Immune Checkpoint Inhibitors and Vasculitis

Patrick Boland; Jacqueline Heath; Sabina Sandigursky

Disclosures

Curr Opin Rheumatol. 2020;32(1):53-56. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: Clinical use of immune checkpoint inhibitor (ICI) therapy has revolutionized the therapeutic landscape of cancer. By activating the immune system using monoclonal anti-CTLA-4 and PD(L)-1 antibodies, remission can be induced in previously terminal cancers. However, these breakthroughs come at a price. Multiple de-novo autoimmune illnesses, termed immune-related adverse events (irAEs), have been reported with patients increasingly being referred to rheumatologists with varying diagnoses. Among these are vasculitic syndromes, which may be limited to an organ or systemic and potentially-life threatening. Relatively little is known about the prevalence, mechanisms, and phenotypes of vasculitis occurring in response to ICIs. Here, we review the literature and describe the frequency and patterns of presentation.

Recent findings: Vasculitis, while infrequent, has been described as an irAE in patients treated with ICI therapy with resultant morbidity and mortality.

Summary: Recognizing the risk and management of immune checkpoint inhibitor induced vasculitis in patients with cancer is important in the daily practice of rheumatology.

Introduction

Immune checkpoint inhibitors (ICIs) are a new class of antineoplastic antibodies blocking inhibitory co-receptors on T cells. There are two classes of immune checkpoint receptor antibodies currently available, targeting either the cytotoxic T lymphocyte associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway. In landmark clinical trials in 2010, the anti-CTLA-4 antibody ipilimumab resulted in remarkable cancer remissions in metastatic melanoma.[1] ICIs, either alone or in combination, have rapidly become the standard of care in the treatment of additional malignant tumor types, including non−small cell lung cancer and urothelial cancers, as well as molecular tumor phenotypes such as deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H).[2]

As a consequence of immune activation during ICI treatment, many patients experience immune related adverse events (irAEs) that can affect virtually every organ system. ICIs have been reported to have distinct toxicities, but with significant overlap. Overall, anti-CTLA-4-associated irAEs occur with greater frequency than those associated with anti-PD-1 pathway drugs. In general, toxicity is greatest when these two classes of agents are combined.[3]

The most common irAEs include fatigue, rash, hypothyroidism, and hepatotoxicity. Colitis occurs more commonly with CTLA-4-directed therapy, and has resulted in intestinal perforation in some cases. Hypophysitis has similarly been reported to occur more commonly with anti-CTLA-4 therapy. In contrast, pneumonitis occurs more commonly with anti-PD-1 agents. Myocarditis is a relatively rare, but often fatal irAE, with mortality approaching 50%, that can be precipitated by either agent.

Rheumatologic adverse events (i.e., signs and symptoms mimicking rheumatic diseases) represent roughly 1–10% of all irAEs[4] and can present up to 18 months after ICI treatment. As such, rheumatologists have become increasingly aware of the range of diagnoses that can be seen with ICIs, which include inflammatory arthritis, myositis and polymyalgia rheumatica (PMR). In addition, various forms of vasculitis have been observed that may mimic primary rheumatic diseases, including large-vessel vasculitides [e.g. giant cell arteritis (GCA)], systemic small-vessel and medium-vessel vasculitides, and organ-specific vasculitis affecting the brain and kidney.[5,6] Intriguingly, the occurrence of irAEs have been associated with improved cancer prognosis, perhaps because they serve as a marker for a vigorous ICI-induced immune response. In this article, we review the biology of ICI mechanisms of action, and the clinical phenotypes of irAE-induced vasculitis.

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