Early Systemic Lupus Erythematosus Research Articles

Targeted metabolomics combined with machine learning to identify and validate new biomarkers for early SLE diagnosis and disease activity

BackgroundThe early diagnosis of systemic lupus erythematosus (SLE) and the assessment of disease activity progression remain a great challenge. Targeted metabolomics has great potential to identify new biomarkers of SLE. MethodsSerum from 44 healthy participants and 89 SLE patients were analyzed using HM400 high-throughput targeted metabolomics. Machine learning (ML) with seven learning models and trained the model several times iteratively selected the two best prediction model in a competitive way, which were independent validated by enzyme-linked immunosorbent (ELISA) with 90 SLE patients. ResultsIn this study, 146 differential metabolites, most of them organic acids, amino acids, and bile acids, were detected between patients with initial SLE and healthy participants, and 8 potential biomarkers were found by intersection of ML and statistics (area under the curve [AUC] > 0.95) showing a significant positive correlation with clinical indicators. In addition, we identified and validated 2 potential biomarkers for SLE classification (P < 0.05, AUC > 0.775; N-Methyl-L-glutamic acid, L-2-aminobutyric acid) showing a significant correlation with the SLE Disease Activity Index. These differential metabolites were mainly involved in metabolic pathways, amino acid biosynthesis, 2-oxocarboxylic acid metabolism and other pathways. ConclusionThis study indicated that the tricarboxylic acid cycle might be associated with SLE drug therapy. We identified 8 diagnostic models biomarkers and 2 biomarkers that could be used to identify initial SLE and distinguish different activity degree, which will promote the development of new tools for the diagnosis and evaluation of SLE.

Digital Gangrene in Early Systemic Lupus Erythematosus: An Uncommon Presentation

Digital Gangrene in Early Systemic Lupus Erythematosus: An Uncommon Presentation

Two cases of successful sirolimus treatment for patients with activated phosphoinositide 3-kinase δ syndrome 1

BackgroundActivated phosphoinositide3-kinase (PI3K) δ syndrome 1 (APDS1) is a novel inborn errors of immunity (IEIs) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD). APDS1 has a spectrum of clinical manifestations. Recurrent respiratory infections, lymphoproliferation, hepatosplenomegaly, hyper-IgM syndrome and autoimmunity are the common symptoms of this disease.Case PresentationPatient 1 presented with recurrent respiratory infections, hepatosplenomegaly and hyper-IgM syndrome. Patient 2 developed early onset systemic lupus erythematosus (SLE)-like disease with resistant thrombocytopenia. c.3061 G > A and c.2314G > A variants in the PIK3CD gene were detected by whole exome sequencing in two patients respectively. c.2314G > A variant in PIK3CD gene of patient 2 is a newly report. After genetic diagnosis, two patients received sirolimus treatment and sirolimus alleviated clinical manifestations, including hepatosplenomegaly in patient 1 and thrombocytopenia in patient 2.ConclusionGenetics diagnosis should be considered in patients with complicated clinical manifestations with no or insufficient response to the conventional therapies. If whole exome sequencing suggests a variant in PIK3CD gene, sirolimus may relieve hepatosplenomegaly and resistant thrombocytopenia. This is the first report of c.2314G > A variant in PIK3CD gene.

Evaluating the Threshold Score for Classification of Systemic Lupus Erythematosus Using the EULAR/ACR Criteria.

To evaluate whether a change in the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria threshold score affects accurate classification of SLE cases compared to disease-based control subjects. We evaluated a range of threshold scores to determine the score that maximizes the accurate classification of early SLE. We conducted a cross-sectional study comparing SLE cases and control patients. A EULAR/ACR criteria score was calculated using baseline information. Sensitivity, specificity, positive likelihood ratios (+LRs), and negative likelihood ratios (-LRs) with 95% CIs were used to evaluate operating characteristics. Threshold scores of 6 to 12 were evaluated in subjects with early disease (ie, disease duration of ≤ 5 years). +LRs > 10 and -LRs < 0.1 provide evidence to rule in or rule out SLE. A total of 2764 patients were included: 1980 SLE cases who fulfilled either the ACR or Systemic Lupus International Collaborating Clinics criteria and 784 control subjects. The EULAR/ACR SLE criteria had a sensitivity of 98% (95% CI 97-98), a specificity of 99% (95% CI 98-100), a +LR of 95.5 (95% CI 48.0-190), and a -LR 0.03 (95% CI 0.02-0.03). The criteria operated well in those with early disease, in women, in men, and in White, Black, Chinese, and Filipino people. A score of 10 maximized the accurate classification of patients with early disease (+LR 174.4, 95% CI 43.8-694.6; -LR 0.03, 95% CI 0.02-0.04). An increase in the threshold score from 10 to 11 resulted in significant worsening in the -LR (threshold score 10: -LR 0.03, 95% CI 0.02-0.03 vs threshold score 11: -LR 0.05, 95% CI 0.04-0.06). The EULAR/ACR SLE classification criteria threshold score of 10 performs well, particularly among those with early disease and across sexes and ethnicities.

Antiphospholipid antibody positivity in early systemic lupus erythematosus is associated with subsequent vascular events.

aPL are found in the blood of 20-30% of patients with SLE. Although aPL cause vascular thrombosis in the antiphospholipid syndrome, it is not clear whether positive aPL levels in early SLE increase risk of subsequent vascular events (VE). In a previous analysis of 276 patients with SLE, we found that early positivity for ≥2 of IgG anti-cardiolipin (anti-CL), IgG anti-β2-glycoprotein I (anti-β2GPI) and anti-domain I of β2-glycoprotein I (anti-DI) showed a possible association with VE. Here we have extended that analysis. Serum samples taken from 501 patients with SLE early in their disease had been tested for IgG anti-CL, anti-β2GPI and anti-DI by ELISA. Complete VE history was available for 423 patients of whom 23 were excluded because VE occurred before the diagnosis of SLE. For the remaining 400 patients we carried out Kaplan-Meier survival analysis to define groups at higher risk of VE. Of 400 patients, 154 (38.5%) were positive for one or more aPL, 27 (6.8%) were double/triple-positive and 127 (31.8%) were single-positive. There were 91 VE in 77 patients, of whom 42 were aPL-positive in early disease. VE were significantly increased in aPL-positive vs aPL-negative patients (P = 0.041) and in double/triple-positive vs single-positive vs aPL-negative patients (P = 0.0057). Omission of the IgG anti-DI assay would have missed 14 double/triple-positive patients of whom six had VE. Double/triple-positivity for IgG anti-CL, anti-β2GPI and anti-DI in early SLE identifies a population at higher risk of subsequent VE.

Longitudinal Immune Cell Profiling in Patients With Early Systemic Lupus Erythematosus.

To investigate the immune cell profiles of patients with systemic lupus erythematosus (SLE), and to identify longitudinal changes in those profiles over time. We employed mass cytometry with 3 different panels of 38-39 markers (an immunophenotyping panel, a Tcell/monocyte panel, and a B cell panel) in cryopreserved peripheral blood mononuclear cells (PBMCs) from 9 patients with early SLE, 15 patients with established SLE, and 14 controls without autoimmune disease. We used machine learning-driven clustering, flow self-organizing maps, and dimensional reduction with t-distributed stochastic neighbor embedding to identify unique cell populations in early SLE and established SLE. We used mass cytometry data of PBMCs from 19 patients with early rheumatoid arthritis (RA) and 23 controls to compare levels of specific cell populations in early RA and SLE. For the 9 patients with early SLE, longitudinal mass cytometry analysis was applied to PBMCs at enrollment, 6 months after enrollment, and 1 year after enrollment. Serum samples were also assayed for 65 cytokines using Luminex multiplex assay, and associations between cell types and cytokines/chemokines were assessed. Levels of peripheral helper T cells, follicular helper T (Tfh) cells, and several Ki-67+ proliferating subsets (ICOS+Ki-67+ CD8 T cells, Ki-67+ regulatory T cells, CD19intermediate Ki-67high plasmablasts, and PU.1high Ki-67high monocytes) were increased in patients with early SLE, with more prominent alterations than were seen in patients with early RA. Longitudinal mass cytometry and multiplex serum cytokine assays of samples from patients with early SLE revealed that levels of Tfh cells and CXCL10 had decreased 1 year after enrollment. Levels of CXCL13 were positively correlated with levels of several of the expanded cell populations in early SLE. Two major helper T cell subsets and unique Ki-67+ proliferating immune cell subsets were expanded in patients in the early phase of SLE, and the immunologic features characteristic of early SLE evolved over time.

The performance of different classification criteria for systemic lupus erythematosus in a real-world rheumatology department.

New classification criteria have been proposed to improve classification of systemic lupus erythematosus (SLE). We aimed to evaluate their performance by determining their sensitivity, specificity and accuracy in a real-world rheumatology department. SLE patients who were enrolled in the Australian Lupus Registry and Biobank were included and compared with controls recruited from other rheumatology clinics. Clinical and immunological features were reviewed, according to ACR 1997, SLICC 2012, EULAR/ACR 2019, or Systemic Lupus Erythematosus Risk Probability Index (SLERPI). Performance of each set of criteria was evaluated for the overall cohort and in a subgroup of patients with early SLE. The study included 394 SLE and 123 control patients with other rheumatological conditions. Sensitivity was highest using SLICC 2012 or SLERPI 2020 criteria. Specificity was highest using ACR 1997 criteria. The SLICC 2012 criteria had the highest overall accuracy at 94.4% (95% CI: 91.7, 97.1%). In the subgroup analysis of SLE patients with early disease, SLICC 2012 performed similarly well. The sensitivity and specificity of each set of classification criteria vary slightly, with SLICC 2012 and SLERPI 2020 having the highest sensitivities and the ACR 1997 criteria having the highest specificity in our patient cohort. All classification criteria serve as good instructional aids for clinicians to understand SLE manifestations. For the Australian Lupus Registry and Biobank, we will continue to use the ACR 1997 and/or SLICC 2012 as entry to the observational cohort.

Lupus or not? SLE Risk Probability Index (SLERPI): a simple, clinician-friendly machine learning-based model to assist the diagnosis of systemic lupus erythematosus

ObjectivesDiagnostic reasoning in systemic lupus erythematosus (SLE) is a complex process reflecting the probability of disease at a given timepoint against competing diagnoses. We applied machine learning in well-characterised patient...

Elevated soluble Tim-3 correlates with disease activity of systemic lupus erythematosus

T cell immunoglobulin and mucin domain-containing molecule-3(Tim-3) has been found to play important roles in systemic lupus erythematosus (SLE), but whether sTim-3 is involved in the development of SLE remains unknown. In this study, we firstly observed an increased expression of plasma sTim-3 in SLE patients, especially active SLE patients. The plasma sTim-3 levels were positively correlated with anti-dsDNA, SLEDAI score, ESR, and urine albumin. The plasma sTim-3 levels were negatively correlated with C3 and C4. The area under the ROC curve (AUC) values indicated that the plasma sTim-3 level was significantly discriminative of early active SLE from stable SLE and HC with high sensitivity and specificity. The present results suggest that sTim-3 might serve as a potential biomarker for promising the disease activity of SLE.

New lupus criteria: a critical view.

To review the validation of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus (SLE). 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. 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.

Genetic heterogeneity in Chinese children with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with extreme clinical heterogeneity and significant differences between populations. Here, we performed whole exome sequencing (WES) in 52 children with SLE from China. The patients all fulfilled the 2012 SLICC criteria for the classification of SLE. Patients were enrolled if they met one of the following criteria: 1. age of disease onset under 5 years; 2. family history of autoimmune disease; 3. syndromic SLE; and 4. complicated conditions, such as life-threatening and refractory SLE. 52 out of 281 newly diagnosed pSLE patients met the inclusion criteria. We identified causative mutations in 12 patients in five different genes: SLC7A7, NRAS, TNFAIP3, PIK3CD, and IDS. The age of onset was under five years in eight patients (8/15, p=0.003) with mutations. Two of 5 patients had a family history of autoimmune disease, with family members developing different autoimmune diseases. Causal mutations were identified in five patients who presented with syndromic SLE (5/5 p=0.000) and in another five patients who presented with primary immunodeficiency diseases (5/5, p=0.000). Causal mutations were detected in 12 of 36 patients with SLEDAI scores>14 (12/36, p=0.023) and in 9 of 17 patients with haematological and renal involvement (9/17, p=0.048). We revealed a significant fraction of monogenic SLE aetiologies using WES (12/52, 23.1%). WES should perform in patients with very early onset SLE (<5 years of age), syndromic SLE, severe SLE (SLEDAI score>14), family history of autoimmune disease, primary immunodeficiency disease and renal and haematological involvement.

Associations Between Classification Criteria Items in Systemic Lupus Erythematosus.

A project aimed at developing new classification criteria for systemic lupus erythematosus (SLE) is based on weighted criteria that include both laboratory and clinical items. Combinations of certain symptoms may occur commonly in SLE, which provides an argument against independently counting these items. The current study was undertaken to evaluate the interrelationship between candidate criteria items in the International Early SLE cohort and in the Euro-Lupus cohort. The International Early SLE cohort included 389 patients, who were diagnosed within 3 years prior to the study. Data on the ACR's 1997 update of the SLE revised criteria, the Systemic Lupus International Collaborating Clinics 2012 criteria, and on 30 additional items were collected. To evaluate the interrelationship of the criteria, a tetrachoric correlation was used to assess the degree of association between different manifestations in the same organ system. The correlations identified in the International Early SLE cohort were validated in the Euro-Lupus cohort. A few relevant correlations were observed among specific clinical cutaneous manifestations (in particular, malar rash correlated with photosensitivity, alopecia, and oral ulcers) and serologic manifestations (anti-Sm and anti-double-stranded DNA and anti-RNA polymerase, anti-Ro and anti-La, and antiphospholipid antibodies), and these results were validated in the Euro-Lupus cohort. The associations within the mucocutaneous domain, hematologic and the specific autoantibodies suggest that within a single domain only the highest ranking item should be counted to avoid overrepresentation. Some of the candidate SLE criteria cluster within domains. Given these interrelationships, multiple criteria within a domain should not be independently counted. These results are important to consider for the structure of new SLE classification criteria.

In an early SLE cohort the ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria classify non-overlapping groups of patients: use of all three criteria ensures optimal capture for clinical studies while their modification earlier classification and treatment

ObjectivesClassification criteria are biased towards classifying long-standing disease. We compared the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)-2019, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and ACR-1997 criteria in...

Autoantibodies in SLE: prediction and the p value matrix.

Autoantibodies (AA) and antinuclear antibodies (ANA) serve as key diagnostic and classification criteria for systemic lupus erythematosus (SLE). More than 200 different AA have been reported in SLE, although only a handful (<20) are considered "mainstream" because they are widely and routinely used in diagnostic, research and clinical medicine. Although the vast majority of AA have been relegated to the diminished status of "orphan" AA, some serve as predictors of SLE because they first appear in very early or subclinical SLE. Some AA are pathogenic, whereas others are thought to protect against or ameliorate disease progression and, hence, taken together can be used as predictive biomarkers of prognosis. Although studies have shown that specific AA are detected in the preclinical phase of SLE and are biomarkers of increased risk of developing the disease, AA are currently not widely used to predict very early SLE in individuals who have low pretest probability of disease. With the advent of multianalyte arrays with analytic algorithms, emerging evidence indicates that when certain combinations of biomarkers, such as the interferon signature and stem cell factor accompany AA and ANA, the predictive power for SLE is markedly increased.

Validation of the new classification criteria for systemic lupus erythematosus on a patient cohort from a national referral center: a retrospective study

AimTo validate Systemic Lupus International Collaborating Clinics (SLICC)-12 and American College of Rheumatology (ACR)-97 classification criteria on a patient cohort from the University Hospital Center Zagreb.MethodsThis retrospective study, conducted from 2014 to 2016, involved 308 patients with systemic lupus erythematosus (SLE) (n = 146) and SLE-allied conditions (n = 162). Patients' medical charts were evaluated by an expert rheumatologist to confirm the clinical diagnosis, regardless of the number of the ACR-97 criteria met. Overall sensitivity and specificity, as well as the sensitivity and specificity according to disease duration, were compared between ACR-97 and SLICC-12 classifications. Predictive value for SLE for both classifications was assessed using logistic regression and receiver operating characteristic (ROC) curves.ResultsThe SLICC-12 criteria had significantly higher sensitivity in early disease, which increased with disease duration. The ACR-97 criteria had higher specificity. The specificity of the SLICC-12 criteria was low and decreased with disease duration. Regression analysis demonstrated the superiority of the SLICC-12 classification criteria over the ACR-97 criteria, with areas under the ROC curve of 0.801 and 0.780, respectively.ConclusionAlthough the SLICC-12 criteria were superior to the ACR-97 and were more sensitive for diagnosing early SLE, their specificity in our population was too low. The sensitivity of the SLICC-12 classification is increased by better defined clinical features within each criterion. Our results contribute to the current initiative for developing new criteria for SLE.

Preclinical and early systemic lupus erythematosus.

The challenge of early diagnosis and treatment is a timely issue in the management of systemic lupus erythematosus (SLE), as autoimmunity starts earlier than its clinical manifestations. Hence, growing efforts for stratification of patients according to the individual risk of developing specific clinical manifestations and/or predicting a better response to a given treatment have led to the proposal of several biomarkers, which require validation for use in clinical practice. In this viewpoint, we aim at distinguishing and discussing the features and the approach to asymptomatic immunological abnormalities potentially heralding the development of SLE, defined as preclinical lupus, and clinical manifestations consistent with SLE not yet fulfilling classification criteria, defined as early lupus. In case of preclinical SLE, careful surveillance using available screening tools is paramount, while patients with early lupus deserve an appropriate and timely diagnosis and, consequently, a proper treatment including hydroxychloroquine as the anchor drug.

Lupus: the new epidemic.

Is systemic lupus erythematosus (SLE) is occurring more frequently now than in decades past? Despite improvements in the identification of patients with SLE, the development of new classification criteria, and the recognition of several biomarkers used alone or in combination, the diagnosis of SLE is still a challenge for clinicians, in particular early in the course of the disease, which makes the recognition of secular trends difficult to ascertain. Lacking a uniform definition of preclinical lupus or incomplete lupus, it is difficult to predict accurately which patients would go on to develop SLE. We will briefly review the classification criteria, early or preclinical SLE, the epidemiology of SLE, antinuclear antibodies-negative SLE, and biomarkers of the disease.

Angiotensin-Converting Enzyme Gene I/D Polymorphism Is Associated With Systemic Lupus Erythematosus Susceptibility: An Updated Meta-Analysis and Trial Sequential Analysis.

Angiotensin-converting enzyme (ACE) gene is indispensable for endothelial control and vascular tone regulatory systems, usually affected in Systemic Lupus Erythematosus (SLE). ACE insertion/deletion (I/D) polymorphism may influence the progress of SLE. Earlier studies have investigated this association without any consistency in results. We performed this meta-analysis to evaluate the precise association between ACE I/D polymorphism and SLE susceptibility. The relevant studies were searched until December, 2017 using Medline (PubMed), Google-Scholar and EMBASE search engines. Twenty-five published studies involving 3,308 cases and 4,235 controls were included in this meta-analysis. Statistically significant increased risk was found for allelic (D vs. I: p = 0.007; OR = 1.202, 95% CI = 1.052–1.374), homozygous (DD vs. II: p = 0.025; OR = 1.347, 95% CI = 1.038–1.748), dominant (DD+ID vs. II: p = 0.002; OR = 1.195, 95% CI = 1.070–1.334), and recessive (DD vs. ID+II: p = 0.023; OR = 1.338, 95% CI = 1.042–1.718) genetic models. Subgroup analysis stratified by Asian ethnicity revealed significant risk of SLE in allelic (D vs. I: p = 0.045; OR = 1.238, 95% CI = 1.005–1.525) and marginal risk in dominant (DD+ID vs. II: p = 0.056; OR = 1.192, 95% CI = 0.995–1.428) models; whereas, no association was observed for Caucasian and African population. Publication bias was absent. In conclusion, ACE I/D polymorphism has significant role in overall SLE risk and it can be exploited as a prognostic marker for early SLE predisposition.

Brief Report: How Do Patients With Newly Diagnosed Systemic Lupus Erythematosus Present? A Multicenter Cohort of Early Systemic Lupus Erythematosus to Inform the Development of New Classification Criteria.

Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of <1 year. Clinical and serologic manifestations were compared between patients diagnosed as having SLE and those diagnosed as having SLE-mimicking conditions. Diagnostic performance of the 1997 American College of Rheumatology (ACR) SLE classification criteria and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria was tested. Data were collected on 389 patients with early SLE and 227 patients with SLE-mimicking conditions. Unexplained fever was more common in early SLE than in SLE-mimicking conditions (34.5% versus 13.7%, respectively; P < 0.001). Features less common in early SLE included Raynaud's phenomenon (22.1% versus 48.5%; P < 0.001), sicca symptoms (4.4% versus 34.4%; P < 0.001), dysphagia (0.3% versus 6.2%; P < 0.001), and fatigue (28.3% versus 37.0%; P = 0.024). Anti-double-stranded DNA, anti-β2 -glycoprotein I antibodies, positive Coombs' test results, autoimmune hemolytic anemia, hypocomplementemia, and leukopenia were more common in early SLE than in SLE-mimicking conditions. Symptoms detailed in the ACR and SLICC classification criteria were significantly more frequent among those with early SLE. Fewer patients with early SLE were not identified as having early SLE with use of the SLICC criteria compared to the ACR criteria (16.5% versus 33.9%), but the ACR criteria demonstrated higher specificity than the SLICC criteria (91.6% versus 82.4%). In this multicenter cohort, clinical manifestations that could help to distinguish early SLE from SLE-mimicking conditions were identified. These findings may aid in earlier SLE diagnosis and provide information for ongoing initiatives to revise SLE classification criteria.

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

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. 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. 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. 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.