Faculty Bibliography

BACKGROUND:Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, provided significantly better renal responses than placebo in a phase 2 trial involving patients with lupus nephritis receiving standard therapy. METHODS:In a phase 3, randomized, controlled trial, we assigned adults with biopsy-proven active lupus nephritis in a 1:1 ratio to receive obinutuzumab in one of two dose schedules (1000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 50) or placebo. All patients received standard therapy with mycophenolate mofetil, along with oral prednisone at a target dose of 7.5 mg per day by week 12 and 5 mg per day by week 24. The primary end point was a complete renal response at week 76, defined by a urinary protein-to-creatinine ratio of less than 0.5 (with protein and creatinine both measured in milligrams), an estimated glomerular filtration rate of at least 85% of the baseline value, and no intercurrent event (i.e., rescue therapy, treatment failure, death, or early trial withdrawal). Key secondary end points at week 76 included a complete renal response with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event. RESULTS:A total of 271 patients underwent randomization; 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 2.0 to 24.8; P = 0.02). A complete renal response at week 76 with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 was observed in more patients in the obinutuzumab group than in the placebo group (42.7% vs. 30.9%; adjusted difference, 11.9 percentage points; 95% CI, 0.6 to 23.2; P = 0.04), and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event was more common with obinutuzumab than with placebo (55.5% vs. 41.9%; adjusted difference, 13.7 percentage points; 95% CI, 2.0 to 25.4; P = 0.02). No unexpected safety signals were identified. More serious adverse events, mainly infections and events related to coronavirus disease 2019, occurred with obinutuzumab than with placebo. CONCLUSIONS:Among adults with active lupus nephritis, obinutuzumab plus standard therapy was more efficacious than standard therapy alone in providing a complete renal response. (Funded by F. Hoffmann-La Roche; REGENCY ClinicalTrials.gov number, NCT04221477.).

OBJECTIVE:Traditional initial treatment regimens for lupus nephritis (LN) used oral glucocorticoids (GC) in starting doses up to 1.0 mg/kg/day prednisone equivalent with or without a preceding intravenous methylprednisolone pulse. More recent management guidelines recommend lower starting oral GC doses following intravenous pulse therapy. As there have been no large studies directly comparing patients receiving low versus high initial oral GC doses, this pooled analysis of high-quality randomised controlled trials (RCTs) aims to evaluate differences in efficacy and safety. METHODS:Published data were analysed from RCTs that assessed variable GC doses in the standard of care (SOC) treatment arms. Patients receiving starting prednisone doses up to 0.5 mg/kg/day (low dose) were compared with 1.0 mg/kg/day (high dose). Complete renal response requiring urine protein-creatinine ratio <0.5 mg/mg (CRR 0.5), CRR or partial renal response (PRR), serious adverse events (SAE) and SAE due to infections at 12 months of treatment were compared between groups. RESULTS:417 patients from SOC arms of five studies were exposed to low-dose initial GC after intravenous pulse, while 521 patients from four studies were treated with high-dose oral GC. In patients with low-dose oral GC, 25.2% achieved CRR 0.5 at 12 months compared with 27.2% in high-dose groups, p=0.54. CRR or PRR was attained in 48.7% low-dose vs 43.6% high-dose patients, p=0.14. SAEs and infection SAEs were less common in the low-dose GC group (19.4% vs 31.6%, p<0.001 and 9.8% vs 16.5%, p=0.012, respectively). CONCLUSIONS:Based on pooled RCT data, there was no significant difference in 12-month renal responses between patients receiving low-dose prednisone following intravenous GC compared with those receiving initial high doses. SAEs were less frequent in patients receiving low-dose initial GC. These findings support the use of lower oral GC doses in LN treatment.

OBJECTIVES/OBJECTIVE:Glucagon-like peptide-1 receptor agonists (GLP1-RA) are an emerging class of medications with demonstrated promise in improving cardiometabolic outcomes. Whether these drugs may be useful in mitigating the cardiac risk associated with SLE remains unknown, and a recent case of drug induced lupus secondary to GLP1-RA use calls the safety of GLP1-RAs in SLE patients into question. Accordingly, this retrospective analysis was initiated to evaluate outcomes of GLP1-RAs in SLE. METHODS:All patients in the NYU Lupus Cohort who had used a GLP1-RA were eligible for inclusion. Patient characteristics were assessed at baseline (most recent rheumatology visit prior to starting GLP1-RA), 1-4 months, and 6-10 months after GLP1-RA initiation. RESULTS:Of the 1211 patients in the cohort, only 24 had received a GLP1-RA. Six were excluded due to insufficient documentation regarding duration of medication use. Of the remaining 18 (median age 50), 17 (94%) were female and 9 (50%) were white. There was one mild-to-moderate flare at 6-10 months, but no patients accumulated new SLE criteria during the follow up period. Compared with baseline, median BMI was reduced by 3% at 1-4 months (p= 0.002) and 13% at 6-10 months (p= 0.001). Nine (50%) patients were initially denied insurance coverage for a GLP1-RA. CONCLUSION/CONCLUSIONS:While limited by a small sample size, this descriptive study showed that GLP1-RAs did not trigger flares above expected background rates and were associated with significantly decreased BMI. Future studies exploring the potential benefits of GLP1-RAs in patients with SLE are warranted.

OBJECTIVE:The 48-week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (JAK inhibitor) and elsubrutinib (BTK inhibitor) alone or in combination (ABBV-599) in adults with moderately to severely active systemic lupus erythematosus (SLE). METHODS:Patients were randomized 1:1:1:1:1 to elsubrutinib 60 mg and upadacitinib 30 mg once daily (ABBV-599 high dose), elsubrutinib 60 mg and upadacitinib 15 mg once daily (ABBV-599 low dose), elsubrutinib 60 mg once daily (QD), upadacitinib 30 mg QD, or placebo QD. The primary endpoint was the proportion of patients achieving both Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and glucocorticoid dose ≤10 mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events. RESULTS:The study enrolled 341 patients. The ABBV-599 low dose and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P = 0.028) and ABBV-599 high dose (48.5%; P = 0.081) versus placebo (37.3%). SRI-4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV-599 high dose versus placebo at weeks 24 and 48. Flares were reduced, and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV-599 high dose versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib. CONCLUSION/CONCLUSIONS:Upadacitinib 30 mg alone or in combination with elsubrutinib (ABBV-599 high dose) demonstrated significant improvements in SLE disease activity and reduced flares and were well tolerated through 48 weeks.

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:Given fibromyalgia (FM) frequently co-occurs with autoimmune disease, this study was initiated to objectively evaluate FM in a multiracial/ethnic cohort of patients with systemic lupus erythematosus (SLE). METHODS:Patients with SLE were screened for FM using the 2016 FM classification criteria during an in-person rheumatologist visit. We evaluated hybrid Safety of Estrogens in Lupus National Assessment (SELENA)-SLE Disease Activity Index (SLEDAI) scores, SLE classification criteria, and Systemic Lupus International Collaborating Clinics damage index. We compared patients with and without FM and if differences were present, compared patients with FM with patients with non-FM related chronic pain. RESULTS:316 patients with SLE completed the FM questionnaire. 55 (17.4%) met criteria for FM. The racial composition of patients with FM differed from those without FM (P = 0.023), driven by fewer Asian patients having FM. There was no difference in SLE disease duration, SELENA-SLEDAI score, or active serologies. There was more active arthritis in the FM group (16.4%) versus the non-FM group (1.9%) (P < 0.001). The Widespread Pain Index and Symptom Severity Score did not correlate with degree of SLE activity (r = -0.016; 0.107) among patients with FM or non-FM chronic pain (r = 0.009; -0.024). Regarding criteria, patients with FM had less nephritis and more malar rash. Systemic Lupus International Collaborating Clinics damage index did not differ between groups. CONCLUSION/CONCLUSIONS:Except for arthritis, patients with SLE with FM are not otherwise clinically or serologically distinguishable from those without FM, and Widespread Pain Index and Symptom Severity Score indices do not correlate with SLEDAI. These observations support the importance of further understanding the underlying biology of FM in SLE.

PURPOSE OF REVIEW/OBJECTIVE:We review the latest guidelines and note special considerations for systemic lupus erythematosus (SLE) patients when approaching vaccination against SARS-CoV-2, influenza, pneumococcus, herpes zoster, and potentially respiratory syncytial virus (RSV) vaccine in the future. RECENT FINDINGS/RESULTS:SLE patients have unique infectious risks due to newer treatments and the nature of the disease itself. It is important to balance the benefit of additional protective immunity from updated vaccines against the possible risk of disease activity exacerbations. SUMMARY/CONCLUSIONS:It is important to continuously evaluate the safety and immunogenicity of updated vaccines specifically for SLE patients. Additionally, the newly approved RSV vaccine should be considered for this population to reduce severe respiratory illness.

BACKGROUND:Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. METHODS:This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. FINDINGS/RESULTS:Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). INTERPRETATIONS/CONCLUSIONS:Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. FUNDING/BACKGROUND:The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

OBJECTIVE:AURORA 2 evaluated the long-term safety, tolerability, and efficacy of voclosporin compared to placebo in patients with lupus nephritis (LN) receiving an additional two years of treatment following completion of the one-year AURORA 1 study. METHODS:Enrolled patients continued their double-blinded treatment of voclosporin or placebo randomly assigned in AURORA 1, in combination with mycophenolate mofetil and low-dose glucocorticoids. The primary objective was safety assessed with adverse events (AEs), biochemical and hematological assessments. Efficacy was measured by renal response. RESULTS:(95% CI -8.4, -2.3) in the control group. Improved proteinuria persisted across three years of treatment leading to more frequent complete renal responses in voclosporin-treated patients (50.9% vs 39.0%; odds ratio 1.74; 95% CI 1.00, 3.03). CONCLUSION/CONCLUSIONS:Data demonstrate the safety and efficacy of long-term voclosporin treatment over 3 years of follow-up in patients with LN.

OBJECTIVE:immunofluorescence test (CLIFT). To address the clinical impact of measuring these antibodies by two different assays, this study leveraged a well-phenotyped multiethnic/racial cohort. METHODS:All patients fulfilled the classification criteria for SLE by at least one of the validated schemes: American College of Rheumatology, Systemic Lupus Erythematosus International Collaborating Clinics and/or American College of Rheumatology/European League Against Rheumatism classification criteria. Patients with one or more simultaneously paired anti-dsDNA by multiplex EIA and CLIFT were identified. Analysis of concordance or discordance, titre comparability of assays and association with hybrid SLE Disease Activity Index score, prevalence of lupus nephritis (LN), ability to predict a flare and classification criteria was performed. RESULTS:207 patients were simultaneously tested by EIA and CLIFT at least once for anti-dsDNA, generating 586 paired results. 377 pairs were concordant and 209 were discordant. 41 of 207 patients always had discordant paired results and 39 patients always had results with titre discordance. In 100 patients with LN, 60 were positive by EIA and 72 by CLIFT. Sensitivities and specificities for patients with LN versus patients without LN were EIA 60% and 47%, and CLIFT 72% and 37%, respectively. 42 patients had flare assessment within 90 days of their paired result. Six of seven patients with mild flares and all four patients with severe flares had concordant positive results. CONCLUSION:Our data demonstrate that discordance of positivity between both assays for anti-dsDNA is relatively common, occurring in a fifth of patients overall and a third of visits. EIA positivity is associated with LN less often than CLIFT positivity. With the significant discordance of results between anti-dsDNA assays, obtaining both CLIFT and EIA assays may be beneficial for classification and routine monitoring of SLE.