The Effect of Sex on Patients with Pre-existing Rheumatoid Arthritis and Immune Checkpoint Inhibitor-induced Inflammatory Arthritis.

Background: Immune checkpoint inhibitors (ICI) are the new pillar of cancer treatment.
ICI upregulate the immune system. This can result in off-target immune-related adverse
events (irAEs). One of the most disabling irAE is immune-related inflammatory arthritis
(ir-IA) resembling rheumatoid arthritis (RA). We aimed to explore sex-related
differences in patients with pre-existing RA exposed to ICI and patients with ir-IA with a
RA-like presentation.

Methods: Adults with rheumatic irAEs from ICI (CTLA-4, PD-1 or PD-L1 inhibitors) or
those with pre-existing rheumatic autoimmune disease exposed to ICI are prospectively
followed at 9 sites in Canada. Clinical characteristics, severity of irAEs according to
Common Terminology Criteria for Adverse Events (CTCAE) and management are
recorded. Data at cohort entry on 126 patients recruited between January 2020 and
May 2022 were available for analysis, [Table 1].

Results: Eleven patients had pre-existing RA, of which 6 (55%) were women and 5 (45%)
were men. Four (67%) women and 2 (40%) men were rheumatoid factor (RF) and/or
anti-cyclic citrullinated (CCP) positive. Three (50%) women and 2 (40%) men had RA
flares, of which 2 women and no men had grade >3 CTCAE flares. Both men and 1/3
women with flares were treated with prednisone, with mean maximum dose higher in
men (36 mg/d) than women (15 mg/d). All 3 women and 1/2 men who flared were
treated with DMARDs.

Twenty patients developed ir-IA with a RA-like presentation, of which 12 (60%) were
men and 8 (40%) were women. Two (25%) women and 1 (8%) man were RF and/or anti-
CCP positive. Four (33%) men and 1 (13%) woman had >3 CTCAE arthritis. Eight (67%)
men and 4 (50%) women were treated with prednisone, with mean maximum dose
higher in men (31 mg/d) than women (25 mg/d). Two (25%) women and 2 (17%) men
were treated with DMARDs. ICI were discontinued in 6 (50%) men and 3 (38%) women.

Conclusions: Our results suggest sex-related differences in irAE: 1. Unlike RA, the
distribution of ir-IA with RA-like presentation does not preferentially affect women, 2. In
both pre-existing RA and ir-IA, more women than men were RF and/or anti-CCP positive,
3. Severe flares were more common in women than men with pre-existing RA, while
severe ir-IA was more common in men, and 4. Discontinuation of ICI was more common

in men than women with ir-IA. Careful clinical phenotyping may provide clues to sex
differences in irAE. Larger studies are needed to confirm these findings.