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.

Chronic Pruritus: A Review.

Importance: Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Approximately 1% of physician visits are for the chief concern of chronic pruritus. Chronic pruritus is associated with adverse outcomes, including impaired sleep and reduced quality of life. Observations: Chronic pruritus can be categorized by etiology into inflammatory, neuropathic, or a combination of inflammatory and neuropathic pruritus. Chronic pruritus is due to inflammation in approximately 60% of patients and may be caused by eczema, psoriasis, or seborrheic dermatitis. Chronic pruritus is due to a neuropathic or mixed etiology in approximately 25% of patients. Neuropathic causes of chronic pruritus include postherpetic neuralgia and notalgia paresthetica and are typically due to localized or generalized nerve dysregulation. Approximately 15% of people with chronic pruritus have other causes including systemic diseases with secondary itch, such as uremic pruritus and cholestatic pruritus, medication-induced pruritus such as pruritus due to immunotherapy, and infectious etiologies such as tinea corporis and scabies. When few primary changes are present, a thorough history, review of symptoms, and laboratory evaluation should be performed, particularly for people with chronic pruritus lasting less than 1 year. Clinicians should consider the following tests: complete blood cell count, complete metabolic panel, and thyroid function testing to evaluate for hematologic malignancy, liver disease, kidney disease, or thyroid disease. First-line treatment for inflammatory chronic pruritus includes topical anti-inflammatory therapies such as hydrocortisone (2.5%), triamcinolone (0.1%), or tacrolimus ointment. Approximately 10% of patients do not respond to topical therapies. In these patients, referral to dermatology and systemic oral or injectable treatments such as dupilumab or methotrexate may be considered. When no underlying systemic disease associated with pruritus is identified, patients are likely to have neuropathic chronic pruritus or mixed etiology such as chronic pruritus of unknown origin. In these patients, neuropathic topical treatments such as menthol, pramoxine, or lidocaine can be used either alone or in combination with immunomodulatory agents such as topical steroids. Other effective therapies for neuropathic pruritus include gabapentin, antidepressants such as sertraline or doxepin, or opioid receptor agonist/antagonists such as naltrexone or butorphanol. Conclusions and Relevance: Chronic pruritus can adversely affect quality of life and can be categorized into inflammatory, neuropathic, or a combined etiology. First-line therapies are topical steroids for inflammatory causes, such as hydrocortisone (2.5%) or triamcinolone (0.1%); topical neuropathic agents for neuropathic causes, such as menthol or pramoxine; and combinations of these therapies for mixed etiologies of chronic pruritus.

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.

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.

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.

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.

Modulation of the kappa and mu opioid axis for the treatment of chronic pruritus: A review of basic science and clinical implications.

Introduction: Treating chronic pruritus is challenging for dermatologists due to the lack of therapeutic options. We review the effects of κ-opioid receptor (KOR) and µ-opioid receptor (MOR) in the modulation of itch, summarize evidence supporting the efficacy and safety of opioid receptor-targeting agents in chronic pruritus, and address clinical considerations. Results: Preclinical studies have found neural pathways underlying detection, transmission, and modulation of itch signaling and spotlighted the importance of neuronal KOR and MOR in itch perception. Clinical reports suggest that opioid axis modulation may be the basis for the successful treatment of chronic itch. Several agents (MOR antagonist naltrexone; KOR agonists nalfurafine and difelikefalin; dual-acting KOR agonists/MOR antagonists butorphanol and nalbuphine) have been evaluated for treating chronic pruritus in case series, small studies, and clinical trials; nalbuphine has progressed through preliminary (phase II/III) studies in uremic pruritus and prurigo nodularis. The antipruritic efficacy of these agents has been observed across multiple disorders with disparate etiologies, suggesting the potential utility of this class to provide a unified approach to chronic pruritus treatment. Conclusions: The relative safety of these agents, including a reduced potential for dependence versus MOR-agonist analgesics, should help overcome resistance to the use of opioid receptor-targeting agents in chronic pruritus treatment.

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.

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.

Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus.

BACKGROUND: Prurigo nodularis (PN) is a chronic disease characterized by intensely pruritic, raised, nodular lesions. Because there are currently no United States Food and Drug Administration-approved therapies specifically for PN, management is highly variable, and no consensus exists on treatment regimens. OBJECTIVE: To provide practical guidance to help United States dermatologists diagnose and effectively treat patients with PN. METHODS: We participated in a roundtable discussion to develop consensus recommendations on diagnosis and treatment of PN from a United States perspective. RESULTS: The core findings in PN are the presence of firm, nodular lesions; pruritus lasting at least 6 weeks; and a history or signs, or both, of repeated scratching, picking, or rubbing. The diagnostic workup involves a complete review of systems, considering potential systemic diseases, and assessment of disease severity, including disease burden and pruritus intensity. Treatment should be selected based on a patient's clinical presentation, comorbidities, and response to prior treatments and should address both neural and immunologic components of pruritus. LIMITATIONS: Data on PN are from anecdotal or small clinical trials, and all treatments are currently used off-label. CONCLUSION: An effective treatment approach for patients with PN should be based on clinical judgment and tailored to the individual needs of the patient.

Epidemiology and Comorbidities of Excoriation Disorder: A Retrospective Case-Control Study.

Excoriation disorder is a psychocutaneous disorder characterized by repetitive skin-picking and associated with significant morbidity. Currently, epidemiological data in patients with excoriation disorder are lacking so we sought to characterize common patient demographics and comorbidities. We conducted a retrospective case-control study comparing 250 patients with excoriation disorder with 250 age-, race- and sex-matched controls identified between 2007 and 2019 at a single tertiary care center. We found that the majority of excoriation disorder patients were female (76%), Caucasian (82%) and unmarried (62%), with a mean age of 49 years. Compared to the matched controls, patients with excoriation disorder had increased odds of several psychiatric illnesses, including obsessive compulsive disorder (odds ratio (OR) 28.48, 95% confidence interval (CI): 1.68, 481.75), substance use disorder (OR 24.33, 95% CI: 5.81, 101.77), post-traumatic stress disorder (OR 8.23, 95% CI: 2.24, 129.40), depression (OR 8.19, 95% CI: 4.86, 13.80), bipolar disorder (OR 7.55, 95% CI: 2.22, 25.65), attention-deficit/hyperactivity disorder (OR 5.63, 95% CI: 1.62, 19.57), and anxiety (OR 5.01, 95% CI: 2.92, 8.62). Only a minority (42%) of patients were given psychiatry referrals and of those referred, a majority (64%) did not follow-up with psychiatry. The outcomes were also generally unfavorable as only 21% of patients experienced a resolution or improvement in their symptoms. This highlights the need for a multidisciplinary approach to manage patients with excoriation disorder, involving both dermatologists and psychiatrists.

Diagnostic and treatment algorithm for chronic nodular prurigo.

Chronic nodular prurigo (CNPG) is a subtype of chronic prurigo, also called prurigo nodularis, and a chronic skin condition characterized by intensely pruritic nodular lesions. Although the exact cause of CNPG is unknown, it appears to result from a repetitive itch-scratch cycle induced by neuronal sensitization to chronic pruritus. CNPG is associated with an underlying dermatologic condition in about half of patients, and it can also be attributed to systemic, neurologic, psychogenic, or unknown causes. For most patients, multiple underlying causes are identified. Patients with CNPG often experience impaired quality of life, sleep disturbance, anxiety, and depression. To encourage consistent and accurate diagnosis and treatment of CNPG across regions, we are proposing a diagnostic and treatment algorithm that includes initial assessment of core symptoms, detailed dermatologic history and clinical examination, patient-reported outcomes, diagnostic workup, and recommended therapies. This information is supplemented with photographs to illustrate clinical appearance and disease severity. Because CNPG is often multifactorial and it can take months to years for lesions to heal, interdisciplinary cooperation and long-term management are important.

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.

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.