Faculty Bibliography

Glucocorticoids (GCs) have revolutionized the management of SLE, providing patients with rapid symptomatic relief and preventing flares when maintained at low dosages. However, there are increasing concerns over GC-associated adverse effects (AEs) and organ damage, which decrease patients' quality of life (QOL) and increase healthcare costs. This highlights the need to balance effective GC use and minimize toxicity in patients with SLE. Herein, we provide an overview of the theoretical considerations and clinical evidence, in addition to the variations and similarities across nine national and eight international recommendations regarding the use of GCs across SLE manifestations and how these compare with real-world usage. In line with this, we propose possible actions toward the goal of GC Stewardship to improve the QOL for patients with lupus while managing the disease burden.

OBJECTIVE/UNASSIGNED:Leveraging the Manhattan Lupus Surveillance Program (MLSP), a population-based registry of cases of systemic lupus erythematosus (SLE) and related diseases, we investigated the proportion of SLE with concomitant rheumatic diseases, including Sjögren's disease (SjD), antiphospholipid syndrome (APLS), and fibromyalgia (FM), as well as the prevalence of autoantibodies in SLE by sex and race/ethnicity. METHODS/UNASSIGNED:Prevalent SLE cases fulfilled one of three sets of classification criteria. Additional rheumatic diseases were defined using modified criteria based on data available in the MLSP: SjD (anti-SSA/Ro positive and evidence of keratoconjunctivitis sicca and/or xerostomia), APLS (antiphospholipid antibody positive and evidence of a blood clot), and FM (diagnosis in the chart). RESULTS/UNASSIGNED:1,342 patients fulfilled SLE classification criteria. Of these, SjD was identified in 147 (11.0%, 95% CI 9.2-12.7%) patients with women and non-Latino Asian patients being the most highly represented. APLS was diagnosed in 119 (8.9%, 95% CI 7.3-10.5%) patients with the highest frequency in Latino patients. FM was present in 120 (8.9%, 95% CI 7.3-10.5) patients with non-Latino White and Latino patients having the highest frequency. Anti-dsDNA antibodies were most prevalent in non-Latino Asian, Black, and Latino patients while anti-Sm antibodies showed the highest proportion in non-Latino Black and Asian patients. Anti-SSA/Ro and anti-SSB/La antibodies were most prevalent in non-Latino Asian patients and least prevalent in non-Latino White patients. Men were more likely to be anti-Sm positive. CONCLUSION/UNASSIGNED:Data from the MLSP revealed differences among patients classified as SLE in the prevalence of concomitant rheumatic diseases and autoantibody profiles by sex and race/ethnicity underscoring comorbidities associated with SLE.

OBJECTIVES/OBJECTIVE:To assess the associations of severe non-adherence to HCQ, objectively assessed by HCQ serum levels, and risks of SLE flares, damage, and mortality over 5 years of follow-up. METHODS:The SLICC Inception Cohort is an international multicenter initiative (33 centers; 11 countries). Serum of patients prescribed HCQ for at least 3 months at enrollment were analyzed. Severe non-adherence was defined by a serum HCQ level <106 ng/ml or <53 ng/ml, for HCQ doses of 400 or 200 mg/d, respectively. Associations with the risk of a flare (defined as a SLEDAI-2K increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/ACR Damage Index (SDI) increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS:Of 1849 cohort subjects, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/ml (244-566); 48 patients (7.3%) had severe HCQ non-adherence. No covariates were clearly associated with severe non-adherence, which was however independently associated with both flare (OR 3.38; 95% CI 1.80-6.42) and an increase in the SDI within each of the first 3 years (HR 1.92 at 3 years; 95% CI 1.05-3.50). Eleven patients died within 5 years, including 3 with severe non-adherence (crude HR 5.41; 95% CI 1.43-20.39). CONCLUSION/CONCLUSIONS:Severe non-adherence was independently associated with the risks of an SLE flare in the following year, early damage, and 5-year mortality.

OBJECTIVE:To estimate direct and indirect costs associated with neuropsychiatric (NP) events in the Systemic Lupus International Collaborating Clinics inception cohort. METHODS:NP events were documented annually using American College of Rheumatology definitions for NP events and attributed to systemic lupus erythematosus (SLE) or non-SLE causes. Patients were stratified into 1 of 3 NP states (no, resolved, or new/ongoing NP event). Change in NP status was characterized by interstate transition rates using multistate modeling. Annual direct costs and indirect costs were based on health care use and impaired productivity over the preceding year. Annual costs associated with NP states and NP events were calculated by averaging all observations in each state and adjusted through random-effects regressions. Five- and 10-year costs for NP states were predicted by multiplying adjusted annual costs per state by expected state duration, forecasted using multistate modeling. RESULTS:A total of 1,697 patients (49% White race/ethnicity) were followed for a mean of 9.6 years. NP events (n = 1,971) occurred in 956 patients, 32% attributed to SLE. For SLE and non-SLE NP events, predicted annual, 5-, and 10-year direct costs and indirect costs were higher in new/ongoing versus no events. Direct costs were 1.5-fold higher and indirect costs 1.3-fold higher in new/ongoing versus no events. Indirect costs exceeded direct costs 3.0 to 5.2 fold. Among frequent SLE NP events, new/ongoing seizure disorder and cerebrovascular disease accounted for the largest increases in annual direct costs. For non-SLE NP events, new/ongoing polyneuropathy accounted for the largest increase in annual direct costs, and new/ongoing headache and mood disorder for the largest increases in indirect costs. CONCLUSION/CONCLUSIONS:Patients with new/ongoing SLE or non-SLE NP events incurred higher direct and indirect costs.

OBJECTIVE:Epidemiologic data for mixed connective tissue disease (MCTD) are limited. Leveraging data from the Manhattan Lupus Surveillance Program (MLSP), a racially/ethnically diverse population-based registry of cases with SLE and related diseases including MCTD, we provide estimates of the prevalence and incidence of MCTD. METHODS:MLSP cases were identified from rheumatologists, hospitals, and population databases using a variety of ICD-9 codes. MCTD was defined as one of the following: 1) fulfillment of our modified Alarcon-Segovia and Kahn criteria which required a positive RNP antibody and the presence of synovitis, myositis, and Raynaud's phenomenon, 2) a diagnosis of MCTD and no other diagnosis of another connective tissue disease (CTD), and 3) a diagnosis of MCTD regardless of another CTD diagnosis. RESULTS:Overall, 258 (7.7%) of cases met a definition of MCTD. Using our modified Alarcon-Segovia and Kahn criteria for MCTD, the age-adjusted prevalence was 1.28 (95%CI 0.72-2.09) per 100 000. Using our definition of a diagnosis of MCTD and no other diagnosis of another CTD yielded an age-adjusted prevalence and incidence of MCTD of 2.98 (95%CI 2.10-4.11) per 100 000 and 0.39 (95%CI 0.22-0.64) per 100 000, respectively. The age-adjusted prevalence and incidence were highest using a diagnosis of MCTD regardless of other CTD diagnoses and were 16.22 (95%CI 14.00-18.43) per 100 000 and 1.90 (95%CI 1.49-2.39) per 100 000 respectively. CONCLUSIONS:The MLSP provided estimates for prevalence and incidence of MCTD in a diverse population. The variation in estimates using different case definitions is reflective of the challenge of defining MCTD in epidemiologic studies.

OBJECTIVES/OBJECTIVE:This integrated analysis evaluates the efficacy and safety of voclosporin, a novel calcineurin inhibitor, at 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and oral glucocorticoids in lupus nephritis (LN) using pooled data from two large phase 2 and phase 3 clinical trials. The purpose was to expand the pool of patients for safety analyses and to increase power for efficacy analyses in patient subpopulations. METHODS:AURA-LV (phase 2) and AURORA 1 (phase 3) were randomized, placebo-controlled, double-blind trials with similar designs and endpoints comparing voclosporin to control in combination with MMF and oral glucocorticoids for the treatment of LN. The primary efficacy outcome of the integrated analysis was complete renal response (CRR) at approximately 1 year (Week 48 data from AURA-LV and Week 52 from AURORA 1). Safety was assessed throughout the trials. RESULTS:Overall, 534 patients (voclosporin 268, control 266) were included in the integrated analysis. Significantly more patients achieved a CRR at 1 year in the voclosporin than control group (43.7% vs. 23.3%, OR 2.76; 95% CI 1.88, 4.05 p<0.0001). The incidence of adverse events (AEs) was similar; 91.4% voclosporin and 87.2% control. Most AEs were mild to moderate in severity; the most commonly reported AEs were classified as infections and infestations (62.2% voclosporin, 54.9% control) and gastrointestinal disorders (45.3% voclosporin, 35.3% placebo). No new or unexpected safety signals were detected. CONCLUSIONS:This integrated analysis demonstrates the efficacy and safety of voclosporin in the treatment of LN across the diverse racial and ethnic groups studied. This article is protected by copyright. All rights reserved.

OBJECTIVES/OBJECTIVE:A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes. METHODS:Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset. RESULTS:Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2. CONCLUSION/CONCLUSIONS:Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.

OBJECTIVE:Using the Manhattan Lupus Surveillance Program (MLSP), a multi-racial/ethnic population-based registry, we compared three commonly used classification criteria for Systemic Lupus Erythematosus (SLE) to identify unique cases and determine the incidence and prevalence of SLE using the EULAR/ACR criteria. METHODS:SLE cases were defined as fulfilling 1997 ACR, SLICC, or EULAR/ACR classification criteria. We quantified the number of cases uniquely associated with each and the number fulfilling all three. Prevalence and incidence using the EULAR/ACR classification criteria and associated 95% confidence intervals (CI) were calculated. RESULTS:1,497 cases fulfilled at least one of the three classification criteria, with 1,008 (67.3%) meeting all three classifications, 138 (9.2%) fulfilling only SLICC criteria, 35 (2.3%) fulfilling only ACR criteria and 34 (2.3%) uniquely fulfilling EULAR/ACR criteria. Patients solely satisfying EULAR/ACR criteria had fewer than four manifestations. The majority classified only by the ACR criteria did not meet any of the defined immunologic criteria. Patients fulfilling only SLICC criteria did so based on the presence of features unique to this system. Using the EULAR/ACR classification criteria, age-adjusted overall prevalence and incidence rates of SLE in Manhattan were 59.6 (95%CI:55.9-63.4) and 4.9 (95%CI 4.3-5.5) per 100,000 population, with age-adjusted prevalence and incidence rates highest among non-Hispanic Black females. CONCLUSION/CONCLUSIONS:Applying the three commonly used classification criteria to a population-based registry identified patients with SLE fulfilling only one validated definition. The most recently developed EULAR/ACR classification criteria revealed similar prevalence and incidence estimates to those previously established for the ACR and SLICC classification schemes.

Background/Purpose: Musculoskeletal (MSK) symptoms are common in SLE, often associate with debilitating pain requiring immunosuppressive treatment. JBT-101 is a non-psychotropic, non-immunosuppressive, cannabinoid receptor 2 agonist that stimulates resolution of inflammation by increased production of specialized pro-resolving mediators and decreased production of inflammatory molecules. Our goal was to test efficacy and safety of JBT-101 for treatment of inflammatory MSK disease in SLE.
Method(s): Adults (18-70 years) meeting SLE ACR criteria with active MSK symptoms (SLEDAI arthritis or BILAG 2004 mild/moderate arthritis), on stable SLE medications and prednisone <=10 mg daily, with average maximum daily pain scores >= 4 on a 10-point numerical rating scale (NRS), were randomized to 12 weeks treatment with placebo (PBO), or 10mg (low), 20mg (med), or 40mg (high) daily of JBT-101. NRS scores were reported daily. Disease activity was assessed at Days 1, 29, 57, 84 and 113; these analyses are pending. The primary endpoint, improvement in NRS score from Days 1 to 84, was analyzed with a mixed effects regression model, that included the screening 7 day average pain NRS and Fibromyalgia Symptom Scale (FSS) scores as covariates to estimate longitudinal trends in NRS and change over time for each treatment group. NRS data up to last day of study treatment were included except days when narcotic analgesics were taken. A secondary endpoint, pain category, was defined using the average 7 day NRS prior to study visits: <= 1 no pain, (>1-<=3) mild, (>3-<=7) moderate, >7 severe.
Result(s): The 101 randomized and treated subjects (Table 1) had a mean screening 7 day average pain NRS=6.6 and mean FSS score of 15.7. FSS scores >=13 are consistent with a fibromyalgia diagnosis; 71.3% had FSS scores >=13. The covariateadjusted estimated change in NRS from Days 1 to 84 was not significantly different between groups:-0.3 PBO,-0.9 low,-1.5 med,-1.2 high (p=.419) (Fig 1). Pairwise-comparisons of active arms versus PBO were not significant (all p >.3, Bonferroni corrected). Among 84 subjects with NRS data at the end of the treatment period at Day 85, pain improved by at least 1 pain category from baseline for 3 (14%) PBO, 10 (45%) low dose, 8 (38%) med dose, and 9 (47%) high dose subjects (p=0.083 overall, Cochran-Mantel-Haenszel C2; p=0.012 pooled active vs PBO, Pearson's C2.). No grade 4 or 5 adverse events (AEs) were observed (Table 2). 75 subjects experienced at least 1 grade 2 or 3 AE: 20 (80%) PBO, 19 (79%) low, 21 (78%) mod, 15 (60%) high. 5 subjects experienced treatment-related AEs resulting in study drug discontinuation: 1 (4%) med, 4 (16%) high, all were Grade 2. 6 subjects experienced serious AEs: 2 (8%) PBO, 3 (11%) med, 1 (4%) high; all unrelated to study drug. 2 subjects in each active arm experienced severe disease flares (excluding MSK domain), compared to 3 in PBO.
Conclusion(s): JBT-101 was safe and well-tolerated. While the pre-specified mixed effects model did not identify significant differences between changes in NRS pain scores in active arms vs. PBO, the frequency of pain category improvement at Day 84 was notably higher in the active arms vs PBO. Further analyses, including those of SLEDAI, BILAG and PGA, may identify patients most likely to respond to JBT-101. NCT03093402