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. 2024 Feb:64:152335.
doi: 10.1016/j.semarthrit.2023.152335. Epub 2023 Dec 8.

Immunomodulator use, risk factors and management of flares, and mortality for patients with pre-existing rheumatoid arthritis after immune checkpoint inhibitors for cancer

Kaitlin R McCarter  1 , Senada Arabelovic  2 , Xiaosong Wang  3 , Taylor Wolfgang  2 , Kazuki Yoshida  4 , Grace Qian  3 , Emily N Kowalski  3 , Kathleen M M Vanni  3 , Nicole R LeBoeuf  5 , Elizabeth I Buchbinder  6 , Lydia Gedmintas  2 , Lindsey A MacFarlane  2 , Deepak A Rao  2 , Nancy A Shadick  2 , Ellen M Gravallese  2 , Jeffrey A Sparks  7
Affiliations

Immunomodulator use, risk factors and management of flares, and mortality for patients with pre-existing rheumatoid arthritis after immune checkpoint inhibitors for cancer

Kaitlin R McCarter et al. Semin Arthritis Rheum. 2024 Feb.

Abstract

Objective: To investigate immunomodulator use, risk factors and management for rheumatoid arthritis (RA) flares, and mortality for patients with pre-existing RA initiating immune checkpoint inhibitors (ICI) for cancer.

Methods: We performed a retrospective cohort study of all patients with RA meeting 2010 ACR/EULAR criteria that initiated ICI for cancer at Mass General Brigham or Dana-Farber Cancer Institute in Boston, MA (2011-2022). We described immunomodulator use and changes at baseline of ICI initiation. We identified RA flares after baseline, categorized the severity, and described the management. Baseline factors were examined for RA flare risk using Fine and Gray competing risk models. We performed a landmark analysis to limit the potential for immortal time bias, where the analysis started 3 months after ICI initiation. Among those who survived at least 3 months, we examined whether RA flare within 3 months after ICI initiation was associated with mortality using Cox regression.

Results: Among 11,901 patients who initiated ICI for cancer treatment, we analyzed 100 pre-existing RA patients (mean age 70.3 years, 63 % female, 89 % on PD-1 monotherapy, 50 % lung cancer). At ICI initiation, 71 % were seropositive, 82 % had remission/low RA disease activity, 24 % were on glucocorticoids, 35 % were on conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and 10 % were on biologic or targeted synthetic DMARDs. None discontinued glucocorticoids and 3/35 (9 %) discontinued DMARDs in anticipation of starting ICI. RA flares occurred in 46 % (incidence rate 1.84 per 1000 person-months, 95 % CI 1.30, 2.37); 31/100 flared within 3 months of baseline. RA flares were grade 1 in 16/46 (35 %), grade 2 in 25/46 (54 %), and grade 3 in 5/46 (11 %); 2/46 (4 %) required hospitalization for RA flare. Concomitant immune-related adverse events occurred in 15/46 (33 %) that flared. A total of 72/100 died during follow-up; 21 died within 3 months of baseline. Seropositivity had an age-adjusted sdHR of 1.95 (95 % CI 1.02, 3.71) for RA flare compared to seronegativity, accounting for competing risk of death. Otherwise, no baseline factors were associated with RA flare, including cancer type, disease activity, RA duration, and deformities. 9/46 (20 %) patients had their ICI discontinued/paused due to RA flares. In the landmark analysis among 79 patients who survived at least 3 months, RA flare in the first 3 months was not associated with lower mortality (adjusted HR 1.24, 95 % CI 0.71, 2.16) compared to no RA flare.

Conclusion: Among patients with pre-existing RA, few changed immunomodulator medications in anticipation of starting ICI, but RA flares occurred in nearly half. RA flares were mostly mild and treated with typical therapies. Seropositivity was associated with RA flare risk. A minority had severe RA flares requiring disruption of ICI, and RA flares were not associated with mortality.

Keywords: Cancer; Flare; Immune checkpoint inhibitors; Immunotherapy; Rheumatoid arthritis.

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Conflict of interest statement

Declaration of Competing Interest Dr. Yoshida has performed consultancy for OM1, Inc. Dr. LeBoeuf has performed consultancy for Bayer, Seattle Genetics, Sanofi, Silverback, and Synox Therapeutics. Dr. Buchbinder serves on an advisory board for Merck, BMS, and Novartis. Dr. Gedmintas has received payment for lectures for Harvard CME of Intensive Review of Internal Medicine and Innovations and New Practices in Internal Medicine. Dr. Rao has received research support from Bristol Myers Squibb, Janssen, and Merck, and performed consultancy for AstraZeneca, Pfizer, GlaxoSmithKine, Aditum, HiFiBio Therapeutics, and Scipher Medicine unrelated to this work. Dr. Gravallese has received grants from the NIH and Rheumatology Research Foundation. Dr. Gravallese has received royalties from Up to Date and textbook “Rheumatology.” Dr. Gravallese has received payment for speaking at IFRA meeting China, Advances in Targeted Therapies Meeting, University of NC, MUSC, and ACR. Dr. Gravallese has received support for attending meeting with Advances in Targeted Therapies and the NIH. Dr. Gravallese serves in a leadership role for the NIH and NIAMs Council member. Dr. Sparks has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, and ReCor unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health.

Figures

Figure 1.
Figure 1.
Cumulative incidence curve of rheumatoid arthritis flare after immune checkpoint inhibitor initiation for A) entire follow-up and B) during the initial 3 months.
Figure 1.
Figure 1.
Cumulative incidence curve of rheumatoid arthritis flare after immune checkpoint inhibitor initiation for A) entire follow-up and B) during the initial 3 months.
Figure 2.
Figure 2.
Cumulative incidence and hazard ratio for mortality by presence/absence of RA flare within 3 months of immune checkpoint inhibitor initiation. The landmark analysis was restricted to patients who survived at least 3 months after immune checkpoint inhibitor initiation (n=79). The model was adjusted for age, sex, cancer type (lung/melanoma/other), cancer duration, and Charlson comorbidity index.
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References

    1. Reid P, Cappelli LC. Treatment of rheumatic adverse events of cancer immunotherapy. Best Pract Res Clin Rheumatol 2022; 36(4): 101805. - PMC - PubMed
    1. Ghosh N, Bass AR. Rheumatic Complications of Immune Checkpoint Inhibitors. Rheum Dis Clin North Am 2022; 48(2): 411–28. - PubMed
    1. van der Kooij MK, Suijkerbuijk KPM, Aarts MJB, et al. Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study. Ann Intern Med 2021; 174(5): 641–8. - PubMed
    1. Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME. Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann Intern Med 2018; 168(2): 121–30. - PubMed
    1. McCarter KR, Wolfgang T, Arabelovic S, et al. Mortality and immune-related adverse events after immune checkpoint inhibitor initiation for cancer among patients with pre-existing rheumatoid arthritis: A retrospective, comparative, cohort study. Lancet Rheumatol. 2023:5(5):e274–e283. - PMC - PubMed

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