Immune-Related Adverse Effects of Cancer Immunotherapy— Implications for Rheumatology

Immune checkpoint inhibitors (ICIs) are increasingly studied and used as therapy for a growing number of malignancies. ICIs work by blocking inhibitory pathways of T-cell activation, leading to an immune response directed against tumors. Such nonspecific immunologic activation can lead to immune-related adverse events (IRAEs). Some IRAEs, including inflammatory arthritis, sicca syndrome, myositis, and vasculitis, are of special interest to rheumatologists. As use of ICIs increases, recognition of these IRAEs and developing treatment strategies will become important. In this review, the current literature on rheumatic and musculoskeletal IRAEs is summarized. The incidence, clinical presentations, and treatment considerations are highlighted.

Key points

  • By blocking inhibitory pathways of T-cell activation, immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (IRAEs), including inflammatory arthritis, myositis, vasculitis, and sicca syndrome.

  • Treatment of ICI-induced rheumatic IRAE requires different considerations than treatment of classic rheumatic conditions.

  • Using ICIs in those with preexisting autoimmunity is possible but with risk of causing a disease flare or a different IRAE.


Interactions between the immune system and cancer are complex, dynamic, and bidirectional. One of the primary roles of the immune system is to recognize and eliminate cells that have undergone malignant transformation, often before a developing tumor can become clinically apparent. In some instances, successful tumor elimination does not occur, and a malignancy may be held in equilibrium where further tumor growth is prevented. Cancers that grow and reach clinical detection, however, have often developed successful strategies to evade naturally occurring host immune responses. To combat this, immunotherapeutic agents are being used to harness the power of the immune system, by increasing the quality or quantity of immune effector cells, eliciting immune responses to specific tumor antigens, or inhibiting mechanisms that cancers develop to evade immunologic surveillance and killing mechanisms.

Immunotherapy approaches to cancer began in the 1980s, when recombinant interleukin (IL)-2 was administered for metastatic melanoma with tumor regression seen in a subset of patients. Since then, cancer vaccines and T-cell infusions have also been used successfully to treat a variety of malignancies. IL-2, T-cell infusions, and cancer vaccines all work by directly activating the immune system, thus augmenting host immune responses against malignancies. Another class of cancer therapies, the main focus of this article, works differently. These therapies, known as immune checkpoint inhibitors (ICI), work in part by targeting immunoregulatory pathways exploited by some cancers. Several inhibitory pathways, known as immunologic checkpoints, play critical roles in maintaining self-tolerance and preventing autoimmunity. Multiple tumor types, however, can appropriate immune checkpoint pathways to increase immune resistance in the tumor microenvironment. T cells require both the interaction of the major histocompatibility complex molecule on an antigen-presenting cell (APC) with the T-cell receptor and the second signal of another ligand-receptor interaction to become activated. An example of this is the interaction between B7 molecules (CD80/86) on APCs with CD28 on T cells. B7 can also bind instead to an inhibitory receptor, cytotoxic lymphocyte antigen 4 (CTLA-4) or CD154 ( Fig. 1 A). When this engagement occurs, the T cell does not become activated. Other immune checkpoints have also been identified and are targets for cancer immunotherapy. Another major immune checkpoint pathway is mediated through the programmed death protein-1 (PD-1) expressed on T cells and programmed death ligand (PD-L)1 expressed on APCs and also on many tumors, where it serves as to dampen the T-cell–mediated response and facilitate immunologic evasion (see Fig. 1 A). ICIs nonspecifically activate T cells by blocking negative costimulatory ligands or receptors on T cells, APCs, and/or tumor cells.

Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Immune-Related Adverse Effects of Cancer Immunotherapy— Implications for Rheumatology
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