Mucocutaneous Manifestations of Recreational Drug Use.

Recreational drug use is increasingly common in the dermatology patient population and is often associated with both general and specific mucocutaneous manifestations. Signs of substance use disorder may include changes to general appearance, skin, and mucosal findings associated with particular routes of drug administration (injection, insufflation, or inhalation) or findings specific to a particular drug. In this review article, we provide an overview of the mucocutaneous manifestations of illicit drug use including cocaine, methamphetamine, heroin, hallucinogens, marijuana, and common adulterants to facilitate the identification and improved care of these patients with the goal being to connect this patient population with appropriate resources for treatment.

The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.

A retrospective cohort study of the efficacy of metronidazole in oral lichen planus.

Lichen planus (LP) is an inflammatory dermatosis with mucosal variants, including oral LP (OLP). OLP has a relapsing chronic course and may significantly affect a patient's quality of life. We analysed the efficacy of metronidazole as a treatment for OLP via a retrospective chart review of patients with a diagnosis of OLP seen at our institution over 10 years. Thirty patients with OLP were treated with metronidazole 500 mg twice daily. Most patients (n = 18; 60%) showed improvement with metronidazole, including 10 (33%) who experienced complete resolution of symptoms. Our results were limited by the retrospective nature of the review and the relatively small cohort size. Given the efficacy, mild side-effect profile and the less immunosuppressive nature of metronidazole vs. alternative systemic treatment options, metronidazole is a reasonable option to try in patients with symptomatic OLP who have failed topical treatment options.

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.

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.

Efficacy and safety of a novel mucoadhesive clobetasol patch for treatment of erosive oral lichen planus: A phase 2 randomized clinical trial.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disorder of the oral mucosa. Currently there is no approved treatment for OLP. We report on the efficacy and safety of a novel mucoadhesive clobetasol patch (Rivelin® -CLO) for the treatment of OLP. METHODS: Patients with confirmed OLP and measurable symptomatic ulcer(s) participated in a randomized, double-blind, placebo-controlled, multicenter clinical trial testing a novel mucoadhesive clobetasol patch (Rivelin® -CLO) in OLP across Europe, Canada, and the United States. Patients were randomized to placebo (nonmedicated), 1, 5, 20 µg Clobetasol/patch, twice daily, for 4 weeks. The primary endpoint was change in total ulcer area compared to baseline. Secondary endpoints included improvement from baseline in pain, disease activity, and quality of life. RESULTS: Data were analyzed and expressed as mean [SD]. One hundred thirty-eight patients were included in the study; 99 females and 39 males, mean age was 61.1 [11.6] years. Statistical analyses revealed that treatment with 20-µg Rivelin® -CLO patches demonstrated significant improvement with ulcer area (p = 0.047), symptom severity (p = 0.001), disease activity (p = 0.022), pain (p = 0.012), and quality of life (p = 0.003) as compared with placebo. Improvement in OLP symptoms from beginning to the end of the study was reported as very much better (best rating) in the 20-µg group (25/32) patients compared to the placebo group (11/30), (p = 0.012). Adverse events were mild/moderate. Candidiasis incidence was low (2%). CONCLUSIONS: Rivelin® -CLO patches were superior to placebo demonstrating statistically significant, clinically relevant efficacy in objective and subjective improvement and, with a favorable safety profile.

Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus.

Pemphigus is a debilitating IgG-mediated autoimmune disease requiring better tolerated, more targeted, and rapid onset therapies. ALXN1830 is a humanized IgG4 antibody that blocks neonatal Fc receptor interactions with IgG. A multicenter, open-label safety and tolerability phase 1b/2 trial (NCT03075904) was conducted in North America from July 2017 to January 2019 and included patients aged ≥18 years with a confirmed diagnosis of pemphigus (vulgaris or foliaceus) and active disease. Dosing included five weekly intravenous doses of ALXN1830 (10 mg/kg) and follow-up through day 112 (study termination). Pharmacokinetics, pharmacodynamics, safety, and efficacy, as evaluated by determining the change in the median pemphigus disease area index, were determined. In this pilot study of eight patients, five weekly infusions of ALXN1830 produced a rapid improvement in the pemphigus disease area index score within 14 days of the first dose. Pemphigus disease area index improvement increased further together with reductions in IgG, circulating immune complexes of IgG, and anti-desmoglein antibodies without affecting albumin, IgM, IgA, or C-reactive protein levels. ALXN1830 was well-tolerated, with headache as the most common adverse event. This study reveals the importance of neonatal Fc receptor in the biology of pemphigus and the potential for use of ALXN1830 in pemphigus treatment.

Identification of a primary antigenic target of epitope spreading in endemic pemphigus foliaceus.

Epitope spreading is an important mechanism for the development of autoantibodies (autoAbs) in autoimmune diseases. The study of epitope spreading in human autoimmune diseases is limited due to the major challenge of identifying the initial/primary target epitopes on autoantigens in autoimmune diseases. We have been studying the development of autoAbs in an endemic human autoimmune disease, Brazilian pemphigus foliaceus (or Fogo Selvagem (FS)). Our previous findings demonstrated that patients before (i.e. preclinical) and at the onset of FS have antibody (Ab) responses against other keratinocyte adhesion molecules in addition to the main target autoantigen of FS, desmoglein 1 (Dsg1), and anti-Dsg1 monoclonal Abs (mAbs) cross-reacted with an environmental antigen LJM11, a sand fly saliva protein. Since sand fly is prevalent in FS endemic regions, individuals in these regions could develop Abs against LJM11. The anti-LJM11 Abs could recognize different epitopes on LJM11, including an epitope that shares the structure similarity with an epitope on Dsg1 autoantigen. Thus, Ab response against this epitope on LJM11 could be the initial autoAb response detected in individuals in FS endemic regions, including those who eventually developed FS. Accordingly, this LJM11 and Dsg1 cross-reactive epitope on Dsg1 could be the primary target of the autoimmune response in FS. This investigation aimed to determine whether the autoAb responses against keratinocyte adhesion molecules are linked and originate from the immune response to LJM11. The anti-Dsg1 mAbs from preclinical FS and FS individuals were employed to determine their specificity or cross-reactivity to LJM11 and keratinocyte adhesion molecules. The cross-reactive epitopes on autoantigens were mapped. Our results indicate that all tested mAbs cross-reacted with LJM11 and keratinocyte adhesion molecules, and we identified an epitope on these keratinocyte adhesion molecules which is mimicked by LJM11. Thus, the cross-reactivity could be the mechanism by which the immune response against an environmental antigen triggers the initial autoAb responses. Epitope spreading leads to the pathogenic autoAb development and ensuing FS among genetically susceptible individuals.

Diagnosis and management of pemphigus: Recommendations of an international panel of experts.

BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.

Walnut antigens can trigger autoantibody development in patients with pemphigus vulgaris through a "hit-and-run" mechanism.

BACKGROUND: Environmental factors, as well as genetic predisposition, are known to be critical for the development of autoimmunity. However, the environmental agents that trigger autoimmune responses have remained elusive. One possible explanation is the "hit-and-run" mechanism in which the inciting antigens that initiate autoimmune responses are not present at the time of overt autoimmune disease. OBJECTIVE: After our previous findings that some allergens can incite autoimmune responses, we investigated the potential role of environmental allergens in triggering autoantibody development in patients with an autoimmune skin disease, pemphigus vulgaris (PV). METHODS: Revertant/germline mAbs (with mutations on variable regions of heavy and light chains reverted to germline forms) of 8 anti-desmoglein (Dsg) 3 pathogenic mAbs from patients with PV were tested for reactivity against a panel of possible allergens, including insects, pollens, epithelia, fungi, and food antigens. RESULTS: All the PV germline mAbs were reactive to antigens from walnut, including the well-known allergen Jug r 2 and an uncharacterized 85-kDa protein component. Sera from patients with PV contained significantly greater levels of anti-Dsg3 autoantibodies than walnut-specific antibodies, suggesting that the autoreactive B-cell response in patients with PV might be initially triggered by walnut antigens but is subsequently driven by Dsg3. CONCLUSION: Our findings suggest that walnut antigens/allergens can initiate autoantibody development in patients with PV through a "hit-and-run" mechanism. The revertant/germline mAb approach might provide a paradigm for the etiological study of other allergic and autoimmune diseases.

Childhood pemphigus foliaceus presenting as a polycyclic eruption: Case report and review of the literature.

Pemphigus foliaceus (PF) is an autoimmune bullous disorder that has occasionally been reported to present as a polycyclic or arcuate eruption in children. We present a case of childhood PF presenting as an annular and polycyclic eruption, which initially led to a diagnostic conundrum and a delay in diagnosis but which ultimately responded well to therapy with systemic steroids and rituximab infusions. We briefly review the literature on polycyclic presentations of PF in childhood as well as the use of rituximab for pediatric pemphigus.

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.

Eosinophils Mediate Tissue Injury in the Autoimmune Skin Disease Bullous Pemphigoid.

Eosinophils are typically associated with unique inflammatory settings, including allergic inflammation and helminth infections. However, new information suggests that eosinophils contribute more broadly to inflammatory responses and participate in local immune regulation and the tissue remodeling/repair events linked with a variety of diseases. Eosinophilic infiltration has long been a histologic hallmark of bullous pemphigoid (BP), a subepidermal autoimmune blistering disease characterized by autoantibodies directed against basement membrane protein BP180. However, the exact role of eosinophils in disease pathogenesis remains largely unknown. We show here that eosinophils are necessary for IgE autoantibody-mediated BP blister formation in a humanized IgE receptor mouse model of BP. Disease severity is IgE dose dependent and correlates with the degree of eosinophil infiltration in the skin. Furthermore, IgE autoantibodies fail to induce BP in eosinophil-deficient mice, confirming that eosinophils are required for IgE-mediated tissue injury. Thus, eosinophils provide the cellular link between IgE autoantibodies and skin blistering in this murine model of BP. These findings suggest a role for eosinophils in autoimmune disease and have important implications for the treatment of BP and other antibody-mediated inflammatory and autoimmune diseases.

Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem).

We have shown that although the IgG response in fogo selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limão Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease.