Disentangling the riddle of systemic lupus erythematosus with antiphospholipid syndrome: blood transcriptome analysis reveals a less-pronounced IFN-signature and distinct molecular profiles in venous versus arterial events.

INTRODUCTION: Systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS) represents a challenging SLE endotype whose molecular basis remains unknown. METHODS: We analysed whole-blood RNA-sequencing data from 299 patients with SLE (108 SLE-antiphospholipid antibodies (aPL)-positive, including 67 SLE-APS; 191 SLE-aPL-negative) and 72 matched healthy controls (HC). Pathway enrichment analysis, unsupervised weighted gene coexpression network analysis and machine learning were applied to distinguish disease endotypes. RESULTS: Patients with SLE-APS demonstrated upregulated type I and II interferon (IFN) pathways compared with HC. Using a 100-gene random forests model, we achieved a cross-validated accuracy of 75.6% in distinguishing these two states. Additionally, the comparison between SLE-APS and SLE-aPL-negative revealed 227 differentially expressed genes, indicating downregulation of IFN-α and IFN-γ signatures, coupled with dysregulation of the complement cascade, B-cell activation and neutrophil degranulation. Unsupervised analysis of SLE transcriptome identified 21 gene modules, with SLE-APS strongly linked to upregulation of the 'neutrophilic/myeloid' module. Within SLE-APS, venous thromboses positively correlated with 'neutrophilic/myeloid' and 'B cell' modules, while arterial thromboses were associated with dysregulation of 'DNA damage response (DDR)' and 'metabolism' modules. Anticardiolipin and anti-ß2GPI positivity-irrespective of APS status-were associated with the 'neutrophilic/myeloid' and 'protein-binding' module, respectively. CONCLUSIONS: There is a hierarchical upregulation and-likely-dependence on IFN in SLE with the highest IFN signature observed in SLE-aPL-negative patients. Venous thrombotic events are associated with neutrophils and B cells while arterial events with DDR and impaired metabolism. This may account for their differential requirements for anticoagulation and provide rationale for the potential use of mTOR inhibitors such as sirolimus and the direct fIIa inhibitor dabigatran in SLE-APS.

Health-related quality of life in patients with ANCA vasculitides compared to rheumatoid arthritis: a cross-sectional comparative study.

OBJECTIVES: There are limited data regarding health-related quality of life (HRQoL) in patients with ANCA-associated vasculitides (AAVs). We aimed to evaluate the HRQoL in patients with AAVs and compare it to another chronic inflammatory disease like RA and to healthy controls (HC). METHODS: This was a multicentre, cross-sectional study of patients with AAVs and RA recruited from three tertiary rheumatology clinics. HRQoL was assessed with the Short Form 36 Health Survey, which included the physical and mental component summary scores (PCS and MCS). Data from 1007 HC served as historical controls. RESULTS: Sixty-six patients with AAVs and 71 with RA were included. Both AAV and RA patients had significantly lower PCS and MCS scores compared with HC (P < 0.05). HRQoL in AAV patients was worse in patients with microscopic polyangiitis compared with granulomatosis with polyangiitis (physical components) and those with high (VDI ≥ 3) vs low (VDI < 3) damage scores while it did not differ between those with active (BVASv3 ≥ 1) vs. inactive (BVASv3 < 1) disease. In contrast, in RA patients, HRQoL correlated both with disease activity (assessed by the DAS28-ESR) and functional impairment/damage (assessed by the HAQ). Although overall patients with RA had similar HRQoL compared with those with AAVs, those with active RA had worse HRQoL compared with those with active AAV. CONCLUSIONS: In patients with AAVs, HRQoL correlated more with organ damage and less with disease activity whereas in RA patients, it correlated with both. These data emphasize the need for AAV therapies aiming at preventing organ damage and thus improving HRQoL.

Can we predict kidney involvement in patients with systemic lupus erythematosus? A retrospective cohort study with independent validation.

OBJECTIVES: To discern predictive factors for incident kidney involvement in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE from the 'Attikon' Lupus cohort were monitored for lupus nephritis (LN), defined by kidney histology and/or classification criteria. Demographic and clinical characteristics at baseline were compared against patients who did not develop LN. LN-free survival curves were generated by Kaplan-Meier. A multivariate Cox proportional hazards model was used to identify independent predictors of LN. Independent validation was performed in the University of Crete Lupus registry. RESULTS: Among the 570 patients in the derivation cohort, 59 exhibited LN as their initial presentation, while an additional 66 developed LN during the follow-up period (collectively, 21.9% incidence). In the latter group, baseline factors predictive of subsequent kidney involvement were male sex (multivariable-adjusted [a]HR 4.31, 95% CI: 1.82-10.2), age of SLE diagnosis below 26 years (aHR 3.71, 95% CI: 1.84-7.48), high anti-dsDNA titre (aHR 2.48, 95% CI: 1.03-5.97) and low C3 and/or C4 (although not statistically significant, aHR 2.24, 95% CI: 0.83-6.05, p= 0.11). A combination of these factors at time of diagnosis conferred an almost 90-fold risk compared with serologically inactive, older, female patients (aHR 88.77, 95% CI : 18.75-420.41), signifying a very high-risk group. Independent validation in the Crete Lupus registry showed concordant results with the original cohort. CONCLUSION: Male sex, younger age and serologic activity at SLE diagnosis are strongly associated with subsequent kidney involvement. Vigilant surveillance and consideration of early use of disease-modifying drugs is warranted in these subsets of patients.

Transcriptomic and proteomic profiling reveals distinct pathogenic features of peripheral non-classical monocytes in systemic lupus erythematosus.

Peripheral blood monocytes propagate inflammation in systemic lupus erythematosus (SLE). Three major populations of monocytes have been recognized namely classical (CM), intermediate (IM) and non-classical monocytes (NCM). Herein, we performed a comprehensive transcriptomic, proteomic and functional characterization of the three peripheral monocytic subsets from active SLE patients and healthy individuals. Our data demonstrate extensive molecular disruptions in circulating SLE NCM, characterized by enhanced inflammatory features such as deregulated DNA repair, cell cycle and heightened IFN signaling combined with differentiation and developmental cues. Enhanced DNA damage, elevated expression of p53, G0 arrest of cell cycle and increased autophagy stress the differentiation potential of NCM in SLE. This immunogenic profile is associated with an activated macrophage phenotype of NCM exhibiting M1 characteristics in the circulation, fueling the inflammatory response. Together, these findings identify circulating SLE NCM as a pathogenic cell type in the disease that could represent an additional therapeutic target.

From first symptoms to diagnosis of systemic lupus erythematosus: mapping the journey of patients in an observational study.

OBJECTIVES: Although increased awareness for systemic lupus erythematosus (SLE) has reduced diagnostic delay, the average time from symptom onset to diagnosis is still long, potentially resulting in adverse outcomes. We mapped the journey of lupus patients from onset of symptoms to disease diagnosis. METHODS: We carried out an observational study of 275 SLE patients with disease duration <6 years. Data were collected from patient charts, interviews and in-person clinical visits. Total delay was divided in i) time from symptom onset to rst physician visit, ii) time from rst visit to assessment by rheumatologist, and iii) time from initial rheumatologist assessment to nal diagnosis. Early diagnosis was de ned as diagnosis within 6 months from symptom onset. RESULTS: Most common initial symptoms were arthritis/arthralgia (74.5%) and rashes (61.8%). Median (IQR) total delay between symptom onset and SLE diagnosis was 24 (54) months. An "early" diagnosis was achieved only in 28.4% of patients, while 55.6% were diagnosed after 12 months, with patients consulting an average of 3 different physicians before reaching diagnosis. Oral ulcers (OR 3.55; 95% CI 1.45-8.70) and malar rash (OR 1.99; 95% CI 1.00-3.94) as initial symptoms, and rst medical assessment by orthopaedic (OR 5.18; 95% CI 1.47-18.20) were independently associated with a delayed diagnosis. The latter was also associated with increased SDI at the time of diagnosis (OR 2.42; 95% CI 1.03-5.69), attributed mainly to neuropsychiatric and thrombotic events. CONCLUSIONS: Diagnosis of SLE is delayed by more than 6 months in three quarters of patients and is associated with more damage accrual.

The Multiple Faces of Systemic Lupus Erythematosus: Pearls and Pitfalls for Diagnosis.

Systemic lupus erythematosus is the prototype multisystem autoimmune disorder characterised by a broad spectrum of organ involvement and a multitude of laboratory abnormalities. Clinical heterogeneity, unpredictable course and lack of pathognomonic clinical and serological features pose a considerable challenge in the diagnosis of SLE. The latter remains largely clinical, typically accompanied however by features of serologic autoimmunity, which are characteristic for the disease. Despite significant improvements in treatment strategies, an early diagnosis often continues to be an unmet need, as the median reported delay from symptom onset to SLE diagnosis is approximately 2 years. Classification criteria are usually used to support the diagnosis, yet with significant caveats. In this article, we provide an updated review of the clinical presentation of lupus and give clues for an accurate diagnosis.

Demyelinating Syndromes in Systemic Lupus Erythematosus: Data From the "Attikon" Lupus Cohort.

Background: The demyelinating syndromes of the central nervous system (CNS) that occur in the context of systemic lupus erythematosus (SLE) may represent a manifestation of neuropsychiatric lupus (NPSLE) or an overlap of SLE and multiple sclerosis (MS). The differential diagnosis between the two entities has important clinical implications because the therapeutic management differs. Objectives: To characterize CNS demyelinating syndromes in a large SLE cohort as neuropsychiatric SLE (NPSLE) or SLE-MS overlap using a multidisciplinary approach and existing diagnostic (for MS) and classification criteria (for SLE). Methods: Patients from the "Attikon" lupus cohort (n = 707) were evaluated for demyelinating syndromes. Clinical, laboratory, and neuroimaging data were recorded for each patient. Following multidisciplinary evaluation and application of criteria, the demyelinating syndrome was attributed to either SLE or MS. Patients with transverse myelitis were not included in this study. Results: We identified 26 patients with demyelinating syndromes (3.7%). Of them, 12 were diagnosed as primary SLE-demyelination (46.2%) and 14 as overlap SLE-MS (53.8%). The two groups did not differ with respect to rheumatologic and neurologic manifestations or autoantibodies. SLE patients with demyelination manifested mild extra-CNS disease mainly involving joints and skin, while severe non-CNS manifestations were rare. However, these patients were less likely to have elevated IgG index (OR 0.055 95% CI: 0.008-0.40) and positive oligoclonal bands (OR 0.09 95% CI: 0.014-0.56), as well as brain lesions in the spinal cord, infratentorial, periventricular, and juxtacortical regions. A single brain region was affected in 9 patients with SLE-demyelination (75%), while all patients with MS-SLE had multiple affected brain regions. MS-SLE overlap was associated with an increased likelihood of neurologic relapses (OR 18.2, 95% CI: 1.76-188), while SLE-demyelination patients were less likely to exhibit neurological deficits (EDSS >0) at the last follow-up visit (50 vs. 78.6% in SLE-MS, respectively). Conclusions: Demyelination in the context of SLE follows a more benign course compared to a frank SLE-MS overlap. Extension of follow-up will ascertain whether patients with SLE-demyelination evolve to MS, or this is a bona fide NPSLE syndrome.

First Diagnosis of Systemic Lupus Erythematosus in Hospitalized Patients: Clinical Phenotypes and Pitfalls for the Non-Specialist.

BACKGROUND: Prompt recognition of systemic lupus erythematosus (SLE) in hospitalized patients presenting with severe disease is essential to initiate treatment. We sought to characterize the phenotype of hospitalized patients with new-onset SLE and estimate potential diagnostic delays. METHODS: An observational study of 855 patients ("Attikon" SLE cohort). Clinical phenotype was categorized according to the leading manifestation that led to hospitalization. Disease features, time to diagnosis, classification criteria, and the SLE Risk Probability Index (SLERPI) were recorded for each patient. RESULTS: There were 191 patients (22.3% of the total cohort) hospitalized due to manifestations eventually attributed to SLE. Main causes of admission were neuropsychiatric syndromes (21.4%), cytopenias (17.8%), nephritis (17.2%), and thrombotic events (16.2%). Although 79.5% of patients were diagnosed within 3 months from hospitalization, in 39 patients diagnosis was delayed, particularly in those with hematological manifestations. At hospitalization, a SLERPI >7 (indicating high probability for SLE) was found in 87.4% of patients. Patients missed by the SLERPI had fever, thrombotic or neuropsychiatric manifestations not included in the algorithm. Lowering the SLERPI threshold to 5 in patients with fever or thrombotic events increased the diagnostic rate from 88.8% to 97.9% in this subgroup, while inclusion of all neuropsychiatric events yielded no additional diagnostic value. CONCLUSION: One in five patients with new-onset SLE manifest disease presentations required hospitalization. Although early diagnosis was achieved in the majority of cases, in approximately 20%, diagnosis was delayed. A lower SLERPI cut-off (≥5) in patients with fever or thrombosis could enhance early diagnosis.

Clinical response trajectories and drug persistence in systemic lupus erythematosus patients on belimumab treatment: A real-life, multicentre observational study.

Objective: To obtain real-world data on outcomes of belimumab treatment and respective prognostic factors in patients with systemic lupus erythematosus (SLE). Methods: Observational study of 188 active SLE patients (median disease duration 6.2 years, two previous immunosuppressive/biological agents) treated with belimumab, who were monitored for SLEDAI-2K, Physician Global Assessment (PGA), LLDAS (lupus low disease activity state), remission (DORIS/Padua definitions), SELENA-SLEDAI Flare Index, SLICC/ACR damage index and treatment discontinuations. Group-based disease activity trajectories were modelled followed by multinomial regression for predictive variables. Drug survival was analysed by Cox-regression. Results: At 6, 12 and 24 months, LLDAS was attained by 36.2%, 36.7% and 33.5%, DORIS-remission by 12.3%, 11.6% and 17.8%, and Padua-remission by 21.3%, 17.9% and 29.0%, respectively (attrition-corrected). Trajectory analysis of activity indices classified patients into complete (25.5%), partial (42.0%) and non-responder (32.4%) groups, which were predicted by baseline PGA, inflammatory rash, leukopenia and prior use of mycophenolate. During median follow-up of 15 months, efficacy-related discontinuations occurred in 31.4% of the cohort, especially in patients with higher baseline PGA (hazard ratio [HR] 2.78 per 1-unit; 95% CI 1.32-5.85). Conversely, PGA improvement at 3 months predicted longer drug retention (HR 0.57; 95% CI 0.33-0.97). Use of hydroxychloroquine was associated with lower risk for safety-related drug discontinuation (HR 0.33; 95% CI 0.13-0.85). Although severe flares were reduced, flares were not uncommon (58.0%) and contributed to treatment stops (odds ratio [OR] 1.73 per major flare; 95% CI 1.09-2.75) and damage accrual (OR 1.83 per mild/moderate flare; 95% CI 1.15-2.93). Conclusions: In a real-life setting with predominant long-standing SLE, belimumab was effective in the majority of patients, facilitating the achievement of therapeutic targets. Monitoring PGA helps to identify patients who will likely benefit and stay on the treatment. Vigilance is required for the prevention and management of flares while on belimumab.

Serious infections in ANCA-associated vasculitides in the biologic era: real-life data from a multicenter cohort of 162 patients.

BACKGROUND: Serious infections (SI) are common in patients with ANCA-associated vasculitides (AAV) like granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Real-life data regarding their incidence and predisposing factors-after the introduction of B cell depleting agents-are limited while data quantifying the risk per treatment modality and year of the disease are missing. Here, we aim to describe in details the incidence and the risk factors for SI in a contemporary AAV cohort. METHODS: Multicenter, observational, retrospective study of AAV patients followed in three tertiary referral centers. RESULTS: We included 162 patients with GPA (63%) and MPA (37%), males 51.9%, mean age 60.9 years, ΑΝCA+ 86%, and generalized disease 80%. During follow-up (891.2 patient-years, mean 5.4 years), 67 SI were recorded in 50 patients at an incidence rate of 7.5 per 100 patient-years. The SI incidence rate was higher during induction with cyclophosphamide (CYC) compared to rituximab (RTX, 19.3 vs. 11.3 per 100 patient-years, respectively) while it was lower and comparable between RTX and other regimens (5.52 vs. 4.54 per 100 patient-years, respectively) in the maintenance phase. By multivariate analysis, plasmapheresis (PLEX) and/or dialysis was a strong predictor for an SI during the 1st year after diagnosis (OR = 3.16, 95% CI 1.001-9.96) and throughout the follow-up period (OR = 5.21, 95% CI 1.93-14.07). In contrast, a higher baseline BVAS (OR = 1.11, 95% CI 1.01-1.21) was associated with SI only during the 1st year. CONCLUSIONS: In this real-life study of patients with AAV, the SI incidence was higher during CYC compared to RTX induction while there was no difference between RTX and other agents used for maintenance therapy. Higher disease activity at baseline and need for PLEX and/or dialysis were independent factors associated with an SI.