Introduction
Combination with an advanced therapy (AT) and immunomodulator (IMM) is commonly used to optimise outcomes in Crohn’s disease (CD) and ulcerative colitis (UC). However, the comparative benefit of IMM co-therapy with different ATs and optimal duration of IMM co-therapy are unclear.
Aims & Methods
We aimed to determine the impact of IMM co-therapy on AT persistence.
We interrogated the Persistence Australian National IBD Cohort (PANIC5) registry of CD and UC patients from 2007-2021. The PANIC registry includes 100% of AT prescribing data in Australia. Non-persistence was defined as failure to dispense prescriptions for over six months. Co-therapy with IMM was defined as concurrent dispensing of a thiopurine (azathioprine or mercaptopurine) or methotrexate during AT use. Kaplan-Meier survival curves were generated and compared using the log-rank test. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).
Results
31,967 CD patients and 13,492 UC patients were included. 44.2% of CD and 37.9% of UC patients had received co-therapy with IMM. IMM co-therapy increased persistence of infliximab in both CD (median Kaplan Meier survival time 50.0 [95% CI 47.3-52.7] vs 27.0 months [95% CI 24.5-29.5], HR=0.68, p<0.001) and UC (35.0 [95% CI 31.4-38.6] vs 18.0 [95% CI 16.2-19.8], HR=0.71, p<0.001). Similarly, IMM co-therapy increased persistence of adalimumab in both CD (48.0 [95% CI 45.6-50.4] vs 25.0 [95% CI 23.3-26.7], HR=0.67, p<0.001) and UC (25.0 [95% CI 19.2-30.8] vs 17.0 [95% CI 14.2-19.8], HR=0.77, p<0.001). IMM co-therapy did not significantly affect persistence of vedolizumab in CD (33.0 [95% CI 27.0-39.0] vs 36.0 [95% CI 31.1-40.9], p=0.43), vedolizumab in UC (45.0 [95% CI 38.7-51.3] vs 48.0 [95% CI 41.8-54.2], p=0.11) or ustekinumab in CD (median survival and 95% CI unable to be calculated as event rate >50%; p=0.13). Ustekinumab was not approved for UC in Australia before 2021; thus no UC data were available.
Subgroup analysis showed a significant difference in anti-tumour necrosis factor inhibitor (TNFi) persistence across CD patients based on IMM timing during TNFi therapy (Table 1; p<0.001). CD patients who had at least three months of IMM before de-escalation had better persistence compared to those who stopped IMM within the first three months of TNFi (96.0 vs 19.0 months, p<0.001). Continuous IMM use during TNFi therapy had intermediate persistence (37.0 months, 95%CI 33.1-40.8). Patients who were not treated with IMM initially but started IMM in the last three months of therapy had the worst persistence (4.0 months, 95%CI 2.7-5.3). A similar pattern was seen in UC (Table 1). There was no difference between thiopurine and methotrexate co-therapy in either CD (p=0.41) or UC (p=0.45).
Table 1 – Median Kaplan Meyer persistence, stratified by timing of immunomodulator usage during anti-tumour necrosis alpha inhibitor (TNFi) therapy
| Crohn’s disease patients on infliximab
(n = 10218) | Crohn’s disease patients on adalimumab
(n = 12916) | Ulcerative colitis patients on infliximab
(n = 6044) | Ulcerative colitis patients on adalimumab
(n=1981) |
| Continued IMM throughout course of TNFi | 37.0 (33.1-40.8) | 33.0 (29.9-36.1) | 39.0 (30.2-47.8) | 26.0 (14.7-37.3) |
| IMM de-escalated after at least 3 months of co-therapy | 96.0 (88.0-104.0) | 86.0 (80.0-92.4) | ** | ** |
| IMM de-escalated within 3 months of initiating TNFi | 19.0 (14.8-23.2) | 20.0 (15.9-24.1) | 11.0 (8.9-13.1) | 12.0 (8.3-15.7) |
| IMM de-escalated within 3 months of initiating TNFi and restarted IMM within the last 3 months before TNFi discontinuation | 4.0 (3.6-4.4) | 4.0 (3.8-4.3) | 5.0 (4.7-5.3) | 4.0 (3.4-4.6) |
| IMM commenced over 3 months after TNFi initiation and continued throughout remainder of TNFi therapy | 46.0 (39.8-52.2) | 44.0 (38.8-49.2) | 46.0 (28.9-63.1) | ** |
| IMM commenced over 3 months after TNFi initiation and de-escalated | 90.0 (79.1-100.9) | 69.0 (63.3-74.8) | 59.0 (48.2-69.8) | ** |
| IMM commenced within the last 3 months of TNFi therapy | 4.0 (2.7-5.3) | 5.0 (4.1-5.8) | 5.0 (4.3-5.7) | 5.0 (2.1-7.9) |
| Not treated with IMM at any time during TNFi therapy | 28.0 (25.6-30.4) | 24.0 (22.4-25.6) | 18.0 (16.2-19.8) | 17.0 (14.2-19.8) |
| P value (log rank) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
** median survival and 95% CI unable to be calculated as event rate >50%
Conclusion
IMM co-therapy significantly improved persistence of TNFi, but not vedolizumab or ustekinumab in both CD and UC. Discontinuing IMM within three months of commencing TNFi was associated with reduced persistence compared to continuing initial co-therapy for longer before de-escalation.
Disclosure
RWL has served as an advisory board member for AbbVie, Aspen, BMS, Celgene, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences and Takeda, and has received research funding from Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer and MRFF.
