Zahi Touma

Objective: SLE is often preceded by a preclinical phase in which autoantibodies and other biomarkers are detectable, offering an opportunity to identify at‐risk individuals for early monitoring and testing interventions to halt progression. To inform an effort to develop SLE risk‐stratification criteria, we conducted a scoping review of longitudinal human studies of biomarkers measured before SLE onset. Methods: Following PRISMA‐ScR, we searched three databases and used a Population, Exposure, Comparator, Outcome framework to select longitudinal studies in which biomarkers were measured before an incident diagnosis or classification of SLE. Study characteristics, biomarkers, and outcomes were extracted from included studies. Results: We included 59 original studies and two meta‐analyses including heterogeneous at‐risk populations, in which the proportion progressing to SLE varied widely. Most evidence concerned conventional serological markers, whereas interferon and cytokine signatures, proteomic panels, and genetic risk scores were examined in fewer, recent cohorts. Few biomarkers were studied across multiple populations or with comparable follow‐up, outcome definitions, and analytic methods, and most associations came from single studies without external validation. Longitudinal biomarker trajectories before onset were rarely characterized, and non‐European populations were under‐represented. Conclusion: his review maps the breadth of candidate biomarkers associated with the risk of developing SLE and the heterogeneity of the evidence supporting them. Building a clinically useful SLE risk‐stratification index will need a shared definition of the at‐risk state, and prospective studies that follow biomarkers over time, in populations from broader geographical regions.

Objective: Examine long-term glucocorticoid usage, safety and prevention of organ damage in patients with SLE treated with belimumab plus standard therapy (ST). Methods: This post hoc analysis from three global long-term extension (LTE) studies (BEL112233, BEL112234 and BEL112626) included patients who completed parent studies BLISS-52, BLISS-76 or LBSL02. All patients in the LTEs received open-label belimumab (10 mg/kg) intravenously every 28 days plus ST. Endpoints included long-term SLE medication use any time after first belimumab dose (in parent or LTE study), organ damage accrual (up to 8 years) and safety (up to 13 years). Results: Altogether, 1304 patients enrolled in the LTE studies; 1299 received ≥1 dose of belimumab and were included in the modified intent to treat population. Of these, 1221 (94%) patients were female and at enrolment had a mean (SD) age and disease duration of 39.7 (11.6) and 7.2 (6.7) years, respectively. Mean (SD) baseline Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores were 8.2 (4.3) and 0.7 (1.2), respectively. The most frequently used SLE concomitant medications at any time after first dose of belimumab were glucocorticoid (GC) (94.1%), antimalarials (74.6%) and immunosuppressants (56.4%). Approximately 50% of patients reduced their GC dose to ≤7.5 mg/day in the first 3 years, increasing to 73.6% by the end of year 8. Mean (SD) changes in SDI score to year 8 did not exceed 0.3 (0.6). Overall, 97.5% of patients had ≥1 adverse event (AE) up to 13 years. While 40.4% had ≥1 serious AE, the incidence of AEs leading to belimumab discontinuation generally remained low over time (10.7%). Conclusions: Patients with SLE treated with belimumab reduced GC use and had minimal to no organ damage progression over 8 years. Robust and consistent safety data up to 13 years support the well-established favourable safety profile of belimumab, with no new safety concerns.

Objectives: SLE is a heterogeneous autoimmune disease with persistent symptoms that profoundly impair quality of life yet are often under-recognized by clinician-assessed instruments. Patient-reported outcomes (PROs) are increasingly incorporated in clinical trials to capture treatment benefit from the patient perspective. However, the responsiveness of PRO instruments and their alignment with clinician-assessed disease activity across distinct SLE trajectories remain incompletely defined. We evaluated the longitudinal responsiveness and convergent validity of PRO measures across predefined disease trajectory classes. Methods: Secondary analysis of pooled patient-level data from two phase III randomized clinical trials of belimumab in adults with active SLE (n = 1908), stratified into four previously derived trajectory classes defined by baseline disease activity and treatment response. PROs included Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue), 36-Item Short Form Survey (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS), EuroQol 5-Dimension 3-level (EQ-5D-3L) and EuroQol Visual Analogue Scale (EQ-VAS). Responsiveness was quantified using standardized response means (SRMs). Convergent validity was evaluated using repeated-measures correlations between within-person changes in PROs and clinician-assessed disease activity measures (SLEDAI-2K, BILAG and Physician’s Global Assessment [PGA]), with sensitivity analyses performed to assess the robustness of findings. Results: FACIT-F and SF-36 PCS generally demonstrated the greatest responsiveness, while EQ-5D-3L showed smaller changes and less consistent responsiveness across classes and timepoints. FACIT-F demonstrated early responsiveness, whereas SF-36 PCS showed sustained responsiveness over later follow-up. PRO changes were most consistently associated with PGA. Sensitivity analyses showed broadly similar patterns. Conclusion: FACIT-F and SF-36 PCS demonstrated the greatest responsiveness and alignment with clinician-assessed disease activity. EQ-5D-3L showed less consistent responsiveness, suggesting domain-specific PROs may better capture treatment benefit in SLE trials and health technology assessments.

Objectives: This study aimed to evaluate the association between antimalarial exposure and renal histopathologic findings at kidney biopsy in patients with LN. Methods: This study was conducted within the University of Toronto Lupus Clinic cohort. To ensure adequate assessment of antimalarial exposure, patients were included if they underwent a kidney biopsy at least 3 months after clinic entry. The kidney biopsy served as the index time point (baseline) for the analysis and corresponded to the clinic visit immediately preceding the biopsy. Antimalarial exposure was defined as use during ≥2 consecutive clinic visits prior to biopsy. Sensitivity analyses evaluated longer durations of continuous antimalarial exposure (≥6 months and ≥1 year). Histopathologic outcomes included proliferative vs non-proliferative LN class, NIH activity index (AI), NIH chronicity index (CI) and interstitial fibrosis and tubular atrophy (IFTA) score. Associations were evaluated using logistic and linear regression models adjusted for demographic, clinical and treatment covariates. Results: The study included 165 patients with biopsy-proven LN (median age 35.3 years; 84.2% female; median disease duration 6.2 years), of whom 50.3% were on antimalarial therapy at baseline. In the adjusted multivariable analyses, antimalarial exposure was not associated with detectable differences in proliferative LN, NIH AI, NIH CI or IFTA score. Sensitivity analyses requiring ≥6 months and ≥1 year of continuous antimalarial exposure yielded similar findings. Conclusions: Antimalarial exposure was not associated with detectable differences in renal histopathologic findings at biopsy. These findings should be interpreted within the limitations of the study design and sample size.

Objective: This study aims to evaluate biomarkers that discriminate systemic lupus erythematosus patients with and without neuropsychiatric involvement. Methods: We searched MEDLINE, Embase, and CENTRAL (inception—March 2024) for studies of blood or cerebrospinal fluid (CSF) analytes in neuropsychiatric systemic lupus erythematosus (NPSLE). Random-effects meta-analyses were conducted for analyte-biofluid pairs with ≥5 independent studies; the remaining data were synthesized narratively. Results: A total of 93 studies were included. Few analyte–biofluid combinations met the criteria for meta-analysis, and most promising biomarkers (intrathecal inflammation, neuronal injury, and reduced neuroprotection) were assessed in only small, heterogeneous studies. The meta-analyses showed higher CSF IL-6 and MCP-1 in NPSLE than non-NPSLE SLE (Hedges’ g 0.81 and 0.66, respectively), a smaller heterogeneous effect for IL-8, and two- to threefold higher odds of NPSLE in patients positive for serum anti-ribosomal P (OR 2.68, 95% CI 2.03–3.53), anti-NR2/NMDAR (2.09, 1.07–4.06), and IgG anticardiolipin (2.36, 1.56–3.59) antibodies. Compared with non-SLE controls, NPSLE generally showed higher CSF soluble mediators than healthy or non-inflammatory neurological comparators, but the levels in CNS infections were often similar or higher. Conclusion: CSF markers of intrathecal inflammation, neuronal injury, and reduced neuroprotection distinguish NPSLE from non-NPSLE SLE but are neither specific for NPSLE nor easily obtainable in routine practice. Classical serum autoantibodies (anti-ribosomal P, anti-NR2, and antiphospholipid antibodies) show modest, phenotype-dependent diagnostic performance. Evidence remains fragmented, with heterogeneous assays, cutoffs, and case definitions, underscoring the need for harmonized multicenter studies to identify robust diagnostic, evaluative, and prognostic biomarkers for overall and manifestation-specific NPSLE.

Objective: Systemic lupus erythematosus (SLE) significantly impacts employment capacity. This study aimed to investigate the impact of burden of disease activity, damage, and treatment on employment outcomes and transitions in patients with SLE. Methods: Using data from a single center, we analyzed employment transitions, adjusted mean disease activity, and organ damage. Sankey diagrams helped visualize transitions between the categories. Multinomial logistic regression identified predictors of final employment status (employed, unemployed, disability benefit, retired, economically inactive, death while employed) for the disease activity and damage domains. Results: Of 1,806 patients, limited transition was observed across employment categories. Of the 1,155 ever employed, 398 patients (34.5%) permanently transitioned out of employment to disability benefits (n = 82) or short‐term sick leave (n = 71). Patients with disability showed high retention alongside significant health vulnerabilities, with the highest severe flare rates (0.3/year) and glucocorticoids use (47.8% on >30 mg/day), with a substantial proportion dying during follow‐up. Early retirement was associated with malignancy, endocrine, and musculoskeletal damage (odds ratio [OR] 2.51, 2.56, and 1.47, respectively), whereas disability showed similar patterns with additional neuropsychiatric (OR 1.87) and renal damage (OR 1.89). Conclusion: There is a lack of transitions between employment categories over the disease course, high persistence in the disability benefits, and economically inactive categories and a low probability of reentry after leaving the workforce. Neuropsychiatric and renal damage are key drivers of disability. Patients who are unemployed and who have disabilities face the worst disease progressions, underscoring the need for early occupational intervention and an unmet need for novel therapeutic treatments.

Introduction: SLE remains a disease of high unmet medical need. Protean manifestations and the lack of clear understanding of aetiology, pathogenesis and disease subgroups make it difficult to develop and employ targeted therapeutic approaches. Community-wide access to a longitudinal, highly curated patient dataset with linked biospecimens and cellular/molecular data is critical to enable advances and is now provided by Lupus Nexus (LNx). In this study, we describe the development of this unique resource with exemplary patient engagement. Methods and analysis: LNx, developed with guidance from over 100 partners, includes a prospective, longitudinal observational study, the Lupus Landmark Study (LLS), that will enrol up to 3500 adults living with lupus into four cohorts and will follow them over 5 years. The registry data comprises medical information, clinician-reported and patient-reported outcomes while the biorepository includes whole blood, urine, saliva, stool and tissue which are available to the research community for a broad range of analyses. Importantly, since all raw data from the biospecimen analyses will be deposited in LNx, it will amass a deep and comprehensive dataset over time. As of 25 March 2026, there are 705 enrolled participants (13.3% new onset, 27.4% extrarenal flare, 23.3% active lupus nephritis and 35% prevalent cases, with 37.6% black, 38% white and 12.6% Asian/Pacific Islander patients). Over 15 400 unique samples have been collected and specific analyses are underway. All data and samples from LNx are available via its Data Repository Exchange and Analytics platforM ( DREAM ). Importantly, a dedicated patient portal within DREAM enables participants to view their study data, connect with others and learn about the research emerging from projects using LNx. Trial registration number: NCT05934149 .

Objective: Despite improvements in overall survival, cardiovascular (CV) events remain a leading cause of death in patients with systemic lupus erythematosus (SLE). Anifrolumab controls disease activity while reducing glucocorticoid use and has been associated with reduced organ‐damage accrual; however, its long‐term efficacy for reducing CV damage is unknown. This study evaluates the effect of anifrolumab plus standard of care (SoC) on long‐term CV damage in SLE compared with real‐world external controls. Methods: We included 354 patients who initiated anifrolumab 300 mg in the Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trials in the cohort of patients who received anifrolumab. The real‐world SoC cohort comprised 561 patients from the University of Toronto Lupus Clinic registry, selected using matched eligibility criteria. Baseline characteristics were balanced using propensity score weighting. Mean changes in CV‐related Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) from baseline to year 4 were estimated using weighted linear‐regression models. Time to first CV event up to four years was assessed using Kaplan–Meier estimators and a Cox regression model. Results: Patients receiving anifrolumab accrued, on average, 0.046 fewer CV‐SDI points at four years (95% confidence interval [CI] −0.074 to −0.018; P = 0.008) compared with patients with real‐world SoC. The hazard ratio for CV events over four years was 0.257 (95% CI 0.0687 to 0.961; P = 0.0583) for patients treated with anifrolumab versus controls with real‐world SoC. Conclusion: These findings suggest that anifrolumab may reduce long‐term CV damage in patients with SLE.

Objectives: Arthritis is a common manifestation of systemic lupus erythematosus (SLE). We examined the prevalence and associations of arthritis subtypes in SLE, focusing on associations with type I interferon (IFN) scores. Methods: In this observational cohort study at the University of Toronto Lupus Clinic (July 1970–August 2024), arthritis was defined clinically as non-deforming arthritis (NDA), Jaccoud’s arthropathy (JA) and arthritis with clinically irreducible deformities (CIDA). Univariable and multivariable (MV) logistic regression was used to assess associations with arthritis subtypes with NDA as reference in the prevalent cohort and subgroup with available IFN scores (reported as high/low). Results: Among 2264 patients, 1248 (55.1%) had arthritis: 908 (72.8%) had NDA, 239 (19.2%) JA, and 101 (8.1%) CIDA. In the multivariable logistic regression analysis, JA was associated with longer disease duration (odds ratio [OR] 1.05 [95% CI: 1.03, 1.08]) and female sex (2.06 [1.11, 3.83]) whereas CIDA was associated with neurological involvement (1.79 [1.13, 2.84]), anti-Ro antibodies (1.71 [1.01, 2.90]), higher adjusted mean joint count (1.09 [1.03, 1.77]) and lower adjusted mean SLEDAI-2K over follow-up (0.89 [0.81, 0.98]) compared with NDA. In patients with available IFN scores (n = 475), CIDA was associated with a low IFN signature in unadjusted analysis, whereas both JA and NDA had a high IFN signature. Conclusion: Distinct clinical and serological patterns differentiate JA and CIDA, suggesting unique underlying mechanisms of deforming arthritis in SLE. Both NDA and JA exhibited a high IFN signature, while CIDA showed a higher joint burden, lower disease activity and lower IFN signature relative to NDA.