Monoclonal antibodies for moderate-to-severe atopic dermatitis: a look at phase III and beyond.

INTRODUCTION: The understanding of atopic dermatitis (AD) pathogenesis has rapidly expanded in recent years, catalyzing the development of new targeted monoclonal antibody treatments for AD. AREAS COVERED: This review aims to summarize the latest clinical and molecular data about monoclonal antibodies that are in later stages of development for AD, either in Phase 3 trials or in the pharmacopoeia for up to 5 years, highlighting the biologic underpinning of each drug's mechanism of action and the potential modulation of the AD immune profile. EXPERT OPINION: The therapeutic pipeline of AD treatments is speedily progressing, introducing the potential for a personalized medical approach in the near future. Understanding how targeting pathogenic players in AD modifies disease progression and symptomatology is key in improving therapeutic choices for patients and identifying ideal patient candidates.

Efficacy and Durability of Intravenous Ertapenem Therapy for Recalcitrant Hidradenitis Suppurativa.

Importance: Hidradenitis suppurativa (HS) is a debilitating follicular skin disorder in which bacterial colonization is typical. Oral antibiotic efficacy can be unreliable; however, selective intravenous antibiotics, specifically ertapenem, may provide favorable clinical outcomes. Objective: To explore optimal course duration, efficacy, and patient satisfaction associated with intravenous ertapenem for HS. Design, Setting, and Participants: This retrospective review of the medical records of 98 patients with HS between 2018 and 2022 measured and evaluated patient outcomes before and after treatment with intravenous ertapenem. Participants were followed up in a telephone survey assessing patient perspectives and satisfaction. All of those included in this study received medical care from the Albert Einstein College of Medicine's Montefiore HS Center. Exposures: Patients were treated with 1 g of ertapenem that was self-administered at home through a peripheral intravenous central catheter using an elastomeric pump for 12 to 16 weeks. Antiandrogens and immunomodulatory biologic therapies initiated prior to ertapenem were maintained throughout the treatment course. Main Outcomes and Measures: The primary outcomes, encompassing clinical severity (evaluated through the HS Physician Global Assessment score [a 6-point scale ranging from clear to very severe] and a numerical rating scale for pain [an 11-point scale in which a score of 0 indicates no pain and a score of 10 indicates the worst possible pain]) and markers of inflammation (such as leukocytes, erythrocyte sedimentation rate, C-reactive protein, and interleukin-6), were measured at baseline, the midcourse of intravenous ertapenem treatment, at the end of the course, and posttherapy. Bacterial abundance was also examined at these 4 points, and patient satisfaction was assessed during follow-up. Results: A total of 98 patients (mean [SD] age, 35.8 [13.0] years; 61 [62.2%] female) with HS were treated with intravenous ertapenem. The self-reported racial distribution included 3 individuals identifying as Asian (3.1%), 59 as Black/African American (60.2%), 13 as White (13.3%), and 23 as either other or unknown (23.5%). Additionally, 24 participants (24.5%) reported Spanish/Hispanic/Latino ethnicity. The mean (SD) treatment duration spanned 13.1 (4.0) weeks, with posttherapy follow-up occurring after 7.8 (3.6) weeks. From baseline to posttherapy follow-up, significant reductions were found in the mean (SD) HS Physician Global Assessment scores (3.9 [1.0] vs 2.7 [1.2]; P < .001) and the numerical rating scale for pain (4.2 [3.3] vs 1.8 [2.7]; P < .001), C-reactive protein (5.4 [11.4] vs 2.4 [2.0] mg/dL; P < .001), interleukin-6 (25.2 [21.1] vs 13.7 [13.9]; P < .001), and leukocytes (11.34 [3.9] vs 10.0 [3.4]; P < .001). At follow-up, 76 patients (78.0%) participated in the telephone survey, where 63 (80.3%) reported medium to high satisfaction; further, 69 (90.8%) would recommend ertapenem to other patients. Conclusions and Relevance: In this retrospective review of medical records and telephone survey, treating HS with intravenous ertapenem, administered for a mean of 13 weeks, was associated with improvement in clinical and inflammatory markers, as well as heightened patient satisfaction. Nonetheless, this approach should be monitored for the emergence of antimicrobial resistance given a longer than standard treatment course.

An Unexpected Postsurgical Phenomenon After Total Knee Arthroplasty: Nummular Eczema: A Case Report and Literature Review.

CASES: Two elderly women each presented with a unilateral, erythematous rash 1 year after total knee arthroplasty (TKA) for osteoarthritis. Both cases were diagnosed as postsurgical nummular eczema (NE) and treated successfully with topical corticosteroids. CONCLUSION: We highlight a novel clinical presentation of postsurgical NE associated with TKA, previously reported only with breast reconstruction. Postsurgical NE may mimic periprosthetic infection or implant-related allergic contact dermatitis. Timely diagnosis and appropriate treatment in these cases prevented unnecessary testing and hospital admission for revision surgery. This case series highlights the varied presentation and wide differential diagnosis associated with postsurgical NE.

Adalimumab efficacy is inversely correlated with body mass index (BMI) in hidradenitis suppurativa.

BACKGROUND: Adalimumab is the only FDA-approved biologic for hidradenitis suppurativa (HS). In the setting of increasing obesity rates worldwide, the relationship between adalimumab efficacy for HS and BMI is essential to understand. We assessed this relationship through markers of disease severity and inflammation. METHODS: Institutional review board-approved retrospective chart review of Montefiore/Einstein HS Center (HSC) patients (n = 57) treated with adalimumab. The relationship between BMI and adalimumab efficacy was assessed through disease severity (HS-Physician Global Assessment [HS-PGA] 0 and Numerical Rating Scale Pain [NRS-Pain]) and inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and interleukin-6 [IL-6]). A BMI ≥ 30 is defined as obese; BMI < 30 is defined as non-obese. RESULTS: The mean age was 35.8 ± 13.0 years. After adalimumab therapy, those with BMI < 30 experienced significant reductions in HS-PGA (-1.5 ± 0.9; P < 0.0001) and NRS-Pain (-1.6 ± 2.1; P < 0.0001), as well as mean decreases in inflammatory markers ESR, CRP, and IL-6 (-17.90 ± 23.6, -0.71 ± 1.4, -5.88 ± 7.9, respectively; P > 0.05). Obese patients (BMI ≥ 30) experienced mean increases in HS-PGA (+0.22 ± 0.8; P > 0.05) and NRS-Pain scores (+1.41 ± 3.5; P > 0.05) as well as mean increases in ESR, CRP, and IL-6 (+2.62 ± 28.3, +0.44 ± 3.0, +2.35 ± 6.9, respectively; P > 0.05). Comparing the cohorts, differences in changes in HS-PGA, NRS-Pain, ESR, and IL-6 after therapy are significantly different (P < 0.05). CONCLUSIONS: We identified significantly lower efficacy of adalimumab in HS patients with BMI ≥ 30 compared to those with BMI < 30. Those with BMI ≥ 30 demonstrated signs of both clinical and physiological deterioration while on adalimumab. Future studies are needed to examine adalimumab dosing for HS patients with high BMI, as well as a critical reconsideration of weight-based therapies.

Chromatin architecture in addiction circuitry identifies risk genes and potential biological mechanisms underlying cigarette smoking and alcohol use traits.

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and newly generated midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ~26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture helps refine neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.

A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons.

BACKGROUND: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap. METHODS: We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring the MDN's "spatial genome," including chromosomal contact landscapes as a critical layer of cell type-specific epigenomic regulation. Low-input Hi-C protocols were applied to 5-10 × 103 dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain. RESULTS: The Hi-C-reconstructed MDN spatial genome revealed 11 "Euclidean hot spots" of clustered chromatin domains harboring risk sequences for SCZ and elevated BMI. Inter- and intra-chromosomal contacts interconnecting SCZ and BMI risk sequences showed massive enrichment for brain-specific expression quantitative trait loci (eQTL), with gene ontologies, regulatory motifs and proteomic interactions related to adipogenesis and lipid regulation, dopaminergic neurogenesis and neuronal connectivity, and reward- and addiction-related pathways. CONCLUSIONS: We uncovered shared nuclear topographies of cognitive and metabolic risk variants. More broadly, our PsychENCODE sponsored Hi-C study offers a novel genomic approach for the study of psychiatric and medical co-morbidities constrained by limited overlap of their respective genetic risk architectures on the linear genome.