Objective: Skin involvement is common in systemic lupus erythematosus (SLE), but may be resistant to conventional treatment. We sought to evaluate the efficacy of anifrolumab (ANI) in refractory cutaneous manifestations of SLE. Methods: Case series of patients with refractory cutaneous SLE from three Rheumatology Departments in Greece. Outcome measures were improvement in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), physician global assessment (PGA) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Clinically relevant improvement in skin was defined as decrease ≥50% (CLASI50) from baseline values. Results: Eighteen patients received ANI; all had active skin involvement at baseline. Mean (SD) SLEDAI and PGA at ANI initiation were 7.4 (2.7) and 1.4 (0.5), respectively, with a mean prednisone dose 4.9 (4.5) mg/day. Mean CLASI (Activity/Damage) at baseline was 13.9 (9.7)/2.9 (4.6). Patients were refractory to a mean 6.3 (1.5) immunomodulatory agents (including hydroxychloroquine and glucocorticoids) before the initiation of ANI. After a mean 8.5 (4.6) months, 89% ( n = 16/18) of patients demonstrated significant improvement in general lupus and cutaneous disease activity, and glucocorticoid tapering. Mean SLEDAI and mean CLASI at last visit were 3.4 (1.9) and 2.1 (2.4)/1.4 (2.2), respectively, and mean daily prednisone dose decreased to 2.4 (2.2). Of note, in this group of highly refractory patients CLASI50 was achieved in 16/18 (89%) patients. One patient discontinued ANI after 4 infusions due to a varicella-zoster virus infection and one patient, who initially responded to treatment with ANI, experienced a skin flare due to temporary discontinuation due to Covid 19 infection. DORIS remission and LLDAS were attained in two (11.1%) and eleven (61.1%) patients, respectively. Conclusion: Anifrolumab is highly effective in various skin manifestations of SLE, even after prior failure to multiple treatments.

To discern predictive factors for incident kidney involvement in patients with SLE. Patients with SLE from the ‘Attikon’ Lupus cohort were monitored for 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 Kaplan–Meier survival curves were generated. 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. 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 hazard ratio (aHR) 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. Male sex, younger age and serological 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.

Objective Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by variable treatment responses. We investigated the transcriptional landscape associated with treatment response and resistance in SLE. Methods Blood was collected from 92 active patients with SLE at baseline and after 6 months (n=32 paired samples) of treatment with cyclophosphamide (n=40), rituximab (n=20), belimumab (n=23), mycophenolate mofetil (n=8) or azathioprine (n=1) and was subjected to RNA sequencing. The response was defined by the Lupus Low Disease Activity State. We identified differentially expressed genes and co-expressed transcript modules. Results Achieving response, irrespective of treatment, was accompanied by downregulation of B cell immunity-related and complement activation-related signatures. Rituximab led to the most profound decrease in the activity of the B cell pathway, while cyclophosphamide uniquely downregulated neutrophil activation pathways. Responders, regardless of medication, showed increased activity in pathways related to neutrophil migration, type I interferon signalling, complement activation and B cell function prior to treatment. A 539-gene signature, enriched in processes related to chemokine signalling, characterised patients with insufficient response to treatment. Conclusions Baseline B cell immunity transcriptional signatures correlate with favourable treatment outcomes—accounting for better responses in serologically active patients in SLE clinical trials—with effective treatment reversing the B cell immunity signature. Cyclophosphamide uniquely targets a neutrophil gene signature linked to severe SLE. Alterations in chemotaxis may represent a mechanism driving resistance to treatment in SLE.

Objectives: Lupus Low Disease Activity State (LLDAS) and Definition of Remission in SLE (DORIS) are associated with improved outcomes in SLE; however, their value in lupus nephritis (LN) remains unexplored. We sought to evaluate their prognostic value on organ damage accrual, renal flares and chronic kidney disease in patients with LN. Methods: Multicentre retrospective cohort study of patients with biopsy-proven LN who achieved renal response. Enrolment date was the time of first renal response. Longitudinal data were analysed using Cox proportional hazards models. Modified LLDAS (mLLDAS) and DORIS (mDORIS) attainment and sustained durations were evaluated. Results: 155 patients with 1703 visits were included. During a median follow-up of 3.5 years (IQR 4.5), 127 patients (81.9%) achieved mLLDAS and 92 (59.4%) achieved mDORIS. Both states demonstrated robust protective effects across all outcomes. For organ damage, mLLDAS attainment was associated with 85% risk reduction (adjusted HR (aHR 0.15, 95% CI 0.07 to 0.32), while mDORIS conferred a 79% reduction (aHR 0.21, 95% CI 0.08 to 0.55). Periods under mLLDAS were also associated with a 73% reduction in renal flare risk (aHR 0.27, 95% CI 0.14 to 0.51), with similar effects for mDORIS. Sustained achievement resulted in progressively greater protection, with the strongest effects seen for ≥24 consecutive months. Early attainment protected against damage accrual (aHR 0.31, 95% CI 0.16 to 0.61) and renal flares (aHR 0.51, 95% CI 0.29 to 1.00). Conclusions: Following renal response, achievement of mLLDAS and mDORIS is strongly associated with improved outcomes in LN patients. Earlier attainment and longer duration in these states confer progressively greater protection.

Objectives: Vaccination against SARS-CoV-2 has been vital in alleviating the spread of the recent pandemic. We aimed to estimate the frequency and type of adverse events related to SARS-CoV-2 vaccine in patients with lupus nephritis (LN), and assess its impact, if any, on the risk of subsequent reactivation of nephritis. Methods: This was a retrospective, multicenter study which included patients with biopsy-proven LN, who had received at least one vaccine dose. Patients who ended up with end-stage kidney disease (ESKD) prior to vaccination or were diagnosed with LN after vaccination were excluded. Adverse events, systemic or local, COVID-19 outcomes (full recovery, death, or long COVID-19), outcome of LN (remission, refractory disease, relapse, ESKD or death), demographics, laboratory measurements, and immunosuppressive regimens were recorded. Results: Sixty-seven patients were included. The median age was 33 (20–46) years. Induction therapy for LN was administered to 92.5% of patients and 74.6% received maintenance therapy. Of these, 94.02% were in remission at vaccination. The BNT162b2 mRNA vaccine was administered in 97.01% of cases, with mild systemic adverse symptoms in 28.35% (myalgias 17.91%, headache 13.43%, arthralgias 13.43%, and fever 10.44%) and local adverse effects in 35.82% (pain 25.37%, swelling 13.43%). Overall, among patients in remission upon vaccination, two (3.17%) experienced a LN relapse within 5.75 (±0.25) months, while 75% of those with active disease at vaccination achieved remission within 21 (±2) months. Conclusions: SARS-CoV-2 vaccination appears safe for LN patients without serious adverse events occurring, and there is no significant impact in the clinical course of the disease.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multisystem involvement and various phenotypes. It follows a relapsing-remitting course, marked by alternating periods of relative inactivity and disease flares that can lead to organ damage, significant morbidity, and increased mortality. Approximately half of patients with SLE develop organ damage within 5 years of diagnosis. Potentially modifiable risk factors for damage include uncontrolled disease activity/severe flares, and glucocorticoid exposure. This review outlines a strategy to reduce disease activity and prevent organ damage, emphasizing early diagnosis, maintenance of low disease activity with minimal corticosteroid use, and flare prevention. Early recognition is crucial to avoid disease progression and prevent the development of more severe phenotypes. The 2019 EULAR classification criteria strike a balance between specificity and sensitivity but exclude ANA-negative patients, who may represent up to 20% of cases at diagnosis. To address this limitation, we introduced the SLE Risk Probability Index (SLERPI), a simple, clinician-friendly, machine learning-based model that does not require ANA positivity as a criterion; a score > 7 in SLERPI has shown 94.2% accuracy. Reducing the frequency and severity of flares is a major treatment goal to prevent organ damage and achieve remission or maintain low disease activity. The 2023 EULAR recommendations suggest the early use of biological agents to control disease activity, reduce flares, and facilitate corticosteroid dose reduction and damage prevention. However, incomplete response or refractory disease remains a significant challenge for both patients and clinicians, with evidence suggesting that response rates decline with each subsequent flare. Globally, new approaches are being explored that target various cellular and molecular pathways, including B cells, T cells, and CAR-T cells. The use of CAR-T cell technology to profoundly deplete B cells has shown promising results.