Does remission in systemic lupus erythematosus according to the 2021 DORIS definition match the treating rheumatologist's judgement?

OBJECTIVES: To assess agreement between the 2021 Definition Of Remission In SLE (DORIS) and physician-judged lupus activity. METHODS: A cross-sectional analysis was conducted of data from a Spanish prospective multicentre study of SLE patients. We applied the 2021 DORIS criteria and assessed whether remission status based on this definition agreed with remission as per physician clinical judgement and reasons for disagreement between them. RESULTS: Out of 508 patients [92% women; mean age (s.d.): 50.4 years (13.7)] studied, 267 (54.4%) met the criteria for 2021 DORIS remission. Based on physicians' judgement, 277 (55.9%) patients were classified as in remission or serologically active clinically quiescent (SACQ). The overall rate of agreement between these assessments was 81.2% (95% CI: 79.9, 82.9%) with a Cohen's kappa of 0.62 (0.55-0.69). Overall, 46 (9.1%) patients were classified as in remission/SACQ by rheumatologists but did not meet the 2021 DORIS criteria for remission. The main reasons for discrepancies were a clinical SLE Disease Activity Index (cSLEDAI) score >0 in 39 patients, a Physician Global Assessment score >0.5 in five patients, and prednisone >5 mg/day in another five patients. CONCLUSIONS: The 2021 DORIS remission is an achievable target in clinical practice. There is substantial agreement between the DORIS definition and physician-judged remission. The discordance was mainly due to physicians classifying some patients with ongoing mild disease activity as in remission. Thus, the standardized DORIS definition should be used to define the target in a treat-to-target strategy for the management of SLE.

Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Novel endothelial progenitor cells populations as biomarkers of damage and remission in systemic lupus erythematosus.

INTRODUCTION: Endothelial progenitor cells (EPCs) are essential for maintenance of vascular homeostasis and stability, key processes in the pathogenesis of systemic lupus erythematosus (SLE). However, the role and phenotypic characterization of EPCs populations in SLE have not been completely elucidated. OBJECTIVE: To identify EPCs specific subpopulations in patients with SLE using a novel flow cytometry tool. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SLE and healthy controls (HC). mRNA and surface protein expression were determined by quantitative PCR (qPCR) and flow cytometry. Clusters identification and characterization were performed using tSNE-CUDA dimensionality reduction algorithms. RESULTS: tSNE-CUDA analysis identified eight different clusters in PBMCs from HC and patients with SLE. Three of these clusters had EPC-like phenotype and the expression was elevated in patients with SLE. Moreover, four SLE-associated subclusters were found mainly expressed in patients with SLE, being only present in patients in remission with SLE and significantly associated with the 2021 Definition of Remission in SLE. Importantly, we also identified specific clusters in SLE patients with organ damage, according to the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI). These clusters showed an EPC-like phenotype, but the expression of angiogenic markers was lower compared to HC or patients without organ damage, suggesting an impaired angiogenic function. CONCLUSION: Our novel approach identified clusters of EPCs in patients with SLE that are associated with remission and damage. Therefore, these clusters might be useful biomarkers to predict disease progression and severity in SLE pathogenesis.

Damage in a large systemic lupus erythematosus cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER) with emphasis on the cardiovascular system: a longitudinal analysis.

OBJECTIVE: To assess organ damage, with emphasis on the cardiovascular system, over the different stages of the disease in a large SLE cohort. METHODS: Multicentre, longitudinal study of a cohort of 4219 patients with SLE enrolled in the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We longitudinally analysed SDI (globally and for each domain) over time only in the 1274 patients whose dates of damage events had been recorded. RESULTS: During the first year after diagnosis of SLE, 20% of the 1274 patients presented with new damage manifestations. At years 2 and 3, new damage was recorded in 11% and 9% of patients. The annual percentage of patients with new damage after year 5 decreased to 5%. In the first year with the disease, most damage was accumulated in the musculoskeletal, neuropsychiatric and renal systems; in later stages, most damage was in the musculoskeletal, ocular and cardiovascular systems. Considering 'cerebrovascular accident' and 'claudication for 6 months' as cardiovascular items, the cardiovascular system was the second most affected system during the early stages of SLE, with 19% of the patients who presented with damage affected at first year after diagnosis. During the late stages, 20-25% of the patients presenting with new damage did so in this modified cardiovascular domain of the SDI. CONCLUSIONS: New damage occurs mainly during the first year following diagnosis of SLE. Cardiovascular damage is relevant in both the early and the late stages of the disease. Strategies to prevent cardiovascular damage should be implemented early after diagnosis of SLE.

Semaphorin3B promotes an anti-inflammatory and pro-resolving phenotype in macrophages from rheumatoid arthritis patients in a MerTK-dependent manner.

Previous works from our group show that Semaphorin3B (Sema3B) is reduced in RA and plays a protective role in a mouse arthritis model. In turn, MerTK plays a protective function in murine arthritis models, is expressed by synovial tissue macrophages and is linked to remission in patients with RA. In this study, we examined the role of Sema3B in the phenotypic characteristics of RA macrophages and the implication of MerTK. Peripheral blood monocytes from RA patients were differentiated into IFN-γ (RA MØIFN-γ) or M-CSF (RA MØM-CSF) macrophages and stimulated with LPS, Sema3B or their combination. Alternatively, RA fibroblast like synoviocytes (FLS) were stimulated with RA MØIFN-γ and RA MØM-CSF supernatants. Gene expression was determined by qPCR and protein expression and activation by flow cytometry, ELISA and western blot. Sema3B down-regulated the expression of pro-inflammatory mediators, in both RA MØIFN-γ and RA MØM-CSF. We observed a similar reduction in RA FLS stimulated with the supernatant of Sema3B-treated RA MØIFN-γ and RA MØM-CSF. Sema3B also modulated cell surface markers in macrophages towards an anti-inflammatory phenotype. Besides, MerTK expression and activation was up-regulated by Sema3B, just as GAS6 expression, Resolvin D1 secretion and the phagocytic activity of macrophages. Importantly, the inhibition of MerTK and neuropilins 1 and 2 abrogated the anti-inflammatory effect of Sema3B. Our data demonstrate that Sema3B modulates the macrophage characteristics in RA, inducing a skewing towards an anti-inflammatory/pro-resolving phenotype in a MerTK-dependant manner. Therefore, here we identify a new mechanism supporting the protective role of Sema3B in RA pathogenesis.

Type I Interferons induce endothelial destabilization in Systemic Lupus Erythematosus in a Tie2-dependent manner.

Endothelial cell (EC) dysfunction is a hallmark of Systemic Lupus Erythematosus (SLE) and Tie2 is a receptor essential for vascular stability. Inflammatory processes promote inhibition of Tie2 homeostatic activation, driving vascular dysfunction. In this work we determined whether type I Interferons (IFN) induce Tie2 signalling-mediated endothelial dysfunction in patients with SLE. Serum levels of Angiopoietin (Ang)-1, Ang-2 and soluble (s)Tie1 in patients with SLE and healthy controls were measured by ELISA. Monocytes from patients with SLE and Human Umbilical Vein EC (HUVEC) were stimulated with IFN-α, IFN-ß (1000 I.U.) or SLE serum (20%). mRNA and protein expression, phosphorylation and translocation were determined by quantitative PCR, ELISA, Western Blot, flow cytometry and confocal microscopy. Viability and angiogenic capacity were determined by calcein and tube formation assays. We found that sTie1 and Ang-2 serum levels were increased and Ang-1 decreased in patients with SLE and were associated with clinical characteristics. Type I IFN significantly decreased Ang-1 and increased Ang-2 in monocytes from patients with SLE. Type I IFN increased sTie1 and Ang-2 secretion and reduced Tie2 activation in HUVEC. Functionally, type I IFN significantly reduced EC viability and impaired angiogenesis in a Tie2 signalling-dependent manner. Finally, SLE serum increased Ang-2 and sTie1 secretion and significantly decreased tube formation. Importantly, Tie1 and IFNAR1 knockdown reversed these effects in tube formation. Overall, type I IFN play an important role in the stability of EC by inhibiting Tie2 signalling, suggesting that these processes may be implicated in the cardiovascular events observed in patients with SLE.

Antimalarials exert a cardioprotective effect in lupus patients: Insights from the Spanish Society of Rheumatology Lupus Register (RELESSER) analysis of factors associated with heart failure.

BACKGROUND/OBJECTIVES: Factors associated with chronic heart failure (CHF) in patients with systemic lupus erythematosus (SLE) have received little attention. Recent data on the use of hydroxychloroquine in the treatment of SARS-CoV-2 infection have cast doubt on its cardiac safety. The factors associated with CHF, including therapy with antimalarials, were analyzed in a large multicenter SLE cohort. METHODS: Cross-sectional study including all patients with SLE (ACR-1997 criteria) included in the Spanish Society of Rheumatology Lupus Register (RELESSER), based on historically gathered data. Patients with CHF prior to diagnosis of SLE were excluded. A multivariable analysis exploring factors associated with CHF was conducted. RESULTS: The study population comprised 117 patients with SLE (ACR-97 criteria) and CHF and 3,506 SLE controls. Ninety percent were women. Patients with CHF were older and presented greater SLE severity, organ damage, and mortality than those without CHF. The multivariable model revealed the factors associated with CHF to be ischemic heart disease (7.96 [4.01-15.48], p < 0.0001), cardiac arrhythmia (7.38 [4.00-13.42], p < 0.0001), pulmonary hypertension (3.71 [1.84-7.25], p < 0.0002), valvulopathy (6.33 [3.41-11.62], p < 0.0001), non-cardiovascular damage (1.29 [1.16-1.44], p < 0.000) and calcium/vitamin D treatment (5.29 [2.07-16.86], p = 0.0015). Female sex (0.46 [0.25-0.88], p = 0.0147) and antimalarials (0.28 [0.17-0.45], p < 0.000) proved to be protective factors. CONCLUSIONS: Patients with SLE and CHF experience more severe SLE. Treatment with antimalarials appears to confer a cardioprotective effect.

Anti-CD26 autoantibodies are involved in rheumatoid arthritis and show potential clinical interest.

OBJECTIVES: Rheumatoid arthritis (RA) patients show low serum levels of the Ag dipeptidyl peptidase IV (DPP-IV/CD26), both soluble CD26 (sCD26) concentration and its DPP-IV activity. The aim of this study was to test if anti-DPP-IV/CD26 Abs (Anti-CD26) cleared sCD26. DESIGN & METHODS: Serum Anti-CD26 and Total titers (as comparison) of isotypes IgA, IgM and IgG as well as sCD26 concentration and DPP-IV activity were measured in a cohort of RA patients undergoing different biological and non-biological therapies (n=105) and controls (n=50). RESULTS: Anti-CD26 levels were increased approximately two-fold for each isotype in RA, were not related to the sCD26 clearance, showed several correlations with disease activity parameters, were significantly higher in smokers and they were not ACPA. Anti-CD26 Igs showed high diagnostic power (82% sensitivity and 96% specificity) and their levels differed amongst the different groups of patients stratified by the type of therapy. CONCLUSIONS: As DPP-IV/CD26 is associated to factors triggering RA in the lung and periodontal tissue, these results suggest that Anti-CD26 isotypes may participate in pathogenesis and may be useful as biomarkers for earlier diagnosis and/or precision medicine.

CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis.

We studied dipeptidyl peptidase IV (DPP-IV, CD26) expression in different T helper cells and serum soluble DPP-IV/sCD26 levels in rheumatoid arthritis (RA) patients, correlated these with disease activity score (DAS), and examined how they were affected by different therapies, conventional or biological (anti-TNF, anti-CD20 and anti-IL6R or Ig-CTLA4). The percentage of CD4+CD45R0+CD26- cells was greatly reduced in patients (up to 50%) when compared with healthy subjects. Three other subsets of CD4 cells, including a CD26high Th1-associated population, changed variably with therapies. Data from these subsets (frequency and staining density) significantly correlated with DAS28 or DAS28 components but different in each group of patients undergoing the different therapies. Th17 and Th22 subsets were implicated in RA as independent CCR4+ and CCR4- populations each, with distinct CD26 expression, and were targeted with varying efficiency by each therapy. Serum DPP-IV activity rather than sCD26 levels was lower in RA patients compared to healthy donors. DPP-IV and sCD26 serum levels were found related to specific T cell subsets but not to disease activity. We conclude that, according to their CD26 expression, different cell subsets could serve to monitor RA course, and an uncharacterized T helper CD26- subset, not targeted by therapies, should be monitored for early diagnosis.