Diversity, equity, and inclusion in genitourinary clinical trials leading to FDA novel drug approval: An assessment of the FDA center for drug evaluation and research drug trials snapshot.

To determine the distribution of race and ethnicity among genitourinary oncology trial participants leading to FDA approval of novel molecular entities/biologics. Secondarily, we evaluated whether the proportion of Black participants in clinical trials increased over time. We quired the FDA Center for Drug Evaluation and Research Drug Trials Snapshot (DTS) between 2015 and 2020 for urologic oncology clinical trials leading to FDA approval of novel drugs. Enrollment data was stratified by race and ethnicity. Cochran-Armitage Trend tests were used to examine changes in Black patient participation over years. Nine clinical trials were identified that led to FDA approval of 5 novel molecular entities for prostate and 4 molecular entities for urothelial carcinoma treatment. Trials for prostate cancer included 5202 participants of which 69.8% were White, 4.0% Black, 11.0% Asian, 3.6% Hispanic, <1% American Indian/Alaska Native or Native Hawaiian/Pacific Islander, 3% other. Trials in urothelial carcinoma had 704 participants of which 75.1% were male, 80.8% White, 2.3% Black, 2.4% Hispanic, <1% American Indian/Alaska Native or Native Hawaiian/Pacific Islander, 5% other. Black participation rates over time did not change for urothelial (P = 0.59) or the combined cancer cohort (P = 0.29). Prostate cancer enrollment trends among Black participant declined over time (P = 0.03). Participants in genitourinary clinical trials leading to FDA approval of novel drugs are overwhelmingly white. Involving stakeholders who represent the needs and interests of underrepresented populations in the design and implementation of clinical trials of novel agents may be a strategy to increase diversity, equity, and inclusion among genitourinary clinical trials.

How Do Experts Treat Patients with Bullous Pemphigoid around the World? An International Survey.

Many treatments are currently proposed for treating patients with bullous pemphigoid (BP). We assessed treatment modalities of BP depending on the different countries, BP extent, and patients' comorbidities. We surveyed worldwide experts about how they treat patients with BP. A total of 61 experts from 27 countries completed the survey. Severe and moderate BP were treated with oral prednisone (61.4 and 53.7%, respectively) or superpotent topical corticosteroids (CSs) (38.6 and 46.3%, respectively). Conventional immunosuppressants were more frequently combined with oral prednisone (74.5%) than with superpotent topical CS (37.5%) in severe BP. Topical CSs were mainly used in Europe in mild (81.1%), moderate (55.3%), and severe (54.3%) BP. In the United States of America and Asia, systemic CSs were mainly proposed for treating severe (77.8 and 100%, respectively), moderate (70 and 77.8%, respectively), and also mild (47.1 and 33.3%, respectively) BP. Most experts reduced the initial dose of oral CS in patients with diabetes mellitus (48.1%) or cardiac insufficiency (40.2%) but rarely changed BP treatment in patients with neurological disorders or neoplasia. This survey showed major differences in the way patients with BP are treated between AmeriPac countries (United State of America, Latin America, and Australia) and Asia on the one hand and Europe and the Middle East on the other hand.

Non-oncology clinical trial engagement in a nationally representative sample: Identification of motivators and barriers.

BACKGROUND: Enrollment in non-oncology clinical trials is often challenging and social determinants that may serve as motivators or barriers to clinical trial enrollment are largely unexplored. We sought to assess engagement in non-oncology clinical trials with a focus on social determinants of health as barriers or motivators toward participation. METHODS: A cross-sectional analysis of non-cancer respondents was conducted using the Health Information National Trends Survey (HINTS) administered in 2020. Our analytic cohort was comprised of respondents with no reported history of cancer. Our primary outcome of interest was trial engagement defined as receiving an invitation to participate in a clinical trial. Secondary outcomes included participation in a clinical trial and reported motivators and barriers to clinical trial participation. RESULTS: A total of 3113 respondents with no reported history of cancer were included. Overall, 8.1% of respondents reported being invited to participate in a clinical trial. Amongst those invited to participate, 47.7% reported participating in a clinical trial. Respondents reported that clinical trial participation was motivated "somewhat" or "a lot" by "wanting to get better" (80.5%), "helping other people" (61.4%), "physician encouragement" (60.6%), "getting a chance to try new care" (60.2%), "family friend encouragement" (54.2%), or "getting paid" (50.0%). Overall, 82.5% of all respondents "don't know anything" or have "a little knowledge" about clinical trials. Reported barriers to clinical trial participation including getting transportation, childcare or paid time off work (48.4%) and standard of care not covered by insurance (62.0%) influenced the decision to participate "somewhat" or "a lot." CONCLUSION: Amongst a nationally representative sample, non-oncology clinical trial invitation is low, but participation amongst those invited is nearly 50%. This highlights the need for clinician engagement in clinical trials. Identifying modifiable social determinants of non-oncologic clinical trial participation may help promote improved engagement.

Modes of Action of Intravenous Immunoglobulin in Bullous Pemphigoid.

Bullous pemphigoid is an autoantibody-mediated skin blistering disease. Previous studies revealed that intravenous Ig is therapeutic in animal models of bullous pemphigoid by saturating the IgG-protective receptor FcRn, thereby accelerating degradation of pathogenic IgG. Sasaoka et al. demonstrate that the inhibitory effects of intravenous Ig on bullous pemphigoid are also associated with negative modulation of cytokine production by keratinocytes.

Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope.

Fogo Selvagem (FS), the endemic form of pemphigus foliaceus, is mediated by pathogenic IgG4 autoantibodies against the amino-terminal extracellular cadherin domain of the desmosomal cadherin desmoglein 1 (Dsg1). Here we define the detailed epitopes of these pathogenic antibodies. Proteolytic footprinting showed that IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide (A129LNSMGQDLERPLELR144) from the EC1 domain of Dsg1 that overlaps the binding site for an adhesive-partner desmosomal cadherin molecule. Mutation of Dsg1 residues M133 and Q135 reduced the binding of FS IgG4 autoantibodies to Dsg1 by ∼50%. Molecular modeling identified two nearby EC1 domain residues (Q82 and V83) likely to contribute to the epitope. Mutation of these residues completely abolished the binding of FS IgG4 to Dsg1. Bead aggregation assays showed that native binding interactions between Dsg1 and desmocollin 1 (Dsc1), which underlie desmosome structure, were abolished by Fab fragments of FS IgG4. These results further define the molecular mechanism by which FS IgG4 autoantibodies interfere with desmosome structure and lead to cell-cell detachment, the hallmark of this disease.

Triggers of oral lichen planus flares and the potential role of trigger avoidance in disease management.

OBJECTIVE: Many patients with oral lichen planus (OLP) report triggers of flares, some of which overlap with triggers of other oral diseases, including oral allergy syndrome and oral contact dermatitis. The purpose of this study was to evaluate the prevalence of commonly reported triggers of OLP flares, their overlap with triggers of other oral diseases, and the potential role of trigger avoidance as a management strategy. STUDY DESIGN: Questionnaire-based survey of 51 patients with biopsy-proven lichen planus with oral involvement seen in an academic dermatology specialty clinic and/or oral pathology clinic between June 2014 and June 2015. RESULTS: Of the participants, 94% identified at least one trigger of their OLP flares. Approximately half of the participants (51%) reported at least one trigger that overlapped with known triggers of oral allergy syndrome, and 63% identified at least one trigger that overlapped with known triggers of oral contact dermatitis. Emotional stress was the most commonly reported trigger (77%). Regarding avoidance, 79% of the study participants reported avoiding their known triggers in daily life. Of those who actively avoided triggers, 89% reported an improvement in symptoms and 70% reported a decrease in the frequency of flares. CONCLUSIONS: Trigger identification and avoidance can play a potentially effective role in the management of OLP.

Mycobacterium bolletii/Mycobacterium massiliense furunculosis associated with pedicure footbaths: a report of 3 cases.

BACKGROUND: Mycobacterium bolletii and Mycobacterium massiliense are recently described species of nontuberculous mycobacteria. Footbaths preceding pedicures at nail salons have been implicated as reservoirs of infection with nontuberculous mycobacteria. To our knowledge, this case series represents the first documented outbreak of M bolletii/M massiliense furunculosis, identified by heat-shock protein 65 gene, hsp65, sequencing, occurring in immunocompetent patrons of a North Carolina nail salon. OBSERVATIONS: We describe 3 cases of lower extremity furunculosis caused by M bolletii/M massiliense associated with pedicure footbaths from the same North Carolina nail salon. Lesions developed within 1 month of the salon visit and were characterized by erythematous, indurated papules and plaques. Histologic examination revealed suppurative granulomatous dermatitis. Mycobacterium bolletii/M massiliense was identified by sequencing the 16S ribosomal RNA (rRNA) and hsp65 genes. All 3 patients responded to different combinations of clarithromycin, doxycycline hydrochloride, azithromycin, and moxifloxacin hydrochloride for complete lesion resolution. CONCLUSIONS: Clinicians should elicit a history of pedicure footbaths and maintain a high level of suspicion when faced with skin lesions of the lower extremities that are culture negative or are refractory to conventional antibiotic therapy. Accurate identification and discrimination of M massiliense and M bolletii is difficult and requires sequencing of multiple gene targets beyond their identical 16S rRNA sequences.

Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss.

: We report here that dysregulation of CD19, a coreceptor that augments B-cell receptor (BCR) signaling, occurs at two B-cell differentiative stages in patients with systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic autoantibody (ANCA) associated small vessel vasculitis (SVV). The naïve B cells of nearly all SLE and ANCA-SVV patients express approximately 20% less CD19 than healthy control (HC) B cells. In contrast, a subset of memory B cells of some SLE and ANCA-SVV Pts (25-35%) express two to fourfold more CD19 than HC B cells. These CD19(hi) memory B cells are activated and exhibit evidence of antigen selection. Proteome array analysis of 67 autoantigens indicates that CD19(hi) SLE Pts exhibit a distinct autoantibody profile characterized by high levels of antibodies to small nuclear ribonucleoproteins and low levels of antiglomerular autoantibodies. These findings have implications for autoreactive B-cell activation and suggest a shared mechanism of B-cell tolerance loss in these two diseases.

Early preplasma cells define a tolerance checkpoint for autoreactive B cells.

Ab-secreting plasma cells (PCs) are the effectors of humoral immunity. In this study, we describe regulation of autoreactive B cells specific for the ribonucleoprotein Smith (Sm) at an early pre-PC stage. These cells are defined by the expression of the PC marker CD138 and normal levels of CD19 and B220. They are present at a high frequency in normal mouse spleen and bone marrow, are Ag dependent, and are located predominantly along the T cell-B cell border and near bridging channels. Anti-Sm pre-PCs also occur at a high frequency in nonautoimmune mice and show additional phenotypic characteristics of PC differentiation. However, while some of these pre-PCs are Ab-secreting cells, those specific for Sm are not, indicating regulation. Consistent with this, anti-Sm pre-PCs have a higher turnover rate and higher frequency of cell death than those that do not bind Sm. Regulation of anti-Sm pre-PCs occurs upstream of the transcriptional repressor, B lymphocyte-induced maturation protein-1, expression. Regulation at this stage is overcome in autoimmune MRL/lpr mice and is accompanied by an altered B lymphocyte stimulator receptor profile. These data reveal a new B cell tolerance checkpoint that is overcome in autoimmunity.