Immune checkpoint inhibitors are becoming increasingly utilized in clinical medicine, particularly in the field of oncology. In basic terms, the mechanism of these medications involves blocking Cytotoxic T Lymphocyte-Associated protein 4 (CTLA-4) or programmed cell death protein 1 pathways, including programmed cell death protein 1 (PD-1) and its associated ligand (PD-L1). This causes immune dysregulation, stimulating the body’s own immune system to develop an immunologic response against cancer cells [4,5,8,9]. In regards to the programmed cell death protein 1 pathway, the binding of PD-L1 to the PD-1 receptor expressed on T-cells decreases T-cell survival, avoiding an autoimmune driven reaction, and thus maintaining tolerance to self-antigens [10]. The relatively recent recognition that cancer cells often exhibit vast expression of PD-L1 has helped to explain their ability to evade T-cell attack; thus, blocking this pathway through the use of checkpoint inhibitors leads to an exaggerated immune response which allows the body’s T-cells to form an immunologic response against tumor cells [11]. The CTLA-4 pathway results in a purposeful immune dysregulation in a similar fashion [4,8].

There have been over 200 reports of rheumatologic immune-related adverse events associated with ICIs, involving diagnoses such as rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, spondylarthritis, and vasculitis [5], with the prevalence estimated to be around 1-10% [12]. In particular, vasculitis due to ICIs is an uncommon adverse effect, ranging from single organ involvement to systemic involvement of small, medium, and large vessels [5,6,13,14]. A systematic review by Daxini et al yielded 20 case reports of ICI-induced vasculitis, in which the predominant reported types of vasculitis were large vessel, such as GCA and isolated aortitis, as well as vasculitis of the CNS, including primary angiitis of the CNS and isolated vasculitis of the PNS [6]. Other cases included Granulomatosis with Polyangiitis (GPA), vasculitic neuropathy, cryoglobulinemic vasculitis, and digital vasculitis. Case reports have been described of single organ involvement of vasculitis in setting of ICI use, including vasculitis involving the testicles, retina, uterus, and brain[6,15-18]. A large-scale observational study by Salem et al, which reported on 31,321 adverse events associated with ICI use, confirmed 82 vasculitis cases [19]. The pathophysiology for these adverse effects is currently unknown, but there are several suggested explanations, such as increasing levels of pre-existing autoantibodies, enhancing T cell activity against self-antigens, in addition to stimulating cytokine release and complement activation [5,20]. In GCA, it is theorized that there is a lack of PD-L1 expression in vessel wall immune cells,  thus leading to unopposed T cell activation and promoting inflammation; similarly, checkpoint inhibitor therapy induced vasculitis may occur via a similar mechanism via the obstruction of the PD-1/PD-L1 pathway [5,21].

A grading system instituted by The American Society of Clinical Oncology rates adverse effects attributed to immunologic agents, ranging from grade 1 (mild reaction) to grade 4 (severe). While an inflammatory vasculitis would in most cases be categorized as a grade 3-4 effect, an explicit grading system has not been established specifically for vasculitis [5,22]. Typically, this requires discontinuing the medication and also considering treatment with steroids and/or immunosuppressive agents, including hydroxychloroquine, rituximab, and cyclophosphamide[5,6,12]. It is important to note that development of any immune related adverse effects can be an indication that the agent is also immunologically effective against the malignancy, and therefore careful thought must be taken prior to prematurely discontinuing the therapy [23,24]. Checkpoint inhibitors are being used more frequently in clinical oncology, and though diagnosis is difficult due to the variability of case presentations, more cases of ICI induced vasculitis will ultimately be recognized. Treatment approach must be individualized and factor in the effect on the patient’s underlying cancer [5].

On the other hand, vasculitis may also occur as a paraneoplastic phenomenon. Many cases of Paraneoplastic Vasculitis (PNV) have been described in literature, including polyarteritis nodosa, retinal vasculitis, giant cell arteritis, and leukocytoclastic vasculitis, in malignancies such as melanoma and leukemia [6,25-28]. 2.5 to 5% of patients diagnosed with vasculitis have been estimated to have a related malignancy, which may not be apparent at initial diagnosis [29]. One study by Solans-Laqué et al reviewed records of all patients diagnosed with vasculitis and solid tumors within 12 months of each other at their institution, only including patients with biopsy proven vasculitis and malignancy [29]. Among the 15 cases described, 7 cases involved patients where the diagnosis of vasculitis preceded the cancer diagnosis, 6 cases where they were diagnosed simultaneously, and 2 diagnoses of vasculitis after malignancy diagnosis. The most common vasculitis was cutaneous leukocytoclastic vasculitis (9 cases), and others were giant cell arteritis, Henoch-Schonlein purpura, and polyarteritis nodosa, while malignancies included carcinoma of urinary organs, lung, and GI tract. 13 of the patients had corresponding disease activity and treatment response between cancer and vasculitis, and in 7 cases vasculitis flare preceded tumor recurrence or progression. Although cases of PNV are rare, the phenomenon is described in various literature. Small vessels are most commonly involved; this includes Leukocytoclastic Vasculitis (LCV), the most common manifestation of PNV which can be seen in up to 50-60% of cases [1,28-33]. Other manifestations include PAN, GPA, MPA, and HSP [28]. PNV is more strongly seen in association with hematologic disorders and malignancies than with solid tumors, however both associations have been described [1,28,31,34,35].

The pathophysiology of this phenomenon is not well understood, but several theories have been postulated. One explanation is that the increased cellular turnover from cancer cells leads to the development of autoantibodies that infiltrate vasculature. There may also be increased release of tumor cytokines and angiogenic factors, causing endothelial damage, vascular permeability and inflammation[28,34,36,37]. Other possible mechanisms involve immune complex deposition as well as direct vascular damage from tumor cells[33,38]. Management of paraneoplastic vasculitis expectedly involves treating the underlying malignancy. Effective treatment of cancer is typically correlated with a clinical improvement in the associated vasculitis[29,39]. Similarly to treatment for immunotherapy induced vasculitis, glucocorticoids and/or other immunosuppressive agents can be used to suppress underlying inflammation in certain cases[29].