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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 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.

Funder: American College of Rheumatology Research and Education Foundation; FundRef: http://dx.doi.org/10.13039/100000960, Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases; FundRef: http://dx.doi.org/10.13039/100000069, Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, 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

ObjectivesExtension of disease beyond the atrioventricular (AV) node is associated with increased mortality in cardiac neonatal lupus (NL). Treatment of isolated heart block with fluorinated steroids to prevent disease progression has been considered but published data are limited and discordant regarding efficacy. This study evaluated whether fluorinated steroids given to manage isolated advanced block prevented development of disease beyond the AV node and conferred a survival benefit.MethodsIn this retrospective study of cases enrolled in the Research Registry for NL, inclusion was restricted to anti-SSA/Ro-exposed cases presenting with isolated advanced heart block in utero who either received fluorinated steroids within 1 week of detection (N=71) or no treatment (N=85). Outcomes evaluated were: development of endocardial fibroelastosis, dilated cardiomyopathy and/or hydrops fetalis; mortality and pacemaker implantation.ResultsIn Cox proportional hazards regression analyses, fluorinated steroids did not significantly prevent development of disease beyond the AV node (adjusted HR=0.90; 95% CI 0.43 to 1.85; p=0.77), reduce mortality (HR=1.63; 95% CI 0.43 to 6.14; p=0.47) or forestall/prevent pacemaker implantation (HR=0.87; 95% CI 0.57 to 1.33; p=0.53). No risk factors for development of disease beyond the AV node were identified.ConclusionsThese data do not provide evidence to support the use of fluorinated steroids to prevent disease progression or death in cases presenting with isolated heart block.

ObjectiveEpidemiological data for primary discoid lupus erythematosus (pDLE) remain limited, particularly for racial/ethnic populations in the USA. The Manhattan Lupus Surveillance Program (MLSP) is a population-based retrospective registry of cases with SLE and related diseases including pDLE in Manhattan and was used to provide estimates of the prevalence and incidence of pDLE across major racial/ethnic populations.MethodsMLSP cases were identified from rheumatologists, hospitals and population databases. Two case definitions were used for pDLE: the primary case definition which was any physician diagnosis found in the chart and a secondary case definition which was limited to cases diagnosed by a rheumatologist and/or dermatologist. Rates among Manhattan residents were age-adjusted, and capture–recapture analyses were conducted to assess case under-ascertainment.ResultsBased on the primary definition, age-adjusted overall prevalence and incidence rates of pDLE among Manhattan residents were 6.5 and 0.8 per 100 000 person-years, which increased to 9.0 and 1.3 after capture–recapture adjustment. Prevalence and incidence rates were approximately two and six times higher, respectively, among women compared with men (pConclusionData from the MLSP provide epidemiological estimates for pDLE among the major racial/ethnic populations in the USA and reveal disparities in pDLE prevalence and incidence by sex and race/ethnicity among Manhattan residents.

ObjectiveA common problem in clinical trials is missing data due to participant dropout and loss to follow-up, an issue which continues to receive considerable attention in the clinical research community. Our objective was to examine and compare current and alternative methods for handling missing data in SLE trials with a particular focus on multiple imputation, a flexible technique that has been applied in different disease settings but not to address missing data in the primary outcome of an SLE trial.MethodsData on 279 patients with SLE randomised to standard of care (SoC) and also receiving mycophenolate mofetil (MMF), azathioprine or methotrexate were obtained from the Lupus Foundation of America-Collective Data Analysis Initiative Database. Complete case analysis (CC), last observation carried forward (LOCF), non-responder imputation (NRI) and multiple imputation (MI) were applied to handle missing data in an analysis to assess differences in SLE Responder Index-5 (SRI-5) response rates at 52 weeks between patients on SoC treated with MMF versus other immunosuppressants (non-MMF).ResultsThe rates of missing data were 32% in the MMF and 23% in the non-MMF groups. As expected, the NRI missing data approach yielded the lowest estimated response rates. The smallest and least significant estimates of differences between groups were observed with LOCF, and precision was lowest with the CC method. Estimated between-group differences were magnified with the MI approach, and imputing SRI-5 directly versus deriving SRI-5 after separately imputing its individual components yielded similar results.ConclusionThe potential advantages of applying MI to address missing data in an SLE trial include reduced bias when estimating treatment effects, and measures of precision that properly reflect uncertainty in the imputations. However, results can vary depending on the imputation model used, and the underlying assumptions should be plausible. Sensitivity analysis should be conducted to demonstrate robustness of results, especially when missing data proportions are high.

Patients with SLE experience multiple, varied symptoms and laboratory abnormalities that occur in different combinations, at different points in time.1 A result of the heterogeneity is that studies on SLE employ several, sometimes conflicting, definitions of the illness. Investigators disagree about when SLE begins; how SLE relates to similar and overlapping rheumatic illnesses; whether SLE-like illnesses of known genetic causes count as SLE; and whether the same diagnosis name should apply when investigators describe stratified populations, for instance, SLE with and without renal disease. Inconsistent definitions lead stakeholders—patients, practising physicians, administrators, epidemiologists and investigators—to count different patients and to develop different opinions about the mechanisms and treatment of SLE. To advocate a consensus vocabulary and conceptual model, in this paper we deconstruct the process of making a diagnosis of SLE by examining its classification and diagnostic criteria, definitions and illness models. We discuss the ways by which stratification biases conclusions and how the purpose for which a stakeholder names a diagnosis determines whom they accept as having this disease. ### Classification and diagnostic criteria When in the mid-19th century Cazenave first used the name lupus erythematosus , SLE was a rare and life-threatening illness.2 3 A century later, as new technologies identified more patients,4–10 physicians found SLE to be more clinically diverse, and often less severe, than they once believed. To improve homogeneity of patient populations identified for clinical studies, investigators developed classification criteria that are specific, binary (SLE is present or not) and time limited (valid only for the extent of a study). The homogeneity of classification criteria is implied but not real. The American College of Rheumatology (ACR) criteria allow 330 different combinations of symptoms and laboratory tests to affirm a diagnosis of SLE.11 Classification criteria are insensitive; they exclude patients who, despite disabling and treatable symptoms, fall below …

Objective To evaluate response duration and identify predictors of transitioning into and out of the response state in patients with SLE receiving standard of care (SoC) in 52-week clinical trials. Methods A multistate model (MSM) allowing for bidirectional transitions between response and non-response states was fit to data on 759 patients with SLE with active disease randomised to SoC. The probability of being in response at 52 weeks, average duration of response (sojourn time) and mean total time in response for SLE Responder Index (SRI-4, SRI-5, SRI-6) and BILAG-based Composite Lupus Assessment (BICLA) were estimated. Predictors of attainment and loss of SRI-5 response were also assessed. Results The MSM estimated probability of being in response at 52 weeks ranged from 42% (SRI-6) to 61% (SRI-4). Mean duration of response ranged from 20.4 weeks (BICLA) to 31.5 weeks (SRI-4). Mean total time in response was 16.4–24.8 weeks. Baseline characteristics predictive of shorter SRI-5 response duration were African descent (p=0.005), longer history of disease (p=0.03), higher anti-dsDNA antibody titres (p=0.039), lower lymphocyte count (p=0.008) and lower haemoglobin (p=0.006). Younger age (p

Objectives:Reactivation of Mycobacterium tuberculosis (TB) is a significant problem with all available tumour necrosis factor (TNF) antagonists when used to treat rheumatoid arthritis (RA), psoriatic arthritis, psoriasis and other inflammatory diseases. Concerns have been raised regarding the appropriate management of patients with latent TB (LTB) exposure (or active TB infection) before initiating TNF antagonists as the safety data of combined treatment with two potentially hepatotoxic medications, methotrexate (MTX) and isoniazid (INH), is lacking. The goal of this study was to investigate the toxicity of MTX and INH treatment in patients with RA before initiating TNF antagonists.Methods:To investigate the toxicity of MTX and INH treatment in patients with RA we performed a retrospective chart review of patients seen at the Bellevue Hospital Arthritis Clinic in New York City between 2002 and 2006. Forty-four patients who were concomitantly treated with both drugs were included. The primary outcome investigated was increase in liver function tests (LFT).Results:Transient increases in LFT were seen in 11% of patients, but in no case was this more than twice the upper limit of normal values. All abnormal LFT resolved spontaneously without intervention. In addition, no patient has developed signs or symptoms of TB reactivation.Conclusions:The use of INH for LTB was well tolerated in patients with RA on a background regimen of MTX. While the risks and benefits of all treatment must always be considered, in our experience the additive risk of INH to MTX in terms of hepatotoxicity was low. None the less it is prudent to follow LFT closely on patients taking this combination.

Background Most clinical trials of new treatments for systemic lupus erythematosus (SLE) have shown weak discrimination between investigational agents and placebo when added to standard of care (SOC). Given that targeted biologics are unlikely to be effective in all patients, it is challenging for these experimental therapies to exceed the high response rates observed with SOC alone in placebo arms. The design of future SLE trials may be improved by considering strategies for reducing placebo response rates and obtaining a better understanding of the within-patient variability in disease activity during follow up. Objectives The goal of this study was to evaluate longitudinal patterns of response in SLE patients who received placebo plus SOC in two completed 52-week clinical trials. Baseline characteristics discriminating early and persistent responders from non-responders to SOC were also examined to identify patient populations who may benefit most from experimental therapies and could be targeted for enrollment in future trials. Methods Data was obtained from the Collective Data Analysis Initiative (CDAI) of the Lupus Foundation of America and included 147 patients from the placebo plus SOC arms of two randomized Phase II/III trials in moderately-to-severely active lupus patients without acute nephritis. A BILAG-based response was evaluated at weeks 12, 24, 36, 48, and 52. Both cross-sectional and longitudinal analyses of response patterns were performed. Clinical variables, including background medications and baseline factors associated with disease severity, that discriminated persistent responders from non-responders were identified using logistic regression. Results The cross-sectional response rates ranged from 37% - 46% between 12 - 52 weeks for patients treated with placebo plus SOC, similar to the placebo response rates estimated in most non-nephritis lupus trials. The response rate decreased to 14.3% (95% CI: 8.6% - 19.9%) when the criterion was complete response, i.e., response at all visits between 12 - 52 weeks. Agreement between response status at 12 weeks and 36–52 weeks was low (kappa =0.15 - 0.25); furthermore only 31% of initial 12 week responders maintained response at all subsequent visits. Factors contributing to non-response to SOC at all visits included more severe disease, as suggested by more organ systems active at baseline, and low C3 levels at baseline. Less aggressive immunosuppression was also associated with non-response. Conclusions An endpoint based on a sustained rather than cross-sectional response may reduce high placebo response rates in SLE trials that continue aggressive SOC and may improve discrimination between effective experimental treatments and SOC. Although there is increasing interest in conducting efficient 12 or 24 week early phase trials, the observed lack of stability in response to SOC over time highlights a potential weakness with shorter studies that use an endpoint of improvement. Our data also confirm earlier reports that the likelihood of response in the placebo group depends on the severity of disease and the aggressiveness of background treatments. Disclosure of Interest M. Kim: None declared, J. Merrill: None declared, K. Kalunian Consultant for: Bristol-Myers Squibb, MedImmune, AstraZeneca, Merck Serono, UCB, and Genentech, B. Hahn Grant/research support from: Bristol-Myers Squibb, Consultant for: Eli Lilly, A. Roach: None declared, P. Izmirly: None declared