Retrospective Cohort Study on the Predictive Value of Primary Non-response to Initial Biologic for Future Biologic Use in Patients with Inflammatory Bowel Disease

Overview

Journal Dig Dis Sci

Specialty Gastroenterology

Date 2025 Jan 4

PMID 39755922

Authors

Mahesh Krishna

Ellen J Spartz

Laura Maas

Vivy Cusumano

Sowmya Sharma

Berkeley Limketkai

Alyssa Parian

Affiliations

Soon will be listed here.

Abstract

Background: The armamentarium of medical therapies to treat inflammatory bowel disease (IBD) continues to grow, which has expanded treatment options, particularly after first biologic failure. Currently, there are limited studies investigating the predictive value of first biologic primary non-response (PNR) on subsequent biologic success. Our objective was to determine if PNR to the first biologic for IBD is predictive of response to subsequent biologic therapy.

Methods: A multicenter retrospective chart review study was performed with patients with IBD that received two or more biologics. PNR was defined as no clinical or symptomatic improvement after at least six weeks of treatment leading to cessation of drug. Patients who stopped their first biologic due to adverse side effects were classified in the intolerance group. Patients with initial significant response to biologic followed by a loss of response were classified as secondary loss of response (SLOR). Data analysis was performed with Python and Excel.

Results: Of the 249 patients that met inclusion criteria, there were 87 patients with PNR, 96 patients with SLOR, and 66 patients with intolerance to their first biologic exposure. Patients with ulcerative colitis (UC: 41.3%, p = 0.0083) and IBD-unclassified (IC: 56.3%, p = 0.0099) were found to have a significantly higher rate of primary non-response compared to patients with Crohn's disease (CD: 25.0%). Patients on adalimumab for their first biologic had a significantly (p = 0.0014) higher rate of PNR (42.7%, UC: 50.0%, CD: 32.7%) compared to those on infliximab (23.0%, UC: 31.0%, CD: 12.1%). Patients with PNR did not have a higher rate of second biologic nonresponse when compared to patients who had SLOR or intolerance to their first biologic. Univariate analyses demonstrated no difference in rates of response to second biologic when switching intra-class or out-of-class.

Conclusion: Ulcerative colitis and IBDU have higher rates of PNR compared to Crohn's disease, but still have high response rates to second biologic agents. Adalimumab may be a suboptimal initial biologic given its higher PNR rate compared to infliximab. Our results support that there is an equally likely chance of response to second biologic after first biologic PNR. Subanalyses evaluating intraclass and out-of-class medication switching showed similar success.

References

Papamichael K, Gils A, Rutgeerts P, Levesque B, Vermeire S, Sandborn W . Role for therapeutic drug monitoring during induction therapy with TNF antagonists in IBD: evolution in the definition and management of primary nonresponse. Inflamm Bowel Dis. 2014; 21(1):182-97. DOI: 10.1097/MIB.0000000000000202. View

Sands B, Sandborn W, Van Assche G, Lukas M, Xu J, James A . Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm Bowel Dis. 2016; 23(1):97-106. DOI: 10.1097/MIB.0000000000000979. View

Feagan B, Sandborn W, Gasink C, Jacobstein D, Lang Y, Friedman J . Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2016; 375(20):1946-1960. DOI: 10.1056/NEJMoa1602773. View

Kawalec P, Mocko P, Malinowska-Lipien I, Brzostek T . Efficacy and safety of ustekinumab in the induction therapy of TNF-α-refractory Crohn's disease patients: a systematic review and meta-analysis. J Comp Eff Res. 2017; 6(7):601-612. DOI: 10.2217/cer-2017-0022. View

Gisbert J, Marin A, McNicholl A, Chaparro M . Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment Pharmacol Ther. 2015; 41(7):613-23. DOI: 10.1111/apt.13083. View

Singh S, George J, Boland B, Vande Casteele N, Sandborn W . Primary Non-Response to Tumor Necrosis Factor Antagonists is Associated with Inferior Response to Second-line Biologics in Patients with Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. J Crohns Colitis. 2018; 12(6):635-643. PMC: 7189966. DOI: 10.1093/ecco-jcc/jjy004. View

Clark-Snustad K, Singla A, Lee S . Efficacy of Infliximab in Crohn's Disease Patients with Prior Primary-Nonresponse to Tumor Necrosis Factor Antagonists. Dig Dis Sci. 2019; 64(7):1952-1958. DOI: 10.1007/s10620-019-05490-0. View

Ben-Horin S, Chowers Y . Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014; 11(4):243-55. DOI: 10.1038/nrgastro.2013.253. View

De T, Zhang H, Alarcon C, Lec B, Avitia J, Smithberger E . Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease. Pharmacogenet Genomics. 2021; 32(1):1-9. PMC: 8578201. DOI: 10.1097/FPC.0000000000000445. View

10.

Feng J, Chen Y, Feng Q, Ran Z, Shen J . Novel Gene Signatures Predicting Primary Non-response to Infliximab in Ulcerative Colitis: Development and Validation Combining Random Forest With Artificial Neural Network. Front Med (Lausanne). 2021; 8:678424. PMC: 8505970. DOI: 10.3389/fmed.2021.678424. View

11.

Peyrin-Biroulet L, Danese S, Argollo M, Pouillon L, Peppas S, Gonzalez-Lorenzo M . Loss of Response to Vedolizumab and Ability of Dose Intensification to Restore Response in Patients With Crohn's Disease or Ulcerative Colitis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018; 17(5):838-846.e2. DOI: 10.1016/j.cgh.2018.06.026. View

12.

Gu B, Venkatesh K, Williams A, Ng W, Corte C, Gholamrezaei A . Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn's disease. World J Gastroenterol. 2022; 28(23):2597-2608. PMC: 9254145. DOI: 10.3748/wjg.v28.i23.2597. View

13.

Verstockt B, Moors G, Bian S, Van Stappen T, Van Assche G, Vermeire S . Influence of early adalimumab serum levels on immunogenicity and long-term outcome of anti-TNF naive Crohn's disease patients: the usefulness of rapid testing. Aliment Pharmacol Ther. 2018; 48(7):731-739. DOI: 10.1111/apt.14943. View