Points to consider for cost-effective use of biological and targeted synthetic DMARDs in inflammatory rheumatic diseases: results from an umbrella review and international Delphi study.

OBJECTIVES: To develop evidence-based points to consider for cost-effective use of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in the treatment of inflammatory rheumatic diseases, specifically rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis. METHODS: Following EULAR procedures, an international task force was formed, consisting of 13 experts in rheumatology, epidemiology and pharmacology from seven European countries. Twelve strategies for cost-effective use of b/tsDMARDs were identified through individual and group discussion. For each strategy, PubMed and Embase were systematically searched for relevant English-language systematic reviews and, for six strategies, additionally for randomised controlled trials (RCTs). Thirty systematic reviews and 21 RCTs were included. Based on the evidence, a set of overarching principles and points to consider was formulated by the task force using a Delphi procedure. Level of evidence (1a-5) and grade (A-D) were determined for each point to consider. Individual voting on the level of agreement (LoA; between 0 (completely disagree) and 10 (completely agree)) was performed anonymously. RESULTS: The task force agreed on five overarching principles. For 10 of 12 strategies, the evidence was sufficient to formulate one or more points to consider, leading to 20 in total, regarding response prediction, drug formulary use, biosimilars, loading doses, low-dose initial therapy, concomitant conventional synthetic DMARD use, route of administration, medication adherence, disease activity-guided dose optimisation and non-medical drug switching. Ten points to consider (50%) were supported by level 1 or 2 evidence. The mean LoA (SD) varied between 7.9 (1.2) and 9.8 (0.4). CONCLUSION: These points to consider can be used in rheumatology practices and complement inflammatory rheumatic disease treatment guidelines to incorporate cost-effectiveness in b/tsDMARD treatment.

Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters.

The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as "biobetters" or "value-added medicines," are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients.

Associations between Patient Global Assessment scores and pain, physical function, and fatigue in rheumatoid arthritis: a post hoc analysis of data from phase 3 trials of tofacitinib.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We examined the degree to which Patient Global Assessment of Disease Activity (PtGA) was driven by patient-reported assessments of pain (Pain), physical function, and fatigue in patients receiving tofacitinib 5 mg twice daily or placebo, each with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: This post hoc analysis used data pooled from three randomized controlled trials in csDMARD-inadequate responder (csDMARD-IR) patients (ORAL Scan: NCT00847613; ORAL Standard: NCT00853385; ORAL Sync: NCT00856544). Using subgroup analysis from 2 × 2 tables, associations between PtGA and Pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at month 3 were evaluated using Pearson's Phi correlation coefficients. To support the main analysis, associations between select patient-reported outcomes (PROs) were also evaluated in csDMARD-naïve (ORAL Start; NCT01039688) and biologic (b)DMARD-IR (ORAL Step; NCT00960440) patients. RESULTS: Across csDMARD-IR treatment groups, low disease activity (defined as PtGA ≤ 20 mm), and moderate (≥ 30%) and substantial (≥ 50%) improvements from baseline in PtGA were associated with mild Pain (Visual Analog Scale score ≤ 20 mm), and moderate (≥ 30%) and substantial (≥ 50%) improvements from baseline in Pain; lack of Pain improvement was associated with little/no improvement in PtGA. In contrast, large proportions of csDMARD-IR patients who reported PtGA improvements did not report HAQ-DI or FACIT-F scores ≥ normative values (≤ 0.25 and ≥ 43.5, respectively) or changes in HAQ-DI or FACIT-F scores ≥ minimum clinically important difference (≥ 0.22 and ≥ 4.0, respectively). Generally, PtGA and Pain outcomes were moderately-to-strongly correlated at month 3 in csDMARD-IR patients, with weaker correlations evident between PtGA and HAQ-DI/FACIT-F outcomes. Similar findings were generally evident in csDMARD-naïve and bDMARD-IR patients. CONCLUSIONS: This analysis supports the role of Pain as a key driver of PtGA in RA; physical function and fatigue play lesser roles in patients' perceptions of disease activity. These findings corroborate the importance of improved PROs and attainment of low symptom states for optimizing patient care. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009); NCT01039688 (registered: December 25, 2009); NCT00960440 (registered: August 17, 2009).

Long-term efficacy and cost-effectiveness of infliximab as first-line treatment in rheumatoid arthritis: systematic review and meta-analysis.

Introduction: Early biological treatment of rheumatoid arthritis (RA) may reverse the autoimmune response in some patients resulting in favorable long-term outcomes. Although the cost-effectiveness of this strategy has been questioned, biosimilar entries warrant the revision of clinical and pharmaco-economic evidence. Areas covered: We conducted a systematic review of randomized controlled trials (RCTs) published up to 24 May 2018 in Pubmed, EMBASE and Cochrane CENTRAL, comparing infliximab with non-biological therapy in patients with RA naïve to methotrexate. We performed meta-analyses for efficacy outcomes at month 6 and years 1 and 2. Six RCTs were identified, involving 1832 patients. At month 6 ACR70 response and remission, and at year 1 ACR20/ACR70 responses and remission were improved significantly with first-line infliximab versus control. The differences were not significant at year 2. We reviewed cost-utility studies, up to 31 October 2018 in PubMed, Cochrane CENTRAL and the CRD HTA databases. Four studies indicated that first-line use of originator infliximab calculated at 2005-2008 prices was not cost-effective. Expert opinion: We demonstrated the efficacy benefits of first-line infliximab therapy up to 1 year in methotrexate-naïve RA. We highlighted the need for standardized reporting of outcomes and conducting cost-effectiveness analyses of first-line biosimilar therapy in RA.

Cost-effective Tapering Algorithm in Patients with Rheumatoid Arthritis: Combination of Multibiomarker Disease Activity Score and Autoantibody Status.

OBJECTIVE: To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)-tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission. METHODS: The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. RESULTS: RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83. CONCLUSION: Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.

The association of fatigue, comorbidity burden, disease activity, disability and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the Quest-RA program.

OBJECTIVES: The aim is to assess the prevalence of comorbidities and to further analyse to which degree fatigue can be explained by comorbidity burden, disease activity, disability and gross domestic product (GDP) in patients with rheumatoid arthritis (RA). METHODS: Nine thousands eight hundred seventy-four patients from 34 countries, 16 with high GDP (>24.000 US dollars [USD] per capita) and 18 low-GDP countries (<24.000 USD) participated in the Quantitative Standard monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid conditions, fatigue (0-10 cm visual analogue scale [VAS] [10=worst]), disease activity in 28 joints (DAS28), and physical disability (Health Assessment Questionnaire score [HAQ]) were assessed. Univariate and multivariate linear regression analyses were performed to assess the association between fatigue and comorbidities, disease activity, disability and GDP. RESULTS: Overall, patients reported a median of 2 comorbid conditions of which hypertension (31.5%), osteoporosis (17.6%), osteoarthritis (15.5%) and hyperlipidaemia (14.2%) were the most prevalent. The majority of comorbidities were more common in high-GDP countries. The median fatigue score was 4.4 (4.8 in low-GDP countries and 3.8 in high-GDP countries, p<0.001). In low-GDP countries 25.4% of the patients had a high level of fatigue (>6.6) compared with 23.0% in high-GDP countries (p<0.001). In univariate analysis, fatigue increased with increasing number of comorbidities, disease activity and disability in both high- and low-GDP countries. In multivariate analysis of all countries, these 3 variables explained 29.4% of the variability, whereas GDP was not significant. CONCLUSIONS: Fatigue is a widespread problem associated with high comorbidity burden, disease activity and disability regardless of GDP.

Patient's global assessment of disease activity and patient's assessment of general health for rheumatoid arthritis activity assessment: are they equivalent?

OBJECTIVES: To assess (A) determinants of patient's global assessment of disease activity (PTGL) and patient's assessment of general health (GH) scores of rheumatoid arthritis (RA) patients; (B) whether they are equivalent as individual variables; and (C) whether they may be used interchangeably in calculating common RA activity assessment composite indices. METHODS: Data of 7023 patients from 30 countries in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) was analysed. PTGL and GH determinants were assessed by mixed-effects analyses of covariance models. PTGL and GH equivalence was determined by Bland-Altman 95% limits of agreement (BALOA) and Lin's coefficient of concordance (LCC). Concordance between PTGL and GH based Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) indices were calculated using LCC, and the level of agreement in classifying RA activity in four states (remission, low, moderate, high) using κ statistics. RESULTS: Significant differences in relative and absolute contribution of RA and non-RA related variables in PTGL and GH ratings were noted. LCC of 0.64 and BALOA of -4.41 to 4.54 showed that PTGL and GH are not equivalent. There was excellent concordance (LCC 0.95-0.99) for PTGL and GH based DAS28, CDAI and RAPID3 indices, and >80% absolute agreement (κ statistics 0.75-0.84) in RA activity state classification for all three indices. CONCLUSIONS: PTGL and GH ratings differ in their determinants. Although they are individually not equivalent, they may be used interchangeably for calculating composite indices for RA activity assessment.

Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study.

INTRODUCTION: Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. METHODS: The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. RESULTS: At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. CONCLUSIONS: Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0.

OBJECTIVE: The OMERACT Drug Safety Working Group focuses on standardization of assessment and reporting of adverse events in clinical trials and longitudinal and observational studies in rheumatology. This group developed the Rheumatology Common Toxicity Criteria (RCTC) in 1999, building on the Oncology Common Toxicity Criteria. At OMERACT 8, a workshop group reviewed the use of the RCTC and other instruments in rheumatology clinical trials to date, to revise and to stimulate its implementation. METHODS: The Working Group drafted a revision of the RCTC after an iterative examination of its contents, terms, and definitions. The RCTC were compared with the Oncology Common Toxicity Criteria (CTC v.2.0), and the Common Terminology Criteria for Adverse Events (CTCAE v.3.0). In addition a pharmaceutical company focus group met to clarify the challenges of application of RCTC terms and definitions, relative to the standard in pharmaceutical clinical trials, i.e., verbatim recording of adverse events followed by mapping to Medical Dictionary of Drug Regulatory Activities (MedDRA) terms. The workshop focused on the proposed revision of RCTC to version 2.0 and on the research agenda, including a validation of the RCTC in future trials. RESULTS: At OMERACT 8, breakout groups amended the contents of the 4 current and 2 new categories of adverse event terms within the draft RCTC v.2.0. Participants recognized the need to standardize the definitions for disease flares, infection, malignancy, and certain syndromes such as drug hypersensitivity and infusion reactions. Moderate consensus (62%) was reached in the final plenary session that the amended RCTC v.2.0 should be promulgated and tested in available trials of anti-tumor necrosis factor agents. CONCLUSION: The RCTC has face validity and construct validity. However, documentation of discrimination and feasibility (the other elements of the OMERACT filter) is needed. Collaboration with drug safety working groups in rheumatology professional organizations is necessary to enable this project.