Background/Purpose: Immune checkpoint inhibitors (ICIs) are being used in the treatment of a variety of malignancies. ICIs target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell-death protein 1 (PD-1) and its ligand PD-L1, which negatively regulate T-cell activation. ICIs can induce widespread manifestations of autoimmunity, which are called immune-related adverse events (irAEs). Rheumatic irAEs have been increasingly reported, with inflammatory arthritis (IA-irAE) being the most common. IA-irAE symptoms can be severe and persistent, even after discontinuation of ICI. We sought to clinically and immunologically characterize a cohort of patients with IA-irAE.

Methods: From patients on ICI therapy for any malignancy, we recruited 15 cases of de novo IA-irAE. IA-irAE had physician-confirmed inflammatory arthritis supplemented by laboratory or imaging studies. As controls, 8 patients with seronegative rheumatoid arthritis (Rh-control), 4 ICI-treated cancer patients without any irAE (ICI control), and age and sex-matched healthy controls (HC) were included. Biospecimens including serum and peripheral blood mononuclear cells (PBMCs) were collected. Fifteen-parameter flow cytometry panels were used to profile T cell exhaustion and senescence phenotypes in PBMCs and serum cytokine levels were measured using Luminex technology.

Results: The majority of IA-irAE patients were treated with pembrolizumab (86.6%). The average onset of inflammatory arthritis was 4.36 months after ICI initiation. The predominant pattern of inflammatory arthritis was polyarticular/symmetric, as well as large joint involvement (66.6%), although patterns seen in spondyloarthopathies were observed as well. Four patients (27%) had positive serologies after the onset of symptoms, without having pre-existing symptoms of arthritis. IA-irAE patients had significantly reduced PD-1 expression on CD8 and CD4 T cells compared to ICI-controls (p = 0.02) and HC (p < 0.0001). In IA-irAE, the senescent T cell population was significantly increased in frequency compared to HC (p = 0.01) and tended to be increased compared Rh-control (p = 0.05). Finally, IA-irAE had elevated levels of pro-inflammatory cytokines IL-6, MIG and IP-10 compared to controls (p = 0.02, 0.001 and 0.007, respectively) and a similar trend was observed in comparison to Rh-controls.

Conclusion: Our preliminary findings suggest that IA-irAE is a distinct clinical entity with a heterogeneous clinical presentation and distinct immune phenotype. The latter suggests that ICI therapy may lead to over-activation of T cells, and sustained inflammation. Further, there is a tendency for these patients to have increased pro-inflammatory cytokines compared to Rh-controls. Increased sample sizes are needed to more definitively conclude whether these alternations can distinguish Rh-irAE from Rh-control, and these studies are ongoing. To our knowledge, this is one of the first studies addressing the immunological basis of IA-irAE, and the connection between IA-irAE and rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-arthritis-induced-by-immune-checkpoint-inhibitor-therapy-a-distinct-clinical-entity-and-immunologic-phenotype/