ObjectivesTo compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA).MethodsThe retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders.Results147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control.ConclusionThe treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.
Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti–PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38 hi CD127 − CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38 hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38 hi CD127 − T cells, which were frequently bound by the therapeutic anti–PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.
BackgroundImmune checkpoint inhibitors (ICI) can potentially cause ICI-inflammatory arthritis (ICI-IA), which often resembles rheumatoid arthritis (RA). In this study, we examined the degree of anticitrullinated peptide antibodies (ACPA) epitope expansion in CCP+ICI-IA and patients with RA.MethodsWe used clinical data and serum from ICI-IA and patients with RA with early disease as well as longstanding disease. A custom, bead-based antigen array was used to identify IgG ACPA reactivities to 18 putative RA-associated citrullinated proteins. Hierarchical clustering software was used to create a heatmap to identify ACPA levels. Additionally, HLA DRB1 typing was performed on ICI-IA patients as well as controls of patients treated with ICI that did not develop ICI-IA (ICI controls).ResultsCompared to patients with CCP+RA, patients with CCP+ICI-IA were older (p<0.001), less likely to have positive rheumatoid factor (p<0.001) and had a shorter duration of symptoms (p<0.001). There were less ACPA levels and a lower number of distinct ACPA epitopes in the serum of patients with ICI-IA compared with longstanding patients with RA (p<0.001). Among those tested for HLA DRB1, there were no differences in the frequency of the shared epitope between those with ICI-IA and ICI controls.ConclusionPatients with ICI-IA had lower ACPA titres and targeted fewer ACPA epitopes than longstanding patients with RA, and there were no significant differences in the presence of the shared epitope between those that developed ICI-IA and ICI controls. It remains to be determined if ICI-IA represents an accelerated model of RA pathogenesis with ICI triggering a transition from preclinical to clinical disease.
BackgroundImmune checkpoint inhibitor associated arthritis (ICI-A) commonly persists for months to years, even after ICI cessation.[1]ObjectivesTo compare the safety and effectiveness of biologic and conventional disease modifying anti-rheumatic drugs (DMARDs) for ICI-A.MethodsRetrospective multicenter observational study. Inclusion: 1) diagnosis of ICI-A and 2) treatment with a tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX). Exclusion: preexisting autoimmune disease. The primary outcome was time to cancer progression from ICI initiation. Patients whose cancer progressed prior to DMARD initiation were excluded from this analysis. The secondary outcome was time to arthritis control from DMARD initiation, defined as grade 1 arthritis and prednisone ≤10mg/day. Cox proportional hazard models were generated, adjusting for confounders. A sensitivity analysis was performed incorporating a time dependent variable “time from ICI initiation to DMARD initiation.”Results147 patients were included, mean (SD) age 60.3 (11.9) years, 66 (45%) females. Sixty percent had received PD1/PDL1 monotherapy, 30% received combination CTLA4/PD1. Eighty percent had stage IV cancer. ICI-A treatment was TNFi in 33 (22%), IL6Ri 42 (29%), MTX 72 (49%) (Table 1). A Kaplan-Meier curve showing time to cancer progression by DMARD is shown inFigure 1. In an unadjusted Cox model with MTX as the reference, time to cancer progression with a TNFi was HR 2.51 (95% CI 0.91-6.93, p=0.075) and for IL6Ri HR 2.36 (95% CI 0.91-6.12, p=0.078). After adjustment for the time dependent variable, time to cancer progression was significantly shorter for TNFi-treated patients compared to MTX, HR 3.27 (95% CI 1.21-8.84, p=0.019). The result for IL6Ri was HR 2.31 (95% CI 0.98-5.41, p=0.055). Time to arthritis control was significantly faster for TNFi compared to MTX, HR 1.91 (95% CI 1.06-3.45, p=0.032) in an adjusted Cox model. Results for IL6Ri were HR 1.66 (95% CI 0.93-2.97, p=0.089). Results for cancer progression and arthritis control were similar in the subset of patients with melanoma.ConclusionTreatment of ICI-A with biologic DMARDs is associated with more rapid arthritis control than with MTX but may be associated with a shorter time to cancer progression. A prospective randomized controlled trial is needed to verify these findings and to identify the optimal approach to managing patients with high grade ICI-A.Reference[1] Braaten TJ, et al Ann Rheum Dis. 2020 Mar;79(3):332-338.Table 1.Patient characteristicsTotalTNFiIL6RMTXp-valueN147 (100%)33 (22%)42 (29%)72 (49%)Age, mean (SD)60.3 (11.9)56.3 (14.0)61.5 (12.5)61.5 (10.1)0.085Sex (female)66 (45%)13 (39%)15 (36%)38 (53%)0.17Race (white)136 (92%)30 (91%)40 (95%)66 (92%)0.18Cancer type0.068Melanoma63 (43%)16 (48%)21 (50%)26 (36%)Non-small cell lung cancer15 (10%)1 (3%)0 (0%)14 (19%)Renal cell carcinoma24 (16%)5 (15%)12 (29%)7 (10%)Bladder cancer7 (5%)1 (3%)3 (7%)1 (4%)Other38 (25%)10 (30%)6 (14%)22 (31%)Cancer stage0.34III26 (18%)7 (21%)6 (14%)13 (18%)IV118 (80%)24 (73%)36 (86%)58 (81%)Checkpoint inhibitor0.91PD1/PDL1 monotherapy101 (69%)24 (73%)28 (67%)49 (68%)Combination (CTLA4/PD1)44 (30%)9 (27%)13 (31%)22 (31%)ICI discontinued for arthritis58 (40%)12 (36%)17 (40%)29 (40%)0.92ICI initiation to DMARD start (days), median (IQR)403 (258,638)411 (284, 622)300 (170, 435)486(258, 675)0.020Duration of DMARD treatment, median (IQR)278 (77, 546)92 (45, 149)309 (63, 483)420 (138, 765)<0.001Maximum glucocorticoid dose, mean (SD)40 (27)53 (27)42 (28)33 (23)0.002Figure 1.Kaplan-Meier curve showing time to cancer progression from time of immune checkpoint inhibitor initiationAcknowledgements:NIL.Disclosure of InterestsAnne Bass: None declared, Noha Abdel-Wahab Speakers bureau: ChemoCentryx, Consultant of: ChemoCentryx, Pankti Reid: None declared, Jeffrey Sparks Consultant of: Bristol Myers Squibb, AbbVie, Amgen, Boehringer Ingelheim, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, Grant/research support from: Bristol Myers Squibb, cassandra calabrese Speakers bureau: Sanofi, Consultant of: Astazenica, Deanna Jannat-Khah: None declared, Nilasha Ghosh: None declared, Divya Rajesh: None declared, Carlos Aude: None declared, Lydia Gedmintas: None declared, Lindsey MacFarlane: None declared, Senada Arabelovic: None declared, Adewunmi Falohun: None declared, Komal Mushtak: None declared, Farah Al Haj: None declared, Adi Diab: None declared, Ami Shah Grant/research support from: Eicos Sciences, Medpace LLC, Arena Pharmaceuticals, Kadmon Corporation, Clifton Bingham Consultant of: Bristol Myers Squibb,: Abbvie, Janssen, Lilly, Pfizer, Sanofi, Moderna, Grant/research support from: Bristol Myers Squibb, Karmela Kim Chan: None declared, Laura Cappelli Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb.
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