterization. In-vivo pharmacodynamics and biochemical studies were performed on adjuvant- induced arthritis model treated with different formulations; MTX-TEF-SOL, TEF-HAp-NP, MTX-HAp-NP, TEF-MTX-HAp-NP, FOLITRAX-10 and AUBAGIO. RESULTS: The size of the optimized formulations, TEF-HAp-NP and MTX-HAp-NP, was found to be 224.3 ± 83.80 nm and 268.3 ± 73.86 nm with drug loading 53.11 ± 0.84% and 67.04 ± 1.12% respectively. In vitro release of TEF from TEF-HAp-NP (70.41 ± 1.22%) and MTX from MTX-HAp-NP (82.43 ± 1.31%) up to 24 h revealed sustained release pattern. Results of the arthritic assessment study showed a significant (P < 0.05) reduction in ankle diameter (61.30 ± 7.42) and arthritis score (2.35 ± 0.24) with a marked restoration of ankle joint micro-architecture in TEF-MTX-HAp-NP treated group. During Hepatotoxicity studies, liver histopathology revealed that the formulation MTX-TEF-HAp-NP was least hepatotoxic with less hepatocyte swelling and fibrous connective tissue proliferation while Folitrax-10 was found to be most hepatotoxic. Biochemical studies revealed that Folitrax-10 significantly (P < 0.05) increased the GOT (313.64 ± 16) and GPT level (334.46 ± 13) while insignificant (P > 0.05) change in GOT (263.68 ± 17) and GPT (229.38 ± 10) level was recorded with TEF-MTX-HAp-NP. CONCLUSIONS: We report that the subcutaneous delivery of TEF-MTX-HAp-NP was most effective as it successfully reduced the dosage by half for maximizing therapeutic efficacy and minimizing side effects. Graphical Abstract ᅟ.
28972441 Efficacy and safety of infliximab: A comparison with other biological disease-modifying an 2018 Jul OBJECTIVES: The intensification of infliximab (IFX) treatment, involving escalation of the dose and shortening of interval, was approved in Japan in July 2009. We consider IFX intensification therapy to be preferable for patients with treatment-resistant active rheumatoid arthritis (RA). We retrospectively compared the efficacy of IFX with that of other bDMARDs in methotrexate (MTX)-resistant patients. METHODS: Patients who satisfied the following criteria were enrolled: (i) those who started bDMARDs between February 2011 and December 2016, and (ii) those who required bDMARDs after 180 d of MTX treatment. We compared 33 patients who had been treated with IFX (IFX group) and 146 who had received other bDMARDs treatment (non-IFX group). RESULTS: IFX was administered at a dose of 6.98 mg/kg/8-week equivalent at 52 weeks. Clinical disease activity index clinical remission (CDAI-CR) was achieved in 49 of the 179 patients at 52 weeks and 13 of these 49 patients received IFX. Logistic regression analysis showed that treatment with IFX was an important variable for the achievement of CDAI-CR at 52 weeks (odds ratio 2.69, 95% confidence interval 1.13-6.42). The severity and frequency of adverse events did not differ. CONCLUSION: Intensification of IFX was effective and well tolerated for MTX resistant patients.
30327328 How to treat patients with rheumatoid arthritis when methotrexate has failed? The use of a 2019 Jan OBJECTIVES: To compare consecutive disease modifying antirheumatic drug (DMARD)-treatment regimes in daily practice in patients with rheumatoid arthritis (RA) who failed on initial methotrexate, while using a multiple propensity score (PS) method to control for the spurious effects of confounding by indication. METHODS: Patients with newly diagnosed RA who had failed initial treatment with methotrexate were selected from METEOR, an international, observational registry. Subsequent DMARD-treatment regimens were categorised as: (1) conventional synthetic DMARD(s) (csDMARD(s)) only (143 patients), (2) csDMARD(s)+glucocorticoid (278 patients) and (3) biological DMARD (bDMARD)±csDMARD(s) (89 patients). Multiple PS that reflect the likelihood of treatment with each treatment-regime were estimated per patient using multinomial regression. Linear mixed model analyses were performed to analyse treatment responses per category (Disease Activity Score (DAS)) after a maximum follow-up duration of 6 and 12 months, and results were presented with adjustment for the multiple PS. RESULTS: After 6 months, follow-up PS-adjusted treatment responses yielded a change in DAS per year (95%  CI) of -2.00 (-2.65 to -1.36) if patients received a bDMARD; of -0.96 (-1.33 to -0.59) if patients received csDMARD(s)+glucocorticoids and of -0.73 (-1.21 to -0.25) if patients received csDMARDs only. These changes were -0.91 (-1.23 to -0.60); -0.43 (-0.62 to -0.23) and -0.39 (-0.66 to -0.13), respectively after 1  year of follow-up. CONCLUSIONS: In this analysis of worldwide common practice data with adjustment for multiple PS, patients with RA who had failed initial treatment with methotrexate monotherapy had a better DAS-response after a subsequent switch to a bDMARD-containing treatment regimen than to a regimen with csDMARD(s) only, with or without glucocorticoids.
28214596 Early non-response to certolizumab pegol in rheumatoid arthritis predicts treatment failur 2018 Jan OBJECTIVES: To compare different early clinical criteria of non-response determined at three months as predictors of clinical failure at one year in patients with rheumatoid arthritis starting therapy with certolizumab pegol. METHODS: Data were derived from a randomised Phase III clinical trial in patients with rheumatoid arthritis who failed to respond to methotrexate monotherapy. Patients included in this post-hoc analysis were treated with certolizumab pegol (400mg qd reduced to 200mg qd after one month) and with methotrexate. The study duration was twelve months. Response at three months was determined with the American College of Rheumatology-50, Disease Assessment Score-28 ESR, Health Assessment Questionnaire and the Clinical Disease Activity Index. The performance of these measures at predicting treatment failure at twelve months defined by the American College of Rheumatology-50 criteria was determined, using the positive predictive values as the principal evaluation criterion. RESULTS: Three hundred and eighty two patients were available for analysis and 225 completed the twelve-month follow-up. At Week 52, 149 (38.1%) patients met the American College of Rheumatology-50 response criterion. Positive predictive values ranged from 81% for a decrease in Health Assessment Questionnaire- Disability index score since baseline >0.22 to 95% for a decrease in Disease Assessment Score-28 score since baseline≥1.2. Sensitivity was≤70% in all cases. Performance of these measures was similar irrespective of the definition of treatment failure at 12months. CONCLUSIONS: Simple clinical measures of disease activity can predict future treatment failure reliably and are appropriate for implementing treat-to-target treatment strategies in everyday practice.
29142030 Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimu 2018 Jan OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647). METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves. RESULTS: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively. CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.
29508096 Low-dose methotrexate in rheumatoid arthritis: a potential risk factor for bisphosphonate- 2018 Jun Bisphosphonate-induced osteonecrosis of the jaw [BIONJ] is a relatively new pathological condition which was first described in the year 2003. The prevalence of BIONJ in patients on oral formulations is around 0.05% within the first 3 years and increases up to 0.2% after 4 years of consumption. Proven systemic risk factors like anemia, uncontrolled diabetes, corticosteroid therapy, and chemotherapy in neoplastic diseases [e.g., high doses of methotrexate up to 30 mg daily] significantly increase the chances of acquiring BIONJ. We present three patients with osteoporosis and rheumatoid arthritis [RA] who consumed oral bisphosphonates [alendronate] for less than 1 year and developed BIONJ within 2 to 5 months of undergoing a traumatic dental procedure. The patients also gave a history of consuming low doses of methotrexate [disease-modifying anti-rheumatic drugs] up to 20 mg weekly for 4 to 10 years. No history of steroid consumption was given by any of the patients. This case series highlights the possibility of rheumatoid arthritis and low-dose methotrexate being potential risk factors for BIONJ. This may be on account of the synergistic effect of methotrexate and bisphosphonates and the pro-inflammatory state created by RA which increased the risk of acquiring BIONJ.
29155973 Tapering versus steady-state methotrexate in combination with tocilizumab for rheumatoid a 2018 Jan 1 OBJECTIVE: To explore whether tocilizumab + tapering MTX has comparable efficacy and safety vs tocilizumab + stable MTX in adult RA patients with inadequate response to MTX. METHODS: This randomized, placebo-controlled non-inferiority study involved patients with severe active RA [28-joint DAS (DAS28) >5.1] who had initiated tocilizumab + MTX at the study start. Patients received open-label tocilizumab (8 mg/kg i.v. every 4 weeks) and open-label MTX. At week 24, patients achieving good/moderate EULAR response were randomized to group A (double-blind MTX taper) or group B (double-blind MTX maintenance); both arms continued open-label tocilizumab. Primary analysis was the proportion of patients maintaining good/moderate EULAR response from week 24 to 60. RESULTS: The study stopped early due to low recruitment, although the predetermined non-inferiority criteria were still met; 427 patients were enrolled to the open-label phase at week 0. At week 24, EULAR good/moderate response was achieved in 272 individuals (64.4%) who were randomized, 136 in each arm (36% withdrew/were not eligible). Additionally, 45.0% achieved DAS28 ⩽3.2, 33.5% achieved remission (DAS28 <2.6) and 64.2% had a DAS28 change ⩾1.2. After week 24 randomization, the proportion of patients maintaining good/moderate EULAR response to week 60 was significantly greater for MTX taper vs stable MTX (76.5 vs 65.4%; P = 0.036), and since the lower limit of the 95% CI was >0.9, the pre-determined criteria for non-inferiority was fulfilled despite reduced recruitment. Safety analysis revealed no unexpected tocilizumab safety signals. CONCLUSIONS: Tapering MTX in patients with RA receiving tocilizumab was non-inferior to continuing stable MTX in maintaining a good/moderate EULAR response. There were no unexpected safety signals; tocilizumab and MTX therapy was generally well tolerated in both groups. Trial registration number: EudraCT 2011-005260-20.
29780382 Extracellular Purine Metabolism Is the Switchboard of Immunosuppressive Macrophages and a 2018 If misregulated, macrophage (Mϕ)-T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF)- and Mϕ colony-stimulating factor (M-CSF)-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FRβ(+)CD39(+)CD73(+) Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint in Mϕ cell fate decision-making and an attractive target to control pathological Mϕs in immune-mediated diseases.
29134891 Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgrou 2018 Jul OBJECTIVES: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations. METHODS: Subgroup analyses (394 patients) of four phase 3 randomized controlled trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD [IR to conventional synthetic DMARDs (csDMARDs)], and RA-BEACON (IR to tumor necrosis factor inhibitors receiving csDMARDs). RESULTS: For American College of Rheumatology 20% improvement (ACR20) response rate, Japanese patients receiving baricitinib 4-mg showed similar improvement compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese patients receiving baricitinib 4-mg also showed greater improvement compared with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies, baricitinib was well-tolerated, with no deaths and one malignancy. In RA-BEGIN and RA-BEAM, herpes zoster rates were higher for Japanese patients than for overall populations; all events were mild/moderate. CONCLUSION: Data for baricitinib, with/without methotrexate, in Japanese subpopulations across all stages of the RA treatment continuum accord with the efficacy/safety profile in overall study populations. Baricitinib appears to be similarly effective in Japanese patients.
28440680 Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: 2018 Jan OBJECTIVES: The objective of this study is to evaluate the efficacy and safety of long-term (64 weeks; 52-week extension of a 12-week study) baricitinib treatment in Japanese patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: Patients (N = 145) with active RA were randomized to placebo, 1mg, 2mg, 4mg, or 8mg baricitinib for the first 12 weeks. During the 52-week extension period, patients on 4mg or 8mg baricitinib remained on the same dose and all other patients were re-randomized to 4mg or 8mg baricitinib. Most patients on 8mg baricitinib were switched to 4mg by week 64 (protocol amendment); data analysis was based on the treatment group at the beginning of the extension period. RESULTS: Increases in the American College of Rheumatology (ACR) response rates (ACR20, ACR50, and ACR70) observed during the first 12 weeks were maintained during the extension period, accompanied by improvements in ACR core components. At week 64, a large proportion of patients (>40%) had low disease activity. Most treatment-related adverse events were mild or moderate; herpes zoster was the most common reason (11/27 patients) for discontinuation. CONCLUSIONS: The efficacy and safety profile of baricitinib was maintained during long-term treatment of Japanese patients with RA and background methotrexate therapy. Clinicaltrials.gov NCT01469013; Funding: Eli Lilly and Incyte.
29482351 Sarilumab: Review of a Second IL-6 Receptor Antagonist Indicated for the Treatment of Rheu 2018 Aug Major Objectives: To review the efficacy, safety, and economics of sarilumab, an interleukin-6 (IL-6) receptor antagonist, in the treatment of rheumatoid arthritis (RA). DATA SOURCES: PubMed (1966 to January 2018), Clinicaltrials.gov (January 2018), and Scopus (1970 to January 2018) were searched using sarilumab, Kevzara, REGN88, and SAR153191. STUDY SELECTION AND DATA EXTRACTION: Human studies published in peer-reviewed publications in English were the primary sources for efficacy and safety. DATA SYNTHESIS: Data from randomized, double-blind, controlled, published clinical studies weeks demonstrated statistically significantly higher American College of Rheumatology (ACR) 20, ACR50, and Disease Activity Score-28 (DAS28) remission response rates and improvements in DAS28 and Health Assessment Questionnaire-Disability Index scores for sarilumab monotherapy versus adalimumab monotherapy (P < 0.05) and for sarilumab versus placebo in patients receiving methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs); P < 0.05. The ACR20 and ACR50 response rates were, respectively, 56-72% and 35-46% for sarilumab, 58% and 30% for adalimumab, and 33-34% and 15-18% for placebo. DAS28 remission rates were 20-34% for sarilumab, 7% for adalimumab, and 7-10% for placebo. Sarilumab has a higher risk for neutropenia than tocilizumab, the other IL-6 inhibitor, but a lower risk for dyslipidemia, injection site reactions, and gastrointestinal perforation. The acquisition costs of sarilumab are expected to be similar to those of most other biologic DMARDs. CONCLUSION: Sarilumab is an alternative to biologic DMARDs or targeted synthetic DMARDs in patients with moderate to severely active RA who have not responded adequately to prior conventional synthetic DMARDs or tumor necrosis factor-α inhibitors.
29760159 Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rhe 2018 Sep OBJECTIVE: To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA). METHODS: In U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, 'MTX+') and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to 'MTX+'. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model. RESULTS: Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to 'MTX+'. DAS28 (adjusted OR (OR(adj)) 2.1, 95% CI 1.4 to 3.2), current smoking (OR(adj) 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (OR(adj) 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively. CONCLUSION: Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up 'MTX+' in DMARD-naive patients with new-onset RA. TRIAL REGISTRATION: NCT01034137; Post-results, ISRCTN26791028; Post-results.
30333289 [Association of short-term efficacy for infliximab in rheumatoid arthritis with plasma con 2018 Sep 28 To investigate the correlation between peripheral concentration of infliximab (IFX) or anti-IFX antibody titers and short-term therapeutic effect of IFX in patients with active rheumatoid arthritis (RA).
 Methods: Twenty patients with active RA were treated with combination of methotrexate (MTX), leflunomide (LEF) with IFX, and the clinical and laboratory index and the side effects were recorded before and after IFX treatment. Twenty healthy subjects were chosen as a control group.
 Results: After 14-week treatment, patients were categorized into good, moderate or no responders according to EULAR remission criteria. There were no significant differences in peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels among the 3 groups, and there were no significant correlations among ΔDAS28-CRP, peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels.
 Conclusion: Peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels can not be used as reliable predictive index for short-term effect of IFX in active RA.
30092680 The three-year efficacy of iguratimod in clinical daily practice in patients with rheumato 2019 Sep Objectives: To assess the middle-term outcome of iguratimod (IGU) in rheumatoid arthritis (RA) patients. Methods: Sixty-nine RA patients (14 males and 55 females, mean age of 64.0 years) receiving IGU-containing therapies were enrolled. We divided these patients into three groups based on the treatment at the baseline: an IGU group, a methotrexate (MTX) plus IGU group, and a biologics plus IGU group. The baseline characteristics and clinical course were evaluated over three years. Predictive factors associated with the achievement of low disease activity (LDA) were statistically analyzed. Results: The survival rate of IGU therapy at 3 years was 40.6%. The disease activity was significantly decreased in the IGU group and MTX plus IGU group compared with the baseline. Furthermore, 38 patients (55.1%) were in remission or had LDA at 3 years. The patient gender, use of prednisolone (PSL) and DAS28-CRP at baseline were the factors associated with the achievement of remission or LDA at three years. Conclusion: IGU was effective without MTX or bDMARDs as well as in combination with MTX. A female gender, no use of PSL and a low DAS28-CRP at the initiation of IGU were associated with clinical remission or LDA achievement at three years.
29572291 Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal 2018 Jun OBJECTIVE: To determine whether a 2-week methotrexate (MTX) discontinuation after vaccination improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA). METHODS: In this prospective randomised parallel-group multicentre study, patients with RA on stable dose of MTX were randomly assigned at a ratio of 1:1 to continue MTX or to hold MTX for 2 weeks after 2016-2017 quadrivalent seasonal influenza vaccine containing H1N1, H3N2, B-Yamagata and B-Victoria. The primary outcome was frequency of satisfactory vaccine response, defined as greater than or equal to fourfold increase of haemagglutination inhibition (HI) antibody titre at 4 weeks after vaccination against ≥2 of four vaccine strains. Secondary endpoints included seroprotection (ie, HI titre ≥1:40) rate, fold change in antibody titres. RESULTS: The modified intention-to-treat population included 156 patients in the MTX-continue group and 160 patients in the MTX-hold group. More patients in MTX-hold group achieved satisfactory vaccine response than the MTX-continue group (75.5% vs 54.5%, p<0.001). Seroprotection rate was higher in the MTX-hold group than the MTX-continue group for all four antigens (H1N1: difference 10.7%, 95% CI 2.0% to 19.3%; H3N2: difference 15.9%, 95% CI 5.9% to 26.0%; B-Yamagata: difference13.7%, 95% CI 5.2% to 22.4%; B-Victoria: difference 14.7%, 95% CI 4.5% to 25.0%). The MTX-hold group showed higher fold increase in their antibody titres against all four influenza antigens (all p<0.05). Change in disease activity was similar between groups. CONCLUSIONS: A temporary MTX discontinuation for 2 weeks after vaccination improves the immunogenicity of seasonal influenza vaccination in patients with RA without increasing RA disease activity. TRIAL REGISTRATION: NCT02897011.