The missing link between itch and inflammation in atopic dermatitis.

Atopic dermatitis is a common skin disease with high morbidity and is associated with severe itch and chronic skin inflammation. In this issue of Cell, Wilson et al. demonstrate that epithelial cells communicate directly with cutaneous sensory neurons via a cytokine to induce itch.

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

INDIVIDUAL ARTICLE: Management of Prurigo Nodularis.

BACKGROUND: Prurigo nodularis (PN) is a chronic disease characterized by intense pruritus and nodular lesions associated with reduced quality of life. Until recently, no US Food and Drug Administration (FDA)-approved therapies have been available for the management of PN. Treatment regimens have been highly variable and clinical management guidelines are lacking overall; formal treatment guidelines do not exist within the US. In 2022, dupilumab became the first FDA-approved medication for PN. Multiple novel agents that target the neuroimmune underpinnings of the disease are currently in development and show promise for this challenging disorder. OBJECTIVE: To review current treatments and emerging therapies for effective management of patients with PN. METHODS: We reviewed publications on PN management identified from PubMed, Embase, Web of Science, and the Cochrane Library. We also included publicly available data on clinical trials for PN therapies reported on the US National Library of Medicine ClinicalTrials.gov, the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) Database, and the European Clinical Trials (EudraCT) Database. RESULTS: The recommended management of PN begins with an assessment of disease severity, including disease burden and pruritus intensity, and evaluation of comorbid medical disorders. Treatment goals include resolution of itch, improvement in nodules or cutaneous lesions, and improvement in quality of life. Therapies should be selected based on a patient’s clinical presentation and comorbidities. Treatment should simultaneously address the neural and immunologic components of PN. Combination therapy, particularly with conventional agents, may be beneficial. LIMITATIONS: Data on most conventional PN treatments are limited to anecdotal reports, small clinical trials, or expert consensus recommendations. No head-to-head comparative trials have evaluated the relative efficacy of conventional and/or emerging agents, or combination therapy. CONCLUSION: An effective treatment approach for patients with PN should reduce pruritus, allow nodular lesions to heal, and improve individual quality of life. The treatment landscape for PN is rapidly evolving with one FDA-approved agent and several new promising therapies on the horizon. J Drugs Dermatol. 2023;22:12(Suppl 2):s15-22.

Successful Treatment of Brunsting-Perry Cicatricial Pemphigoid With Dupilumab.

Brunsting-Perry is a rare variant of cicatricial pemphigoid, characterized by subepidermal bullae localized to the head and neck. Currently, treatment relies on non-specific immunosuppression, which in many cases, does not lead to a remission of treatment or significant clinical improvement. Dupilumab, a human monoclonal antibody against IL-4 receptor alpha, has been shown to provide relief of allergic inflammatory lesions and is the first biologic agent approved for the treatment of moderate-to-severe atopic dermatitis. We present the case of a 63-year-old patient with history of Brunsting-Perry cicatricial pemphigoid who proved refractory to multiple conventional therapies but was successfully treated with a dupilumab regimen of 300 mg every two weeks. This case suggests the potential role of dupilumab in the management of Brunsting-Perry cicatricial pemphigoid. J Drugs Dermatol. 2021;20(10):1113-1115. doi:10.36849/JDD.6032.

Novel therapies in the treatment of atopic dermatitis.

Atopic dermatitis (AD) is a common cutaneous condition characterized by epidermal barrier disruption, severe skin inflammation, and pruritus. As a result of our growing understanding of disease pathogenesis, the therapeutic armamentarium to manage AD is rapidly expanding. Moving beyond broadly immunosuppressive agents, newer therapies for AD offer more targeted immunomodulation in the forms of phosphodiesterase 4 inhibitors, Janus kinase inhibitors, and anticytokine monoclonal antibodies. While such therapies are generally considered safer than traditional immunosuppressive agents that have been used off label for AD for decades, they are not without risk entirely. In some cases, potential side effects may be difficult to manage. This review summarizes current views on AD pathogenesis and discusses these novel and emerging therapies, including a discussion of the mechanisms of action, potential side effects, and limitations of current clinical trials for each drug. While the rapid and prolific expansion of therapies to treat AD is encouraging, additional studies are needed to adequately evaluate the long-term safety, efficacy, and generalizability among different age groups and disease subtypes.

Afamelanotide for Treatment of the Protoporphyrias: Impact on Quality of Life and Laboratory Parameters in a US Cohort.

BACKGROUND: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited. METHODS: Here, we report on all adults who received at least one dose of afamelanotide at the Massachusetts General Hospital Porphyria Center from 2021 to 2022. Changes in the time to phototoxic symptom onset, QoL, and laboratory parameters were assessed before and during treatment with afamelanotide. RESULTS: A total of 29 patients with protoporphyria were included, 26 of whom (72.2%) received ≥2 afamelanotide implants. Among the patients who received ≥2 implants, the median time to symptom onset following sunlight exposure was 12.5 min (IQR, 5-20) prior to the initiation of afamelanotide and 120 min (IQR, 60-240) after treatment (p < 0.001). Improvements in QoL during afamelanotide treatment were measured using two QoL tools, with good correlation observed between these two instruments. Finally, we found no improvements in the median levels of metal-free erythrocyte protoporphyrin, plasma protoporphyrin, or liver biochemistries during versus prior to the initiation of afamelanotide treatment. CONCLUSIONS: This study highlights a dramatic clinical benefit of afamelanotide in relation to light tolerance and QoL in protoporphyria, albeit without improvement in protoporphyrin levels or measures of liver function.

Advanced aging skin and itch: addressing an unmet need.

Itch is the most common skin disorder in the elderly and frequently diminishes quality of life in this population. The high prevalence of pruritus in elderly patients is attributed in part to the decline in the normal physiology of the advanced aging skin, and reflects poor hydration, impaired skin barrier, and altered neural function, all ultimately contributing to inflammation and pruritus. As the elderly population continues to grow, practitioners need to be aware of how to evaluate and manage pruritus, recognizing the common conditions contributing to itch in elderly patients as well as the challenges of treatment in this group. Ultimately, management of pruritus will require an individually tailored approach that is guided by a patient's general health, severity of symptoms, and the potential adverse effects of itch therapies.

Light-Related Cutaneous Symptoms of Erythropoietic Protoporphyria and Associations With Light Sensitivity Measurements.

Importance: Erythropoietic protoporphyria (EPP) is a rare and underdiagnosed genetic disease characterized by painful sensitivity to light. A better understanding and characterization of its light-induced cutaneous symptoms may aid in the identification of EPP in patients. Objectives: To describe the cutaneous symptoms of erythropoietic protoporphyria (EPP) and to determine if these symptoms are associated with the degree of light sensitivity. Design, Setting, and Participants: This was a cross-sectional study of adolescent and adult (≥15 years) patients with EPP across the US conducted by a single academic hospital via a remotely administered survey, measurements of light sensitivity by light dosimetry and by text message symptom assessments. Data analyses were conducted from November 2020 to April 2022. Exposures: Sunlight exposure. Main Outcomes and Measures: Self-reported symptoms and association with measured light sensitivity. Results: The study sample consisted of 35 patients with EPP (mean [SD] age, 39.1 (15.5) years; 21 [60%] female; 14 [40%] male; 35 [100%] White individuals). The patients' median [range] skin tone was 3.0 (1.0-8.0), based on self-reporting from 1 (lightest) to 12 (darkest). A total of 24 participants completed the light dosimeter measurements. Phototoxic reactions were characterized by pain (97%; 34 patients), burning (97%; 34), tingling (97%; 34), pruritus (83%; 29), allodynia (89%; 31), improvement of symptoms with cold (89%; 31), achiness (24%; 12), fatigue (46%; 16), mild swelling (83%; 29), severe swelling (63%; 22), erythema (51%; 18), petechiae (40%; 14), skin cracking (43%; 15), scabbing (46%; 16), scarring (66%; 23), and other chronic skin changes (40%; 14). Patients with EPP reported that their hands, feet, and face were most sensitive to light and that their shoulders and legs were least sensitive; 25.7% (9 patient) reported no chronic skin changes, and 5.7% (2 patients) reported never having had any visible symptoms. None of these findings varied with the degree of light sensitivity except that lower overall light sensitivity was associated with lower ranked sensitivity of the neck and arms. Conclusions and Relevance: The findings of this cross-sectional study suggest that patients with EPP have distinctive cutaneous symptoms that may aid in identification of this underdiagnosed disease. Characteristic EPP symptoms include light-induced cutaneous burning pain and occasional swelling, particularly over the hands, with a prodrome of pruritus and paresthesias. Minimal skin changes or the absence of visible skin changes during reactions to light, including lack of erythema, do not exclude an EPP diagnosis nor suggest low EPP disease burden.

The use of mycophenolate mofetil for the treatment of autoimmune and chronic idiopathic urticaria: experience in 19 patients.

BACKGROUND: There is a paucity of investigation on which to base the treatment of chronic urticaria after a patient fails maximum therapy with antihistamines. One prospective, open-label, uncontrolled study suggested that mycophenolate mofetil may be a successful second-line therapy. OBJECTIVE: We sought to evaluate the efficacy and safety of mycophenolate mofetil in 19 patients with autoimmune and chronic idiopathic urticaria. METHODS: In a retrospective chart review, records of patients with autoimmune and chronic idiopathic urticaria who were evaluated between 2001 and 2009 were analyzed. RESULTS: Improvement in urticaria was observed in 89% of patients, specifically 91% of patients with autoimmune urticaria and 88% with chronic idiopathic urticaria. Time to initial improvement ranged from 1 to 9 weeks. In 59% of these patients, complete control of urticaria was achieved, which included 70% of patients with autoimmune urticaria and 43% with chronic idiopathic urticaria. Mean time to complete control was 14 weeks, with a range of less than 1 to 31 weeks. The dose of mycophenolate mofetil at complete control ranged from 1000 to 6000 mg divided twice daily. Mycophenolate mofetil was tapered in 7 of these 10 patients after an average of 7 weeks. Six of the 7 patients tapered then discontinued mycophenolate mofetil with remissions lasting between 2 and 16 weeks up to when the chart review ended. Mycophenolate mofetil was well tolerated with no serious infections or laboratory abnormalities. Gastrointestinal symptoms were most common. LIMITATIONS: This was a retrospective chart analysis. The number of patients was relatively small. CONCLUSIONS: Mycophenolate mofetil is a useful and well-tolerated second-line therapy for patients with autoimmune and chronic idiopathic urticaria in whom antihistamines and other therapeutic agents have failed.

JAK in the [Black] Box: A Dermatology Perspective on Systemic JAK Inhibitor Safety.

Janus kinase (JAK) inhibitors are immunomodulatory agents with broad potential for use within dermatology. However, the US Food and Drug Administration has recently placed additional warning labels on JAK inhibitors given concern for an increased risk of major adverse cardiovascular events, malignancy, venous thromboembolism, and mortality. Here, we summarize recent efficacy and safety data of multiple JAK inhibitors including tofacitinib, upadacitinib, baricitinib, and abrocitinib. JAK inhibitors have high efficacy in treating psoriatic arthritis and atopic dermatitis, but carry an increased risk of venous thromboembolism and cardiovascular events relative to other approved treatments. Here, we provide current considerations on balancing the benefits of JAK inhibitors with potentially serious, but low-absolute risk, safety concerns.

Progressive macular hypomelanosis.

Progressive macular hypomelanosis is an under-recognized disorder characterized by the presence of numerous ill-defined hypopigmented macules and patches on the trunk of young adults. Although common, particularly in Fitzpatrick skin types IV-VI, this condition is frequently misdiagnosed and treated inadequately with antifungals or topical steroids resulting in patient frustration. The exact pathogenesis of progressive macular hypomelanosis is unknown; however, recent studies suggest hypopigmentation results from decreased melanin formation and altered melanosome distribution in response to Proprionibacterium. While there are no well-established or consistently effective therapies for progressive macular hypomelanosis, our growing understanding of its pathogenesis urges consideration of alternative treatment strategies. Here, we report five patients with progressive macular hypomelanosis who benefitted from topical and systemic antimicrobial therapy and summarize the current clinical, pathological and treatment paradigms of this disorder.

Astrocyte secreted proteins selectively increase hippocampal GABAergic axon length, branching, and synaptogenesis.

Astrocytes modulate the formation and function of glutamatergic synapses in the CNS, but whether astrocytes modulate GABAergic synaptogenesis is unknown. We demonstrate that media conditioned by astrocytes, but not other cells, enhanced GABAergic but not glutamatergic axon length and branching, and increased the number and density of presynaptically active GABAergic synapses in dissociated hippocampal cultures. Candidate mechanisms and factors, such as activity, neurotrophins, and cholesterol were excluded as mediating these effects. While thrombospondins secreted by astrocytes are necessary and sufficient to increase hippocampal glutamatergic synaptogenesis, they do not mediate astrocyte effects on GABAergic synaptogenesis. We show that the factors in astrocyte conditioned media that selectively affect GABAergic neurons are proteins. Taken together, our results show that astrocytes increase glutamatergic and GABAergic synaptogenesis via different mechanisms and release one or more proteins with the novel functions of increasing GABAergic axon length, branching and synaptogenesis.

Vulvar Pruritus: A Review of Clinical Associations, Pathophysiology and Therapeutic Management.

Vulvar pruritus is an unpleasant sensation and frequent symptom associated with many dermatologic conditions, including infectious, inflammatory and neoplastic dermatoses affecting the female genitalia. It can lead to serious impairment of quality of life, impacting sexual function, relationships, sleep and self-esteem. In this review, common conditions associated with vulvar itch are discussed including atopic and contact dermatitis, lichen sclerosus, psoriasis and infectious vulvovaginitis. We review the potential physiologic, environmental and infectious factors that contribute to the development of vulvar itch and emphasize the importance of addressing their complex interplay when managing this disruptive and challenging symptom.

Hypertrophic discoid lupus erythematosus.

Hypertrophic discoid lupus erythematosus is a distinct form of chronic cutaneous (discoid) lupus, which is characterized by hyperkeratotic plaques that typically are observed over the face, arms, and upper trunk. We present the case of a 43-year-old man with verrucous plaques that were distributed symmetrically over the face, who initially was treated with oral antibiotics and topical glucocorticoids for acne vulgaris. A biopsy specimen confirmed the diagnosis of hypertrophic discoid lupus erythematosus. The clinical and histopathologic features of this clinical variant are reviewed.

Phototherapy for Itch.

Phototherapy is an effective treatment modality for many types of pruritus. Although the exact mechanisms by which phototherapy reduces itch vary across pruritic conditions, its effects may result from immune suppression and/or neural modulation. In this article, the authors review the efficacy of different types of phototherapy for common inflammatory and noninflammatory pruritic conditions and discuss common side effects, such as erythema and exacerbation of pruritus. Although phototherapy may be an effective and relatively safe option for skin-directed treatment of chronic itch, barriers may exist for individual patients.

Systemic drug-related intertriginous and flexural exanthema (SDRIFE).

A 72-year-old man with a history of metastatic melanoma presented with a two-day history of erythematous and edematous plaques, with scattered bullae on the neck, chest, axillae, and inguinal and gluteal folds, which began five days after infusion of an experimental drug. The clinical and histopathologic findings were consistent with systemic drug-related intertriginous and flexural exanthema (SDRIFE), which is an uncommon drug reaction that results in symmetric erythema that affects the buttocks, groin, and/or thighs as well other flexural folds. The clinical manifestations of SDRIFE are highly characteristic and include distinctive primary cutaneous lesions with a specific distribution and course; however, heterogeneity exists with respect to histopathologic features, skin test results, and in vitro investigations. The exact mechanism of SDRIFE remains unknown but is thought to result from a type IV delayed hypersensitivity immune response. Treatment is symptomatic and includes topical or oral glucocorticoids.

Yellow nail syndrome.

A 70-year-old man presented with a three-year history of thickened and slow growing, yellow-to-green, discolored fingernails and toenails with loss of lunulae and cuticles. He also had a concurrent history of chronic sinusitis with persistent productive cough. His presentation was consistent with the diagnosis of yellow nail syndrome (YNS), which is a rare disorder classically characterized by the triad of yellow dystrophic nails, lymphedema, and respiratory tract abnormalities but which more frequently manifests with only two of three features. The exact mechanism of YNS remains unknown; however, it is thought to reflect functional and/or anatomic defects in the lymphatic vasculature. Treatment options are limited and often unsuccessful, but spontaneous remission occurs in approximately 30 percent of affected patients.

Invasive squamous-cell carcinoma and arsenical keratoses.

A 42-year-old man presented with a six-month history of a slowly-enlarging ulcer on his right sole, a 30-year history of altered pigmentation of the trunk and extremities, and hyperkeratotic papules of the palms and soles. Histopathologic examination showed an invasive squamous-cell carcinoma of the right sole and hyperkeratosis with keratinocyte atypia of the left finger and left lateral foot. The clinical and histopathologic findings are consistent with chronic arsenicism, which most commonly occurs in the setting of drinking contaminated water or after occupational exposure. Evaluation should include a physical examination, basic laboratory work-up, and measurement of a 24-hour urine arsenic concentration. Vigilant surveillance for the development of cutaneous malignancies is required. Oral retinoids may be helpful in reducing hyperkeratosis secondary to chronic arsenicism.