Methotrexate Inadequate Responders Research Articles

POS0059 CARDIOVASCULAR RISK AND ADVANCED THERAPIES RETENTION IN RHEUMATOID ARTHRITIS: RESULTS FROM THE OBRI

BackgroundCardiovascular disease (CVD) and CVD risk factors are highly prevalent in rheumatoid arthritis (RA) and associated with morbidity and mortality. We previously reported an association between CVD risk factors and higher disease activity and disability.[1]However, whether CVD risk factors influence advanced therapy drug retention is not well known.ObjectivesWe aimed to test the hypothesis that CVD risk factors are associated with lower retention of biologic and targeted synthetic disease modifying antirheumatic drugs (bDMARD, tsDMARD) among methotrexate inadequate responders (MTX-IR).MethodsParticipants enrolled in the Ontario Best Practices Initiative (OBRI) RA registry were included if they initiated their first bDMARD or tsDMARD, had at least one follow-up visit after initiation and available baseline data on CVD risk factors. Patients were grouped by number of baseline CVD risk factors (0, 1 or >1), including hypertension, dyslipidemia, diabetes, obesity (body mass index ≥30) and current smoking. The primary outcome was time-to-discontinuation of a first bDMARD or tsDMARD. Multivariable Cox proportional hazards model, adjusted for clinically important confounders, estimated the association between CVD risk factors and drug retention. Sensitivity analyses for exploring types of discontinuation (primary failure, secondary failure and adverse events) were performed.ResultsA total of 877 patients were included. The majority were new initiators of bDMARDs (89%). The mean (SD) age was 57 (12) years and 79% were females. At least 1 CVD risk factor was present in 75%, most commonly hypertension (33%). The most common reasons for treatment discontinuation were primary failure (N=72), secondary failure (n=126) or adverse events (N=133), compromising 64% of all cause discontinuation. Patients without CVD risk factors had longer drug survival with a mean of 31 months, compared to 28 and 27 months in patients with 1 or > 1 CVD risk factors, respectively. In multivariate analysis, the presence of at least 1 CVD risk factor was not associated with a higher risk of medication discontinuation overall (HR 1.12, 95%CI 0.89-1.40, p=0.32), nor was the presence of ≥ 2 CVD risk factors (HR 1.20, 95% CI 0.93-1.54, p=0.16) (Figure 1). However, CVD risk factors were associated with discontinuation due to the composite of treatment failure and adverse events; and ≥ 2 CVD risk factors was strongly associated with secondary treatment failure (Table 1).ConclusionMore than half of biologic naïve RA patients who had inadequate response to methotrexate will discontinue their initial bDMARD or tsDMARD. The presence of more than 1 CVD risk factor, compared to no risk factors, is associated with reduced bDMARD/tsDMARD retention. This appears to be driven by secondary treatment failure. Further investigation into the possible mechanisms by which CVD comorbidity contributes to treatment failure is required.Reference[1]Cui K, Movahedi M, Bombardier C, Kuriya B. Cardiovascular risk factors are negatively associated with rheumatoid arthritis disease outcomes.Ther Adv Musculoskelet Dis. 2021;13:1759720X20981217. Published 2021 Feb 15. doi:10.1177/1759720X20981217AcknowledgementsAcknowledgment: OBRI investigators. Ontario Best Practices Research Initiative (OBRI) was funded by peer-reviewed grants from the Canadian Institute for Health Research, Ontario Ministry of Health and Long-Term Care, Canadian Arthritis Network, and unrestricted grants from AbbVie, Amgen, Aurora, BMS, Celgene, Gilead, Hospira, Janssen, Lilly, Medexus, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and UCB.Disclosure of InterestsNone Declared.

Inhibition of structural joint damage progression with upadacitinib in rheumatoid arthritis: 1-year outcomes from the SELECT phase 3 program

ObjectivesTo evaluate the inhibition of progression of structural joint damage through week 48 in patients with moderately to severely active RA receiving upadacitinib as monotherapy or in combination with MTX.MethodsRadiographic progression was assessed in two phase 3 randomized controlled trials. MTX-naïve patients were randomized to upadacitinib 15 or 30 mg once daily or MTX monotherapy (SELECT-EARLY, n = 945), while MTX inadequate responders (IRs) were randomized to upadacitinib 15 mg once daily or adalimumab 40 mg every other week or placebo added to background MTX (SELECT-COMPARE, n = 1629). The mean changes from baseline in modified total Sharp score (mTSS), joint space narrowing and erosion scores were determined. Data were analysed both by linear extrapolation for missing data imputation and treatment switching and as observed.ResultsIn patients naïve or with limited exposure to MTX (SELECT-EARLY), mean changes from baseline to week 48 in mTSS were 0.03 for upadacitinib 15 mg, 0.14 for upadacitinib 30 mg and 1.00 for MTX based on linear extrapolation (P < 0.001 for both upadacitinib doses vs MTX). Among patients with an inadequate response to MTX (SELECT-COMPARE), the mean change from baseline in mTSS was significantly reduced in the upadacitinib 15 mg plus MTX group vs placebo plus MTX (0.28 vs 1.73; P < 0.001). The mean change from baseline in the adalimumab plus MTX group was 0.39.ConclusionUpadacitinib monotherapy or in combination with background MTX was effective in inhibiting the progression of structural joint damage through week 48 in MTX-naïve and MTX-IR patients with RA.Trial registrationClinicalTrials.gov (https://clinicaltrials.gov), NCT02706873 and NCT02629159

POS0446 FILGOTINIB-TREATED RHEUMATOID ARTHRITIS PATIENTS WITH HIGH BASELINE NEUTROPHIL-TO-LYMPHOCYTE RATIO SHOW BETTER CLINICAL RESPONSE RATES AND PATIENT-REPORTED OUTCOMES

Background:Rheumatoid arthritis (RA) is a systemic inflammatory disease which includes increased innate and myeloid immune cell activation. Filgotinib (FIL), an oral JAK1 inhibitor, has shown safety and efficacy in three phase 3 studies (FINCH1-3) in adults with moderately-to-severely active RA. The baseline (BL) neutrophil-to-lymphocyte ratio (NLR) in RA has been associated with a positive response to anti-tumor necrosis factor (TNF) therapy1 and a negative response to DMARD triple therapy2. We previously reported a BL signature of clinical response in the FINCH2 (bDMARD-IR) population which included a neutrophil component3.Objectives:We conducted a post-hoc analysis to explore whether the BL NLR was associated with response to treatment in the FINCH studies.Methods:Clinical data of 3273 RA patients (pts) enrolled in the FINCH clinical trials (FINCH3, methotrexate (MTX)-naïve: NCT02886728; FINCH1, MTX-Inadequate Responder (IR): NCT02889796; FINCH2, bDMARD-IR: NCT02873936) were retrospectively analyzed for a relationship between the BL NLR and composite clinical endpoints (ACR-N, DAS28CRP, or CDAI) or PROs (Pain VAS, FACIT Fatigue, HAQ-DI) through week 24. Pts were classified as High or Low BL NLR using a cutpoint (2.7) identified as an independent predictor of treatment failure in a published RA study2. Adjusted clinical outcomes were estimated based on mixed effects linear regression models including geographic region and demographics covariates.Results:57% of pts enrolled in the FINCH trials were classified as BL NLR-High (Table 1) and FINCH3 NLR-High pts showed higher BL DAS28(CRP). FINCH1 and FINCH3 FIL+MTX-arm NLR-High pts demonstrated significantly better DAS28(CRP) response compared to NLR-Low pts (Figure 1). DAS28(CRP) differences between NLR-High and NLR-Low were detectable as early as Week 2 for FIL200mg + MTX and were sustained through Week 24. FINCH1 and FINCH3 FIL200mg + MTX NLR-High pts also demonstrated sustained clinical and PRO improvements over NLR-Low, including CDAI, ACR-N, Pain VAS, FACIT Fatigue, and HAQ-DI. The strength of these associations was dose-dependent; pts that received FIL100mg + MTX demonstrated weaker but directionally consistent trends in both populations. No significant association between NLR subgroup and clinical efficacy was observed in FINCH2 FIL+MTX-arm pts, FIL-monotherapy (FINCH3) pts, or adalimumab+MTX (FINCH1) pts.Conclusion:In FINCH1 (MTX-IR) and FINCH3 (MTX-naïve), FIL200mg + MTX -arm NLR-High pts demonstrate better sustained clinical response and PRO scores compared to NLR-Low pts. These data are the first to report an association between the BL NLR and therapeutic response in large randomized RA clinical trials. Future studies on pathobiologies reflected by the NLR biomarker may clarify its potential to guide RA disease management.

AB0785 REAL LIFE EXPERIENCE OF METHOTREXATE BASED DUAL COMBINATION DMARDS IN PSORIATIC ARTHRITIS- RESULTS FROM KARNATAKA PSORIATIC ARTHRITIS COHORT (KPsAC)

Background:Biologics have been the focus of recent treatment guidelines and ‘Treat to Target’ strategies for both psoriasis (PsO) &amp; psoriatic Arthritis (PsA). However, in day-today practice, combination DMARDs anchored around methotrexate are mainstay in majority of patients.Objectives:To describe experience and effectiveness of Methotrexate in combination with conventional DMARDs in Karnataka Psoriatic Arthritis Cohort.Methods:Treatment information was extracted from KPsAC (n=549) which is a cross sectional, non-interventional study conducted across 17 rheumatology practicing centres in Karnataka, India using a structured proforma. This study was approved by respective Ethical committee. Information on efficacy was extracted for various csDMARDs in combination with methotrexate. Standard disease activity outcome measures were used for assessing the response to therapy (DAPSA, PASI, HAQ, MDA5). All participating rheumatologists underwent training to calculate PASI and other outcome scores.Results:Nearly half of the patients in our cohort were on methotrexate (44%) monotherapy. Proportion of patients who received combination csDMARD anchored on methotrexate were 29%. The choice of add on csDMARD was as per clinician discretion or subject preference. Patients were divided in to three groups based on treatments they were receiving at the time of study: Methotrexate (Mtx)+Leflunomide (Lef), Mtx+Sulfasalazine (SSz) and Mtx+Apremilast(Apr). Their characteristics along with outcome measures are depicted in table 1. In Mtx+Apr group: remission or low disease activity was present in 42%, HAQ score of &lt;0.5 was seen in 82%, and only one patient had a PASI of &gt; 10. PASI was significantly lower in the Mtx+Apr group compared to Mtx+Lef group (p&lt;0.009) and Mtx +Ssz group (p &lt; 0.020)Conclusion:Apremilast is an orally administered, small molecule inhibitor of phosphodiesterase 4 (PDE4)**. In this observational study, 3 groups of methotrexate plus csDMARD- leflunomide, sulphasalazine and apremilast fared similarly for articular domain of PsA. However, in cutaneous domain, PASI was significantly lower in apremilast + methotrexate group. To our knowledge, this is the first real life report of the use of combination DMARDs in unselected PsA patients demonstrating effectiveness of apremilast in cutaneous domain. Methotrexate remains anchor DMARD for treatment of PsA in 2/3rdof PsA patients. Addition of apremilast to methotrexate inadequate responders appears to be beneficial in PsA with persistent cutaneous disease. However, being an observational study, this needs to be confirmed in controlled clinical trials.

P213 High baseline serum IL-6 predicts increased sarilumab treatment response for patient reported symptoms and health-related quality of life among RA patients with inadequate response to MTX

Abstract Background IL-6, a key cytokine in rheumatoid arthritis (RA) pathogenesis, is elevated in patient serum and synovial fluid. However, the impact of baseline IL-6 levels on patient-reported RA symptoms and health-related quality of life (HRQoL) following IL-6 blockade has not been explored. Sarilumab targets IL-6 receptor alpha, and sarilumab+methotrexate (MTX) significantly improved clinical and patient-reported outcomes vs MTX alone among MTX inadequate responders (IR) in MOBILITY/NCT01061736. This post-hoc analysis evaluated whether baseline IL-6 levels predict greater improvements in symptoms and HRQoL with sarilumab+MTX vs MTX. Methods 1,193 patients with moderate-to-severely active RA received MTX or MTX plus subcutaneous sarilumab at 200 mg (recommended dose) or 150 mg (recommended for management of laboratory abnormalities) every 2 weeks (q2w) and were grouped into tertiles according to baseline IL-6 levels. Patient-reported RA symptoms and HRQoL were measured at baseline and post-treatment (Weeks [W] 24 and 52). Results Baseline IL-6 tertiles among 1193 patients were 1.6-9.6 (low), 9.8-30.7 (medium), and 31.2-648.7 pg/mL (high). At baseline, patients with high IL-6 had greater disease activity, more radiographic structural damage, elevated CRP levels, and worse HRQoL (pain visual analog scale [VAS], SF36-physical component scores [PCS], and sleep VAS) vs those with low IL-6 (nominal p &amp;lt; 0.05) and generally reported greater improvements in symptoms and HRQoL with sarilumab+MTX vs placebo+MTX. Significant differences (nominal p &amp;lt; 0.005) between high and low tertiles were evident in improvement of pain VAS (W52) and SF-36 PCS (W24/W52) with sarilumab 200 mg q2w vs placebo, SF-36 mental component scores (both doses; W52) and FACIT-fatigue scores (both doses; W24/W52) vs placebo. Treatment-emergent adverse events were similar across IL-6 tertiles. Conclusion Among MTX-IR RA patients, high baseline IL-6 may predict better improvements in symptoms and HRQoL with sarilumab vs placebo, which was consistent with previous analyses across clinical/radiographic endpoints in the same study population. Disclosures V. Strand: Consultancies; AbbVie, Amgen, AstraZeneca, Biogen, BMS, Celltrion, CORRONA, Crescendo, Genentech/Roche, GSK, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi and U. J. Msihid: Corporate appointments; Employee of Sanofi. Shareholder/stock ownership; Sanofi. T. Kimura: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. A. Boyapati: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. G. St John: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. W. Wei: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc.

Cost-Effectiveness of a JAK1/JAK2 Inhibitor vs a Biologic Disease-Modifying Antirheumatic Drug (bDMARD) in a Treat-to-Target Strategy for Rheumatoid Arthritis.

BackgroundBaricitinib is a janus kinase (JAK1/JAK2) inhibitor developed for the treatment of patients suffering from rheumatoid arthritis (RA). Treating RA to the target of remission is current common practice. Cost-effectiveness of different treat-to-target (T2T) strategies, especially ones including new treatments is important for development and preference policy for treatment centers. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines are currently unclear about preference between a JAK1/JAK2 versus a biological disease-modifying antirheumatic drug (bDMARD).ObjectiveThe main goal of this paper was to evaluate the cost-effectiveness of baricitinib versus first biological for methotrexate inadequate responders in a T2T strategy using a Markov model that incorporates hospital costs as well as societal costs. Costs and utilities over five years were compared between the two strategies.MethodsA Monte Carlo simulation model was developed to conduct cost–utility analysis from the societal perspective over 5 years. Health states were based on the DAS28-erythrocyte sedimentation rate (ESR) categories. Effectiveness of baricitinib was retrieved from randomized controlled trials. Effectiveness of all other treatments, health state utilities, medical costs, and productivity loss were retrieved from the Dutch RhEumatoid Arthritis Monitoring (DREAM) cohorts. Annual discount rates of 1.5% for utility and 4% for costs were used. Probabilistic sensitivity analysis was employed to incorporate uncertainty and assess robustness of the results.ResultsProbabilistic sensitivity analysis results showed the baricitinib strategy yielded lower costs and higher utility over a 5-year period. Scenario analyses showed the baricitinib strategy to be cost-effective in both the moderate and severe RA populations.ConclusionResults suggest that the use of a JAK1/JAK2 inhibitor instead of a bDMARD in a T2T approach is cost-effective in csDMARD refractory RA patients.

Diacerein for the treatment of rheumatoid arthritis in patients with inadequate response to methotrexate: a pilot randomized, double-blind, placebo-controlled add-on trial.

To evaluate the efficacy and safety of diacerein in patients with rheumatoid arthritis (RA) who are methotrexate inadequate responders (MTX-IR). In this pilot, multicenter, double-blind, placebo-controlled trial, MTX-IR RA patients were randomized to either diacerein or matching placebo as add-on treatment to MTX for 24weeks. Efficacy and safety were evaluated every 4weeks until week 28. Primary and secondary efficacy endpoints were the percentage of patients achieving the ACR20 criteria and a moderate EULAR response at week 24, respectively. Forty patients were equally randomized to both study treatments; 16 and 19 participants completed the study in the diacerein and the placebo arms, respectively. Baseline characteristics were similar in both groups, except that tender joint count, DAS28-ESR score, and non-steroidal anti-inflammatory drug consumption were higher in the placebo arm. The ACR20 response at week 24 was similar in the diacerein and placebo groups (65% vs 45%, P = .20). However, treatment response according to the EULAR criteria was better in patients taking diacerein (75% vs 25% of moderate response, P = .002). In the 35 patients with assessments through week 28, diacerein was superior to placebo in ACR20 at weeks 24 and 28 (both 81% vs 47%, P = .04). Incidence of adverse events was comparable in both arms, with only chromaturia being more common with diacerein than placebo (40% vs 10%, P = .03). These preliminary results show the potential benefits of diacerein on pain, joint function, and disease activity in MTX-IR RA patients. ClinicalTrials.gov Identifier: NCT01264211 Key Points • Diacerein has shown positive effects on rheumatoid arthritis symptoms. • A good safety profile of diacerein has been observed when it was administered as add-on therapy to methotrexate in patients with rheumatoid arthritis.

Long-Term Radiographic and Patient-Reported Outcomes in Patients with Rheumatoid Arthritis Treated with Tofacitinib: ORAL Start and ORAL Scan Post-hoc Analyses.

IntroductionHere we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function.MethodsThis was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP).ResultsMean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of < 1.9 most closely approximated CDAI remission (≤ 2.8). Tofacitinib appeared to inhibit joint damage in the presence of persistent inflammation compared with MTX. More patients receiving tofacitinib or MTX with CDAI remission or low disease activity (LDA) at month 6 reported normative HAQ-DI scores (< 0.5) at month 24 than did those with CDAI MDA/HDA.ConclusionRegardless of treatment, in both MTX-naïve and MTX-IR patients, remission or LDA at month 6 was associated with successful long-term outcomes: inhibition of structural progression and normative HAQ-DI scores. Long-term outcomes were similar when patients achieved CDAI remission or a DAS28CRP of < 1.9, confirming that this is an appropriate cut-off for remission with DAS28CRP. Tofacitinib potentially inhibits joint damage even with persistent inflammation.FundingPfizer Inc.Trial registrationClinicaltrials.gov identifiers: NCT01039688 and NCT00847613.Electronic supplementary materialThe online version of this article (10.1007/s40744-018-0113-7) contains supplementary material, which is available to authorized users.

Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and long-term outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background MTX. RAPID3 scores were calculated at baseline, month (M)6, and M24, and defined as remission (≤ 3), low (LDA; > 3–≤ 6), moderate (MDA; > 6–≤ 12), or high disease activity (HDA; > 12). Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and radiographic non-progression (modified Total Sharp Scores ≤ 0) at M24 were evaluated by M6 RAPID3 response. Among patients receiving tofacitinib 5 or 10 mg BID, respectively, 42.2 and 51.5% (ORAL Start) and 29.8 and 39.0% (ORAL Scan) achieved RAPID3 remission/LDA at M6. Most patients maintained/improved RAPID3 responses at M24. A higher proportion of patients in RAPID3 remission/LDA versus MDA/HDA at M6 achieved CDAI remission, reported normative HAQ-DI scores (< 0.5), and achieved both normative HAQ-DI scores and radiographic non-progression at M24. Patients achieving RAPID3 remission/LDA after 6-month treatment with tofacitinib 5 or 10 mg BID have improved long-term outcomes versus patients with MDA/HDA. These findings support the use of RAPID3 to monitor longer-term disease activity in conjunction with physician-assessed measures.

Similar Improvements in Patient-Reported Outcomes Among Rheumatoid Arthritis Patients Treated with Two Different Doses of Methotrexate in Combination with Adalimumab: Results From the MUSICA Trial.

In patients with rheumatoid arthritis (RA), combination treatment with methotrexate (MTX) and adalimumab is more effective than MTX monotherapy. From the patients' perspective, the impact of reduced MTX doses upon initiating adalimumab is not known. The objective was to evaluate the effects of low and high MTX doses in combination with adalimumab initiation on patient-reported outcomes (PROs), in MTX-inadequate responders (MTX-IR) with moderate-to-severe RA. MUSICA was a randomized, double-blind, controlled trial evaluating the efficacy of 7.5 or 20mg/week MTX, in combination with adalimumab for 24weeks in MTX-IR RA patients receiving prior MTX ≥ 15mg/week for ≥ 12weeks. PROs were recorded at each visit, including physical function, health-related quality-of-life, work productivity, quality-of-sleep, satisfaction with treatment medication, sexual impairment due to RA, patient global assessment of disease activity (PGA), and patient pain. Last observation carried forward was used to account for missing values. At baseline, patients in both MTX dosage groups had similar demographics, disease characteristics, and PRO scores. Overall, initiation of adalimumab led to significant improvements from baseline in the PROs assessed for both MTX dosage groups. Improvements in presenteeism from baseline were strongly correlated with corresponding improvements in SF-36 (vitality), pain, and physical function. Physical and mental well-being had a good correlation with improvement in sleep. Overall, improvements in disease activity from baseline were correlated with improvements in several PROs. The addition of adalimumab to MTX in MTX-IR patients with moderate-to-severe RA led to improvements in physical function, quality-of-life, work productivity, quality of sleep, satisfaction with treatment medication, and sexual impairment due to RA, regardless of the concomitant MTX dosage. AbbVie. Clinicaltrials.gov identifier, NCT01185288.

Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti-rheumatic Drugs: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

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 6months. 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.

Achieving comprehensive disease control in patients with early and established rheumatoid arthritis treated with adalimumab plus methotrexate versus methotrexate alone

ObjectiveTo evaluate the achievement of comprehensive disease control (CDC) following 1 year of treatment with adalimumab+methotrexate versus methotrexate alone and whether early achievement of remission (at week 24 or 26)...

Estimated medical expenditure and risk of job loss among rheumatoid arthritis patients undergoing tofacitinib treatment: post hoc analyses of two randomized clinical trials

Objectives. RA causes high disability levels and reduces health-related quality of life, triggering increased costs and risk of unemployment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. These post hoc analyses of phase 3 data aimed to assess monthly medical expenditure (MME) and risk of job loss for tofacitinib treatment vs placebo. Methods. Data analysed were from two randomized phase 3 studies of RA patients (n = 1115) with inadequate response to MTX or TNF inhibitors (TNFi) receiving tofacitinib 5 or 10 mg twice daily, adalimumab (one study only) or placebo, in combination with MTX. Short Form 36 version 2 Health Survey physical and mental component summary scores were translated into predicted MME via an algorithm and concurrent inability to work and job loss risks at 6, 12 and 24 months, using Medical Outcomes Study data. Results. MME reduction by month 3 was $100 greater for tofacitinib- than placebo-treated TNFi inadequate responders (P < 0.001); >20 and 6% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ⩾16%, and risk of future job loss decreased ∼20% (P < 0.001 vs placebo). MME reduction by month 3 was $70 greater for tofacitinib- than placebo-treated MTX inadequate responders (P < 0.001); ⩾23 and 13% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ⩾31% and risk of future job loss decreased ⩾25% (P < 0.001 vs placebo). Conclusion. Tofacitinib treatment had a positive impact on estimated medical expenditure and risk of job loss for RA patients with inadequate response to MTX or TNFi.

Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (≥17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)–4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28–4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.

Exploring a new ultrasound score as a clinical predictive tool in patients with rheumatoid arthritis starting abatacept: results from the APPRAISE study

ObjectivesTo explore whether changes in a composite (power Doppler/greyscale ultrasound (PDUS)) synovitis score, developed by the OMERACT-EULAR-Ultrasound Task Force, predict disease activity outcomes in rheumatoid arthritis (RA).MethodsPatients with RA who...

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

ObjectivesTo study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX).MethodsIn this...

Long-term safety and efficacy of treatment with subcutaneous abatacept in Japanese patients with rheumatoid arthritis who are methotrexate inadequate responders

Objective. To assess the long-term safety, immunogenicity, and efficacy of subcutaneous (SC) abatacept in combination with methotrexate (MTX) in Japanese patients with rheumatoid arthritis who were MTX inadequate responders, in a long-term extension (LTE) to a double-dummy, double-blind study (NCT01001832).Methods. Patients, who had previously received SC or intravenous (IV) abatacept with MTX (6–8 mg/week) for 24 weeks, received SC abatacept (125 mg/week) with MTX for an additional 52 weeks. Safety, immunogenicity, and efficacy were assessed.Results. The LTE included 112 patients. SC abatacept was generally well tolerated in the LTE, with no new safety signals. American College of Rheumatology 20, 50, and 70 response rates, disease activity score 28 (C-reactive protein) remission rates (< 2.6), and Health Assessment Questionnaire-Disability Index response rates (≥ 0.3 improvement from baseline) achieved at the end of the double-blind period were maintained over the LTE and were comparable in patients who received SC or IV abatacept in the double-blind period. Seropositivity for immunogenicity occurred in 4 (3.6%) patients. Self-injection of SC abatacept was well controlled and not associated with additional safety events.Conclusions. SC abatacept had acceptable safety and was well tolerated and effective over the LTE (76 weeks in total), with low rates of immunogenicity in Japanese patients.

Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate

ObjectivesTo investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate.MethodsIn this phase IIb study, 301...

MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study

ObjectiveTo evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX)...

THU0156 Impact of Golimumab on Physical Function and Employability of Patients with Rheumatoid Arthritis: 5-Year Data from 3 Phase III Clinical Trials

ObjectivesTo assess the impact of golimumab (GLM) on physical function and employability in patients with rheumatoid arthritis (RA) with various prior treatment histories, after 5 years of therapy.MethodsThe efficacy and...