1. Introduction

The notion of immune system manipulation to achieve antitumor effect entails decades of basic research effort, but it has only recently achieved broad clinical implementation in the field of oncology. Better understanding of tumor genetics and immune surveillance mechanisms is necessary to fight cancer in a more efficient and effective way ^[1]. While our immune system recognizes cancer cells, it is restrained by various “checkpoints”; molecules such as cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand PD-L1 act as brakes restricting T cell effector functions. This process is important for homeostasis and autoimmunity prevention in healthy organisms, but on the other hand it dampens critical T cell cytotoxic functions against tumor cells in cancer patients. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies which target checkpoint molecules and have significant clinical efficacy, rendering immune checkpoint blockade an emerging therapeutic approach in cancer ^[2]. There is a major expansion in the number of clinical trials involving multiple immunotherapy agents in a variety of cancer types, with lung cancer, melanoma, breast cancer, lymphoma and head and neck cancer being the most studied ones ^[3].

The widespread implementation of ICIs over the last decade has provided important data on their toxicity profile ^[4]. The attenuation of T cell inhibitory mechanisms by ICIs leads to hyperactivation of the immune system; as probably expected, this associates with a variety of adverse events characterized by inflammation. Target sites of these adverse events, usually termed as immune-related adverse events (ir-AEs) can include every tissue in the human body, including the gastrointestinal tract, endocrine glands, liver and skin, while cardiovascular, pulmonary and rheumatic ir-AEs are also reported ^[5].

In this review, rheumatic manifestations in the context of ICI therapy will be discussed. Musculoskeletal and non-musculoskeletal clinical manifestations will be separately analyzed, along with current data concerning imaging and treatment.

2. Discussion

Rheumatic ir-AEs are relatively common and are increasingly recognized. Even though in most cases they are mild/moderate and not life-threatening, they should be diagnosed and managed early since they are associated with pain and functional impairment. Moreover, in light of newer evidence that musculoskeletal ir-AEs may correlate with a favorable tumor response, the appropriate management of these patients by a multidisciplinary team comprised of oncologists and rheumatologists appears to be of critical significance; in this way, patients may be treated effectively and immunotherapy could be maintained.

Rheumatic ir-AEs can be classified as musculoskeletal and non-musculoskeletal. Overall, musculoskeletal manifestations induced by ICI therapy are relatively common, developing in approximately 5%–7.7% of patients according to the prospective studies reported so far. The clinical syndromes most often described are inflammatory arthritis, PMR and myositis. A rheumatology referral is needed in all cases of new-onset inflammatory arthralgia or joint swelling. In most cases of inflammatory arthritis and PMR, ICI therapy may be continued; the majority of patients respond to steroids of less than 20 mg of prednisolone. ICI-induced myositis may have atypical features such as muscle pain or even normal CPK levels. Usually it is the most severe musculoskeletal manifestation induced by ICIs and frequently requires permanent immunotherapy cessation and treatment with high-dose steroids.

The most common forms of non-musculoskeletal rheumatic ir-AEs are sicca, vasculitides and sarcoidosis/sarcoid-like reactions. Cases of SLE and SSc are extremely rare. Of note, ICI-induced rheumatic syndromes appear to have significant differences from their idiopathic counterparts. For example, in most cases, ICI-induced inflammatory arthritis does not have the typical features of RA. Table 1 summarizes all major differences between ICI-induced syndromes and idiopathic counterparts. These data point to the direction that rheumatic ir-AEs are indeed novel clinical entities that should be thoroughly investigated and may not share common pathogenetic mechanisms with idiopathic rheumatic diseases.

In conclusion, the management of ir-AEs in oncologic patients ideally requires a multidisciplinary team with the participation of a rheumatologist. Rheumatic ir-AEs are relatively common; these manifestations should be managed effectively in order to preserve the quality of life of patients with cancer. Large-scale, prospective studies are needed to better delineate the prevalence and clinical characteristics of ICI-induced rheumatic syndromes and to develop relevant therapeutic guidelines.

Table 1. Main differences between ICI-induced rheumatic syndromes and their idiopathic counterparts.

ICI = immune checkpoint inhibitor, RA = rheumatoid arthritis, PMR = polymyalgia rheumatica, ILD = interstitial lung disease, ANCA = antineutrophil cytoplasmic antibodies, DMARDs = disease-modifying antirheumatic drugs, SLE = systemic lupus erythematosus.