Faculty Bibliography

Chimeric antigen receptor (CAR) T-cell therapy, long transformative in oncology, is now rapidly emerging as a frontier in autoimmune rheumatic diseases, particularly systemic lupus erythematosus (SLE), driven by accumulating evidence of deep B-cell depletion, immune "resetting," and durable drug-free remission in early studies, yet its translation into rheumatology demands mastery of formidable logistical, regulatory, clinical, and ethical complexities that span institutional readiness, multidisciplinary team formation, stringent regulatory compliance, sophisticated operational workflows, comprehensive patient selection and education, meticulous clinical management of both classical toxicities (CRS, ICANS, ICAHT) and autoimmune-specific reactions such as LICATS, robust financial and resource planning, and long-term follow-up extending 15 years or more; successful implementation requires coordinated expertise among rheumatologists, hematologist-oncologists, cellular therapy units, pharmacists, research coordinators, and ICU-capable teams, all embedded within disciplined communication structures, harmonized SOPs, validated PROs, biorepository governance frameworks, and adherence to national and international cellular therapy standards; in parallel, investigators must anticipate bottlenecks such as apheresis access, manufacturing slot scarcity, competing trial enrollment, fluctuating SLE phenotypes, and heterogeneity-driven signal variability, while sustaining patient engagement over years through education, navigation support, and transparent risk/benefit communication; finally, collaboration with industry partners, clinical trial networks, and patient-advocacy organizations is essential for overcoming operational barriers, securing financial sustainability, and ensuring ethical stewardship, so that CAR T-cell clinical trials in autoimmunity can be executed safely, rigorously, and with maximal therapeutic promise for patients.

BACKGROUND:Individuals with autoimmune diseases (AD) on immunosuppressants often have suboptimal responses to COVID-19 vaccine. We evaluated the efficacy and safety of additional COVID-19 vaccines in those treated with mycophenolate mofetil/mycophenolic acid (MMF/MPA), methotrexate (MTX), and B cell-depleting therapy (BCDT), including the impact of withholding MMF/MPA and MTX. METHODS:In this open-label, multicenter, randomized trial, 22 participants taking MMF/MPA, 26 taking MTX, and 93 treated with BCDT who had suboptimal antibody responses to initial COVID-19 vaccines (2 doses of BNT162b2 or mRNA-1273 or 1 dose of AD26.COV2.S) received an additional homologous vaccine. Participants taking MMF/MPA and MTX were randomized (1:1) to continue or withhold treatment around vaccination. The primary outcome was the change in anti-Wuhan-Hu-1 receptor-binding domain (RBD) concentrations at 4 weeks post-additional vaccination. Secondary outcomes included adverse events, COVID-19 , and AD activity through 48 weeks. RESULTS:Additional vaccination increased anti-RBD concentrations in participants taking MMF/MPA and MTX , irrespective of immunosuppressant withholding. BCDT-treated participants also demonstrated increased anti-RBD concentrations, albeit lower than MMF/MPA- and MTX-treated cohorts. COVID-19 occurred in 33% of participants; infections were predominantly mild and included only three non-fatal hospitalizations. Additional vaccination was well-tolerated, with low frequencies of severe disease flares and adverse events. CONCLUSION/CONCLUSIONS:Additional COVID-19 vaccination is effective and safe in individuals with ADs treated with immunosuppressants, regardless of whether MMF/MPA or MTX is withheld. CLINICALTRIALS/RESULTS:gov (NCT05000216; registered August 6, 2021: https://clinicaltrials.gov/ct2/show/NCT05000216).

OBJECTIVE:This study characterized the impact of voclosporin on kidney histology in patients with lupus nephritis (LN) who had protocolized repeat kidney biopsies in the AURORA clinical trials. METHODS:Patients were randomized to voclosporin or placebo treatment for up to three years; all patients received mycophenolate mofetil and low-dose glucocorticoids. Patients had baseline kidney biopsies within 6 months prior to study start and repeat biopsies after approximately 18 months of study treatment. The revised NIH indices for LN activity (AI) and chronicity (CI) were calculated, in addition to semi-quantitative assessment of vascular and tubular lesions. RESULTS:Sixteen patients in the voclosporin group and 10 patients in the control group had both baseline and repeat kidney biopsies. Patient clinical characteristics were similar at baseline. In the voclosporin group, most (n=13) patients had pure class IV lesions (pure class V, n=1; mixed, n=2). In the control group, three patients had pure class IV (pure class III, n=3; pure class V, n=1; mixed, n=3). Most of the voclosporin-treated patients had no change in CI (n=8) or a change ≤2 (n=6); control-treated patients also had no change in CI (n=3) or a change ≤2 (n=6). No trends in vascular lesions or tubular compartment changes were observed. CONCLUSION/CONCLUSIONS:Outcomes from this small subgroup show exposure to study treatment was not associated with nephrotoxicity based on histopathologic evaluation after 18 months. These data are reassuring and further contribute to the safety profile of voclosporin for the treatment of adults with active LN.

OBJECTIVES/OBJECTIVE:This 1-year long-term extension (LTE) study (NCT04451772) followed the 48-week phase 2 SLEek study (NCT03978520) that evaluated upadacitinib (a Janus kinase inhibitor) alone or combined with elsubrutinib (a Bruton's tyrosine kinase inhibitor) in adults with moderately to severely active systemic lupus erythematosus (SLE). The objective was to evaluate the efficacy and safety of an additional 56 weeks of treatment. METHODS:Patients randomised to upadacitinib 30 mg one time per day (QD) or upadacitinib 30 mg/elsubrutinib 60 mg QD (upadacitinib/elsubrutinib) in the SLEek study continued their assigned treatment during the LTE. Patients originally receiving placebo switched to upadacitinib/elsubrutinib in the LTE. Assessments through week 104 included SLE Responder Index-4 (SRI-4), British Isles Lupus Assessment Group-based Combined Lupus Assessment (BICLA), Lupus Low Disease Activity State (LLDAS), change from baseline in glucocorticoid dose, flare events and adverse events. RESULTS:This LTE analysis included 127 patients. Efficacy responses for the groups receiving upadacitinib, upadacitinib/elsubrutinib and placebo to upadacitinib/elsubrutinib were maintained or increased from weeks 48 to 104 (week 104: SRI-4: 82.1%, 85.4% and 61.3%; BICLA: 69.2%, 78.0% and 54.8%; LLDAS: 60.0%, 78.0% and 34.4%). From weeks 48 through 104, the mean daily glucocorticoid dose was reduced, and the incidence of flares was maintained or further reduced in all treatment groups. Safety profiles were similar to those observed in the primary SLEek study. CONCLUSIONS:In this LTE study, upadacitinib monotherapy and upadacitinib/elsubrutinib combined were well tolerated and continued to demonstrate beneficial effects on SLE disease activity, glucocorticoid dose and flares through 104 weeks.

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.

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.

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.