Rheumatoid arthritis: Evolving recognition of a common disease.

Rheumatoid arthritis (RA) is a highly prevalent autoimmune disease and the most common form of autoimmune inflammatory arthritis. Studies of RA pathogenesis have contributed significantly to understanding the basis for complex immune-mediated disease, identified key steps in the development of autoimmune activation and joint damage in RA, and led to the development of targeted therapies that opened up the era biologic therapy. Current studies are linking differences in gene expression to abnormalities in cellular function that will help optimize therapy for individual patients and advance the goal of personalized medicine. Our evolving understanding and current important issues in RA are highlighted.

European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance.

BACKGROUND/OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. METHODS: We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. RESULTS: Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement. CONCLUSIONS: Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

Performance of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in early disease, across sexes and ethnicities.

OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to <3 years (n=196) and ≥5 years (n=879). Among patients with 1 to <3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 81%). The EULAR/ACR criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). Among women, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 83%) and better specificity than the SLICC criteria (94% vs 82%). Among white patients, the EULAR/ACR criteria had better sensitivity than the ACR criteria (95% vs 83%) and better specificity than the SLICC criteria (94% vs 83%). The EULAR/ACR criteria performed well among black patients (sensitivity of 98%, specificity 100%), and had better sensitivity than the ACR criteria among Hispanic patients (100% vs 86%) and Asian patients (97% vs 77%). CONCLUSIONS: The EULAR/ACR 2019 criteria perform well among patients with early disease, men, women, white, black, Hispanic and Asian patients. These criteria have superior sensitivity than the ACR criteria and/or superior specificity than the SLICC criteria across many subgroups.

2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus.

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus.

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.

Multicriteria decision analysis process to develop new classification criteria for systemic lupus erythematosus.

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.

Use of Consensus Methodology to Determine Candidate Items for Systemic Lupus Erythematosus Classification Criteria.

OBJECTIVE: Given the complexity and heterogeneity of systemic lupus erythematosus (SLE), high-performing classification criteria are critical to advancing research and clinical care. A collaborative effort by the European League Against Rheumatism and the American College of Rheumatology was undertaken to generate candidate criteria, and then to reduce them to a smaller set. The objective of the current study was to select a set of criteria that maximizes the likelihood of accurate classification of SLE, particularly early disease. METHODS: An independent panel of international SLE experts and the SLE classification criteria steering committee (conducting SLE research in Canada, Mexico, United States, Austria, Germany, Greece, France, Italy, and Spain) ranked 43 candidate criteria. A consensus meeting using nominal group technique (NGT) was conducted to reduce the list of criteria for consideration. RESULTS: The expert panel NGT exercise reduced the candidate criteria for SLE classification from 43 to 21. The panel distinguished potential "entry criteria," which would be required for classification, from potential "additive criteria." Potential entry criteria were antinuclear antibody (ANA) ≥ 1:80 (HEp-2 immunofluorescence), and low C3 and/or low C4. The use of low complement as an entry criterion was considered potentially useful in cases with negative ANA. Potential additive criteria included lupus nephritis by renal biopsy, autoantibodies, cytopenias, acute and chronic cutaneous lupus, alopecia, arthritis, serositis, oral mucosal lesions, central nervous system manifestations, and fever. CONCLUSION: The NGT exercise resulted in 21 candidate SLE classification criteria. The next phases of SLE classification criteria development will require refinement of criteria definitions, evaluation of the ability to cluster criteria into domains, and evaluation of weighting of criteria.

Common Language Description of the Term Rheumatic and Musculoskeletal Diseases (RMDs) for Use in Communication With the Lay Public, Healthcare Providers, and Other Stakeholders Endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).

A European League Against Rheumatism-American College of Rheumatology working group consisting of practicing and academic rheumatologists, a rheumatology researcher, and a patient representative created a succinct general statement describing rheumatic and musculoskeletal diseases (RMDs) in adults and children in language that can be used in conversations with the lay public, media, healthcare providers, and other stakeholders. Based on the literature review, several elements were deemed important for inclusion in the description of RMDs. First, RMDs encompass many different diseases that can affect individuals at any age, including children. Second, there are various pathophysiological pathways underlying different RMDs. Third, the impact of RMDs on individuals and society should be emphasized. The working group agreed that the language should be comprehensible to the lay public. Thus, the following description of RMDs has been developed: "Rheumatic and musculoskeletal diseases (RMDs) are a diverse group of diseases that commonly affect the joints, but can affect any organ of the body. There are more than 200 different RMDs, affecting both children and adults. They are usually caused by problems of the immune system, inflammation, infections, or gradual deterioration of joints, muscles, and bones. Many of these diseases are long term and worsen over time. They are typically painful and limit function. In severe cases, RMDs can result in significant disability, having a major impact on both quality of life and life expectancy." This description can be used by rheumatology groups, researchers, and those who work in advocacy and education related to RMDs.

Common language description of the term rheumatic and musculoskeletal diseases (RMDs) for use in communication with the lay public, healthcare providers and other stakeholders endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).

A European League Against Rheumatism-American College of Rheumatology working group consisting of practising and academic rheumatologists, a rheumatology researcher and a patient representative created a succinct general statement describing rheumatic and musculoskeletal diseases (RMDs) in adults and children in language that can be used in conversations with the lay public, media, healthcare providers and other stakeholders. Based on the literature review, several elements were deemed important for inclusion in the description of RMDs. First, RMDs encompass many different diseases that can affect individuals at any age, including children. Second, there are various pathophysiological pathways underlying different RMDs. Third, the impact of RMDs on individuals and society should be emphasised. The working group agreed that the language should be comprehensible to the lay public. Thus, the following description of RMDs has been developed: 'Rheumatic and musculoskeletal diseases (RMDs) are a diverse group of diseases that commonly affect the joints, but can affect any organ of the body. There are more than 200 different RMDs, affecting both children and adults. They are usually caused by problems of the immune system, inflammation, infections or gradual deterioration of joints, muscles and bones. Many of these diseases are long term and worsen over time. They are typically painful and limit function. In severe cases, RMDs can result in significant disability, having a major impact on both quality of life and life expectancy.' This description can be used by rheumatology groups, researchers and those who work in advocacy and education related to RMDs.

Developing and Refining New Candidate Criteria for Systemic Lupus Erythematosus Classification: An International Collaboration.

OBJECTIVE: To define candidate criteria within multiphase development of systemic lupus erythematosus (SLE) classification criteria, jointly supported by the American College of Rheumatology and the European League Against Rheumatism. Prior steps included item generation and reduction by Delphi exercise, further narrowed to 21 items in a nominal group technique exercise. Our objectives were to apply an evidence-based approach to the 21 candidate criteria, and to develop hierarchical organization of criteria within domains. METHODS: A literature review identified the sensitivity and specificity of the 21 candidate criteria. Data on the performance of antinuclear antibody (ANA) as an entry criterion and operating characteristics of the candidate criteria in early SLE patients were evaluated. Candidate criteria were hierarchically organized into clinical and immunologic domains, and definitions were refined in an iterative process. RESULTS: Based on the data, consensus was reached to use a positive ANA of ≥1:80 titer (HEp-2 cells immunofluorescence) as an entry criterion and to have 7 clinical and 3 immunologic domains, with hierarchical organization of criteria within domains. Definitions of the candidate criteria were specified. CONCLUSION: Using a data-driven process, consensus was reached on new, refined criteria definitions and organization based on operating characteristics. This work will be followed by a multicriteria decision analysis exercise to weight criteria and to identify a threshold score for classification on a continuous probability scale.

Performance of Antinuclear Antibodies for Classifying Systemic Lupus Erythematosus: A Systematic Literature Review and Meta-Regression of Diagnostic Data.

OBJECTIVE: To review the published literature on the performance of indirect immunofluorescence (IIF)-HEp-2 antinuclear antibody (ANA) testing for classification of systemic lupus erythematosus (SLE). METHODS: A systematic literature search was conducted in the Medline, Embase, and Cochrane databases for articles published between January 1990 and October 2015. The research question was structured according to Population, Intervention, Comparator, Outcome (PICO) format rules, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed where appropriate. Meta-regression analysis for diagnostic tests was performed, using the ANA titer as independent variable, while sensitivity and specificity were dependent variables. RESULTS: Of 4,483 publications screened, 62 matched the eligibility criteria, and another 2 articles were identified through reference analysis. The included studies comprised 13,080 SLE patients in total, of whom 12,542 (95.9%) were reported to be IIF-ANA positive at various titers. For ANA at titers of 1:40, 1:80, 1:160, and 1:320, meta-regression gave sensitivity values of 98.4% (95% confidence interval [95% CI] 97.6-99.0%), 97.8% (95% CI 96.8-98.5%), 95.8% (95% CI 94.1-97.1%), and 86.0% (95% CI 77.0-91.9%), respectively. The corresponding specificities were 66.9% (95% CI 57.8-74.9%), 74.7% (95% CI 66.7-81.3%), 86.2% (95% CI 80.4-90.5%), and 96.6% (95% CI 93.9-98.1%), respectively. CONCLUSION: The results of this systematic literature review and meta-regression confirm that IIF-ANAs have high sensitivity for SLE. ANAs at a titer of 1:80 have sufficiently high sensitivity to be considered as an entry criterion for SLE classification criteria, i.e., formally test other classification criteria for SLE only if ANAs of at least 1:80 have been found.

Multicenter Delphi Exercise to Identify Important Key Items for Classifying Systemic Lupus Erythematosus.

OBJECTIVE: The American College of Rheumatology and the European League Against Rheumatism embarked on a project to reevaluate classification criteria for systemic lupus erythematosus (SLE). The first phase of the classification project involved generation of a broad set of items potentially useful for classification of SLE and their selection for use in a subsequent forced-choice decision analysis. METHODS: A large international group of expert lupus clinicians was invited to participate in a 2-step process to generate, rate, and select items based on their importance in diagnosing early and established SLE, via a web-based survey. RESULTS: A total of 135 and 147 experts were invited to participate in the item-generation and item-reduction process, respectively. Of 145 items generated, item reduction resulted in 40 candidate items moving forward to the next phase. Key features for classifying both early and established SLE included characteristic autoantibodies, specific renal features, and skin manifestations. A small majority (51%) stated that 1 organ system would be sufficient for classifying SLE, but that additional typical laboratory features (antinuclear antibody, anti-double-stranded DNA) would be required. Notably, 85% of the expert group would positively classify SLE if renal pathology alone showed lupus nephritis. CONCLUSION: The Delphi exercise resulted in a set of 40 candidate criteria for the classification of SLE for subsequent assessment. This study comprised the largest panel ever involved in the development of SLE classification criteria, providing a broadly representative view of the current approach to classification of SLE.

Serum biomarkers of inflammation and muscle strength among women with systemic lupus erythematosus.

OBJECTIVES: Muscle strength is an important determinant of physical function in women with systemic lupus erythematosus (SLE). Serum biomarkers of inflammation, including interleukin-6 (IL-6) and C-Reactive Protein (CRP), are associated with differences in muscle strength among individuals without rheumatologic disease. We examined whether serum levels of IL-6 and CRP are associated with upper and lower extremity muscle strength among adult women with SLE. METHODS: One hundred thirty-six women with SLE participated in this cross-sectional study. High-sensitivity CRP was analyzed by nephelometry. IL-6 serum levels were analyzed by high sensitivity enzyme-linked immunosorbent assay. Upper and lower extremity muscle strength were assessed by grip strength and peak torque of knee extension and flexion, respectively. Regression analyses modeled associations of CRP and IL-6 with upper and lower extremity muscle strength controlling for age, SLE duration, physical activity, prednisone use, BMI, plaquenil use, and pain. RESULTS: Higher serum levels of IL-6 and CRP were associated with significantly weaker upper and lower extremity muscle strength even when controlling for covariates. CONCLUSIONS: Increased serum IL-6 and CRP are associated with clinically significant differences in upper and lower extremity muscle strength and may be useful in identifying those at risk for weakness and decreased physical function.

Folic Acid Supplementation Is Suboptimal in a National Cohort of Older Veterans Receiving Low Dose Oral Methotrexate.

OBJECTIVES: Co-prescription of folic acid in patients receiving low dose oral methotrexate is recommended because it reduces adverse events and prolongs the use of methotrexate (MTX). However, little is known about how often new users of methotrexate are co-prescribed folic acid, and what factors are associated with its use. We aimed to determine the prevalence, predictors of, and persistence of folic acid use in a population-based cohort of MTX users with rheumatic diseases. METHODS: Using a national, administrative database of patients seen through the Veterans Health Administration (VHA) that included pharmacy and laboratory data, we performed an observational cohort study of veterans over 65 years old who were new users of MTX. We used log-binomial regression to identify independent predictors of folic acid use and Kaplan Meyer survival analysis to examine persistence of folic acid over time. RESULTS: We studied 2467 incident users of MTX. 27% of patients were not prescribed folic acid through the VHA pharmacy within 30 days of MTX initiation. Patients who did not see a rheumatologist were 23% less likely to receive folic acid compared to patients who did have a rheumatologist visit during the baseline period (RR (95% CI) 0.77 (0.72, 0.82). These results remained unchanged even after adjusting for demographic, clinical, and other factors (adjusted RR (95% CI) 0.78 (0.74, 0.85)). After 20 months, only 50% of patients continued to receive folic acid. CONCLUSIONS: In a nationwide VHA cohort of new users of oral MTX, many patients did not receive folic acid or discontinued it over time. Rheumatologists were more likely to prescribe folic acid than other providers. These data highlight the need to improve patient safety for users of methotrexate by standardizing workflows for folic acid supplementation.

Implementation of disease activity measurement for rheumatoid arthritis patients in an academic rheumatology clinic.

BACKGROUND: Treat-to-target is the recommended strategy for the management of rheumatoid arthritis (RA) and involves regular assessment of disease activity using validated measures and subsequent adjustment of medical therapy if patients are not in remission or low disease activity. Recommendations published in 2012 detailed the preferred disease activity measures but there have been few publications on implementation of disease activity measures in a real-world clinic setting. METHODS: Plan-Do-Study-Act (PDSA) methodology was used over two cycles with a goal of increasing provider measurement of disease activity during all RA patient visits. In PDSA cycle 1, we implemented a paper-based form to help providers assess disease activity in RA patients. PDSA cycle 2 included the creation of separate patient and physician forms for collection of information, identification of patients prior to their clinic visit and incorporation of medical assistants into the workflow. RESULTS: The first PDSA cycle improved the number of RA patients with documented disease activity measures from 24 % over a 4-week period, to an average of 44 % over an 8-week period. The second PDSA cycle showed a sustained and dramatic improvement, with 85 % of patients having a disease activity measure recorded over a 27-week period. CONCLUSIONS: Implementation of disease activity measurement in a typical academic rheumatology clinic can be achieved by standardizing workflow using a simple paper form.