BACKGROUND:Toll-like receptors (TLR) 7 and 8 (TLR7/8) are activators of innate and adaptive immunity contributing to lupus pathogenesis. In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose-finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active systemic lupus erythematosus (SLE). METHODS:Participants were eligible if they were aged 18-75 years with moderate-to-severe SLE, with or without cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication before the screening period. Participants were recruited from 132 centres in 22 countries. In Part 1, participants were randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily. Following the enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks. Random allocation was stratified by region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score. The primary objective was to evaluate the dose-response relationship of enpatoran, using British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on multiple comparison procedure-modelling analysis. Study visits were scheduled from week 0 to week 24, followed by a 2-week safety follow-up period for participants who chose not to enter the long-term extension. From weeks 2 to 12, glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated. Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, vital signs, and routine chemistry and haematology) were assessed at all study visits. The trial was registered at ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing. FINDINGS:Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran). One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for the efficacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years (IQR 33-51). At week 24, the study did not meet its primary objective of identifying a statistically significant dose-response relationship for enpatoran in BICLA response rate (p=0·14). BICLA response rates at week 24 were higher with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1-4·0], 50 mg: 36 [49%] of 74; OR 1·5 [95% CI 0·8-2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9-2·8]) versus placebo (37 [39%] of 94). The most common treatment-emergent adverse event was diarrhoea, in four (6%) of 71, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and seven (7%) of 95 participants in the placebo group. Serious adverse events were reported in one (1%) of 71, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran and placebo, respectively. INTERPRETATION:In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates versus placebo; however, the primary objective of a statistically significant dose-dependent effect on disease activity based on BICLA response was not met. Enpatoran was well tolerated across all dose groups. FUNDING:Merck Healthcare (Darmstadt, Germany).

BACKGROUND:Toll-like receptor (TLR)7 and TLR8 are nucleic-acid sensors involved in lupus pathogenesis. We aimed to investigate the efficacy and safety of enpatoran, an oral small-molecule TLR7/8 inhibitor, in participants with active skin manifestations of cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). METHODS:WILLOW is a phase 2, randomised, double-blind, placebo-controlled, basket, dose-finding study conducted across 132 centres in 22 countries, enrolling patients into two cohorts (A and B) with different eligibility criteria. In Cohort A of the trial, we enrolled participants aged 18-75 years who had CLE only or SLE with mild or no extra-mucocutaneous disease activity (British Isles Lupus Assessment Group [BILAG]-2004 scores 1B, C, or D), and a Cutaneous Lupus Disease Area and Severity Index-activity (CLASI-A) score of 8 or higher. Participants were randomised (1:1:1:1) to receive placebo or enpatoran at a dose of 25 mg, 50 mg, or 100 mg twice per day for 24 weeks, in combination with standard of care. The primary objective was to evaluate the dose-response relationship of enpatoran in reducing disease activity, based on the percentage change from baseline in CLASI-A total score at week 16, analysed with a multiple comparison procedure-modelling approach. Efficacy analyses were done in the full analysis set of all randomly allocated participants. Safety was assessed in all patients who received at least one dose of study treatment. There was no involvement of people with lived experience of CLE or SLE in study design. This trial is registered with ClinicalTrials.gov (NCT05162586; completed); results from Cohort B will be reported separately. FINDINGS:Between May 4, 2022, and Feb 6, 2024, 463 patients were screened for eligibility across cohorts A and B; 102 participants were randomly assigned within Cohort A and received treatment (safety population). Two participants (n=1 each from the enpatoran 25 mg and 50 mg groups) were randomly allocated to Cohort A but were subsequently found to have had BILAG scores ≥1A and 2B at screening and were therefore deemed ineligible and excluded; thus 100 participants were analysed for efficacy (placebo group n=26; enpatoran 25 mg group n=23; enpatoran 50 mg group n=25; enpatoran 100 mg group n=26). Participants in the full analysis set had a median age of 47 years (IQR 36-55); 77 (77%) were female, 23 (23%) were male, and 48 (48%) were White. At week 16, enpatoran had a significant, dose-dependent effect on CLASI-A score, with adjusted mean changes from baseline of -64 percentage points (95% CI -70 to -58) in the enpatoran 25 mg group, -68 percentage points (-75 to -61) in the enpatoran 50 mg group, and -72 percentage points (-80 to -64) in the enpatoran 100 mg group, versus -44 percentage points (-55 to -33) in the placebo group (p=0·0002 for dose-response relationship). The most common treatment-emergent adverse event was upper respiratory tract infection, which occurred in two (8%) of 24 patients in the enpatoran 25 mg group, four (15%) of 26 in the enpatoran 50 mg group, five (19%) of 26 in the enpatoran 100 mg group, and two (8%) of 26 in the placebo group. Overall, one (4%) participant in the placebo group, one (4%) in the enpatoran 100 mg group, and two (8%) in the enpatoran 25 mg group had serious adverse events; none were reported with enpatoran 50 mg. INTERPRETATION:Enpatoran showed a significant and dose-dependent effect on disease activity in participants with active cutaneous manifestations of CLE or SLE, and was well tolerated. FUNDING:Merck Healthcare KGaA, Darmstadt, Germany.

O010 / #827 Topic:AS07 - Cutaneous Lupus Late-Breaking Abstract ABSTRACT CONCURRENT SESSION 01: FINDINGS FROM LUPUS CLINICAL TRIALS 22-05-2025 1:40 PM - 2:40 PM No treatment is approved for cutaneous lupus erythematosus (CLE), which may occur in the presence or absence of systemic lupus erythematosus (SLE). Enpatoran is an oral small molecule toll-like receptor 7/8 inhibitor, with potential to modulate processes central to CLE and SLE pathophysiology. WILLOW (NCT05162586) is a Phase II randomized double-blind placebo-controlled dose-finding parallel adaptive study in adults with SLE or CLE receiving standard of care to evaluate the efficacy and safety of enpatoran. WILLOW Cohort A enrolled patients with CLE or SLE who had active lupus rash. Patients with Cutaneous Lupus Disease Area and Severity Index-Activity (CLASI-A) score ≥ 8 CLE were enrolled; they had CLE only, or SLE with mild or no extramucocutaneous disease activity [British Isles Lupus Assessment Group 2004 < 1B, C, D]). Patients were randomized 1:1:1:1 to 1 of 3 doses of enpatoran or placebo for 24 weeks, with an additional 2-week safety follow-up for patients not choosing to enter the long-term extension. The primary objective was to evaluate the dose-response relationship of enpatoran in reducing disease activity, based on change from baseline in CLASI-A score at Week 16. Secondary endpoints included change from baseline in Physician’s Global Assessment at Weeks 16 and 24, clinically meaningful corticosteroid (CS) reduction, and occurrence of Cutaneous Lupus Activity-Investigator Global Assessment 0 or 1 at Week 16 and Week 24. Exploratory endpoints included CLASI-A improvement ≥ 50%/70% (CLASI-50/70). Treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of special interest and laboratory parameters were collected from Day 1 to the end of safety follow-up. 102 patients were randomized, and 100 patients were included for efficacy evaluation (placebo n = 26; enpatoran low dose n = 23; mid dose n = 25; high dose n = 26). 77.0% of patients were female, and 58.0% had CLE only. At baseline, 59.0% of patients were receiving systemic CS, 38.0% immunosuppressants and 76.0% antimalarials; 71% had moderate-to-severe disease (CLASI-A ≥ 10). The primary outcome was achieved. At Week 16, a significant dose response for enpatoran in reducing CLASI-A from baseline was detected (p = 0.0002) (Table 1). Table 1 Dose-response relationship of enpatoran in reducing disease activity based on change from baseline in CLASI-A score at Week 16 (FAS; N = 100) Furthermore, up to 91.3% of patients receiving enpatoran achieved CLASI-50, and up to 60.9% achieved CLASI-70 at Week 16, compared with 38.5% and 11.5% of patients, respectively, receiving placebo. Enpatoran was well tolerated across all study doses. High-dose enpatoran was associated with a higher rate of TEAEs (Table 2) than lower doses or placebo; the most frequently reported TEAEs were infections and infestations. Table 2 Treatment-emergent adverse events (SAS; N = 102) Enpatoran demonstrated a significant dose response in change from baseline in CLASI-A compared with placebo at Week 16 in patients with CLE or SLE and was well tolerated.Acknowledgments:The authors wish to thank Dominika Weinelt for their support with the study conduct and analysis. Medical writing support was provided by Nicole Jones on behalf of Amica Scientific, Macclesfield, UK, and sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany.

Background: Palmoplantar pustular psoriasis (PPPP) is characterized by sterile pustules on the palms and soles. Comorbidities include inflammatory arthritis, thyroid dysfunction, and metabolic syndrome, though psychiatric burden is poorly characterized.1 Intrinsic hand dermatitides (IHD) are a group of common, multifactorial conditions causing skin barrier dysfunction of the hands. Associated conditions include elevated BMI, cardiovascular disease, and psychiatric disorders.2,3 Although PPPP and IHD share clinical features, their comorbidities are primarily discussed separately in the literature without direct comparison.1,4 Methods We performed a retrospective analysis to evaluate the prevalence of metabolic and psychiatric conditions among patients with PPPP or IHD (confirmed by review of physician note) seen at MHealth Fairview between 1/1/2010-12/31/2019. Comorbidity data was collected using ICD-10 codes. Significance was calculated using logistic regression.

Background Lupus erythematosus (LE) is an autoimmune condition that is associated with significant detriments to quality of life and daily functioning. TikTok, a popular social networking platform for sharing short videos, provides a unique opportunity to understand experiences with LE within a nonclinical sample, a population that is understudied in LE research. This is the first qualitative study that explores LE experiences using the TikTok platform. Objective This study aims to evaluate the disease-related experiences of TikTok users with LE using qualitative and content analysis. Methods TikTok videos were included if the hashtags included #lupus, were downloadable, were in English, and involved the personal experience of an individual with LE. A codebook was developed using a standardized inductive approach of iterative coding until saturation was reached. NVivo (Lumivero), a qualitative analysis software platform, was used to code videos and perform content analysis. Inductive thematic analysis was used to derive themes from the data. Results A total of 153 TikTok videos met the inclusion criteria. The most common codes were experiences with symptoms (106/153, 69.3%), mucocutaneous symptoms (61/153, 39.9%), and experiences with treatment (59/153, 38.6%). Experiences with symptoms and mucocutaneous symptoms had the greatest cumulative views (25,381,074 and 14,879,109 views, respectively). Five thematic conclusions were derived from the data: (1) mucocutaneous symptoms had profound effects on the mental health and body image of TikTok users with LE; (2) TikTok users’ negative experiences with health care workers were often derived from diagnostic delays and perceptions of “medical gaslighting”; (3) TikTok users tended to portray pharmacologic and nonpharmacologic interventions, such as diet and naturopathic remedies, positively, whereas pharmacologic treatments were portrayed negatively or referred to as “chemotherapy”; (4) LE symptoms, particularly musculoskeletal symptoms and fatigue, interfered with users’ daily functioning; and (5) although TikTok users frequently had strong support systems, feelings of isolation were often attributed to battling an “invisible illness.” Conclusions This study demonstrates that social media can provide important, clinically relevant information for health practitioners caring for patients with chronic conditions such as LE. As mucocutaneous symptoms were the predominant drivers of distress in our sample, the treatment of hair loss and rash is vital in this population. However, pharmacologic therapies were often depicted negatively, reinforcing the significance of discussions on the safety and effectiveness of these treatments. In addition, while TikTok users demonstrated robust support systems, feelings of having an “invisible illness” and “medical gaslighting” dominated negative interactions with others. This underscores the importance of providing validation in clinical interactions.

Adult patients with dermatomyositis from an academic tertiary referral centre experienced a range in durations of diagnostic delay, which were dependent on social, disease and diagnostic factors. About one-quarter of patients experienced a diagnostic delay >= 12 months, with a median of 3.5 months. Symptoms at initial presentation, zip code, skin biopsy results and treatment with systemic corticosteroids were associated with diagnostic delay duration.

Background: Dermatomyositis necessitates prompt diagnosis due to associated morbidity, mortality, and risk of underlying malignancy. However, patients with dermatomyositis often experience diagnostic delays (DDs) due to diverse clinical manifestations and nonspecific laboratory and imaging findings. We aim to characterize DDs in dermatomyositis and determine how DDs are affected by social and disease factors.

What is known about this subject in regard to women and their families? The impact of pemphigus on both female and male fertility is unknown. What is new from this article as messages for women and their families? Infertility rates in patients with pemphigus do not appear increased relative to age- and sex- matched controls in the general dermatology population, even when considering patients with a diagnosis associated with infertility. Introduction The impact of pemphigus on male and female infertility is unknown. Infertility affects up to 15% of couples and counseling patients on impact on fertility when given a new medical diagnosis is an important part of medical care.1 In women, the diagnosis of pemphigus tends to occur at a time when fertility is rapidly declining, making this information even more important. One prior case series described 9 patients with pemphigus vulgaris, 8 of whom were unable to become pregnant.2 Our goal was to further determine rates of infertility in patients with pemphigus. Materials and methods A retrospective chart review was performed for patients of reproductive age (ages 15–49) with a diagnosis of pemphigus vulgaris or foliaceus, as confirmed by laboratory testing or clinician assessment, at the University of Minnesota MHealth Dermatology Clinic from 2005 to 2019. Each chart was assessed for diagnosis or mention of infertility via chart review and included review of obstetric/gynecology, primary care, and endocrinology notes as well as utilization of the keyword search function for "infertility." Mutually exclusive groups were defined as "definite infertility" (DI; meeting criteria as per obstetrician/ynecologist clinician assessment and/or formal infertility definition), "reproductive issues" (RI; infertility or recurrent pregnancy loss discussed in any clinician notes, though the diagnosis was not confirmed by clinician and/or infertility definition), and having a "diagnosis associated with infertility" (DAI) as is listed in Table 1. We assessed all the above groups so as not to miss an association with pemphigus and infertility. Patients with pemphigus were compared to age- and sex- matched control patients who had been evaluated in our general dermatology clinic without a diagnosis of pemphigus. We then compared controls to those with DI as well as to those with those RI and DAI using Fisher's exact tests. Measures assessed included demographics, rates of infertility, and for patients who met criteria for infertility, the severity of their pemphigus, associated comorbidities, and medications taken. Table 1 - Demographic characteristics of pemphigus versus control patients Control (%) Pemphigus (%) No. (%) 46 (50.0) 46 (50.0) Mean age (SD) 48.5 (9.0) 47.5 (8.8) Sex Female 31 (67.4) 32 (69.6) Male 14 (30.4) 14 (30.4) Other (F at Birth) 1 (2.2) 0 (0.0) Chemotherapya (throughout the lifespan) 4 (8.7) 5 (10.9) Cyclophosphamide 1 (2.2) 0 (0.0) Diabetes 5 (10.9) 4 (8.7) Infertility No infertility 42 (91.3) 34 (73.9) Definite infertilityb 2 (4.3) 3 (6.5) Reproductive issuesc 2 (4.3) 3 (6.5) Disease associated with infertilityd 0 (0.0) 6 (13.0) aChemotherapy associated with infertility searched and/or extracted from notes (not including cyclophosphamide) were ifosfamide, chlorambucil, cisplatin, procarbazine, busulfan, methotrexate, trastuzumab, doxorubicin, paclitaxel, pembrolizumab, ipilimumab, systemic 5-fluorouracil.bMeeting criteria as per obstetrician/gynecologist clinician assessment and/or formal infertility definition.cInfertility or recurrent pregnancy loss discussed in any clinician notes, though the diagnosis was not confirmed by obstetrician/gynecologist clinician and/or meeting criteria of formal infertility definition.dObstetric, gynecologic, and endocrine conditions associated with infertility which were extracted from notes included polycystic ovarian syndrome, endometriosis, uterine polyps/fibroids, pelvic inflammatory disease, recurrent bacterial vaginosis, abnormal uterine bleeding, ovarian torsion, mumps, and undescended testes. Results Of 46 patients of reproductive age with pemphigus, 3 (6.5%) had DI, 3 (6.5%) had RI, and 6 (13.0%) had DAI (Table 1). Two patients with either RI or a DAI had vaginal involvement of their pemphigus; no patients with DI had genitourinary involvement (Table 2). Demographic information collected for pemphigus patients with and without fertility were similar. Compared to patients with pemphigus and no fertility issues, patients with DI and RI did not have more severe disease as assessed by rates of hospitalizations and desmoglein titers. Rates of rituximab usage were similar. No patients with pemphigus had received cyclophosphamide. Compared to controls, there was no statistically significant difference in rates of infertility in patients with DI (P = 1.0; 4.3% controls vs 6.5% pemphigus), in patients with DI and RI (P = .739; 8.7% vs 13.0%), or in patients with DI, RI, and DAI (P = .052; 8.7% vs 26.1%). Table 2 - Demographic characteristics of pemphigus patients with and without infertility Overall No infertility Infertility (DI + RI + DAI) No. (%) 46 (100.0) 34 (73.9) 12 (26.1) Mean age (SD) 47.5 (8.76) 48.9 (8.0) 43.6 (10.0) Mean age in years at pemphigus diagnosis (SD) 39.6 (10.53) 41.2 (10.4) 35.5 (10.3) Sex Female 32 (69.6) 20 (58.8) 12 (100.0) Male 14 (30.4) 14 (41.2) 0 (0.0) Race African 3 (8.6) 1 (4.3) 2 (16.7) African American 2 (5.7) 1 (4.3) 1 (8.3) Asian 4 (11.4) 3 (13.0) 1 (8.3) Chose not to answer 1 (2.9) 0 (0.0) 1 (8.3) Native Hawaiian/Pacific Islander 1 (2.9) 1 (4.3) 0 (0.0) White 24 (68.6) 17 (73.9) 7 (58.3) Missing 11 11 0 Ethnicity American 26 (61.9) 18 (58.1) 8 (72.7) American (Ashkenazi Jewish) 1 (2.4) 1 (3.2) 0 (0.0) Caucasian 4 (9.5) 4 (12.9) 0 (0.0) Hispanic/Latino 2 (4.8) 2 (6.5) 0 (0.0) Indian 1 (2.4) 1 (3.2) 0 (0.0) Latino 1 (2.4) 1 (3.2) 0 (0.0) Native Hawaiian/Pacific Islander 1 (2.4) 1 (3.2) 0 (0.0) Not Hispanic or Latino 2 (4.8) 1 (3.2) 1 (9.1) Pakistani 1 (2.4) 1 (3.2) 0 (0.0) Somali 3 (7.1) 1 (3.2) 2 (18.2) Missing 4 3 1 Pemphigus hospitalization 6 (13.0) 4 (11.8) 2 (16.7) Pemphigus primary sites Mucous membranes only 6 (13.0) 4 (11.8) 2 (16.7) Skin only 11 (23.9) 8 (23.5) 3 (25.0) Skin + mucous membranes 29 (63.0) 22 (64.7) 7 (58.3) Diabetes 4 (8.7) 4 (11.8) 0 (0.0) Mean number of pregnancies (SD) 2.3 (1.99) 2.3 (1.4) 2.4 (2.5) Mean number of living children (SD) 1.9 (1.26) 2.1 (1.1) 1.6 (1.4) Mucous membrane sites of involvement Oral 34 (73.9) 26 (76.5) 8 (66.7) Eyes 6 (13.0) 3 (8.8) 3 (25.0) Nose 10 (21.7) 10 (29.4) 0 (0.0) Esophagus 9 (19.6) 6 (17.6) 3 (25.0) Vagina 6 (13.0) 4 (11.8) 2 (16.7) Penis/Scrotum 0 (0.0) 0 (0.0) 0 (0.0) Urethra 2 (4.3) 1 (2.9) 1 (8.3) Anus 2 (4.3) 1 (2.9) 1 (8.3) Dsg 1 ELISA titer (units) Mean (SD) 174.7 (688.60) 211.4 (798.4) 68.6 (78.8) Median [range] 9.0 [0.0, 4100.0] 5.5 [0.0, 4100.0] 64.0 [1.0, 240.0] Dsg 3 ELISA titer (units) Mean (SD) 256.4 (374.52) 301.5 (383.5) 136.2 (340.5) Median [range] 98.0 [0.0, 1400.0] 144.0 [0.0, 1400.0] 12.0 [0.0, 1040.0] Cyclophosphamide 0 (0.0) 0 (0.0) 0 (0.0) Current or previous chemotherapy 5 (10.9) 4 (11.8) 1 (8.3) Comorbidities 9 (19.6) 6 (17.6) 3 (25.0) Henoch Schonlein purpura 1 (2.2) 1 (2.9) 0 (0.0) Inflammatory arthritis 1 (2.2) 0 (0.0) 1 (8.3) Possible T1DM (unmasked with prednisone) 1 (2.2) 1 (2.9) 0 (0.0) Raynaud's phenomenon 1 (2.2) 1 (2.9) 0 (0.0) Spondylo-arthropathy (HLA-B27+, 1:320 ANA) 1 (2.2) 1 (2.9) 0 (0.0) Thyroid disease 4 (8.7) 2 (5.9) 2 (16.7) Methotrexate 4 (8.7) 3 (8.8) 1 (8.3) Rituximab 21 (45.7) 16 (47.1) 5 (41.7) Discussion Infertility rates in patients with pemphigus do not appear increased relative to the general dermatology population, even when considering patients with possible RI and DAI. This information can aid in counseling patients of reproductive age diagnosed with this condition. Larger prospective studies are needed to confirm these findings. This was a single-center, retrospective chart review at an institution without a dedicated Reproductive Endocrinology and Infertility clinic, which may underestimate rates of infertility. Although the rates of infertility approached significance when including RI, and DAI in addition to DI, including these categories likely overestimates rates of infertility. Conflicts of interest The authors made the following disclosures: D.R.P. is a consultant for Biogen, Inc. and Pfizer, Inc., and a clinical trials investigator for Pfizer, Inc., EMD Serono, Priovant, Emerald Health, Kadmon, and Argenx. B.S. is a consultant for Argenx and has served as a clinical trials investigator for Argenx, AstraZeneca, and Elorac. The other authors have no conflicts of interest to disclose. Funding Supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. Study approval The authors confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies. Author contributions SAK and BS developed the study and wrote the manuscript. AH was a subspecialty contributor to manuscript development. DRP assisted with methodology and design. RF provided statistical analysis.

Introduction: Black, Indigenous, and People of Color (BIPOC) experience greater morbidity and mortality from autoimmune connective tissue diseases (AICTDs); thus, equitable access to randomized controlled trials (RCTs) for AICTDs is a scientific and ethical imperative. Drug safety and efficacy may not be optimized until participants reflect disease epidemiology. This scoping review examines race and ethnicity in RCTs investigating biologic and small molecule agents for AICTDs.

Background Aberrant toll-like receptor (TLR) 7/8 activation is thought to be involved in both lupus pathogenesis and glucocorticoid resistance. Enpatoran, a selective and potent dual inhibitor of TLR7/8 that is in development for cutaneous and systemic lupus erythematosus (CLE/SLE), was well tolerated by healthy participants and patients hospitalized with COVID-19 pneumonia. We report evaluation of the glucocorticoid-sparing effect of enpatoran and a trial design to assess its efficacy and safety in patients with SLE and/or CLE. Methods Cytokine concentrations and gene expression changes were measured in stimulated human peripheral blood mononuclear cells (PBMCs) from healthy donors after treatment with dexamethasone, TLR7/8 inhibitor, or both. A Phase II basket design, proof-of-concept, dose-finding, randomized, double-blind, placebo-controlled 24-week study in patients with SLE and/or CLE (WILLOW; NCT05162586), which will also assess glucocorticoid sparing, was designed. Results In healthy donor PBMCs, synergy was observed between TLR7/8 inhibitor and dexamethasone. Combination treatment inhibited cytokine release (interleukin-6) with greater potency than either treatment alone and reduced the expression of nuclear factor-kappa B and interferon-regulated genes. Glucocorticoid sparing will be evaluated by a mandatory tapering schedule in the WILLOW study, which has two cohorts (figure 1). Cohort A will enroll patients with CLE or SLE with predominantly active lupus rash. Cohort B, in two parts, will enroll SLE patients with moderate-to-severe systemic disease activity; Part 1 will assess clinical signal and Part 2 may be adapted to improve dose finding. The primary objectives are to evaluate the dose-response relationship of enpatoran in reducing disease activity based on CLASI-A or BICLA. The secondary objectives include evaluating effects on disease control and clinically meaningful glucocorticoid reduction. Conclusions Enpatoran is a novel TLR7/8 inhibitor and may enable glucocorticoid dose reduction in patients with SLE and CLE. The WILLOW study incorporates multiple novel elements including a basket design and evaluation of glucocorticoid sparing.