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      Scleroderma Secondary to Pembrolizumab: A Case Report and Review of 19 Cases of Anti-PD-1-Induced Scleroderma

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          Abstract

          Immune checkpoint inhibitors are increasingly being used to treat various malignancies. Despite their efficacy, they are known to potentially cause immune-related adverse effects, including dermatological manifestations. A rare cutaneous immune-related adverse effect is scleroderma, which has been reported to occur with anti-programmed cell death-1 (PD-1) agents such as pembrolizumab and nivolumab. This may present with skin tightening and hardening at any point during or after immunotherapy. We present the case of a 54-year-old Caucasian woman who, following 16 doses of pembrolizumab for breast cancer, developed clinical features of scleroderma confirmed on histology. She was initially treated with oral corticosteroids, followed by oral psoralen-UVA, with poor response, but eventually improved with methotrexate. A literature review revealed 12 other cases of scleroderma following pembrolizumab treatment and 6 cases of scleroderma following nivolumab treatment. Males and females were both affected, and their ages ranged from 33 to 81 years. Scleroderma developed at different stages of pembrolizumab or nivolumab therapy. Although scleroderma is not commonly drug-induced, anti-PD-1 agents may be a rare cause and it is important to elicit an accurate drug history, including immunotherapy, in such cases.

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          Most cited references29

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          Transforming growth factor β--at the centre of systemic sclerosis.

          Transforming growth factor β (TGF-β) has long been implicated in fibrotic diseases, including the multisystem fibrotic disease systemic sclerosis (SSc). Expression of TGF-β-regulated genes in fibrotic skin and lungs of patients with SSc correlates with disease activity, which points to this cytokine as the central mediator of pathogenesis. Patients with SSc often develop pulmonary arterial hypertension (PAH), a particularly lethal complication caused by vascular dysfunction. Several genetic diseases with vascular features related to SSc, such as familial PAH and hereditary haemorrhagic telangiectasia, are caused by mutations in the TGF-β-sensing ALK-1 signalling pathway. These observations suggest that increased TGF-β signalling causes both vascular and fibrotic features of SSc. The question of how latent TGF-β becomes activated in local SSc tissues is, therefore, central to the understanding of SSc. Both TGF-β1 and TGF-β3 can be activated by integrins αvβ6 and αvβ8, whose upregulation in bronchial epithelial cells can activate TGF-β in SSc lungs. Other αv integrins, thrombospondin-1 or altered TGF-β sequestration by matrix proteins might be important in other target tissues. How the immune system triggers this process remains unclear, although links between inflammation and TGF-β activation are emerging. Together, these observations provide an increasingly secure framework for understanding TGF-β in SSc pathogenesis.
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            Complete remissions following immunotherapy or immuno-oncology combinations in cancer patients: the MOUSEION-03 meta-analysis

            Immunotherapy has determined unprecedented long-term responses in several hematological and solid tumors. In the MOUSEION-03 study, we conducted a meta-analysis to determine the possibility of achieving complete remissions (CR) with immunotherapy or immuno-oncology combinations in cancer patients.
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              Pembrolizumab: first global approval.

              R Poole (2014)
              Pembrolizumab [Keytruda(®) (US)], a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. Pembrolizumab has received its first global approval for the treatment of advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory review in the EU. This article summarizes the milestones in the development of pembrolizumab leading to this first approval for the treatment of malignant melanoma.
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                Author and article information

                Journal
                Case Rep Oncol
                Case Rep Oncol
                CRO
                CRO
                Case Reports in Oncology
                S. Karger AG (Basel, Switzerland )
                1662-6575
                6 September 2023
                Jan-Dec 2023
                6 September 2023
                : 16
                : 1
                : 846-856
                Affiliations
                [a ]Department of Dermatology, Mater Dei Hospital, Msida, Malta
                [b ]Department of Pathology, Mater Dei Hospital, Msida, Malta
                [c ]Department of Oncology, Sir Anthony Mamo Oncology Centre, Msida, Malta
                Author notes
                Correspondence to: Stephanie Farrugia, stephanie.f.farrugia@ 123456gov.mt
                Article
                533373
                10.1159/000533373
                10601745
                37900813
                d0139383-ba7e-4043-bd2c-e058420e1d43
                © 2023 The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) ( http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

                History
                : 28 February 2023
                : 24 July 2023
                : 2023
                Page count
                Figures: 4, Tables: 2, References: 29, Pages: 11
                Funding
                There was no funding received for this article.
                Categories
                Case Report

                Oncology & Radiotherapy
                scleroderma,pembrolizumab,nivolumab,anti-programmed cell death-1 agents,immunotherapy,case report

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