Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Sex-Related Differences in Dispensation of Rheumatic Medications in Older Patients With Inflammatory Arthritis: A Population-Based Study.

OBJECTIVE: The aim of our study was to compare dispensation of rheumatic medications between older male and female patients with early rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: This retrospective cohort study was performed using health administrative data from Ontario, Canada (years 2010-2017), on patients with incident RA and PsA, who were aged ≥ 66 years at the time of diagnosis. Yearly dispensation of rheumatic drugs was compared between older male and female patients for 3 years after diagnosis using multivariable regression models, after adjusting for confounders. The groups of drugs included in the analysis were disease-modifying antirheumatic drugs (DMARDs) classified as conventional synthetic DMARDs (csDMARDs) and advanced therapy (biologic DMARDs and targeted synthetic DMARDs), nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and oral corticosteroids. Results were reported as odds ratios (ORs) with 95% CIs. RESULTS: We analyzed 13,613 patients (64% female) with RA and 1116 patients (57% female) with PsA. Female patients with RA were more likely to receive opioids (OR 1.39, 95% CI 1.22-1.58 to OR 1.51, 95% CI 1.32-1.72) and NSAIDs (OR 1.14, 95% CI 1.04-1.25 to OR 1.16, 95% CI 1.04-1.30). Dispensation of DMARDs showed no sex difference in either group. Subgroup analyses showed more intense use of advanced therapy in the RA cohort and of csDMARDs in the PsA cohort when patient and physician sex was concordant. CONCLUSION: This study did not identify any sex difference in the use of DMARDs among older patients with RA and PsA. The reasons for the higher use of opioids and NSAIDs among female patients with RA warrant further research.

Effects of Radiotherapy for Malignancy in Systemic Sclerosis: A Systematic Review.

OBJECTIVE: Concerns regarding offering radiotherapy to patients with systemic sclerosis (SSc) stem from the potential worsening of SSc manifestations and radiotherapy toxicity. We conducted a systematic review to evaluate the effects of radiotherapy on SSc outcomes and radiotherapy-related toxicity. METHODS: MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were searched for SSc and radiotherapy. Inclusion criteria were SSc diagnosis, subsequent cancer development, and radiotherapy exposure. Outcomes were SSc manifestations (cutaneous thickening, pulmonary fibrosis, and SSc flare) and radiotherapy toxicity (acute and late) using Common Terminology Criteria for Adverse Events for grading. Grade 1 and 2 toxicities were categorized as nonsevere and grade 3 to 5 toxicities as severe. RESULTS: Of 121 patients with SSc undergoing radiotherapy (mean age 56.4 years, 83.3% female, median radiotherapy dose 50 Gy), most did not show worsened SSc skin thickening (74.5%) or pulmonary complications (74%) post radiotherapy. In retrospective studies, the average rates of acute adverse effects were 57.3% for nonsevere and 25.8% for severe, whereas the rates of late adverse effects were 32.4% for nonsevere and 24% for severe. CONCLUSION: Although most patients with SSc do not exhibit significant worsening of SSc manifestations post radiotherapy, there is a variable risk of acute and late toxicity. These findings suggest that although radiotherapy may be a viable option for patients with cancer with SSc, it requires caution.

Understanding the Employment Landscape in People With Systemic Sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) can restrict employment participation. Our objectives were to comparatively evaluate health factors, work factors, and workplace accommodations between those who are employed and those who recently gave up employment. METHODS: A cross-sectional study was conducted of employed and recently working, but now unemployed, individuals with SSc. Demographics, employment sectors, health factors, flare frequency, work context, and information about the need, availability, and use of workplace supports were collected. RESULTS: Participants were 140 individuals (108 [77.1%] women, 32 [22.9%] men), of whom 110 (78.6%) were employed and 30 (21.4%) were unemployed. Participants worked in education/health/sciences/arts (n = 51, 36.4%), sales/retail (n = 23, 16.5%), banking/insurance/business/technology (n = 22, 15.7%), government (n = 15, 10.7%), construction/utilities (n = 10, 7.1%), and manufacturing/agriculture/mining/logging (n = 10, 7.1%). Employed participants had a lower mean age (48.4 vs 54.3 yrs), and higher level of education (77.3% with postsecondary education vs 22.7% without). Those who had no flares were more frequently employed (41.7%), compared to those who had 1 to 2 flares (35.2%) and ≥ 3 flares (23.1%). The availability of workplace accommodations differed significantly between the employed and unemployed: flexible hours (74.5% vs 40%, P = 0.0005), more rest periods (73.6% vs 46.7%, P = 0.0001), special equipment (82.7% vs 46.7%, P < 0.0001), and work schedule flexibility (66.4% vs 33.3%, P = 0.003). CONCLUSION: Health factors alone do not differentiate those who are employed and those who gave up employment. This study lays the groundwork for where SSc-specific efforts in workplace policies and practices should be directed, especially workplace support.

Understanding sex-related differences in healthcare utilisation among patients with inflammatory arthritis: a population-based study.

OBJECTIVES: Our aim was to compare patterns of musculoskeletal-related healthcare utilisation between male and female patients before and after the diagnosis of inflammatory arthritis (IA). METHODS: We used Ontario administrative health data to create three inception cohorts of adult patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) diagnosed between April 2010 and March 2017. Healthcare utilisation indicators including visits to physicians, and use of musculoskeletal imaging and laboratory tests were assessed in each year for 3 years before and after diagnosis and compared between male and female patients using regression models adjusting for sociodemographic factors and comorbidities. Results were reported as ORs with 95% CIs for female patients compared with male patients. RESULTS: A total of 41 277 patients with RA (69% female), 8150 patients with AS (51% female) and 6446 patients with PsA (54% female) were analysed.Similar trends of sex-related differences were observed in all three cohorts. Before diagnosis, female patients were more likely to visit rheumatologists (OR 1.32-2.28) and family physicians (OR 1.03-1.15) for musculoskeletal reasons, whereas male patients were more likely to visit the emergency for musculoskeletal reasons (OR 0.76-0.87). A similar female predominance was observed regarding musculoskeletal imaging and laboratory tests before diagnosis. After diagnosis, female patients were more likely to remain in rheumatology care (OR 1.12-1.24). CONCLUSION: Female patients with IA have higher healthcare utilisation than male patients which may indicate biological differences in disease course or sociocultural differences in healthcare-seeking behaviour.

Advances in SLE classification criteria.

This year, the American College of Rheumatology (ACR) 1982 classification criteria for systemic lupus erythematosus (SLE) celebrate their 40th anniversary. From this start, the quest for optimal SLE criteria has led to the 1997 ACR update, the 2012 publication of the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and, in 2019, the European League Against Rheumatism (EULAR)/ACR classification criteria. The latter have since been externally validated in more than two dozen studies and have become the gold standard inclusion criterion of SLE clinical trials. This comprehensive review attempts to follow the evolving success story of SLE classification, highlighting relevant decisions and their rationale, and discussing consequences for the way SLE is defined and managed.

Serological abnormalities that predict progression to systemic autoimmune rheumatic diseases in antinuclear antibody-positive individuals.

OBJECTIVE: We investigated the autoantibody (autoAb) profiles in ANA+ individuals lacking systemic autoimmune rheumatic disease (SARD) and early SARD patients to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next 2 years in ANA+ individuals. METHODS: Using custom antigen (Ag) microarrays, 144 IgM and IgG autoAbs were surveyed in 84 asymptomatic and 123 symptomatic (48 UCTD and 75 SARD patients) ANA+ individuals. AutoAbs were compared in ANA+ individuals lacking a SARD diagnosis with ≥2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset. RESULTS: We show that ANA+ individuals have autoAb to many self-Ags that are not being captured by current screening techniques and very high levels of these autoAbs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more autoAgs than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of autoAbs. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years of follow-up the levels of autoAbs remained remarkably stable regardless of whether individuals progressed or not. CONCLUSION: Our findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of autoAb testing.

Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis.

OBJECTIVES: The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. METHODS: This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint. RESULTS: Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups. CONCLUSION: Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95.

New lupus criteria: a critical view.

PURPOSE OF REVIEW: To review the validation of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus (SLE). RECENT FINDINGS: Positive antinuclear antibodies, which constitute the obligatory entry criterion of the EULAR/ACR criteria, were found in the vast majority of SLE patients worldwide, with 97% (94-100%) of patients antinuclear antibodies positive in studies investigating EULAR/ACR criteria performance. Combined over the publications, EULAR/ACR criteria sensitivity was 92% (range 85-97%). Specificity varied more relevantly, with the publications published after the EULAR/ACR 2019 criteria showing 93% (83-98%) specificity. Of particular relevance is the good performance of the EULAR/ACR criteria seen in pediatric SLE as well as in early SLE. SUMMARY: The new classification criteria have been investigated in an impressive number of cohorts worldwide, adding to the data from the EULAR/ACR criteria project cohort. It is critical to strictly keep to the attribution rule, that items are only counted if there is no more likely alternative explanation than SLE, the domain structure, where only the highest weighted item in a domain counts, and the limitation to highly specific tests for antibodies to double-stranded DNA.

New EULAR/ACR 2019 SLE Classification Criteria: defining ominosity in SLE.

OBJECTIVE: To determine the ominosity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Systemic Lupus Erythematosus Classification Criteria by determining its predictive role for disease severity in the first 5 years following diagnosis. METHODS: 867 patients with systemic lupus erythematosus (SLE) from the Toronto Lupus Clinic were included (all first 12 months after SLE diagnosis). The EULAR/ACR criteria score was calculated based on baseline information. To determine disease severity in the first 5 years after diagnosis, adjusted mean SLE Disease Activity Index 2000 (AMS), flares, remission and immunosuppressive treatment were used as outcomes. The Systemic Lupus International Collaborating Clinics (SLICC) registry comprised the validation cohort. RESULTS: Based on receiver operating characteristic analysis, a EULAR/ACR score of 20 was used as a threshold to compare outcomes between groups. In the first 5 years of disease course, patients with a score of ≥20 had higher AMS scores (p<0.001) and were more likely to ever experience a flare (p<0.001). These patients had lower probabilities of achieving remission and higher requirements for immunosuppressives. Results were confirmed in the SLICC validation cohort. Patients with a score of ≥20 had higher AMS during the first 5 years of disease (5.4 vs 3.1% and ≥20 vs <20 respectively, p≤0.001). The score correlated with AMS (r=0.43, p≤0.001) in the same time frame. CONCLUSION: A EULAR/ACR score of ≥20 is an indicator of ominosity in SLE. Patients with a score of ≥20 were characterised by a more active disease course throughout the first 5 years. These criteria provide prognostic information regarding disease severity in the first 5 years following diagnosis.

Effectiveness of initial methotrexate-based treatment approaches in early rheumatoid arthritis: an elicitation of rheumatologists' beliefs.

OBJECTIVES: To quantify rheumatologists' beliefs about the effectiveness of triple therapy (MTX + HCQ + SSZ) and other commonly used initial treatments for RA. METHODS: In a Bayesian belief elicitation exercise, 40 rheumatologists distributed 20 chips, each representing 5% of their total weight of belief on the probability that a typical patient with moderate-severe early RA would have an ACR50 response within 6 months with MTX (oral and s.c.), MTX + HCQ (dual therapy) and triple therapy. Parametric distributions were fit, and used to calculate pairwise median relative risks (RR), with 95% credible intervals, and estimate sample sizes for new trials to shift these beliefs. RESULTS: In the pooled analysis, triple therapy was perceived to be superior to MTX (RR 1.97; 1.35, 2.89) and dual therapy (RR 1.32; 1.03, 1.73). A pessimistic subgroup (n = 10) perceived all treatments to be similar, whereas an optimistic subgroup (n = 10) believed triple therapy to be most effective of all (RR 4.03; 2.22, 10.12). Similar variability was seen for the comparison between oral and s.c. MTX. Assuming triple therapy is truly more effective than MTX, a trial of 100 patients would be required to convince the pessimists; if triple therapy truly has no-modest effect (RR <1.5), a non-inferiority trial of 475 patients would be required to convince the optimists. CONCLUSION: Rheumatologists' beliefs regarding the effectiveness of triple therapy vary, which may partially explain the variability in its use. Owing to the strength of beliefs, some may be reluctant to shift, even with new evidence.

Acquired low immunoglobulin levels and risk of clinically relevant infection in adult patients with systemic lupus erythematosus: a cohort study.

OBJECTIVE: Infection is a leading cause of death in the SLE population. Low immunoglobulin levels might be a potential risk for infection. We aimed to assess whether acquired low levels of any type of immunoglobulin increase the risk of clinically relevant infection in adult patients with SLE. METHODS: We compared adult SLE patients who had acquired any low immunoglobulin levels (IgA, IgM or IgG) for 2 years with patients with normal or high levels with respect to clinically relevant infection (defined as infections requiring intravenous or oral antibiotics) in a prospective cohort study. Group balance was achieved using propensity score adjustment, matching and inverse probability weighting. Primary analysis was time to event using Cox-regression modelling adjusting for potential confounders. Sensitivity analyses were conducted to examine several exposure and outcome definitions. RESULTS: Patients with hypogammaglobulinaemia had longer disease duration, more lupus nephritis history, higher proteinuria and more accumulated damage. Low IgA level was associated with increased risk of clinically relevant infection [hazard ratio (HR): 2.24, 95% CI: 1.61, 3.12] while low IgG (HR: 1.15, 95% CI: 0.84, 1.59) or low IgM (HR: 0.95, 95% CI: 0.73, 1.23) was not. Low immunoglobulin recovery in the first year was 2.5% (11), second year 8.2% (36), third year 10.1% (44) and fourth year 18.4% (80), and 60% (263) of acquired hypogammaglobulinaemia recovered over 4 years. CONCLUSION: The majority of acquired hypogammaglobulinaemia in adult patients with SLE is transient. Only low acquired IgA was associated with increased risk of infection among adult patients with SLE. Whether immunoglobulin replacement provides additional protective effect requires further investigation.

Immunoglobulin levels in systemic lupus erythematosus: A narrative review.

Immunoglobulins play a fundamental role in the protection of the human body against internal and external threats. They also contribute to the immune system homeostasis and maintenance of self-tolerance. Hypogammaglobulinemia is occasionally encountered in routine clinical practice by rheumatologists. Low levels of immunoglobulins can occur as primary or secondary issues and may predispose patients to various forms of infection. However, the impact of the low immunoglobulin level abnormality varies with the underlying condition. In this narrative review, we shed light on the overall types and functions of immunoglobulins for clinicians. We discuss important principles of immunoglobulin measurements. We then consider the primary and secondary causes of low immunoglobulins with a special focus on hypogammaglobulinemia in patients with systemic lupus erythematosus (SLE).

Predictors of progression in systemic sclerosis patients with interstitial lung disease.

Systemic sclerosis (SSc) is a systemic autoimmune disease affecting multiple organ systems, including the lungs. Interstitial lung disease (ILD) is the leading cause of death in SSc.There are no valid biomarkers to predict the occurrence of SSc-ILD, although auto-antibodies against anti-topoisomerase I and several inflammatory markers are candidate biomarkers that need further evaluation. Chest auscultation, presence of shortness of breath and pulmonary function testing are important diagnostic tools, but lack sensitivity to detect early ILD. Baseline screening with high-resolution computed tomography (HRCT) is therefore necessary to confirm an SSc-ILD diagnosis. Once diagnosed with SSc-ILD, patients' clinical courses are variable and difficult to predict, although certain patient characteristics and biomarkers are associated with disease progression. It is important to monitor patients with SSc-ILD for signs of disease progression, although there is no consensus about which diagnostic tools to use or how often monitoring should occur. In this article, we review methods used to define and predict disease progression in SSc-ILD.There is no valid definition of SSc-ILD disease progression, but we suggest that either a decline in forced vital capacity (FVC) from baseline of ≥10%, or a decline in FVC of 5-9% in association with a decline in diffusing capacity of the lung for carbon monoxide of ≥15% represents progression. An increase in the radiographic extent of ILD on HRCT imaging would also signify progression. A time period of 1-2 years is generally used for this definition, but a decline over a longer time period may also reflect clinically relevant disease progression.

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.

OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.

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.

Classifying and diagnosing systemic lupus erythematosus in the 21st century.

The EULAR/ACR 2019 classification criteria for SLE constitute a current and optimized clinical approach to SLE classification. Classification is still not based on molecular approaches and the results from large studies using polyomics may be interpreted as demonstrating the relevance of the genetic and environmental background rather than splitting SLE into several entities. In fact, an association study within the EULAR/ACR classification criteria project found associations between manifestations only within organ domains. This independency of various organ manifestations argues for SLE as one disease entity. The current review article will therefore concentrate on the clinical and immunological manifestations of SLE and on what we have already learned in this century. Moreover, the structure and essential rules of the EULAR/ACR 2019 classification criteria will be discussed. While classification and diagnosis are distinct concepts, which have to remain clearly separated, information derived from the process towards the classification criteria is also useful for diagnostic purposes. Therefore this article also tries to delineate what classification can teach us for diagnosis, covering a wide variety of SLE manifestations.

New Criteria for Lupus.

PURPOSE OF THE REVIEW: Classification criteria define the patient population for clinical trials and translational studies, but also influence current understanding of the disease. This review attempts to delineate the development from the American College of Rheumatology (ACR) 1982 to the European League Against Rheumatism (EULAR)/ACR 2019 classification criteria for systemic lupus erythematosus (SLE). RECENT FINDINGS: The new EULAR/ACR classification criteria use antinuclear antibodies (ANA) as an entry criterion. (Non-infectious) fever is the one new criterion. All criteria items now have individual weights (from 2 to 10) and are structured in domains, within which only the highest item is counted. There is one common attribution rule, counting criteria only if there is no more likely alternative explanation. Ten points are sufficient for classification. The new criteria have reached a sensitivity of 96.1% and a specificity of 93.4%. The new EULAR/ACR 2019 classification criteria for SLE build on the previous criteria sets, adding fever only as a new criteria item. The new structure is reflective of the current diagnostic approach and has led to improved statistical performance.

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.