Sahil Sekhon

Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis

ABSTRACT Psoriasis is a chronic, inflammatory, immune-mediated skin condition that affects 3 to 4% of the adult US population, characterized by well-demarcated, erythematous plaques with silver scale. Psoriasis is associated with many comorbidities including cardiometabolic disease and can have a negative impact on quality of life. The current armamentarium of psoriasis treatment includes topical therapies, phototherapy, oral immunosuppressive therapies, and biologic agents. Over the past 2 decades, there has been rapid development of novel biologic therapies for the treatment of moderate-to-severe plaque psoriasis. This article will review the role of IL-12, IL-23, and IL-17 in the pathogenesis of psoriasis and the monoclonal antibodies (ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab) that target these cytokines in the treatment of this disease.

Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands.

To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5′ and 3′ untranslated region sequences (AREG‐UTR) led to a >10‐fold increase in hAREG expression compared to an otherwise‐identical construct containing only the coding region (AREG‐CDR). AREG‐UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG‐CDR mice. Histologically, AREG‐UTR mice presented with marked epidermal hyperplasia of tail skin (2.1‐fold increase in epidermal thickness with a 9.5‐fold increase in Ki‐67+ cells) accompanied by significantly increased CD4+ T‐cell infiltration. Dorsal skin of AREG‐UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG‐UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki‐67+ cells. To determine the response of AREG‐UTR animals to a pro‐inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG‐UTR and wild type mice (1.7‐ and 2.2‐fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.

Frequency and Management of Sleep Disturbance in Adults with Atopic Dermatitis: A Systematic Review

IntroductionIntense nocturnal pruritus as well as the complex pathophysiology of atopic dermatitis (AD) can severely affect sleep and become a major factor in negatively impacting quality of life in adults. However, much of the literature on sleep disturbance in AD patients is on the pediatric population, and it is not well studied in adults. Furthermore, limited studies are available to guide effective management of sleep disturbance in AD in general. We review the literature to present the studies that have investigated the relationship between AD and its effect on sleep in adults and provide an approach for clinicians caring for this population.MethodsA systematic literature search was conducted through the PubMed and EMBASE databases using the search terms “atopic dermatitis” OR “eczema” AND “sleep.” The articles generated by the search and their references were reviewed.ResultsA high prevalence of sleep disturbance is experienced by adults with AD. The likelihood of sleep disturbance is much higher in patients with AD compared to those without AD. Sleep disturbance appears to worsen with AD severity. Pruritus and scratching appear to be large contributors to sleep disturbance in adult patients with AD.ConclusionIt is important that clinicians evaluate the severity of AD and ask general questions about itching, sleep, impact on daily activities, and persistence of disease during each patient visit and follow-up with the complaint of sleep disturbance. Management of sleep disturbance in AD should focus on adequate disease control of AD as well as possible medical interventions to help improve sleep. The pathophysiology of sleep disturbance in AD is extremely complex, and further research is needed to better understand the interplay of the immune system, circadian rhythm, and environmental factors implicated in both AD and sleep.

Review of the Mechanism of Action of Coal Tar in Psoriasis

Abstract Purpose: Crude coal tar and its derivatives have been used in modern medicine for the treatment of psoriasis since at least 1925 as part of the Goeckerman regimen. To this day, coal tar remains a safe and highly effective option for the treatment of psoriasis vulgaris. However, the mechanism by which coal tar has its therapeutic effect is unknown. This review summarizes current knowledge of the mechanism by which coal tar has its therapeutic effect in the treatment of psoriasis vulgaris. Material and methods: A Pubmed search was conducted on March 13, 2017 for relevant English language journal articles on the subject and were relevant journal articles were included in this review. Results: Crude coal tar consists of thousands of ingredients, many of which are unidentified. Of these ingredients, the most research has gone into analyzing polycyclic aryl hydrocarbons. These hydrocarbons are thought to be the most likely component of crude coal tar that leads to its effects in psoriasis. Of the aryl hydrocarbons, carbazole has been the most well studied in psoriasis and is hypothesized as being responsible for the treatment efficacy of crude coal tar. Conclusions: Polycyclic aryl hydrocarbons, and specifically carbazole, are thought to be the mechanism by which crude coal tar has its effect in psoriasis. However, further research is warranted to fully characterize the mechanism of action of crude coal tar, with the potential to create new therapies for psoriasis.

Factors contributing to facial asymmetry in identical twins.

Background: This study examines the potential contributions of environmental factors to variations in facial symmetry between identical twins. Methods: Identical male and female twins were recruited from the Twins Days Festival in 2009 and 2010. Subjects independently completed a comprehensive questionnaire on their medical and personal history, and then posed for digital facial photography from several different angles. Eight facial features from these photographs were measured using Adobe Photoshop, and these facial features were then analyzed against survey responses between twins through multivariate regressions. Results: A total of 147 pairs of identical twins were included. Twins who slept primarily prone had greater nasal midline deviation (p = 0.047) and oral commissure asymmetry (p = 0.027). Tooth extractions were significantly associated with canting of the plane of occlusion (p = 0.043), and use of dentures was associated with nasal midline deviation (p = 0.032) and oral commissure asymmetry (p = 0.007). Smoking was associated with canting of the plane of occlusion (p = 0.049) and upper eyelid ptosis (p = 0.023). Lastly, headaches were also associated with nasal midline deviation (p = 0.024). Conclusion: Exogenous factors such as prone sleep position, tooth extractions, dentures, and smoking are significant risk factors for facial asymmetry. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Guselkumab for the treatment of moderate-to-severe plaque psoriasis

ABSTRACT Introduction: Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis. Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis. Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.

Neuromodulation in Inflammatory Skin Disease

Inflammatory skin diseases are difficult to treat because of a lack of available treatment options for severe disease. However, recent advances have shown that vagus nerve stimulation can be used to decrease inflammation and reduce disease severity in rheumatoid arthritis and inflammatory bowel disease. Changes in cytokine profiles observed in these studies are similar to those seen with use of biologics in inflammatory skin disease, suggesting that they act along similar pathways to disrupt chronic inflammation and treat inflammatory disease. This commentary explores the existing evidence demonstrating the efficacy of neuromodulation in inflammatory disease, and outlines reasons why these findings could translate to the dermatology setting to treat inflammatory skin disease.

Clinical utility of ixekizumab in the treatment of moderate-to-severe plaque psoriasis

Psoriasis vulgaris is a chronic, immune-mediated systemic disease that affectŝ7.5 million people in the US. It can be treated with many therapies, often in combination, which include topicals, phototherapy, oral systemics, and biologics. Biologic agents target specific components of the immune system involved in the pathogenesis of psoriasis including TNF-alpha, IL-12, IL-17, and IL-23. The biologic ixekizumab, approved for the treatment of moderate–severe plaque psoriasis in the US, targets IL-17. This review describes the role of IL-17 in psoriasis, the mechanism by which ixekizumab targets this cytokine, and the clinical utility of ixekizumab.

Recent Developments in Atopic Dermatitis

In this article, we review recent updates in the comorbidities, quality of life effects, pathophysiology, management techniques, and therapeutics for AD. Atopic dermatitis (AD) is a bothersome and common skin disease affecting ∼10.7% of children in the United States. This skin condition significantly decreases quality of life in not only patients, but in their families as well. Pediatricians are often the first physicians to diagnose and manage these patients and thus are relied on by families to answer questions about this disease. AD is complex, multifactorial, and has historically had limited therapeutic options, but the landscape of this disease is now rapidly changing. Pathways contributing to the pathogenesis of this disease are continually being discovered, and new therapies for AD are being developed at an unprecedented rate. With this article, we will review the current guidelines regarding the management of AD, outline updates in the current understanding of its pathophysiology, and highlight novel developments available for the treatment of this burdensome disease.

Oral Retinoids in Dermatology

Retinoids have been used in dermatology since the 1940s when vitamin A was first used to treat acne vulgaris. Currently, three retinoids are approved for dermatologic indications in the United States: acitretin for moderate-to-severe psoriasis vulgaris, isotretinoin for severe recalcitrant nodular acne vulgaris, and bexarotene for cutaneous T-cell lymphoma. This chapter will review the pharmacology of each of these medications, including mechanism of action, pharmacokinetics, and metabolism. Indications, use, dosage, and efficacy of each medication will be discussed. Safety and tolerability, as well as patient monitoring during therapy, will also be reviewed.