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Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy

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Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy biology Review Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy Anca Bobircă 1,†, Florin Bobircă 2,†, Ioan Ancuta 1,†, Alesandra Florescu 3, Vlad Pădureanu 4,* , 5, 6, 7 8 Dan Nicolae Florescu *, Rodica Pădureanu * , Anca Florescu and Anca Emanuela Mus, etescu 1 Department of Internal Medicine and Rheumatology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; [email protected] (A.B.); [email protected] (I.A.) 2 Department of General Surgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; fl[email protected] 3 Department of Rheumatology, Emergency Clinical County Hospital of Craiova, 200642 Craiova, Romania; [email protected] 4 Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania 5 Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania 6 Department of Internal Medicine, Emergency Clinical County Hospital of Craiova, 200642 Craiova, Romania 7 Department of Internal Medicine and Rheumatology, Dr. I Cantacuzino Hospital, 030167 Bucharest, Romania; anca-teodora.fl[email protected] 8 Department of Rheumatology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; [email protected] * Correspondence: [email protected] (V.P.); dan.fl[email protected] (D.N.F.); [email protected] (R.P.) † All these authors contributed equally to this work. Citation: Bobirc˘a,A.; Bobirc˘a,F.; Ancuta, I.; Florescu, A.; P˘adureanu, Simple Summary: Cancer therapy has evolved over the years, immunotherapy being the most used V.; Florescu, D.N.; P˘adureanu, R.; for untreatable malignant tumors. Immune checkpoint inhibitors decrease the ability of tumor cells Florescu, A.; Mus, etescu, A.E. to escape the immune system. Although immune checkpoint inhibitors have a significant impact Rheumatic Immune-Related Adverse in the treatment of cancer, they are associated with various adverse effects, mostly inflammation. Events—A Consequence of Immune The adverse events related to the immune system may affect basically every tissue in the human Checkpoint Inhibitor Therapy. Biology body, including the digestive tract, endocrine glands, liver, skin, cardiovascular, pulmonary and, also, 2021, 10, 561. https://doi.org/ rheumatic systems. In this review, we address the rheumatic immune-related adverse events related 10.3390/biology10060561 to immunotherapy by depicting the characteristics, diagnostic approach and treatment options. Academic Editors: Rongtuan Lin and Abstract: The advent of immunotherapy has changed the management and therapeutic methods Alessandra Soriani for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, Received: 6 May 2021 which works by interfering with cancer cell growth via various pathways and stages of the cell Accepted: 16 June 2021 cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape Published: 20 June 2021 the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic Publisher’s Note: MDPI stays neutral adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune with regard to jurisdictional claims in system hyperactivation, which, as expected, is associated with various adverse events defined by published maps and institutional affil- inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect iations. any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the Copyright: © 2021 by the authors. diagnostic approach and management. Licensee MDPI, Basel, Switzerland. This article is an open access article Keywords: immune checkpoint inhibitors; immune-related adverse events; arthritis; pneumonitis distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Biology 2021, 10, 561. https://doi.org/10.3390/biology10060561 https://www.mdpi.com/journal/biology Biology 2021, 10, 561 2 of 14 1. Introduction The advent of immunotherapy has changed the management and therapeutic options methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. Immunotherapy may be divided into two types: passive and active. Immunoglobulins are considered to be a passive therapy method and bind to tumor-associated antigens, causing the immune system to clear them. The active type of immunotherapy works by activating the immune system to destroy tumor cells and target tumor antigens. Immune checkpoint inhibitor (ICI) therapy is considered an active category of immunotherapy [1,2]. Cell surface receptors such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) are targeted by ICIs, which cause tumor cells to be destroyed by the immune system. Nowadays, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved, after several clinical trials, the following immune checkpoint- blocking antibodies in cancer patients: anti-CTLA-4 (Ipilimumab); anti-PD-1 (Nivolumab, pembrolizumab and cemiplimab) and anti-PD-L1 (atezolizumab, avelumab and durval- umab) [3,4]. Ipilimumab was first approved for late-stage surgically unresectable melanoma in 2011 by the FDA based on the results of the MDX010-020 trial and is nowadays approved for the treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancer, in combination with Nivolumab [5]. Nivolumab was first approved by the FDA in 2014 for late-stage unresectable/metastatic melanoma, following the outcome of the CheckMate-037 trial, which proved to have fewer toxic adverse events than Ipilimumab [6]. Currently, Nivolumab is approved for both small and non-small cell lung carcinoma, advanced renal cancer, Hodgkin’s lymphoma, recurrent or metastatic squamous cell cancer of the head and neck, urothelial cancer, colorectal cancer and hepatocellular carcinoma [7]. Pembrolizumab, a human IgG4k monoclonal antibody against PD-1, was first ap- proved in 2014 after the clinical trial NCT01295827 for patients with metastatic melanoma who were refractory to CTLA-4 treatment [8]. After several clinical trials, pembrolizumab is currently approved for metastatic non-small- cell lung cancer, metastatic non-squamous non-small cell lung cancer, non-small cell lung cancer, recurrent or metastatic squamous cell cancer of the head and neck, Hodgkin’s lymphoma, urothelial cancer, third-line therapy for locally advanced or metastatic gastric/gastroesophageal junction/esophageal adenocarci- noma, mediastinal large B-cell lymphoma, hepatocellular carcinoma, Merkel cell carcinoma and metastatic renal cell carcinoma, with several levels of recommendations [9]. Cemiplimab was first approved by the FDA in 2018 for the treatment of locally ad- vanced, metastatic cutaneous squamous cell carcinoma in patients who are not candidates for a curative surgery of radiation [10]. Avelumab received FDA approval in 2015 following the JAVELIN Merkel 200 trial for metastatic Merkel cell carcinoma with progressive disease or after chemotherapy and is nowadays also approved for urothelial carcinoma and renal cell carcinoma [11]. Durvalumab was approved in 2016 for the treatment of inoperable or metastatic urothelial bladder cancer and later approved for stage III non-small cell lung cancer [12]. Atezolizumab received its first approval in 2016 for locally advanced or metastatic urothelial carcinoma based on the IMvigor210 trial. Later on, it became approved following several clinical trials for metastatic non-small cell lung cancer, non-squamous non-small cell lung cancer, extensive-stage small-cell lung cancer and locally advanced or metastatic triple-negative breast cancer [3]. Biology 2021, 10, 561 3 of 14 2. Mechanism of Development of Immune-Related Adverse Events ICIs work by inhibiting the signal pathways that suppress tumor destruction mediated by T cells. T-lymphocytes normally play an important role in the cell-mediated clearance of cancer cells. Antigen-presenting cells are activated in the presence of a non-self cell, such as a tumor cell. A tumor antigen is incorporated and presented by cells, such as dendritic cells or macrophages, via a major histocompatibility complex, which then binds to a T-cell receptor. T cells become activated in the presence of a costimulatory interaction, such as the one represented by the CD28 receptor, initiating a cascade of antitumor activity. Various inhibitor receptors are upregulated during the T-cell activation process, acting as immune checkpoints to limit the overstimulation of the immune response. The CTLA-4 and PD-1 pathways, which have the normal function of suppressing
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