Background/Purpose: Immune checkpoint inhibitors (ICI), an important type of cancer therapy, can cause adverse events through immune activation. Inflammatory arthritis (IA) due to ICI treatment is increasingly appreciated as prevalent and morbid, but genetic risk factors are not understood. In this pilot study, we aimed to evaluate the frequency of HLA class I and II alleles associated with traditional forms of inflammatory arthritis in a group of patients with ICI-induced IA as compared to population controls.

Methods: High resolution HLA typing was performed on 27 patients with ICI-induced IA and 726 controls who were prospective bone marrow donors at our institution. Genotyping at the shared epitope (SE) locus (HLA-DRB1) was also performed on 220 rheumatoid arthritis (RA) cases. Allele-positivity rates were compared using Fisher’s exact test. The frequency of having at least one SE allele was compared between ICI-induced IA patients and both population and RA controls.

Results: The average age was 60.2 (SD 12.1) years and 12 patients (44.4%) were female. Patients were treated with ICIs targeting CTLA-4, PD-1, and/or PD-L1. Melanoma was the most common tumor type (N=9), followed by non-small cell lung cancer (N=6). Other tumor types were renal cell carcinoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, mycosis fungoides, colon, endometrial, esophageal, and breast cancers. Of the included patients, 26 were of European descent and one was African American. In the 26 patients of European descent, 16 (61.5%) had at least one SE allele, significantly different from the European descent bone marrow donor controls where 299 (41.2%) had at least one SE allele (OR=2.3, p=0.04). Of individual class I or II alleles, only the allele-positivity rate of DRB1*04:05 was statistically different between groups. There were trends toward higher allele-positivity rates for HLA A*03:01, B*52:01, and C*12:02 in ICI-induced IA (Table 1). The ICI-induced IA population did not differ significantly from RA cases of European descent in frequency of having at least one SE allele, but they were more likely to be negative for rheumatoid factor and anti-cyclic citrullinated peptide antibody (Table 2).

Conclusion: Patients with ICI-induced IA who were of European descent were more likely to have at least one shared epitope allele compared to bone marrow donor controls. Further statistically powered studies are warranted to establish whether immunogenetic framework modifies the risk of developing IA from ICI therapy.