An Assessment of Ustekinumab Immunogenicity in Perianal Crohn's Disease

Introduction: Perianal fistulas occur in over 20% of patients with Crohn’s disease (CD). While anti-tumor necrosis factor (anti-TNF) agents have been associated with fistula closure, they are also associated with immunogenicity. Here, we sought to assess the immunogenicity of a novel biologic, ustekinumab (UST), in patients with perianal fistulizing CD. Methods: A retrospective review of electronic health records from a tertiary care center between January 2017-January 2022 was conducted. Adult patients with a documented history of perianal CD and treatment with UST were included. Perianal disease was defined as clinical documentation of a perianal fistula or abscess. Patient demographics, inflammatory bowel disease history, and biologic history were collected. Results: We identified 152 patients with perianal CD who were treated with UST; 56% were male. Average age was 40.1 years (SD 12.5) and median CD duration was 15 years (range 2-48). Eighty-four percent of patients had previously been on infliximab (IFX) and 77% on adalimumab (ADA) with an average duration of 3.2 years (SD 4.7). Therapy was changed due to antibody formation in 22.2% of IFX-treated patients and in 6.4% of ADA-treated patients. While on UST, 59% required dose escalation; 23% were also treated with an immunomodulator. Although 56.6% of patients continued UST therapy, the most common indications for cessation were primary (35%) and secondary (38%) nonresponse. Two patients changed therapy due to undetectable UST levels with antibody levels of 1501ng/mL and 1768ng/mL. One patient was on UST for < 1 year due to antibody development and had prior antibodies to IFX and ADA. In the 2nd patient, the duration of and adherence to UST was unclear; they had prior antibodies to ADA. A 3rd patient on UST and methotrexate had an antibody level of 103ng/mL with a drug level of 5.2ug/mL after 2.6 years on therapy. Their therapy was changed shortly after due to ongoing disease activity. Conclusion: In this cohort of perianal CD patients, low rates of immunogenicity to UST were found. Over 50% of patients were on prior biologics including anti-TNFs. While 25% of patients developed anti-TNF antibodies with 16% of patients changing therapy due to antibody formation, clinically significant UST antibodies leading to drug cessation were seen in only 2 patients (1.3% of our cohort). This study provides additional evidence for low rates of immunogenicity to UST in a phenotypic subset of Crohn’s patients with perianal disease (Table 1). Table 1. - Therapy with Ustekinumab. Percentages based on the total number of patients with available data per respective variable Steroids Within 6 Months of Therapy n (%) 53 (39.3) Dose Escalated n (%) 59 (39.6) Average Time to Escalation yr (SD) 1.2 (1.1) Immunomodulator During Therapy n (%) 32 (23.0) Discontinued Therapy n (%) 66 (43.4) Average Time to Discontinuation yr (SD) 1.5 (1.4) Reason for Stopping Primary Nonresponse n (%) 23 (35.4) Secondary Nonresponse n (%) 25 (38.4) Antibody Development n (%) 2 (3.1) Adverse Event n (%) 4 (6.2)