Martin J. Bergman

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force

Background Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. Objective To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. Methods A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. Results The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). Conclusions The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study

IntroductionWe analyzed the prevalence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA) and its association with traditional CV risk factors, clinical features of RA, and the use of disease-modifying antirheumatic drugs (DMARDs) in a multinational cross-sectional cohort of nonselected consecutive outpatients with RA (The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Program, or QUEST-RA) who were receiving regular clinical care.MethodsThe study involved a clinical assessment by a rheumatologist and a self-report questionnaire by patients. The clinical assessment included a review of clinical features of RA and exposure to DMARDs over the course of RA. Comorbidities were recorded; CV morbidity included myocardial infarction, angina, coronary disease, coronary bypass surgery, and stroke. Traditional risk factors recorded were hypertension, hyperlipidemia, diabetes mellitus, smoking, physical inactivity, and body mass index. Unadjusted and adjusted hazard ratios (HRs) (95% confidence interval [CI]) for CV morbidity were calculated using Cox proportional hazard regression models.ResultsBetween January 2005 and October 2006, the QUEST-RA project included 4,363 patients from 48 sites in 15 countries; 78% were female, more than 90% were Caucasian, and the mean age was 57 years. The prevalence for lifetime CV events in the entire sample was 3.2% for myocardial infarction, 1.9% for stroke, and 9.3% for any CV event. The prevalence for CV risk factors was 32% for hypertension, 14% for hyperlipidemia, 8% for diabetes, 43% for ever-smoking, 73% for physical inactivity, and 18% for obesity. Traditional risk factors except obesity and physical inactivity were significantly associated with CV morbidity. There was an association between any CV event and age and male gender and between extra-articular disease and myocardial infarction. Prolonged exposure to methotrexate (HR 0.85; 95% CI 0.81 to 0.89), leflunomide (HR 0.59; 95% CI 0.43 to 0.79), sulfasalazine (HR 0.92; 95% CI 0.87 to 0.98), glucocorticoids (HR 0.95; 95% CI 0.92 to 0.98), and biologic agents (HR 0.42; 95% CI 0.21 to 0.81; P < 0.05) was associated with a reduction of the risk of CV morbidity; analyses were adjusted for traditional risk factors and countries.ConclusionIn conclusion, prolonged use of treatments such as methotrexate, sulfasalazine, leflunomide, glucocorticoids, and tumor necrosis factor-alpha blockers appears to be associated with a reduced risk of CV disease. In addition to traditional risk factors, extra-articular disease was associated with the occurrence of myocardial infarction in patients with RA.

RAPID3 (Routine Assessment of Patient Index Data 3), a Rheumatoid Arthritis Index Without Formal Joint Counts for Routine Care: Proposed Severity Categories Compared to Disease Activity Score and Clinical Disease Activity Index Categories

Objective To compare 4 categories (high, moderate, and low severity, and near-remission) of RAPID3 (Routine Assessment of Patient Index Data 3), an index without formal joint counts, which is scored in < 10 seconds to 4 categories of the DiseaseActivity Score (DAS28) and Clinical Disease Activity Index (CDAI) in patients with rheumatoid arthritis (RA). Methods All patients complete a Multidimensional Health Assessment Questionnaire (MDHAQ) at each visit. A physician/assessor 28-joint count and erythrocyte sedimentation rate (ESR) were completed in 285 patients with RA in usual care by 3 rheumatologists to score DAS28, CDAI, and RAPID3. RAPID3 includes the 3 MDHAQ patient self-report RA Core Data Set measures for physical function, pain, and patient global estimate. Proposed RAPID3 (range 0–10) severity categories of high (> 4), moderate (2.01–4), low (1.01–2), and near-remission (≤ 1) were compared to DAS (0–10) activity categories of high (> 5.1), moderate (3.21–5.1), low (2.61–3.2), and remission (≤ 2.6), and CDAI (0–76) categories of > 22, 10.1–22.0, 2.9–10.0, and ≤ 2.8. Additional RAPID scores, which add to RAPID3 a physician/assessor or patient self-report joint count and/or assessor global estimate, were also analyzed. Statistical significance was analyzed using Spearman correlations, cross-tabulations, and kappa statistics. Results All RAPID scores were correlated significantly with DAS28 and CDAI (rho > 0.65, p < 0.001). Overall, 78%–84% of patients who met DAS28 or CDAI moderate/high activity criteria met similar RAPID severity criteria, and 68%–77% who met DAS28 or CDAI remission/low activity criteria also met similar RAPID criteria. RAPID3 was as informative as other indices. Conclusion RAPID3 provides a feasible, informative quantitative index for busy clinical settings.

Remission and rheumatoid arthritis: Data on patients receiving usual care in twenty-four countries

OBJECTIVE To compare the performance of different definitions of remission in a large multinational cross-sectional cohort of patients with rheumatoid arthritis (RA). METHODS The Questionnaires in Standard Monitoring of Patients with RA (QUEST-RA) database, which (as of January 2008) included 5,848 patients receiving usual care at 67 sites in 24 countries, was used for this study. Patients were clinically assessed by rheumatologists and completed a 4-page self-report questionnaire. The database was analyzed according to the following definitions of remission: American College of Rheumatology (ACR) definition, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), clinical remission assessed using 42 and 28 joints (Clin42 and Clin28), patient self-report Routine Assessment of Patient Index Data 3 (RAPID3), and physician report of no disease activity (MD remission). RESULTS The overall remission rate was lowest using the ACR definition of remission (8.6%), followed by the Clin42 (10.6%), Clin28 (12.6%), CDAI (13.8%), MD remission (14.2%), and RAPID3 (14.3%); the rate of remission was highest when remission was defined using the DAS28 (19.6%). The difference between the highest and lowest remission rates was >or=15% in 10 countries, 5-14% in 7 countries, and <5% in 7 countries (the latter of which had generally low remission rates [<5.5%]). Regardless of the definition of remission, male sex, higher education, shorter disease duration, smaller number of comorbidities, and regular exercise were statistically significantly associated with remission. CONCLUSION The use of different definitions of RA remission leads to different results with regard to remission rates, with considerable variation among countries and between sexes. Reported remission rates in clinical trials and clinical studies have to be interpreted in light of the definition of remission that has been used.

RAPID3 (Routine Assessment of Patient Index Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): Agreement with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, scored in five versus more than ninety seconds

To compare the Routine Assessment of Patient Index Data 3 (RAPID3) on a Multidimensional Health Assessment Questionnaire (MDHAQ) with the Disease Activity Score (DAS28), Clinical Disease Activity Index (CDAI), and individual core data set measures for correlations, agreement of activity levels, and time to score.

The Prevalence and Characteristics of Fibromyalgia in the 2012 National Health Interview Survey

Background Most knowledge of fibromyalgia comes from the clinical setting, where healthcare-seeking behavior and selection issues influence study results. The characteristics of fibromyalgia in the general population have not been studied in detail. Methods We developed and tested surrogate study specific criteria for fibromyalgia in rheumatology practices using variables from the US National Health Interview Survey (NHIS) and the modification (for surveys) of the 2010 American College of Rheumatology (ACR) preliminary fibromyalgia criteria. The surrogate criteria were applied to the 2012 NHIS and identified persons who satisfied criteria from symptom data. The NHIS weighted sample of 8446 persons represents 225.7 million US adults. Results Fibromyalgia was identified in 1.75% (95% CI 1.42, 2.07), or 3.94 million persons. However, 73% of identified cases self-reported a physician’s diagnosis other than fibromyalgia. Identified cases had high levels of self-reported pain, non-pain symptoms, comorbidity, psychological distress, medical costs, Social Security and work disability. Caseness was associated with gender, education, ethnicity, citizenship and unhealthy behaviors. Demographics, behaviors, and comorbidity were predictive of case status. Examination of the surrogate polysymptomatic distress scale (PSD) of the 2010 ACR criteria found fibromyalgia symptoms extending through the full length of the scale. Conclusions Persons identified with criteria-based fibromyalgia have severe symptoms, but most (73%) have not received a clinical diagnosis of fibromyalgia. The association of fibromyalgia-like symptoms over the full length of the PSD scale with physiological as well as mental stressors suggests PSD may be a universal response variable rather than one restricted to fibromyalgia.

RAPID3, an Index to Assess and Monitor Patients with Rheumatoid Arthritis, Without Formal Joint Counts: Similar Results to DAS28 and CDAI in Clinical Trials and Clinical Care

RAPID3 (routine assessment of patient index data 3) is a pooled index of the 3 patient-reported American College of Rheumatology rheumatoid arthritis (RA) Core Data Set measures: function, pain, and patient global estimate of status. Each of the 3 individual measures is scored 0 to 10, for a total of 30. Disease severity may be classified on the basis of RAPID3 scores: >12 = high; 6.1-12 = moderate; 3.1-6 = low; < or =3 = remission. RAPID3 scores are correlated with the disease activity score 28 (DAS28) and clinical disease activity index (CDAI) in clinical trials and clinical care, and are comparable to these indices in capacity to distinguish active from control treatments in clinical trials. RAPID3 on a multidimensional health assessment questionnaire (MDHAQ) is scored in 5 to 10 seconds, versus 90 to 94 seconds for a formal 28-joint count, 108 seconds for a CDAI, and 114 seconds for a DAS28. An MDHAQ can be completed by each patient at each visit in the waiting room in 5 to 10 minutes, as a component of the infrastructure of routine care, with minimal effort of the rheumatologist and staff, to provide RAPID3 scores as well as additional data including a self-report joint count, fatigue, review of systems, and recent medical history. In all rheumatic diseases RAPID3 is able to provide a baseline quantitative value, and to quantitatively monitor and document improvement or worsening over time.

Is Fatigue an Inflammatory Variable in Rheumatoid Arthritis (RA)? Analyses of Fatigue in RA, Osteoarthritis, and Fibromyalgia

Objective. To investigate whether fatigue is an inflammatory (rheumatoid arthritis; RA) variable, the contributions of RA variables to fatigue, and the levels of fatigue in RA compared with osteoarthritis (OA) and fibromyalgia (FM). Methods. We studied 2096 RA patients, 1440 with OA, and 1073 with FM in a clinical setting, and 14,607 RA, 3173 OA, and 2487 patients with FM in survey research. We partitioned variables into inflammatory and noninflammatory factors and examined variable contribution to fatigue (0–10 visual analog scale). Results. Factor analysis identified Disease Activity Score-28 (DAS28) and swollen (SJC) and tender joint count (TJC) as a physician-inflammation factor, and patient global assessment, pain, Health Assessment Questionnaire, and fatigue as patient components. Fatigue demonstrated weak correlations with erythrocyte sedimentation rate (ESR; r = 0.071) and SJC (r = 0.112), weak to fair correlations with TJC (r = 0.294), physician global assessment of RA activity (r = 0.384), and DAS28 (r = 0.399), but strong correlation with patient global assessment of severity (r = 0.567). In hierarchical regression analysis, patient global explained 43.1% of DAS28 fatigue variance; when SJC, TJC, and ESR were entered, the explained variance increased to 43.7%. In reverse order, SJC, TJC, and ESR explained 9.2% of the variance, but explained variance increased to 43.7% when patient global was added. The mean clinic fatigue scores were RA 4.9, OA 4.8, FM 7.6; mean survey scores were RA 4.5, OA 4.4, FM 6.3. Adjusted for age and sex, RA and OA fatigue scores were not significantly different. Conclusion. Inflammatory components of the DAS28 contribute minimally to fatigue. RA and OA fatigue levels do not differ. Fatigue is not an inflammatory variable and has no unique association with RA or RA therapy.

MDHAQ/RAPID3 to recognize improvement over 2 months in usual care of patients with osteoarthritis, systemic lupus erythematosus, spondyloarthropathy, and gout, as well as rheumatoid arthritis.

ObjectiveTo analyze whether MDHAQ (Multidimensional Health Assessment Questionnaire) scores for physical function (FN), pain, Patient Global Estimate (PATGL), and RAPID3 (Routine Assessment of Patient Index Data, a composite of these 3 measures) document improvement in patients with osteoarthritis, systemic lupus erythematosus, spondyloarthropathy, and gout, similarly to rheumatoid arthritis. MethodsIn a solo rheumatology practice, every patient completes an MDHAQ/RAPID3 and is assigned a Physician Global Estimate (DOCGL) at every visit. Mean and median FN (0–10 scale), pain (0–10), PATGL (0–10), RAPID3 (0–30), and DOCGL (0–10) were computed at first visit and 2 months later in 141 new patients with 5 diagnoses. Proportions with RAPID3 high (>12), moderate (6.1–12), and low (3.1–6) severity and remission (⩽3) were computed. Differences between baseline and 2-month follow-up for each diagnosis were analyzed using paired t tests. Mean changes over 2 months across 5 diagnoses were compared using analysis of variance. ResultsMean baseline scores for all measures were in narrow ranges for all 5 diagnoses: FN 1.5 to 2.5, pain 4.2 to 5.9, PATGL 4.3 to 5.6, RAPID3 10.1 to 13.7, and DOCGL 2.4 to 4.0. Improvement for FN was 9.4% to 26.8% in all diagnoses but osteoarthritis, for pain 20.2% to 35.3% in all diagnoses, PATGL 11.3% to 30.4%, RAPID3 16.8% to 27.5%, and for DOCGL 23.8% to 36.4%, similar in 5 diagnostic groups. ConclusionsMDHAQ, RAPID3, and DOCGL document similar baseline and improvement scores in patients with 5 diagnoses. These quantitative data may supplement traditional narrative, “gestalt” descriptions in usual care of patients with any rheumatic disease.

Proposed severity and response criteria for Routine Assessment of Patient Index Data (RAPID3): results for categories of disease activity and response criteria in abatacept clinical trials.

Background. An index is needed to assess the status of patients with rheumatoid arthritis (RA), as none of the existing measures are applicable to all individual patients. The 28-joint Disease Activity Score (DAS28) is the most specific and widely used index. Routine Assessment of Patient Index Data (RAPID3) is an index containing only the 3 patient self-report core dataset measures, without a laboratory test or formal joint count, and with simple scoring. RAPID3 is correlated significantly with DAS28, but calculated in 5–10 seconds on a Multidimensional Health Assessment Questionnaire (MDHAQ), compared to 114 seconds for DAS28. Methods. DAS28 (0–10 scale) categories for high, moderate, and low activity, and remission (≤ 2.6, 2.6–3.2, 3.21–5.1, and > 5.1, respectively) and proposed RAPID3 (0–30 scale) categories for severity (0 ≤ 3, 3.1–6, 6.1–12, and > 12) were compared in patients taking abatacept and control-treated patients at the endpoint of the Abatacept in Inadequate Response to Methotrexate (AIM) and the Abatacept Trial in Treatment of Anti-TNF INadequate Responders (ATTAIN) clinical trials, using cross-tabulations and kappa statistics. Results. Overall, 92%–99% of patients classified as having high DAS28 activity had high or moderate RAPID3 severity, while 64%–83% in DAS28 remission had RAPID3 low severity or remission; 50%–82% of patients with good or poor EULAR responses had good or poor RAPID3 responses. Kappa values ranged from 0.25 to 0.48, and weighted kappas from 0.32 to 0.52, indicating fair to moderate agreement for the 2 indices. Conclusion. Proposed RAPID3 severity and response categories yield comparable results to DAS28 and EULAR criteria in AIM and ATTAIN. DAS28 is more specific for clinical trials. RAPID3 does not preclude also scoring DAS28, and may be informative in the infrastructure of routine care.