Acquired lipodystrophy associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors have become the mainstay of treatment for metastatic melanoma. This article presents a new case of acquired generalised lipodystrophy (AGL) during anti-programmed cell death-1 (anti-PD-1) therapy and a systematic review of the literature with an aim to further understand the pathogenesis. A comprehensive search was conducted using PubMed, Embase, MEDLINE and Cochrane Central databases. We identified four cases of lipodystrophy associated with anti-PD-1 immunotherapy, including our own. Of these, three were associated with nivolumab, and one with pembrolizumab. Body composition changes occurred at a median of 7 months after anti-PD-1 initiation. All cases reported AGL, with subcutaneous fat loss affecting majority of the body. There were three reported cases of insulin resistance associated with AGL. AGL should be a recognised adverse event associated with anti-PD-1 therapy.

Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.

BACKGROUND: The treatment response to new immunotherapy in advanced melanoma patients remains varied between individuals. Immune-related cutaneous side effects might have prognostic value. OBJECTIVE: To determine whether development of ≥1 of the 3 immune-mediated cutaneous events (eczema, lichenoid reaction, or vitiligo-like depigmentation) is associated with improved progression-free survival. METHODS: A cohort study of adults with stage IIIC-IV melanoma treated with pembrolizumab or nivolumab during May 1, 2012-February 1, 2018, at Westmead Hospital, Sydney, Australia. Treatment response was based on iRECIST version 1.1. RESULTS: In total, 82 patients of an average age of 59.9 years were included. Median follow-up was 40.7 months; 33 patients had ≥1 target skin reaction. Skin reactions developed in one-third of individuals by 6 months. At any given time, the instantaneous risk of disease progression and death was lower for individuals who had ≥1 cutaneous adverse event (CAE) develop. Compared with individuals with no CAE, the hazard ratio for disease progression and death for individuals who had ≥1 CAE develop was 0.46 (95% confidence interval 0.23-0.91; P = .025) by the time-dependent Cox proportional hazards model. LIMITATIONS: Single-center study. CONCLUSION: This study demonstrates an association between the development of ≥1 of 3 CAEs and improved progression-free survival in this cohort of patients.

Retrospective evidence on outcomes and experiences of pregnancy and childbirth in epidermolysis bullosa in Australia and New Zealand.

BACKGROUND: Pregnancy in epidermolysis bullosa (EB) has not been comprehensively studied. OBJECTIVE: We aimed to develop a foundational database, which could provide peri-obstetric advice in EB. METHODS: Survey questionnaires were sent to obstetricians, unaffected mothers of EB babies, and mothers with EB. Results were analyzed using chi-square, Fisher exact, and t-tests. RESULTS: Out of 1346 obstetricians surveyed, 195 responded, and only 14 had encountered EB. All recommended normal vaginal delivery (NVD), except for one elective Caesarean section (CS). We received responses from 75 unaffected mothers who had delivered EB babies. They had significantly more complications in their EB pregnancies compared to their non-EB pregnancies. A further 44 women with various types of EB who had given birth responded. Most delivered via NVD and had no significant increase in complications in both their EB and non-EB pregnancies. In both groups, there were no significant differences in blistering at birth in babies delivered via NVD and CS. CONCLUSION: In conclusion, most patients with EB who are capable of giving birth do not have an increased risk for pregnancy-related complications and NVD appears to be safe. Awareness of this data amongst obstetricians and dermatologists should lead to improved quality of care for mothers and babies affected with EB.

Acute Truncal Lymphedema Secondary to Axillary Metastatic Melanoma Presenting Like Cellulitis.

There are reported cases of diphencyprone used in treating cutaneous metastases of melanoma. Here, we report a patient with previous primary melanoma on his left back treated with surgical excision and lymphadenectomy, followed by radiotherapy for the recurrent tumor on the primary site. Despite radiotherapy and treatment with dabrafenib and trametinib, in-transit metastases have developed and topical diphencyprone was applied to these metastases. Six weeks later, the patient developed fever and a spreading erythematous tender indurated plaque covering the left side of the body including axillae, back, and flank, clinically suggestive of cellulitis. Systemic antibiotic therapy did not improve the condition and a biopsy showed sparse lymphocytic infiltrate. With the diagnosis of possible acute lymphedema, a CT scan was requested that showed significant axillary lymph node metastasis. The fever was considered secondary to dabrafenib and trametinib therapy. This case highlights that, in patients with lymphadenectomy, atypical forms of lymphedema on the body may appear. Truncal lymphedema is an infrequent event.

PD-1 inhibitors induced bullous lichen planus-like reactions: a rare presentation and report of three cases.

The introduction of immunotherapy such as antiprogrammed death1 (anti-PD1) monoclonal antibodies has changed the scenario of treatment in cancer. Apart from their impressive efficacy profiles, they are better tolerated than the anticytotoxic T-lymphocyte-associated protein 4 antibodies. Dermatological adverse events such as pruritus and rash have been reported in various clinical trials. We report three cases of anti-PD1-induced bullous lichen planus (LP)-like reactions encountered in our institution. These patients developed LP-like papules and annular plaques with vesicles or crusted centres. Histology showed LP-like changes with negative immunofluorescence. Vesiculobullous lesions in patients treated with anti-PD1 therapies require a careful clinicopathological evaluation.

Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies.

Anti-programmed cell death 1 (anti-PD1) antibodies such as pembrolizumab have shown improved progression-free and overall survival in patients with advanced melanoma. Of 124 patients reviewed in Westmead Hospital from May 2012 to November 2015, treated with pembrolizumab for advanced melanoma, we encountered three cases of bullous pemphigoid (BP). We have previously reported a case of BP. In two recent cases, BP was diagnosed early and treated promptly with potent topical or oral steroid. Patients on anti-PD1 antibodies are at a higher risk of developing cutaneous immune-related adverse events such as lichenoid reactions, eczema and vitiligo. No cases of BP were encountered in the previously published cohort of 260 melanoma patients treated with BRAF inhibitors; as such, it appears that BP is associated with anti-PD1 treatment rather than metastatic melanoma. BP appears to be another immune-related adverse event, and clinicians should have a low threshold for performing cutaneous biopsies and immunofluorescence studies in patients on anti-PD1 therapies.

Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with metastatic melanoma.

Ipilimumab is a new anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that stimulates the immune response against melanoma. A 50-year-old man received ipilimumab for metastatic melanoma as part of a clinical trial. Two weeks after drug initiation, he developed a widespread oedematous erythema with sterile pustules. The histological examination showed subcorneal pustulosis formation with eosinophils. The clinical-pathological correlation was consistent with acute generalized exanthematous pustulosis. The symptoms resolved within 25 days after discontinuation of ipilimumab. We suspect that neutrophilic accumulation under the epidermis in this patient is a phenomenon similar to intraepithelial neutrophils aggregating on the surface epithelium over laminar propria in ipilimumab-induced colitis. To our knowledge, this is the first reported case of acute generalized exanthematous pustulosis associated with ipilimumab use in metastatic melanoma patients.

Retrospective evidence on outcomes and experiences of pregnancy and childbirth in epidermolysis bullosa in Australia and New Zealand.

BACKGROUND: Pregnancy in epidermolysis bullosa (EB) has not been comprehensively studied. OBJECTIVE: We aimed to develop a foundational database, which could provide peri-obstetric advice in EB. METHODS: Survey questionnaires were sent to obstetricians, unaffected mothers of EB babies, and mothers with EB. Results were analyzed using chi-square, Fisher exact, and t-tests. RESULTS: Out of 1346 obstetricians surveyed, 195 responded, and only 14 had encountered EB. All recommended normal vaginal delivery (NVD), except for one elective Caesarean section (CS). We received responses from 75 unaffected mothers who had delivered EB babies. They had significantly more complications in their EB pregnancies compared to their non-EB pregnancies. A further 44 women with various types of EB who had given birth responded. Most delivered via NVD and had no significant increase in complications in both their EB and non-EB pregnancies. In both groups, there were no significant differences in blistering at birth in babies delivered via NVD and CS. CONCLUSION: In conclusion, most patients with EB who are capable of giving birth do not have an increased risk for pregnancy-related complications and NVD appears to be safe. Awareness of this data amongst obstetricians and dermatologists should lead to improved quality of care for mothers and babies affected with EB.