EULAR/eumusc.net standards of care for rheumatoid arthritis: cross-sectional analyses of importance, level of implementation and care gaps experienced by patients and rheumatologists across 35 European countries.

OBJECTIVE: As part of European League against Rheumatism (EULAR)/European Musculoskeletal Conditions Surveillance and Information Network, 20 user-focused standards of care (SoCs) for rheumatoid arthritis (RA) addressing 16 domains of care were developed. This study aimed to explore gaps in implementation of these SoCs across Europe. METHODS: Two cross-sectional surveys on the importance, level of and barriers (patients only) to implementation of each SoC (0-10, 10 highest) were designed to be conducted among patients and rheumatologists in 50 European countries. Care gaps were calculated as the difference between the actual and maximum possible score for implementation (ie, 10) multiplied by the care importance score, resulting in care gaps (0-100, maximal gap). Factors associated with the problematic care gaps (ie, gap≥30 and importance≥6 and implementation<6) and strong barriers (≥6) were further analysed in multilevel logistic regression models. RESULTS: Overall, 26 and 31 countries provided data from 1873 patients and 1131 rheumatologists, respectively. 19 out of 20 SoCs were problematic from the perspectives of more than 20% of patients, while this was true for only 10 SoCs for rheumatologists. Rheumatologists in countries with lower gross domestic product and non-European Union countries were more likely to report problematic gaps in 15 of 20 SoCs, while virtually no differences were observed among patients. Lack of relevance of some SoCs (71%) and limited time of professionals (66%) were the most frequent implementation barriers identified by patients. CONCLUSIONS: Many problematic gaps were reported across several essential aspects of RA care. More efforts need to be devoted to implementation of EULAR SoCs.

Patients with rheumatoid arthritis facing sick leave or work disability meet varying regulations: a study among rheumatologists and patients from 44 European countries.

OBJECTIVES: To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system's performance, across European countries. METHODS: We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates. RESULTS: Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (ß=-0.5 (95% CI -0.9 to -0.2) and ß=-0.5 (95% CI -1.0 to -0.1), respectively). The Scandinavian and Bismarckian system scored best on patients' and rheumatologists' perceptions of regulations and system performance. CONCLUSIONS: There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country's wealth.

Upadacitinib versus placebo or adalimumab with background methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate: a subgroup analysis of a phase III randomized controlled trial in Central and Eastern European patients.

BACKGROUND: In the randomized, phase III, global SELECT-COMPARE study, upadacitinib 15 mg demonstrated efficacy at week 12 versus placebo and adalimumab with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX, which was maintained over 48 weeks. This post hoc analysis of SELECT-COMPARE reports the efficacy and safety of upadacitinib in Central and Eastern European (CEE) patients. METHODS: Patients were randomized 2:2:1 to upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week, and continued MTX. Efficacy and safety were assessed through 48 weeks. Primary endpoints were the achievement of ≥20% improvement in American College of Rheumatology response criteria and Disease Activity Score in 28 joints with C-reactive protein <2.6 responses at week 12 for upadacitinib versus placebo. No statistical comparisons were conducted. RESULTS: A total of 596 patients from 12 CEE countries were randomized. At week 12, a numerically greater proportion of patients receiving upadacitinib versus placebo or adalimumab achieved ≥20% improvement in American College of Rheumatology response criteria (72% versus 33% and 59%), Disease Activity Score in 28 joints with C-reactive protein <2.6 (26% versus 4% and 11%), low disease activity and remission, and improved physical function, with results maintained over 48 weeks. Upadacitinib treatment numerically inhibited structural progression versus placebo at week 26. Serious infection and herpes zoster rates were numerically higher with upadacitinib versus adalimumab (2.7 versus 1.7 and 2.3 versus 1.1 events/100 patient-years, respectively) over 48 weeks. CONCLUSION: Consistent with the global population of patients with rheumatoid arthritis and an inadequate response to MTX, in CEE patients, upadacitinib 15 mg demonstrated clinical and functional improvements versus placebo and adalimumab, radiographic improvements versus placebo, and reasonable safety, over 48 weeks.

Long-Term Efficacy and Safety of Biosimilar CT-P10 Versus Innovator Rituximab in Rheumatoid Arthritis: 48-Week Results from a Randomized Phase III Trial.

OBJECTIVE: The aim of this study was to investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks. METHODS: In this multinational, randomized, double-blind trial, adults with active RA received up to two courses of CT-P10, US-RTX, or EU-RTX alongside methotrexate. Efficacy endpoints included Disease Activity Score 28-joint count (DAS28) and American College of Rheumatology (ACR) response rates. Pharmacokinetics, pharmacodynamics, immunogenicity, and safety were also assessed. RESULTS: Of 372 patients randomized to the study drug, 330 (88.7%) completed the second treatment course. Mean change from baseline to week 48 in DAS28-C-reactive protein was comparable in the CT-P10 and combined rituximab (US-RTX and EU-RTX) groups (- 2.7 and - 2.6, respectively). ACR20, ACR50, and ACR70 response rates at week 48 indicated no differences between groups (80.6%, 55.4%, and 31.7% vs. 79.8%, 53.9%, and 33.7% in the CT-P10 and combined rituximab groups, respectively). Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, antidrug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic, pharmacodynamic, and safety profiles. CONCLUSION: CT-P10 was similar to EU-RTX and US-RTX in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety up to week 48. CLINICALTRIALS. GOV IDENTIFIER: NCT02149121.

Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study.

BACKGROUND: CT-P13 (Remsima®, Inflectra®) is a biosimilar of the infliximab reference product (RP; Remicade®) and is approved in Europe and elsewhere, mostly for the same indications as RP. The aim of this study was to compare the 54-week efficacy, immunogenicity, pharmacokinetics (PK) and safety of CT-P13 with RP in patients with ankylosing spondylitis (AS), with a focus on patient-reported outcomes (PROs). METHODS: This was a multinational, double-blind, parallel-group study in patients with active AS. Participants were randomized (1:1) to receive CT-P13 (5 mg/kg) or RP (5 mg/kg) at weeks 0, 2, 6 and then every 8 weeks up to week 54. To assess responses, standardized assessment tools were used with an intention-to-treat analysis of observed data. Anti-drug antibodies (ADAs), PK parameters, and safety outcomes were also assessed. RESULTS: Of 250 randomized patients (n = 125 per group), 210 (84.0 %) completed 54 weeks of treatment, with similar completion rates between groups. At week 54, Assessment of Spondylo Arthritis international Society (ASAS)20 response, ASAS40 response and ASAS partial remission were comparable between treatment groups. Changes from baseline in PROs such as mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; CT-P13 -3.1 versus RP -2.8), Bath Ankylosing Spondylitis Functional Index (BASFI; -2.9 versus -2.7), and Short Form Health Survey (SF-36) scores (9.26 versus 10.13 for physical component summary; 7.30 versus 6.54 for mental component summary) were similar between treatment groups. At 54 weeks, 19.5 % and 23.0 % of patients receiving CT-P13 and RP, respectively, had ADAs. All observed PK parameters of CT-P13 and RP, including maximum and minimum serum concentrations, were similar through 54 weeks. The influence of ADAs on PK was similar in the two treatment groups. Most adverse events were mild or moderate in severity. There was no notable difference between treatment groups in the incidence of adverse events, serious adverse events, infections and infusion-related reactions. CONCLUSIONS: CT-P13 and RP have highly comparable efficacy (including PROs) and PK up to week 54. Over a 1-year period, CT-P13 was well tolerated and displayed a safety profile comparable to RP; no differences in immunogenicity were observed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01220518 . Registered 4 October 2010.

Determinants of discordance in patients' and physicians' rating of rheumatoid arthritis disease activity.

OBJECTIVE: To assess the determinants of patients' (PTGL) and physicians' (MDGL) global assessment of rheumatoid arthritis (RA) activity and factors associated with discordance among them. METHODS: A total of 7,028 patients in the Quantitative Standard Monitoring of Patients with RA study had PTGL and MDGL assessed at the same clinic visit on a 0-10-cm visual analog scale (VAS). Three patient groups were defined: concordant rating group (PTGL and MDGL within ±2 cm), higher patient rating group (PTGL exceeding MDGL by >2 cm), and lower patient rating group (PTGL less than MDGL by >2 cm). Multivariable regression analysis was used to identify determinants of PTGL and MDGL and their discordance. RESULTS: The mean ± SD VAS scores for PTGL and MDGL were 4.01 ± 2.70 and 2.91 ± 2.37, respectively. Pain was overwhelmingly the single most important determinant of PTGL, followed by fatigue. In contrast, MDGL was most influenced by swollen joint count (SJC), followed by erythrocyte sedimentation rate (ESR) and tender joint count (TJC). A total of 4,454 (63.4%), 2,106 (30%), and 468 (6.6%) patients were in the concordant, higher, and lower patient rating groups, respectively. Odds of higher patient rating increased with higher pain, fatigue, psychological distress, age, and morning stiffness, and decreased with higher SJC, TJC, and ESR. Lower patient rating odds increased with higher SJC, TJC, and ESR, and decreased with lower fatigue levels. CONCLUSION: Nearly 36% of patients had discordance in RA activity assessment from their physicians. Sensitivity to the "disease experience" of patients, particularly pain and fatigue, is warranted for effective care of RA.

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.

Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study.

INTRODUCTION: Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). METHODS: The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. RESULTS: Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies. CONCLUSIONS: In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Physical inactivity in patients with rheumatoid arthritis: data from twenty-one countries in a cross-sectional, international study.

OBJECTIVE: Regular physical activity is associated with decreased morbidity and mortality. Traditionally, patients with rheumatoid arthritis (RA) have been advised to limit physical exercise. We studied the prevalence of physical activity and associations with demographic and disease-related variables in patients with RA from 21 countries. METHODS: The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) is a cross-sectional study that includes a self-report questionnaire and clinical assessment of nonselected consecutive outpatients with RA who are receiving usual clinical care. Frequency of physical exercise (>or=30 minutes with at least some shortness of breath, sweating) is queried with 4 response options: >or=3 times weekly, 1-2 times weekly, 1-2 times monthly, and no exercise. RESULTS: Between January 2005 and April 2007, a total of 5,235 patients from 58 sites in 21 countries were enrolled in QUEST-RA: 79% were women, >90% were white, mean age was 57 years, and mean disease duration was 11.6 years. Only 13.8% of all patients reported physical exercise>or=3 times weekly. The majority of the patients were physically inactive with no regular weekly exercise: >80% in 7 countries, 60-80% in 12 countries, and 45% and 29% in 2 countries, respectively. Physical inactivity was associated with female sex, older age, lower education, obesity, comorbidity, low functional capacity, and higher levels of disease activity, pain, and fatigue. CONCLUSION: In many countries, a low proportion of patients with RA exercise. These data may alert rheumatologists to motivate their patients to increase physical activity levels.