Gender-Based Differences in Response to Tumor Necrosis Factor Inhibitor Therapies for Ulcerative Colitis: Individual Participant Data Meta-Analyses of Clinical Trials

Overview

Journal Inflamm Bowel Dis

Publisher Oxford University Press

Specialty Gastroenterology

Date 2022 Apr 2

PMID 35366313

Authors

Manasi Agrawal

Francesca Petralia

Adam Tepler

Laura Durbin

Walter Reinisch

Jean-Frederic Colombel

Shailja C Shah

Affiliations

Soon will be listed here.

Abstract

Background: Gender-based differences are reported in inflammatory bowel diseases (IBD) pathogenesis, but their impacts on IBD outcomes are not well known. We determined gender-based differences in response to treatment with tumor necrosis factor inhibitor (TNFi) therapies in individuals with ulcerative colitis (UC).

Methods: We used the Yale University Open Data Access (YODA) platform to abstract individual participant data from randomized clinical trials to study infliximab and golimumab as induction and maintenance therapies in moderately to severely active UC. Using multivariable logistic regression, we examined associations between gender and the endpoints of clinical remission, mucosal healing, and clinical response for each study individually and in a meta-analysis.

Results: Of 1639 patients included in induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Subcutaneous [PURSUIT-SC], active ulcerative colitis trials [ACT] 1 and 2) and 1280 patients included in maintenance trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Maintenance [PURSUIT-IM], ACT 1 and 2), 696 (42.5%) and 534 (41.7%) were women, respectively. In a meta-analysis of induction trials, the adjusted odds ratios (aORs) of clinical remission (aOR, 0.55; 95% CI, 0.31-0.97), mucosal healing (aOR, 0.47; 95% CI, 0.27-0.83), and clinical response (aOR, 0.51; 95% CI, 0.29-0.90) in the treatment arm and of clinical remission in the placebo arm (aOR, 0.34; 95% CI, 0.15-0.82) were lower in men compared to women. There were no differences in outcomes by gender in the treatment and placebo arms in the meta-analysis of maintenance trials.

Conclusions: Men are less likely to achieve clinical remission, mucosal healing, and clinical response compared to women during induction treatment with TNFi for UC, but not during the maintenance phase. Future studies delineating the mechanisms underlying these observations would be informative.

Citing Articles

Influence of biological sex in inflammatory bowel diseases.

Tshikudi D, Bernstein C, Mishra S, Ghia J, Armstrong H Nat Rev Gastroenterol Hepatol. 2025; .

PMID: 39962330 DOI: 10.1038/s41575-025-01038-y.

Sex-Based Disparities in Treatment and Healthcare Utilization in Patients with Ulcerative Colitis: A Systematic Review and Meta-Analysis.

Shah Y, Sebastian S, Dahiya D, Gangwani M, Satiya J, Rao A J Clin Med. 2025; 13(24.

PMID: 39768465 PMC: 11728175. DOI: 10.3390/jcm13247534.

Spatial profiling of the mouse colonic immune landscape associated with colitis and sex.

Holm M, Stepanauskaite L, Backstrom A, Birgersson M, Socciarelli F, Archer A Commun Biol. 2024; 7(1):1595.

PMID: 39613949 PMC: 11606951. DOI: 10.1038/s42003-024-07276-1.

Comparison of accelerated and standard infliximab induction regimens in acute severe ulcerative colitis using propensity score analysis: a retrospective multicenter study in China.

Liu X, Li H, Tian F, Xie Y, Zhang X, Zhi M Gastroenterol Rep (Oxf). 2024; 12:goae051.

PMID: 38855349 PMC: 11162152. DOI: 10.1093/gastro/goae051.

The 2023 Impact of Inflammatory Bowel Disease in Canada: The Influence of Sex and Gender on Canadians Living With Inflammatory Bowel Disease.

Targownik L, Bollegala N, Huang V, Windsor J, Kuenzig M, Benchimol E J Can Assoc Gastroenterol. 2023; 6(Suppl 2):S55-S63.

PMID: 37674498 PMC: 10478807. DOI: 10.1093/jcag/gwad011.

References

Glintborg B, Ostergaard M, Dreyer L, Krogh N, Tarp U, Hansen M . Treatment response, drug survival, and predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor necrosis factor α therapy: results from the nationwide Danish DANBIO registry. Arthritis Rheum. 2011; 63(2):382-90. DOI: 10.1002/art.30117. View

Nasuno M, Miyakawa M, Tanaka H, Motoya S . Short- and Long-Term Outcomes of Infliximab Treatment for Steroid-Refractory Ulcerative Colitis and Related Prognostic Factors: A Single-Center Retrospective Study. Digestion. 2017; 95(1):67-71. DOI: 10.1159/000452459. View

Elderman M, van Beek A, Brandsma E, De Haan B, Savelkoul H, de Vos P . Sex impacts Th1 cells, Tregs, and DCs in both intestinal and systemic immunity in a mouse strain and location-dependent manner. Biol Sex Differ. 2016; 7:21. PMC: 4820953. DOI: 10.1186/s13293-016-0075-9. View

Ungaro R, Mehandru S, Allen P, Peyrin-Biroulet L, Colombel J . Ulcerative colitis. Lancet. 2016; 389(10080):1756-1770. PMC: 6487890. DOI: 10.1016/S0140-6736(16)32126-2. View

Peyrin-Biroulet L, Sandborn W, Sands B, Reinisch W, Bemelman W, Bryant R . Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Am J Gastroenterol. 2015; 110(9):1324-38. DOI: 10.1038/ajg.2015.233. View

Sprakes M, Ford A, Warren L, Greer D, Hamlin J . Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: a large single centre experience. J Crohns Colitis. 2012; 6(2):143-53. DOI: 10.1016/j.crohns.2011.07.011. View

Shah S, Khalili H, Chen C, Ahn H, Ng S, Burisch J . Sex-based differences in the incidence of inflammatory bowel diseases-pooled analysis of population-based studies from the Asia-Pacific region. Aliment Pharmacol Ther. 2019; 49(7):904-911. DOI: 10.1111/apt.15178. View

Favalli E, Biggioggero M, Crotti C, Becciolini A, Raimondo M, Meroni P . Sex and Management of Rheumatoid Arthritis. Clin Rev Allergy Immunol. 2018; 56(3):333-345. DOI: 10.1007/s12016-018-8672-5. View

Sera F, Armstrong B, Blangiardo M, Gasparrini A . An extended mixed-effects framework for meta-analysis. Stat Med. 2019; 38(29):5429-5444. DOI: 10.1002/sim.8362. View

10.

Rutgeerts P, Sandborn W, Feagan B, Reinisch W, Olson A, Johanns J . Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005; 353(23):2462-76. DOI: 10.1056/NEJMoa050516. View

11.

Torres J, Mehandru S, Colombel J, Peyrin-Biroulet L . Crohn's disease. Lancet. 2016; 389(10080):1741-1755. DOI: 10.1016/S0140-6736(16)31711-1. View

12.

Goodman W, Garg R, Reuter B, Mattioli B, Rissman E, Pizarro T . Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol. 2014; 7(5):1255-65. PMC: 4139459. DOI: 10.1038/mi.2014.15. View

13.

Goodman W, Havran H, Quereshy H, Kuang S, De Salvo C, Pizarro T . Estrogen Receptor α Loss-of-Function Protects Female Mice From DSS-Induced Experimental Colitis. Cell Mol Gastroenterol Hepatol. 2018; 5(4):630-633.e1. PMC: 6008827. DOI: 10.1016/j.jcmgh.2017.12.003. View

14.

Aldridge J, Pandya J, Meurs L, Andersson K, Nordstrom I, Theander E . Sex-based differences in association between circulating T cell subsets and disease activity in untreated early rheumatoid arthritis patients. Arthritis Res Ther. 2018; 20(1):150. PMC: 6053769. DOI: 10.1186/s13075-018-1648-2. View

15.

Vermeire S, Satsangi J, Peeters M, Parkes M, Jewell D, Vlietinck R . Evidence for inflammatory bowel disease of a susceptibility locus on the X chromosome. Gastroenterology. 2001; 120(4):834-40. DOI: 10.1053/gast.2001.22453. View

16.

Shah S, Khalili H, Gower-Rousseau C, Olen O, Benchimol E, Lynge E . Sex-Based Differences in Incidence of Inflammatory Bowel Diseases-Pooled Analysis of Population-Based Studies From Western Countries. Gastroenterology. 2018; 155(4):1079-1089.e3. DOI: 10.1053/j.gastro.2018.06.043. View

17.

Lagana B, Zullo A, Scribano M, Chimenti M, Migliore A, Picchianti Diamanti A . Sex Differences in Response to TNF-Inhibiting Drugs in Patients With Spondyloarthropathies or Inflammatory Bowel Diseases. Front Pharmacol. 2019; 10:47. PMC: 6360251. DOI: 10.3389/fphar.2019.00047. View

18.

Biank V, Friedrichs F, Babusukumar U, Wang T, Stoll M, Broeckel U . DLG5 R30Q variant is a female-specific protective factor in pediatric onset Crohn's disease. Am J Gastroenterol. 2006; 102(2):391-8. DOI: 10.1111/j.1572-0241.2006.01011.x. View

19.

Schroeder K, Tremaine W, Ilstrup D . Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987; 317(26):1625-9. DOI: 10.1056/NEJM198712243172603. View

20.

Dimitrijevic M, Arsenovic-Ranin N, Bufan B, Nacka-Aleksic M, Kosec D, Pilipovic I . Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation. 2020; 43(6):2312-2331. DOI: 10.1007/s10753-020-01302-0. View