Anti-PD-1 Immunotherapy-Induced Flare of a Known Underlying Relapsing Vasculitis Mimicking Recurrent Cancer

Abstract

Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)—an antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis—in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD‐1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T‐cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD‐1 in GPA self‐tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti‐PD‐1 blockade. Key Points Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology. Patients with rheumatologic disorders have increased risk of reactivation with PD‐(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment. Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study

“…Psoriasis (n=24, 23%), thyroiditis (n=14, 13%), rheumatoid arthritis (n=12, 11%) and polymyalgia rheumatica (n=8, 8%) were most common. Other clinically relevant disorders were identified such as inflammatory bowel diseases (IBD, n=6, 6%), systemic lupus erythematosus (n=4, 4%), multiple sclerosis (n=3, 3%), sarcoidosis (n=2, 2%) and vasculitis (n=2, 2%) including one case 15 of granulomatosis with polyangiitis.…”

“…More frequent exacerbations were seen among those with clinically active AD at baseline and in patients receiving chronic immunosuppressants. With respect to ADs of clinical concern, such as neurological (eg, multiple sclerosis, Guillain-Barré syndrome) or IBD, exacerbations did not appear more frequent but perhaps were more aggressive as most resulted in CPI discontinuation (online supplementary table 4), 15 although this latter finding could be biased by physician comfort level and experience. Figure 2 Swimmers plot denoting time on checkpoint inhibitors (CPI) treatment in patients with (A) renal cell carcinoma and (B) urothelial carcinoma with pre-existing autoimmune disorder (AD) with time to onset of AD exacerbation and/or new immunerelated adverse event (irAE) and time of CPI discontinuation.…”

“…concerns, clinical experience is relatively limited and the literature consists mostly of retrospective series and case reports. [8][9][10][11][12][13][14][15] Recognizing the scarcity of data, we sought to investigate the safety and antitumor activity of CPI in patients with advanced RCC and UC with pre-existing AD across multiple centers to capture real-world evidence.…”

CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1

“…The development of autoimmune small-vessel vasculitis has been observed after checkpoint inhibitor therapy (21)(22)(23)(24), indicating a relevant role of immune checkpoint molecules in the disease process. However, no molecular alterations of such molecules in the immune system of patients with AAV have been reported so far.…”

“…In parallel, increasing reports of immune-related adverse events were noted (irAEs) ( 20 ). In fact, several forms of vasculitis have been reported to develop or re-activate after checkpoint inhibitor therapy, including AAV ( 21 – 24 ).…”