Ab1079 checkpoint Inhibitor-Associated Arthritis: Phenotypes and Cytokine Associations

Abstract

BackgroundImmune checkpoint inhibitors (CI) have revolutionized cancer management, but can also cause immune-related adverse events. Five percent of CI-treated patients develop inflammatory arthritis, but it is poorly defined phenotypically and immunologically.ObjectivesTo characterize phenotypes of CI-associated arthritis, and compare cytokine levels in these patients to rheumatoid arthritis (RA) and osteoarthritis (OA) controls.MethodsPatients referred for CI-associated arthralgia or arthritis were prospectively enrolled in an institutional registry. Serum was collected when patients underwent phlebotomy for a clinical indication. We used a Luminex Human Magnetic Assay to measure levels of IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, TNF, IFN-γ, PD-L1, CCL2, CXCL2, CXCL13, OSM, CCL20, GM-CSF, CXCL-11 in CI-treated patients, and in stored serum from 7 RA patients (matched for medication, age, sex, CDAI) and 4 OA patients (age, sex matched). All comparisons were planned a priori.ResultsThirty-six patients were enrolled 5/1/18-1/25/19. Median [IQR] age was 67[58-78], 18(50%) were female, 14(39%) were smokers and 13(36%) had melanoma. Twenty-two (61%) were on anti-PD1 or PD-L1 monotherapy, and the remainder were on combination CI. Phenotypes included 1. Small joint involvement in 17(47%), 2. Exclusively large joint involvement in 6(17%), 3. Arthralgia without arthritis in 9(25%), and 4. Polymyalgia rheumatica in 4(11%). In all, 7(19%) had concomitant tenosynovitis or enthesitis, mostly accompanying large joint arthritis or arthralgia (6/7). Median CDAI at entry was 11[7-23] and median ESR 29[18-44]. The majority (58%) of patients with the small joint phenotype were RF and/or CCP positive and one had erosive disease, compared to none with the large joint phenotype. ANA positivity was common (74%) and did not vary across phenotypes. Median time of symptom onset was 4[0.8-12] months after CI initiation. Median follow up was 7[3-22] months but only 5(14%) had resolution of arthritis off medication during that period. 22(61%) required CI discontinuation, 5(14%) due to arthritis. 29(81%) required steroids including 15(42%) who required >20mg prednisone. 19(53%) required a synthetic DMARD and 5(14%) required a biologic DMARD. Of 33 patients with known cancer status, 15(45%) had a complete response, 5(15%) a partial response, 5(15%) “stable” disease, 6(18%) progression, and 2(6%) died. Cytokines were measured in 22 patients, who were similar to the cohort as a whole except for more CCP positivity (p=0.02). CI patients with the small joint phenotype had higher levels of IL-6 than RA controls (p=0.04) (Figure 1) and IL-6 levels trended higher in the small joint vs. exclusively large joint phenotype (Figure 2). The B cell chemoattractant CXCL13, a factor produced by T peripheral helper cells in RA synovium1, trended higher in the serum of CI patients (Figure 3). Other cytokine levels did not differ significantly in patients with the small joint vs. exclusively large joint phenotype, or in CI-arthritis patients vs. cont...

Checkpoint Inhibitor–Associated Arthritis

“…Given the reporting bias inherent in case reports and case series, the phenotypic frequencies described in our study may not be accurate, and an assessment of arthritis phenotypes in large prospective cohorts is needed to confirm our findings. Since the date of our literature search, more publications pertaining to ICI arthritis have been published, 29,30 highlighting the rapidly changing horizon in this field. Finally, we have limited our systematic review to patients treated with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, but other immune checkpoint-targeted therapies are under study (anti-TIM, −LAG, etc) and may also be associated with ICI arthritis.…”