Purpose: Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies. Experimental Design: Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN). Results: Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions. Conclusions: As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023–9. ©2016 AACR.
Urticaria is a common, mast cell-driven disease presenting with wheals or angioedema or both. In the last years, urticaria has increasingly attracted notice to clinicians and researchers, last but not least inspired by the approval of omalizumab, an anti-IgE antibody, for urticaria treatment. There is wide consensus on the clinical classification based on duration and elicitation. However, the pathogenesis is incompletely understood. This review summarizes current guidelines for the management and novel insights in the pathogenesis of urticaria with special focus on their impact on clinical praxis. The classification of urticaria subgroups is mainly based on clinical criteria: acute and chronic urticaria (CU). Chronic urticaria comprises both chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU) that includes physical and non-physical urticarias. Recent research focused on characterizing the role of cells and mediators involved in the pathogenesis of urticaria, identifying the mechanisms of mast cell activation, and investigating underlying autoimmune processes in chronic spontaneous urticarial. Currently, non-sedating antihistamines and omalizumab, an antiimmunoglobulin E antibody, are recommended for the therapy of chronic urticaria, as both exhibit a favorable efficacy and safety profile. Novel therapeutic strategies aim at specifically targeting cells and mediators involved in the pathogenesis of urticaria.
Switching from immunotherapy to targeted therapy in metastasized melanoma can be complicated by a cytokine release syndrome (CRS). CRS is a serious complication, which is induced by high levels of circulating cytokines, associated with T-cell engagement and proliferation, and results in a constellation of symptoms with variable organ involvement. We report 2 patients with BRAF V600 mutant melanoma who were previously treated with anti-PD-1±anti-LAG-3 antibodies and were switched to BRAF/MEK-inhibitors because of progressive disease. Both cases depict the complexity of interactions occurring during sequential treatment with immune checkpoint inhibitors and kinase inhibitors. Early identification and management of CRS is crucial to decrease its toxicity and improve safety of further drugs to be given in a therapeutic ladder.
Background Hymenoptera stings are a major cause of anaphylaxis. Various risk factors are discussed in literature. This study aims to investigate potential risk factors for severe sting reactions in wasp (Vespula spp.) and honeybee (Apis mellifera) venom allergic patients and analyses the correlation between diagnostic test results and the severity of the allergic reaction. Methods 480 patients suffering from wasp or honeybee venom allergy were included in this retrospective case series. Only individuals allergic to Vespula spp. but not to other vespids such as Polistes were considered. The severity of their systemic field sting reaction was analysed with regard to the amount of specific IgE antibodies to whole venom extracts and to major allergens of honeybee and/or wasp venom. Furthermore, the following potential risk factors for severe sting reactions were examined: age, sex, latency time, skin symptoms, baseline serum tryptase levels and the concentration of venom inducing a positive intracutaneous test. Results The two following indicators for severe systemic sting reactions in honeybee and wasp venom allergic patients have been identified: a short latency time and the absence of skin symptoms. The patient’s age and baseline serum tryptase levels have been found to positively correlate with the grade of the sting reaction only in individuals allergic to wasp venom. No correlation could be found between the degree of sensitisation and the severity of the allergic reaction. Neither the amount of specific IgE antibodies to whole venom extracts nor to major allergens were significantly associated with the severity of the sting reaction. Conclusion The clinical history is essential for the allergological workup and therapeutic decision on Hymenoptera venom allergies. A short latency time and the absence of skin symptoms are indicators for severe systemic sting reactions, followed by the patient’s age and baseline serum tryptase levels.
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