AB0761 HISTOPATHOLOGY OF CHECKPOINT INHIBITORS INDUCED ARTHRITIS: RETROSPECTIVE ANALYSIS OF 3 CASES
Authors: M. D. B. Laurent, A. Sandrone, D. R. Silvana, C. Frank, P. Renaud, C. Galant, B. Lauwerys, P. Durez
Journal: Annals of the Rheumatic Diseases (2021)

Background: Induced arthritis (IA) is a rare immune related adverse event occurring in 0.5 to 2% of patients exposed to Immune (irAEs) Checkpoint Inhibitors (CPI). In some patients, this condition may be severe and long lasting even after CPI cessation. Cross-reactivity between tumor- and self-antigens was considered in the etiology of several cases of irAEs but disease mechanisms in IA remain elusive. We systematically collect synovial tissue of patients with IA (Ethical Committee B403201942386). Objectives: Here, we report the histopathological findings from ultrasound guided (USG) synovial biopsies from the 3 first patients of our cohort. The immune cell infiltration in CPI IA patients is compared to the histopathological findings in rheumatoid arthritis. Methods: Patients were referred through their oncologist after the onset of an arthritis in the context of a CPI therapy. The diagnostic of arthritis was confirmed by a rheumatologist and by ultrasound assessment. USG biopsies were performed before initiation of specific therapies. Pathological and immunohistochemical analyses include semi quantitative scoring of the following: synovial hyperplasia, fibrinoid necrosis, chorion cellular infiltrate, vascular hyperplasia, CD3-, CD20-, CD68- and CD138-positive cells. All patients gave written informed consent. Results: Three patients went through the USG biopsy procedure: 2 males and 1 female. No adverse events were recorded. All patients had metastatic neoplasms and time-to-arthritis was on average 6.7 months after CPI initiation. The USG biopsies were performed from 1 week after the onset of the IA to 16 months. The target joints displayed strong synovial thickening on ultrasound. Histological and immunohistochemistry studies showed light to moderate synovial hyperplasia and inflammatory cell infiltration of the sublining by macrophages and T cells, but no or little B cells (Table 1). Table 1. Clinical Characteristics and histopathological analyses on synovial biopsies. Patient 1 Patient 2 Patient 3 Cancer uterus bladder lungs Biopsied joint first metatarsophalangial joint wrist knee Time-to-synovial biopsy 1 week 2 months 16 months Grey scale on ultrasound 3/3 3/3 3/3 Hematoxylin-eosin staining: synovial hyperplasia fibrinoid necrosis chorion cellular infiltrate vascular hyperplasia + + ++ 0 + ++ + ++ + 0 0/+ ++ Immunochemistry staining: CD3 CD20 CD68 CD138 + ++ + 0 0 0/+ ++ 0/+ ++ 0 0 0/+ Conclusion: USG synovial biopsies have been safely performed and the histopathological analysis have confirmed the synovitis with mainly a macrophage infiltrate (myeloid pattern). IA synovitis is characterized by synovial hyperplasia and macrophage and T cell infiltration of the sublining. Increased collaboration between oncologists and rheumatologists is needed to create opportunities for referral of patients between the two specialties and optimize treatment. Further analyses (such as global or single-cell RNA sequencing) are needed to learn more about IA physiopathology. References: [1]Humby F, Lewis M, Ramamoorthi N &amp; al. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Ann Rheum Dis. 2019 Jun;78(6):761-772. doi: 10.1136/annrheumdis-2018-214539. [2]Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018 Jan 11;378(2):158-168. doi: 10.1056/NEJMra1703481. PMID: 29320654. Disclosure of Interests: Meric de Bellefon Laurent: None declared, Aspeslagh Sandrone: None declared, Di Romana Silvana: None declared, Cornelis Frank: None declared, Poncin Renaud: None declared, Christine Galant: None declared, Bernard Lauwerys Employee of: Bernard Lauwerys is currently employed at UCB Biopharma, Patrick Durez: None declared