Susan Manzi

This study attempted to quantify the bias expected due to partly interval censored (IC) outcomes in the estimated association between hydroxychloroquine (HCQ) taper/cessation and time to disease flare among individuals with systemic lupus erythematosus (SLE). Using data-driven simulations, we estimated bias expected due to IC using real-world data from the Systemic Lupus International Collaborating Clinics inception cohort. The time-varying exposure of interest was a binary indicator of hydroxychloroquine tapering/cessation. The composite outcome was lupus flare, defined as lupus hospitalizations or increases in disease activity or medication dose. The two latter components were IC, as they were recorded only at annual assessment, without a precise date. For the unknown IC event times, a "true" event time was randomly generated from a uniform distribution of the time between two assessments. Each simulated sample was analyzed separately imputing unknown event times (for IC outcomes) either at the midpoint or endpoint of the interval between the two adjacent yearly assessments. Results of multivariable Cox proportional hazards models, adjusted for demographics, drugs, and clinical variables, using either "true" or imputed IC event times were compared. The 1,543 SLE patients were followed for a median of 42.2 months. During follow-up, 396 participants tapered/stopped HCQ and 1,187 experienced a flare. The adjusted uncorrected hazard ratio (HR) was 1.51 (95%CI: 1.30, 1.75) and 1.40 (95%CI: 1.21, 1.62) for midpoint and endpoint imputations, respectively. Data-driven simulations showed that imputation of IC event times resulted in a small but systematic bias toward the null that was consistently larger for endpoint than for midpoint imputation. IC events induced bias toward the null in the estimated association between HCQ taper/cessation and lupus flares. Data-driven simulations are useful for quantitative bias analyses in complex situations, as they allow accounting for relevant characteristics of a particular real-world dataset.

The multinational, phase 3, double-blind, placebo-controlled TULIP-SC trial evaluated the efficacy and safety of subcutaneous anifrolumab in adults who have moderate-to-severe SLE activity, despite receiving standard therapy. Adults with SLE received subcutaneous anifrolumab 120 mg or placebo once weekly for 52 weeks (1:1 randomization). Only the primary endpoint (treatment difference in BILAG-based Composite Lupus Assessment [BICLA] response at 52 weeks) was formally tested in a pre-planned interim analysis; key secondary and other endpoints were tested in the full analysis. At the interim analysis (220 patients, anifrolumab: n=109; placebo: n=111), the primary endpoint was met (anifrolumab vs placebo: 59.4% vs 43.9%; BICLA response difference [95% confidence interval]=15.5% [2.3-28.6%], p=0.0211). The full analysis included 367 patients (anifrolumab: n=184; placebo: n=183). Versus placebo, more patients treated with anifrolumab attained a BICLA response whilst maintaining low/reduced oral glucocorticoid doses through Week 52 (56.2% vs 34.0%; difference=22.3% [12.3-32.2] p<0.0001), and the time to first sustained BICLA response was reduced (Hazard ratio=2.2 [1.5-3.2]; p<0.0001). Treatment differences in Week 52 DORIS remission and Low Lupus Disease Activity State attainment rates favored anifrolumab over placebo (14.2% [5.6-22.8%], p=0.0012, and 14.1% [4.6-23.6%], p=0.0038). The frequencies of serious adverse events were 11.9% with anifrolumab and 10.4% with placebo; the frequencies of herpes zoster were 3.8% and 1.1%, respectively. Consistent with the well-established profile of intravenous anifrolumab, subcutaneous anifrolumab demonstrated significant, clinically meaningful treatment benefits when added to standard therapy, and an acceptable safety profile in patients with moderate to severe SLE.

Systemic lupus erythematosus (SLE) remains a deadly disease, yet our ability to predict adverse outcomes is poor. Mitochondria are organelles recognised by the immune system when released from cells, and antimitochondrial antibodies (AMA) can be detected in people with SLE. We assessed AMA as markers of nephritis, arterial vascular events (AVE), and other outcomes including mortality. We studied sera and data from 1114 participants of the Systemic Lupus International Collaborating Clinics inception cohort. We measured antiwhole mitochondria (AwMA), antimitochondrial DNA (AmtDNA), and antimitochondrial RNA (AmtRNA) antibodies by direct Enzyme-Linked ImmunoSorbent Assays (ELISAs). Separate multivariable Cox proportional hazards regression models estimated associations of either baseline or most recent measures of AMA with the outcomes, adjusted for biological sex, age, medications, and other clinical factors. Interactions of AMA with biological sex were tested for each outcome. All AMA titres were elevated in SLE vs healthy individuals. Higher AMA levels were associated with a higher hazard of nephritis, with the strongest associations for most recent AmtDNA (adjusted hazard ratio [aHR] =1.61 for increase of 1 SD, 95% CI 1.43-1.82) and AmtRNA (aHR =1.59, 1.46-1.73). Higher baseline AwMA levels predicted early mortality (aHR =1.19, 1.02-1.40). Most recent AmtDNA (aHR =1.68, 1.28-2.19) was associated with higher mortality throughout the follow-up. For AVE, the impact of higher AmtRNA was stronger in females. Baseline and most recent assessments of AMA levels may help identify individuals at higher risk of severe outcomes in SLE, including mortality. Integrating AMA into precision medicine strategies will allow deeper exploration of lupus heterogeneity.

Using hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. This observational study included patients (n=2010) across the Systemic Lupus International Collaborating Clinics (SLICC), Wisconsin, International, and French studies, who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified a HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for SLE Disease Activity Index 2000 (SLEDAI-2K ≥6). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. Among 1842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1150 ng/mL, and 1.7-fold higher with cumulative HCQ dose per 1000g increase. Blood levels ≥1150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1150 ng/mL). The therapeutic reference range for HCQ blood level monitoring is 750-<1150 ng/ml. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.

We aimed to compare clinical outcomes between patients in the Allegheny Health Network rheumatoid arthritis (RA) care pathway and patients receiving usual care.
The care pathway initiative implements guideline-based best practice alongside multi-disciplinary team-based care. Clinical and insurance claims data were extracted to compare the proportion of patients in clinical disease activity index (CDAI)-based remission and evaluate health care utilization and per member per month (PMPM) costs of care.
The RA care pathway cohort included 817 patients, and the usual care cohort included 3651 patients. The care pathway cohort had a significantly higher proportion of patients achieving remission at 6, 12, and 24 months (33.5% vs 20.3%, hazard ratio 1.53, 95% confidence interval 1.11-2.10, p = 0.008 at 24 months), and on average, 64 days earlier than usual care. This trend was also observed when including low disease activity patients with patients in remission and in a subgroup analysis of newly-diagnosed RA. RA-related PMPM costs were significantly higher in the care pathway group and primarily related to higher baseline CDAI, comorbidities, and biologic/targeted synthetic disease modifying anti-rheumatic drug use and switching.
Patients in our RA care pathway were more likely to achieve remission than usual care. PMPM RA costs were higher compared to usual care. We plan to use a longer follow-up to investigate if improved clinical outcomes result in reduced direct and indirect costs, to study the impact of individual team-based care interventions, and to validate our findings in other populations.

ObjectiveTo investigate the effects of belimumab (BEL) on systemic lupus erythematosus (SLE) mucocutaneous and vasculitis manifestations.MethodsThis post hoc, integrated Belimumab Summary of Lupus Efficacy (Be-SLE) analysis pooled data from five international Phase 3, randomized, placebo (PBO)-controlled BEL trials (BLISS-52 [NCT00424476; conducted in 2007-2009], BLISS-76 [NCT00410384; 2007-2009], BLISS-SC [NCT01484496; 2011-2015], North East Asia [NCT01345253; 2011-2015], EMBRACE [NCT01632241; 2013-2018]). Adults with active SLE and Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 (BLISS-52, BLISS-76) or ≥8 (BLISS-SC, North East Asia, EMBRACE), randomized to BEL (10 mg/kg/month intravenously or 200 mg/week subcutaneously) or PBO, plus standard therapy (ST) were included. Mucocutaneous and vasculitis manifestations (listed below) were measured (baseline and every 4 weeks) for 52 weeks using SELENA-SLEDAI and British Isles Lupus Assessment Group (BILAG).ResultsOf 3086 patients (BEL,
= 1869; PBO,
= 1217), 85% (BEL and PBO) by SELENA-SLEDAI and 58% (BEL) and 62% (PBO) by BILAG (moderate or severe activity) had mucocutaneous manifestations, and <10% had vasculitis at baseline. At Week 52, significantly more BEL-treated than PBO-treated patients demonstrated improvements in SELENA-SLEDAI (59% vs 49%;
< .0001) and BILAG (54% vs 43%;
< .0001) mucocutaneous domains. Significant differences between-treatment favored BEL at Week 52 for resolution of all SELENA-SLEDAI items (vasculitis, rash, alopecia, and mucosal ulcers), and nine of 20 BILAG items (mild maculopapular eruption, localized active discoid lesions, mild alopecia, small mucosal ulceration, malar erythema, subcutaneous nodules, swollen fingers, major cutaneous vasculitis including ulcers, and minor cutaneous vasculitis).ConclusionPatients with SLE treated with BEL plus ST experienced significant improvements in most mucocutaneous and vasculitis manifestations compared with patients receiving PBO plus ST. These data provide additional support for the use of BEL in SLE and show that it is associated with skin improvements.

To investigate the long-term impact of anifrolumab versus placebo on lupus low disease activity state (LLDAS) and definition of remission in systemic lupus erythematosus (DORIS) attainment in patients with systemic lupus erythematosus (SLE).
This post hoc analysis included patients with moderate to severe SLE who were randomly assigned to receive intravenous anifrolumab 300 mg or placebo (once every 4 weeks) in the 52-week, phase 3 TULIP-1/TULIP-2 trials and continued with the same treatment in the 3-year long-term extension. LLDAS/DORIS rates over time were analysed using a stratified Cochran-Mantel-Haenszel approach and logistic regression. Time to first LLDAS/DORIS was estimated using Cox regression. Cumulative time and percentage of time in LLDAS/DORIS were assessed using an analysis of covariance. All P values are nominal.
This analysis included 369 patients (anifrolumab n = 257, placebo n = 112). After 4 years of treatment (at Week 208), 36.9% of anifrolumab-treated patients versus 17.1% of placebo-treated patients were in LLDAS (odds ratio [OR], 2.7; 95% CI, 1.3-5.5; P = .0081); 30.3% versus 18.3% were in DORIS (OR, 1.9; 95% CI, 1.0-3.9; P = .0663). Time to first LLDAS and DORIS favoured anifrolumab versus placebo (LLDAS: hazard ratio, 1.56; 95% CI, 1.18-2.09; P = .0024; DORIS: hazard ratio, 1.50; 95% CI, 1.04-2.22; P = .0373). Cumulative time in LLDAS and DORIS was greater with anifrolumab than that with placebo (P = .0004 and P = .0032, respectively).
LLDAS and DORIS remission, which are associated with favourable outcomes such as reduced damage and mortality in patients with SLE, are attainable and sustainable treatment targets with long-term anifrolumab treatment.

IntroductionT Cell autoantibodies, TIgG and TIgM, as well as the T Cell-bound complement protein fragment C4d (TC4d) are novel diagnostic biomarkers that have demonstrated high specificity and sensitivity for SLE. The present study aims to characterize the clinical performance characteristics of the emergent T Cell biomarkers in a multi-center clinical validation cohort.MethodsA cohort of 400 adult patients enrolled across 3 academic and 2 community-based autoimmune rheumatic centers, comprised of 105 SLE patients, 173 patients with autoimmune rheumatic diseases (ARD), 83 apparently healthy volunteers (AHV) and 39 other (non-autoimmune) disease (OD) controls were tested for TC4d, TIgG, TIgM and an extensive autoantibody profile. Diagnostic specificity was assessed against the ARD, AHV and OD groups, individually. Semi-quantitative flow cytometry analysis included TIgG and TIgM autoantibodies, cell-bound complement activation products (CB-CAPs), TC4d, erythrocyte-bound C4d (EC4d) and B lymphocyte-bound C4d (BC4d). Conventional autoantibodies and soluble complement proteins, C3 and C4, were assessed by ELISA and immunoturbidimetry, respectively.ResultsROC analysis distinguishing ANA-positive (ANA+) SLE (N = 91) from ARD, TIgG, BC4d and TC4d demonstrated AUC values 0.81, 0.80 and 0.79, respectively, outperforming anti-dsDNA (0.72), C3 (0.69), TIgM (0.67), C4 (0.66) and anti-Smith (0.61). A similar ranking of discriminatory power was observed in ROC analysis distinguishing ANA+ SLE vs. OD as well as ANA+ SLE vs. AHV. At 95% diagnostic specificity for SLE vs. AHV, the sensitivity (95% CI) of TC4d, TIgG and TIgM for SLE was 58.1% (48.1 – 67.7%), 31.4% (22.7 – 41.2%) and 29.5% (21.0 – 39.2%), respectively. The T Cell SLE biomarkers uniquely identified 19% (20/105) of SLE patients who were otherwise negative (serologically inactive) for conventional SLE autoantibodies and had normal serum complement levels. Among the serologically inactive SLE subset, the T Cell SLE biomarkers collectively identified 53% of subjects.ConclusionsThe novel SLE biomarkers TC4d, TIgG and TIgM consistently outperform conventional markers across multiple cohorts. Their integration enhances diagnostic sensitivity, especially in SLE-specific autoantibody negative patients with normal complement levels. When coupled with conventional biomarkers, these novel tests may enable earlier and more accurate SLE detection, leading to more timely diagnosis and treatment.

ObjectivesThis study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort.MethodsPatients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions.Results1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC −$C1372; IC −$C2507), remission on-treatment (DC −$C973; IC −$C2604,) LDA-TC (DC −$C1158) and mLLDAS (DC −$C1040). There were no cost differences between remission/LDA states.ConclusionsOur data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.