Background: The pathogenesis of rheumatic immune-related adverse events (irAEs) from checkpoint inhibitor cancer immunotherapy directed against programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) remains unknown, even though they are a consequence of pharmacologic inhibition of a specific immune mechanism. Given that some irAEs resemble polymyalgia rheumatica (PMR) or giant cell arteritis (GCA), a disease whose pathogenesis is poorly understood, observations regarding the pathogenesis of PMR-like or GCA-like irAEs are of significant interest. One proposed pathogenic mechanism involves generalized immune activation leading to a spectrum of subclinical disease. Interrogation of this hypothesis may be aided by PET/CT, which is frequently utilized for oncological staging purposes but is also useful in classical PMR or GCA diagnosis. If PMR or GCA irAEs merely represent a spectrum of generalized immune activation, low-grade subclinical PMR or GCA-related changes on PET/CT might be expected to be seen in patients who receive immunotherapy, irrespective of whether they develop clinically evident rheumatic irAEs.
Objectives: This study investigated whether such changes occurred in patients receiving immunotherapy who did not develop clinically evident rheumatic irAEs.
Methods: Consecutive patients exposed to PD-1 or PD-L1 inhibitor immunotherapy at a single center had scintigraphic uptake calculated by a nuclear medicine physician experienced in assessment of vasculitis. Patients were included if they had had 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging both within the two weeks prior to immunotherapy initiation and after at least eleven weeks of immunotherapy. Patients who went on to develop a rheumatic irAE were excluded, as were patients with scintigraphic evidence of liver metastases owing to their potential influence on scoring of uptake. Quantification of 18F-FDG uptake by maximum standardized uptake values (maximum standard unit value, SUVmax) was performed at sites relevant to PMR or GCA (17 sites relevant to PMR, 17 sites relevant to GCA) in paired scans, and the difference calculated.
Results: Twenty-four patients receiving nivolumab, pembrolizumab or avelumab met the inclusion criteria, primarily for melanoma, non-small cell lung cancer, or lymphoma. The mean age was 67 at the time of the first scan, 71% were male, and 66% had a complete or partial oncological response at best response. No statistically or clinically significant difference in SUVmax was noted at any PMR or GCA-relevant anatomical site interrogated. Latent class analysis did not reveal clusters identifiable by cancer type, best response, or presence of combination therapy.
Conclusion: Patients treated with PD-1/PD-L1 inhibitors without clinically evident rheumatic irAEs do not develop subclinical PMR or GCA-like changes on PET/CT. This supports the proposition that PMR-like and GCA-like irAEs are a distinct entity with stochastic onset, and do not simply represent generalized immune activation induced by immunotherapy.
Acknowledgements: David Liew is the recipient of the Ronald John Gleghorn Bursary from the University of Melbourne.
Disclosure of Interests: David Liew: None declared, Aurora Poon: None declared, Christopher McMaster: None declared, Claire Owen Speakers bureau: Roche, Jessica Leung Speakers bureau: GIlead, Novartis, Albert Frauman: None declared, Jonathan Cebon: None declared, Andrew Scott: None declared, Russell Buchanan: None declared
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