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Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation

Immune checkpoint inhibitor-induced inflammatory arthritis….. not as transient as you may think!

Citation: Braaten TJ, Brahmer JR, Forde PM, et al.  Ann Rheum Dis 2020;79:332-338

There remain many unanswered questions in the development and management of immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) and very few prospective studies in this patient population exist.  What is increasingly recognized, is the persistence of ICI-IA in many individuals, in some cases months or years after ICI cessation.

In this study, Braaten and colleagues sought to define factors associated with ICI-IA persistence and the impact of persistent arthritis, and its treatment, on cancer outcomes.  Conduced at Johns Hopkins Arthritis Center in the United States, patients with rheumatologist confirmed ICI-IA were recruited over a 42-month period and patients in whom ICI were discontinued were included in this study.  A total of 60 patients were included with an average follow-up of 12 months (range 1-24 months) after ICI cessation.  Over half of patients (53.3%) had active arthritis (defined as synovitis/enthesitis/dactylitis/tender joints or inability to taper immunosuppression without return of ICI-IA symptoms) at their last follow-up visit which ranged from 1-24 months after ICI cessation.  To explore factors associated with ICI-IA Kaplan-Meier curves were used and showed that those treated with combination immunotherapy and those with ≥2 additional immune-related adverse events (irAEs) were more likely to have persistent inflammatory arthritis.  Although not statistically significant, there was a trend towards more persistent arthritis in those with a better anti-tumour response.  Duration of ICI exposure was also positively correlated with arthritis persistence, in that those treated with ICI longer tended to have more persistent arthritis.

Immunomodulatory treatment for ICI-IA was required in 75% of patients with the majority receiving systemic or intra-articular steroids (80%).  Conventional synthetic disease-modifying antirheumatic drugs (CsDMARDs) and biologic disease-modifying anti-heumatic drugs (bDMARDs) were used in 19 and 11 patients respectively.  Importantly, of the 24 patients with exposure to CsDMARDs or bDMARDs, 4 (16.7%) experienced cancer progression which was not statistically significant from those not receiving DMARDs in whom cancer progression occurred in 8 of 36 (22.2%) of patients.

In summary, this study was the first to prospectively and systematically evaluate factors associated with ICI-IA persistence.  Patients who may be at higher risk of persistent ICI-IA include; those who have received combination ICI therapy, longer duration of ICI exposure and prior development of other irAEs.  Patients who develop ICI-IA may require prolonged immunosuppression, in this study up to 24 months after ICI cessation, which can theoretically have implications for the antitumour immune response.   In this study, treatment of the ICI-IA with CsDMARDs or bDMARDs did not appear to negatively impact the anti-tumour response and in fact many patients with persistent ICI-IA appeared to have better cancer outcomes.  This study again, raises important questions regarding optimal management and specifically timing of DMARD initiation.  Patients with risk factors for persistent ICI-IA may benefit from earlier initiation and more aggressive immunosuppressive therapy to control their arthritis.

Article summary by:  Janet Roberts (Janet3.roberts@nshealth.ca)