Examining the clinical and radiological landscape of rhupus: navigating the challenges in disease classification.

Rhupus, in the broad sense, refers to an overlap between rheumatoid arthritis (RA) and lupus. However, there is a paucity of data on the appropriate diagnostic/classification criteria that should be used to define rhupus. Hence, we undertook this narrative review to analyze the clinical characteristics, radiology, and treatment with a focus on diagnostic challenges and defining features of rhupus. The databases of Medline/PubMed, Scopus, and DOAJ were searched for relevant articles using the following keywords: ("Rhupus"), ("lupus" AND "erosive" AND "arthritis"), and ("lupus" AND "rheumatoid arthritis" AND "overlap"). Studies have used a variety of classification criteria for rhupus of which a combination of the latest classification criteria for RA and lupus along with positive anti-cyclic citrullinated peptide, anti-Smith, and anti-dsDNA antibodies seem most relevant. The majority of rhupus cohorts report the onset of the disease as RA (two-thirds of rhupus patients) followed by the development of features of lupus at an average interval of 3-11.3 years. The radiographic features and distribution of erosions are similar to RA. However, ultrasonography and MRI reveal erosions in pure lupus related arthritis as well. This makes the reliability of radiologic tools for the evaluation of rhupus supportive at the most. Extra-articular features in rhupus are mild with major organ involvement in the form of neuropsychiatric lupus and lupus nephritis being rare. We have further discussed the fallacies of the various classification criteria and proposed a theme for classifying rhupus which needs to be tested and validated in future studies. Our current state of understanding supports rhupus as an overlap of SLE and RA with articular disease similar to RA with the extra-articular disease being milder than SLE. Developing standardized classification criteria for rhupus will help in the early diagnosis and prevention of articular damage in patients with rhupus.

What can we learn from DNA methylation studies in lupus?

During the past twenty years, a wide range of studies have established the existence of epigenetic alterations, particularly DNA methylation changes, in lupus. Epigenetic changes might have different contributions in children-onset versus adult-onset lupus. DNA methylation alterations have been identified and characterized in relation to disease activity and damage, different lupus subtypes and responses to drugs. However, to date there has been no practical application of these findings in the clinical milieu. In this article, we provide a review of key studies showing the relationship between DNA methylation and the many clinical aspects related to lupus. We also propose several options, in relation to the range of methodological developments and experimental design, that could optimize these findings and make them amenable for use in clinical practice.

Classification of systemic lupus erythematosus in children and adults.

Systemic Lupus Erythematosus (SLE) is an autoimmune multisystem disease with a variable clinical phenotype and no single clinical, laboratory or pathological feature that can be used as a gold standard for disease classification or diagnosis. Classification criteria have been developed in an attempt to define homogenous groups of SLE patients for clinical research. They have been mainly validated in adult cohorts, given the much lower prevalence of SLE before puberty. The three commonly used sets of current classification criteria and their validation studies to date are described in this review. Challenges relating to classification of SLE patients, including important differences across age-groups and ethnicities, are explored along with future directions in the classification of SLE.

Systemic lupus erythematosus - Are children miniature adults?

Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease that can affect any organ system and cause significant damage and organ failure. Disease-onset during childhood (juvenile-onset SLE) is associated with less typical autoantibody patterns, diffuse organ involvement, more damage already at diagnoses, and a higher need of immunomodulating treatment, including corticosteroids, when compared to adult-onset SLE. Differences in the molecular pathophysiology within SLE, and over-representation of patients with "genetic SLE" contribute to differences in clinical presentation and treatment responses between children and adults. This manuscript summarizes currently available literature focusing on parallels and differences between clinical pictures, known pathomechanisms, and available treatment options in juvenile- versus adult-onset SLE.

Limited sensitivity and specificity of the ACR/EULAR-2019 classification criteria for SLE in JSLE?-observations from the UK JSLE Cohort Study.

OBJECTIVES: This study aimed to test the performance of the new ACR and EULAR criteria, that include ANA positivity as entry criterion, in JSLE. METHODS: Performance of the ACR/EULAR-2019 criteria were compared with Systemic Lupus International Collaborating Clinics (SLICC-2012), using data from children and young people (CYP) in the UK JSLE Cohort Study (n = 482), with the ACR-1997 criteria used as reference standard. An unselected cohort of CYP positive for ANA (n = 129) was used to calculate positive/negative predictive values of the criteria. RESULTS: At both first and last visits, the number of patients fulfilling the different classification criteria varied significantly (P < 0.001). The sensitivity of the SLICC-2012 criteria was higher when compared with that of the ACR/EULAR-2019 criteria at first and last visits (98% vs 94% for first visit, and 98% vs 96% for last visit; P < 0.001), when all available CYP were considered. The ACR/EULAR-2019 criteria were more specific when compared with the SLICC-2012 criteria (77% vs 67% for first visit, and 81% vs 71% for last visit; P < 0.001). Significant differences between the classification criteria were mainly caused by the variation in ANA positivity across ages. In the unselected cohort of ANA-positive CYP, the ACR/EULAR-2019 criteria produced the highest false-positive classification (6/129, 5%). CONCLUSION: In CYP, the ACR/EULAR-2019 criteria are not superior to those of the SLICC-2012 or ACR-1997 criteria. If classification criteria are designed to include CYP and adult populations, paediatric rheumatologists should be included in the consensus and evaluation process, as seemingly minor changes can significantly affect outcomes.

Avoiding misclassification of thrombotic primary antiphospholipid syndrome as systemic lupus erythematosus (SLE): What are the best-performing SLE classification criteria?

BACKGROUND: Systemic lupus erythematosus (SLE) and Primary Antiphospholipid Syndrome (PAPS) overlap clinical and immunological features. Therefore, misclassification of PAPS patients as SLE is a concern. The ACR/EULAR 2019 SLE classification has never been studied in PAPS. OBJECTIVE: To verify if the ACR/EULAR 2019 SLE classification can correctly classify a PAPS patient as not having SLE and compare its performance with the SLICC 2012 SLE classification. Methods: One-hundred thrombotic PAPS patients who fulfilled the Sidney criteria were consecutively screened and those who attended the inclusion criteria were submitted to ACR/EULAR 2019 and SLICC 2012 classifications. RESULTS: Sixty-seven PAPS patients were included in this study. The majority was female (89.6%) with median age at study inclusion of 45 years (35-53) and median PAPS disease duration of 13 years (8-19). PAPS correct classification was observed more often with ACR/EULAR 2019 than SLICC 2021 criteria (94.0% vs. 64.2%; p < 0.001). The 4 misclassified patients in ACR/EULAR 2019 were also misclassified in SLICC 2012. The comparison of misclassified patients to those correctly not classified as SLE resulted, for both criteria, in higher frequencies of hematological domain [ACR/EULAR 2019 (100% vs. 28.6%, p = 0.010) and SLICC 2012 (95.8% vs. 11.6%, p < 0.001)]. Further analysis of hematological manifestations revealed that for the ACR/EULAR 2019 leukopenia (100% vs. 22.2%, p = 0.004) and for the SLICC 2012 leukopenia/lymphopenia (91.7% vs. 7%, p < 0.001) were more frequent in misclassified group. Proteinuria (20.8% vs. 0%, p = 0.004) and low complement (45.8% vs. 20.9%, p = 0.033) were also more often observed in the incorrectly SLICC 2012 classified patients. CONCLUSION: ACR/EULAR 2019 had high accuracy for distinguishing PAPS from SLE, whereas the SLICC 2012 incorrectly classified more than one third of the PAPS patients as having SLE.

Interventions for cutaneous disease in systemic lupus erythematosus.

BACKGROUND: Lupus erythematosus is an autoimmune disease with significant morbidity and mortality. Cutaneous disease in systemic lupus erythematosus (SLE) is common. Many interventions are used to treat SLE with varying efficacy, risks, and benefits. OBJECTIVES: To assess the effects of interventions for cutaneous disease in SLE. SEARCH METHODS: We searched the following databases up to June 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, Wiley Interscience Online Library, and Biblioteca Virtual em Saude (Virtual Health Library). We updated our search in September 2020, but these results have not yet been fully incorporated. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions for cutaneous disease in SLE compared with placebo, another intervention, no treatment, or different doses of the same intervention. We did not evaluate trials of cutaneous lupus in people without a diagnosis of SLE. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were complete and partial clinical response. Secondary outcomes included reduction (or change) in number of clinical flares; and severe and minor adverse events. We used GRADE to assess the quality of evidence. MAIN RESULTS: Sixty-one RCTs, involving 11,232 participants, reported 43 different interventions. Trials predominantly included women from outpatient clinics; the mean age range of participants was 20 to 40 years. Twenty-five studies reported baseline severity, and 22 studies included participants with moderate to severe cutaneous lupus erythematosus (CLE); duration of CLE was not well reported. Studies were conducted mainly in multi-centre settings. Most often treatment duration was 12 months. Risk of bias was highest for the domain of reporting bias, followed by performance/detection bias. We identified too few studies for meta-analysis for most comparisons. We limited this abstract to main comparisons (all administered orally) and outcomes. We did not identify clinical trials of other commonly used treatments, such as topical corticosteroids, that reported complete or partial clinical response or numbers of clinical flares. Complete clinical response Studies comparing oral hydroxychloroquine against placebo did not report complete clinical response. Chloroquine may increase complete clinical response at 12 months' follow-up compared with placebo (absence of skin lesions) (risk ratio (RR) 1.57, 95% confidence interval (CI) 0.95 to 2.61; 1 study, 24 participants; low-quality evidence). There may be little to no difference between methotrexate and chloroquine in complete clinical response (skin rash resolution) at 6 months' follow-up (RR 1.13, 95% CI 0.84 to 1.50; 1 study, 25 participants; low-quality evidence). Methotrexate may be superior to placebo with regard to complete clinical response (absence of malar/discoid rash) at 6 months' follow-up (RR 3.57, 95% CI 1.63 to 7.84; 1 study, 41 participants; low-quality evidence). At 12 months' follow-up, there may be little to no difference between azathioprine and ciclosporin in complete clinical response (malar rash resolution) (RR 0.83, 95% CI 0.46 to 1.52; 1 study, 89 participants; low-quality evidence). Partial clinical response Partial clinical response was reported for only one key comparison: hydroxychloroquine may increase partial clinical response at 12 months compared to placebo, but the 95% CI indicates that hydroxychloroquine may make no difference or may decrease response (RR 7.00, 95% CI 0.41 to 120.16; 20 pregnant participants, 1 trial; low-quality evidence). Clinical flares Clinical flares were reported for only two key comparisons: hydroxychloroquine is probably superior to placebo at 6 months' follow-up for reducing clinical flares (RR 0.49, 95% CI 0.28 to 0.89; 1 study, 47 participants; moderate-quality evidence). At 12 months' follow-up, there may be no difference between methotrexate and placebo, but the 95% CI indicates there may be more or fewer flares with methotrexate (RR 0.77, 95% CI 0.32 to 1.83; 1 study, 86 participants; moderate-quality evidence). Adverse events Data for adverse events were limited and were inconsistently reported, but hydroxychloroquine, chloroquine, and methotrexate have well-documented adverse effects including gastrointestinal symptoms, liver problems, and retinopathy for hydroxychloroquine and chloroquine and teratogenicity during pregnancy for methotrexate. AUTHORS' CONCLUSIONS: Evidence supports the commonly-used treatment hydroxychloroquine, and there is also evidence supporting chloroquine and methotrexate for treating cutaneous disease in SLE. Evidence is limited due to the small number of studies reporting key outcomes. Evidence for most key outcomes was low or moderate quality, meaning findings should be interpreted with caution. Head-to-head intervention trials designed to detect differences in efficacy between treatments for specific CLE subtypes are needed. Thirteen further trials are awaiting classification and have not yet been incorporated in this review; they may alter the review conclusions.

New classification criteria for systemic lupus erythematosus.

PURPOSE OF REVIEW: To compare the recently published European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE with the Systemic Lupus International Collaborating Centers (SLICC) criteria and the earlier ACR criteria, focusing on their key concepts. RECENT FINDINGS: Although the SLICC criteria introduced numbers of new criteria items, the new EULAR/ACR criteria added only noninfectious fever, based on an early SLE cohort study and an SLE patient survey, and condensed hematological, mucocutaneous and neurological items. Whereas the SLICC criteria maintained the overall structure familiar from the ACR criteria, the EULAR /ACR criteria use antinuclear antibodies (ANA) as an obligatory entry criterion, have weighted criteria and group these in domains. Where the SLICC criteria greatly increased sensitivity, losing some specificity, the EULAR/ACR criteria increased specificity again, for excellent classification criteria performance. SUMMARY: Despite differences in structure and statistical performance, the EULAR/ACR and SLICC criteria agree on the importance of both immunological and clinical findings, on the high impact of lupus nephritis by histology, and on most clinical items.

Novel paradigms in systemic lupus erythematosus.

The heterogeneity of systemic lupus erythematosus (SLE), long recognised by clinicians, is now challenging the entire lupus community, from geneticists to clinical investigators. Although the outlook for patients with SLE has greatly improved, many unmet needs remain, chief of which is the development of safer and more efficacious therapies. To develop innovative therapies, a far better understanding of SLE pathogenesis as it relates to the array of clinical phenotypes is needed. Additionally, to efficiently achieve these goals, the lupus community needs to refine existing clinical research tools and better adapt them to overcome the obstacles created by the heterogeneity of manifestations. Here, we review progress towards the ultimate goal of safely reducing disease activity and preventing damage accrual and death. We discuss the new classification criteria from the European League Against Rheumatism and American College of Rheumatology, novel definitions of remission and low lupus disease activity, and new proposals for the histological classification of lupus nephritis. Recommendations for the treatment of SLE and novel approaches to drug development hold much promise to further enhance SLE outcomes.

Management strategies and future directions for systemic lupus erythematosus in adults.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the loss of self-tolerance and formation of nuclear autoantigens and immune complexes resulting in inflammation of multiple organs. The clinical presentation of SLE is heterogeneous, can involve one or more organs, including the skin, kidneys, joints, and nervous system, and take a chronic or relapsing and remitting disease course. SLE is most common in women and in those of non-white ethnicity. Because of the multitude of presentations, manifestations, and serological abnormalities in patients with SLE, diagnosis can be challenging. Therapeutic approaches predominantly involve immunomodulation and immunosuppression and are targeted to the specific organ manifestation, with the aim of achieving low disease activity. Despite many treatment advances and improved diagnostics, SLE continues to cause substantial morbidity and premature mortality. Current management strategies, although helpful, are limited by high failure rates and toxicity. An overreliance on corticosteroid therapy contributes to much of the long-term organ damage. In this Seminar, we outline the classification criteria for SLE, current treatment strategies and medications, the evidence supporting their use, and explore potential future therapies.

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.

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.

OBJECTIVES: Classification 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 an early (median 48 months) systemic lupus erythematosus (SLE) cohort. METHODS: Patients diagnosed with SLE (n=690) or control diseases (n=401). Sensitivity, specificity of the criteria and time-to-classification were calculated. Modified classification algorithms were derived from a random 80% and validated in the remaining 20% of the dataset running multiple iterations. RESULTS: At last assessment, sensitivities of ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria were 85.7%, 91.3% and 88.6%, with specificities 93.0%, 93.8% and 97.3%, respectively. Both SLICC and EULAR/ACR enabled earlier classification. Only 76.7% of patients with SLE met all three criteria suggesting non-overlapping groups. Notably, unclassified patients had high prevalence of British Isles Lupus Assessment Group moderate/severe manifestations (43.3%-60%) and SLICC/ACR organ damage (30%-50%). At diagnosis, criteria missed 25.6%-30.5% of patients. Modification of EULAR/ACR and SLICC algorithms to include hypocomplementaemia and/or positive anti-phospholipid antibodies as alternative entry criterion, and/or allow classification with fewer clinical criteria from multiple organs, increased their sensitivity at diagnosis (median 82.0% and 86.2%) and overall (93.7% and 97.1%) with modest decreases in specificity. Importantly, patients who were still missed by the modified criteria had lower incidence of major organ involvement, use of immunosuppressive/biological therapies and organ damage. CONCLUSIONS: The SLICC and EULAR/ACR are more sensitive than the ACR and the EULAR/ACR criteria have superior specificity in early SLE, although patients with significant disease can be missed. Combination and/or modification of the classification algorithms may enhance their sensitivity, allowing earlier classification and treatment of more patients with high disease burden.

Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort.

OBJECTIVES: Remission in systemic lupus erythematosus (SLE) is defined through a combination of 'clinical SLE Disease Activity Index (cSLEDAI)=0', 'physician's global assessment (PGA) <0.5' and 'prednisone (PDN) ≤5 mg/day'. We investigated the performance of these items, alone or in combination, in defining remission and in predicting SLICC/ACR Damage Index. METHODS: We tested seven potential definitions of remission in SLE patients followed-up for ≥5 years: PDN ≤5 mg/day; PGA <0.5; cSLEDAI=0; PGA <0.5 plus PDN ≤5 mg/day; cSLEDAI=0 plus PGA <0.5; cSLEDAI=0 plus PDN ≤5 mg/day; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5. The effect of these definitions on damage was evaluated by Poisson regression analysis; the best performance was identified as the lowest Akaike and Bayesian information criterion (AIC and BIC). Positive and negative predictive values in identifying no damage increase were calculated. RESULTS: We included 646 patients (mean±SD disease duration 9.2±6.9 years). At multivariate analysis, ≥2 consecutive year remission according to all definitions protected against damage (OR, 95% CI: PGA <0.5 0.631, 0.444 to 0.896; cSLEDAI=0 0.531, 0.371 to 0.759; PGA <0.5 plus PDN ≤5 mg/day 0.554, 0.381 to 0.805; cSLEDAI=0 plus PGA <0.5 0.574, 0.400 to 0.826; cSLEDAI=0 plus PDN ≤5 mg/day 0.543, 0.376 to 0.785; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5 0.532, 0.363 to 0.781, p<0.01 for all), except PDN ≤5 mg/day, which required four consecutive years (OR 0.534, 95% CI 0.325 to 0.877, p=0.013). Positive and negative predictive values were similar; however, cSLEDAI=0 showed the best performance (AIC 1082.90, BIC 1109.72, p<0.0001). Adding PGA <0.5 and/or PDN ≤5 mg/day to cSLEDAI=0 decreased remission duration (-1.8 and -1.5 year/patient, respectively) without increasing cSLEDAI=0 performance in predicting damage accrual. CONCLUSIONS: cSLEDAI=0 is the most attainable definition of remission, while displaying the best performance in predicting damage progression in the short-to-mid-term follow-up.

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.

A comparative study on clinical and serological characteristics between patients with rhupus and those with systemic lupus erythematosus and rheumatoid arthritis.

BACKGROUND: The concomitant presence of two autoimmune diseases - systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) - in the same patient is known as rhupus. We evaluated a group of patients with rhupus to clarify further their clinical, serological and immunogenic features in a multi-centre cohort. In addition, the study aimed to explore the utility of the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) SLE classification criteria in our group of patients with rhupus. METHODS: This was a cross-sectional study. We included rhupus patients from 11 different rheumatology departments, and compared them to SLE and RA patients at a ratio of 2:1. All information was recorded following a pre-established protocol. RESULTS: A total of 200 patients were included: 40 rhupus patients and 80 each of SLE and RA patients as controls. Disease duration was similar among SLE and rhupus groups (around 13 years), but the RA group had a significantly lower disease duration. Main clinical manifestations were articular (94.2%), cutaneous (77.5%) and haematological (72.5%). Rhupus patients had articular manifestations similar to those expected in RA. Only 10% of rhupus patients had renal involvement compared with 25% of those with SLE (p < 0.05), while interstitial lung disease was more common in patients affected by RA. The 2019 EULAR/ACR SLE criteria were met in 92.5% of the rhupus patients and in 96.3% of the SLE cohort (p > 0.05). Excluding the joint domain, there were no differences between the numbers of patients who met the classification criteria. CONCLUSION: Rhupus patients follow a particular clinical course, with full expression of both SLE and RA in terms of organ involvement, except for a lower prevalence of kidney affection. The new 2019 EULAR/ACR SLE criteria are not useful for differentiating SLE and rhupus patients. A new way of classifying autoimmune diseases is needed to identify overlapping clusters.

Disease activity and damage in hospitalized lupus patients: a Sabah perspective.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune disease with variable levels of activity that may wax and wane within the same patient over the years. In view of the scarcity of data about lupus in the East Malaysian population, we aimed to study the disease activity and damage index in patients with SLE hospitalized in a tertiary center in Sabah, East Malaysia. METHODS: We retrospectively studied all patients with SLE admitted from 1 January 2013 to 31 December 2015. Demographic data, clinical features, treatment received, SLEDAI and SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) criteria and outcomes were collected. RESULTS: There were 108 patients studied whereby 88.9% were females. They had a mean age of 31.4 ± 11.02 years at admission and were multiethnic in origin. The mean number of ACR criteria for SLE was 5.03 ± 1.5 at the time of diagnosis. There were 158 hospitalizations during the 3 years. The main causes of hospitalization were flare of SLE (66.5%), infection (57.6%), renal biopsy (15.5%) and others (11.4%). Active nephritis (65%), cutaneous (44.4%) and hematological involvement (40.2%) were the three commonest manifestations. There was concurrent flare of SLE and infection in 41.1% of the admissions. The mean SLEDAI score at admission was 10.8 ± 7.20, with a mean SLEDAI of 9.3 ± 6.9 in those without damage and 11.9 ± 7.21 in those with damage (p-value = 0.026). The median SLICC score was 1 with a mean of 0.93 ± 1.07. There were nine deaths (5.6%) during the study period and all patients were females. Compared with those who survived, they had a significantly higher SLEDAI score of 15.80 ± 8.2 (p-value = 0.0207) and a SLICC score of 2.70 ± 1.6 (p-value <0.001). CONCLUSION: SLE is more common among the indigenous population of Sabah, the Kadazan-Dusun, which has not been shown before this study. Disease characteristics were, however, similar to reports from the Asia-Pacific region. Acute flare of SLE and infection remained the main causes of admission and readmissions and was present in 44.4% of the mortalities in our cohort.

Evolving phenotype of systemic lupus erythematosus in Caucasians: low incidence of lupus nephritis, high burden of neuropsychiatric disease and increased rates of late-onset lupus in the 'Attikon' cohort.

OBJECTIVE: This study aimed to analyse the phenotype of systemic lupus erythematosus (SLE) at first presentation and during follow-up in a newly established SLE cohort based at 'Attikon' University Hospital. The hospital combines primary, secondary and tertiary care for the region of Western Attica, Greece. METHODS: This study comprised a mixed prevalent and incident cohort of 555 Caucasian patients diagnosed with SLE according to American College of Rheumatology 1997 criteria and/or the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) 2012 criteria. Demographic and clinical characteristics, patterns of severity, treatments and SLICC damage index were recorded for each patient at the time of diagnosis and at last evaluation. RESULTS: The mean age at lupus diagnosis was 38.3 years (standard deviation = 15.6 years), with a median disease duration at last follow-up of two years (interquartile range 1-11). At initial presentation, the most common 'classification' manifestations were arthritis (73.3%), acute cutaneous lupus (65%) and unexplained fever (25%), while among symptoms not included in any criteria set, Raynaud's phenomenon (33%) was the most common. Kidney and neuropsychiatric involvement as presenting manifestations were present in 10.3% and 11.5% cases, respectively. Irreversible damage accrual was present in 17.8% within six months of disease diagnosis, attributed mainly to thrombotic and neuropsychiatric disease. At last evaluation, 202 (36.4%) patients had developed severe disease, of whom more than half were treated with pulse cyclophosphamide. CONCLUSION: In this cohort of Caucasian patients, lupus nephritis is not as common as in older cohorts, while neuropsychiatric disease is emerging as a major frontier in lupus prevention and care. These data may help to document changes in the natural history and treatment of SLE over time and may have implications for its early recognition and management.

Application of the 2019 European League Against Rheumatism/American College of Rheumatology systemic lupus erythematosus classification criteria in clinical practice: a single center experience.

Originally developed as research tools, different classification criteria sets for systemic lupus erythematosus (SLE) are also used to diagnose SLE in routine clinical care. The recently developed European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 criteria set is noted to perform better than previous SLE classification criteria. This study applied the new criteria schema to a tertiary center SLE cohort, ascertained its performance, and identified the clinical characteristics of patients who did not fulfill these criteria. From the 217 patients who were included, 11 (5%) did not meet the new criteria, mainly because of the antinuclear antibody entry criterion, resulting in a diagnostic sensitivity of 94%. Within this group, we found that constitutional and renal manifestations were unusual. Additionally, specific SLE antibodies as well as hypocomplementemia were less likely to be present. We did not observe a statistically significant difference in outcomes between the two groups of patients (fulfilling vs. unfulfilling the new criteria). We conclude that the EULAR/ACR criteria may misclassify a small subset of SLE patients with milder disease. It is important to be cognizant of key clinical and serologic features of these patients and treat them accordingly to prevent further irreversible damage.

Cytokine Profiles in Autoantibody Defined Subgroups of Systemic Lupus Erythematosus.

The aim of this study was to evaluate how the cytokine profiles differed between autoantibody based subgroups of systemic lupus erythematosus (SLE). SLE is a systemic autoimmune disease, characterized by periods of flares (active disease) and remission (inactive disease). The disease can affect many organ systems, e.g., skin, joints, kidneys, heart, and the central nervous system (CNS). SLE patients often have an overproduction of cytokines, e.g., interferons, chemokines, and interleukins. The high cytokine levels are part of the systemic inflammation, which can lead to tissue injury. In the present study, SLE patients were divided into five groups based on their autoantibody profiles. We thus defined these five groups: ANA negative, antiphospholipid (aPL) positive, anti-Sm/anti-RNP positive, Sjögren's syndrome (SS) antigen A and B positive, and patients positive for more than one type of autoantibodies (other SLE). Cytokines were measured using Mesoscale Discovery (MSD) multiplex analysis. On the basis of the cytokine data, ANA negative patients were the most deviating subgroup, with lower levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-12/IL-23p40, and interferon gamma-induced protein (IP)-10. Despite low cytokine levels in the ANA negative group, autoantibody profiles did not discriminate between different cytokine patterns.

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.