Immune checkpoint inhibitors (ICIs) are associated with a variety of rheumatic adverse events (Rh-irAEs). Among these reactions, vasculitis is relatively rare but can be severe enough to influence therapy. There is limited data to guide the workup and management of these patients. However, there are trends in the literature that can help to inform the Rheumatologist’s choices.

What are common patterns of Immune Checkpoint Inhibitor related vasculitis (ir-Vasculitis)?

Large, medium, and small vessel vasculitis have been reported in the literature in association with ICI exposure.  In the CanRIO cohort, ir-Vasculitis was rare, comprising 1.5% of all Rh-irAEs.  Review of various registries places the rate of vasculitis among irAEs at less than 1%.  In the largest systematic review published to date, the most common types of vasculitis include giant cell arteritis, aortitis, primary angiitis of the central nervous system, and vasculitic neuropathy.  The most frequent agents associated with ir-vasculitis were Ipilimumab, Pembrolizumab, and Nivolumab; the most commonly used ICIs.  The median time to symptom onset was 3 months from ICI exposure. The most common underlying malignancy reported was melanoma, though this may reflect literature bias; melanoma was the first tumour type for which ICI therapy became standard of care.

Various other types of vasculitis have been reported to affect medium vessel (lymphocytic vasculitis of the uterine/ovarian vessels), small vessel (ANCA vasculitis, renal limited vasculitis, digital vasculitis, cryoglobulinemia, IgA vasculitis), and single organ vasculitis (cutaneous vasculitis, retinal vasculitis, isolated testicular vasculitis). 

Are there risk factors for ir-Vasculitis?

The risk factors for ir-Vasculitis are largely unknown due to the rarity of these conditions.  The available data from patients with pre-existing autoimmune diseases exposed to ICIs suggests an increased risk for Rh-irAEs.  There is insufficient evidence to support this concept for ir-Vasculitis. However, there is a single case of a patient with pre-existing PR3 ANCA positivity (asymptomatic) developing ANCA vasculitis after exposure to Pembrolizumab. Conversely, there is a single case of a patient with known Eosinophilic Granulomatosis with Polyangiitis (EGPA), treated successfully with Ipilimumab and Pembrolizumab without a flare of vasculitis.

What specific work-up should be considered?

A common theme among the growing body of literature of Rh-irAEs emphasizes the need to quickly exclude progression of the primary malignancy prior to diagnosing an irAE. This may require a multidisciplinary approach.  Once this has been accomplished, investigations should be determined by the clinical phenotype.  Work-up should follow the standard approach taken with the idiopathic form of the suspected vasculitis.  Importantly, sero-negativity appears to be relatively frequent among ir-Vasculitis as it is among ICI related inflammatory arthritis. ICI related ANCA Vasculitis is a good example of this.

What is the approach to management?

Currently, no evidence-based guidelines exist for ir-Vasculitis. Treatment has generally followed standard practice for the analogous primary vasculitis. Treatment needs to be tailored to the severity of the ir-Vasculitis.  Based on the available cases, stopping the suspected ICI followed by initiating glucocorticoids has generally been the initial approach.  The needs for additional immune suppression is currently guided by expert opinion and will require multidisciplinary input. Data on re-challenge with ICIs is limited and must be assessed on a case-by-case basis. Relapse after discontinuation of the culprit ICI and completion of treatment is rare but a case of relapsing PR3+ vasculitis is reported.

Last update February by Dr. Daniel Ennis 2021:  See vasculitis module for references.