Immune Checkpoint Inhibitor Related Rheumatological Complications: Cooperation between Rheumatologists and Oncologists

Abstract

In cancer, immune checkpoint inhibitors (ICIs) improve patient survival but may lead to severe immune-related adverse events (irAEs). Rheumatic irAEs are a distinct entity that are much more common in a real-life than in clinical trial reports due to their unspecific symptoms and them being a rare cause of hospitalization. This review focuses on an interdisciplinary approach to the management of rheumatic irAEs, including cooperation between oncologists, rheumatologists, and immunologists. We discuss the immunological background of rheumatic irAEs, as well as their unique clinical characteristics, differentiation from other irAEs, and treatment strategies. Importantly, steroids are not the basis of therapy, and nonsteroidal anti-inflammatory drugs should be administered in the front line with other antirheumatic agents. We also address whether patients with pre-existing rheumatic autoimmune diseases can receive ICIs and how antirheumatic agents can interfere with ICIs. Interestingly, there is a preclinical rationale for combining ICIs with immunosuppressants, particularly tumor necrosis factor α and interleukin 6 inhibitors. Regardless of the data, the mainstay in managing irAEs is interdisciplinary cooperation between oncologists and other medical specialties.

Keywords: cancer immunotherapy; immune checkpoint inhibitors; immune-related adverse events; rheumatic adverse events.

Figure 1

Immunological synapse with stimulatory/inhibitory receptors and interactions between immune cells. Checkpoint inhibitory agents (in a solid line frame) registered by European Medicines Agency and/or U.S. Food and Drug Administration are presented (in green color) with examples of molecules that are currently under evaluation in clinical trials (in red color). Two signals are required to induce T-cell response: (1) presentation of the antigen bound to major histocompatibility complex (MHC) on the antigen-presenting cell (APC) surface followed by its recognition by the specific T-cell receptor (TCR) (left-hand side), and (2) cluster of differentiation (CD) 28 and CD80/CD86 interaction—second stimulating signal (right-hand side). Ligands on APCs (stimulatory/inhibitor receptors) determine the response of T cells. With immune checkpoint inhibitors, activated T cells release inflammatory cytokines that act against malignant cells and can cause immune-related adverse events as an off-target effect. The presented mechanisms of immunosuppressive agents (in a dotted line frame) are simplified. Classic immunosuppressive/immunomodulatory agents are in violet. New medications with more precise, tailored action modes, such as biologics or tyrosine kinase inhibitors, are in black. They are registered in rheumatic diseases but can also be used to manage rheumatic immunologic-related adverse events of immunologic checkpoint inhibitors in oncology. Abbreviations: APC—antigen-presenting cell, CD—cluster of differentiation, CTLA-4—cytotoxic T-lymphocyte antigen 4, GAL9—galectin 9, ICOS/ICOSL—inducible T-cell co-stimulator/ligand, IFN—interferon, IL—interleukin, LAG-3—lymphocyte activation gene 3 protein, PD-1/PD-L1 programmed cell death protein 1/ligand, TIGIT—T-cell immunoreceptor with immunoglobulin and ITIM domains, TIM-3—T-cell immunoglobulin mucin receptor 3, VISTA/VISTA-R—V-domain Ig suppressor of T-cell activation/receptor, TCR—T-cell receptors, TNFα—tumor necrosis factor alpha.