Introduction

JAK inhibitors (JAKi) are small molecules capable of crossing the placenta via passive diffusion or active extracellular transport from early pregnancy.¹ Data on the risks of in utero JAKi exposure are limited,² particularly regarding pregnancy outcomes, infant infections, vaccine responses, and childhood development.

Aims & Methods

We conducted a multicenter retrospective JAKi and pregnancy observational study supported by the ECCO Collaborative Network for Exceptionally Rare Case Reports (CONFER). Pregnant women with inflammatory bowel disease (IBD) exposed to tofacitinib (TOFA), upadacitinib (UPA), or filgotinib (FILGO) during pregnancy were enrolled from 21 centers across 15 countries. Data collected included maternal demographics, IBD characteristics, disease activity, medication use - including timing and duration of JAKi exposure - along with maternal, pregnancy, and infant outcomes.

Results

Of 43 JAKi exposed pregnancies, 17 (39.5%) were unplanned. Disease activity was present in 22 (51.2%) of the pregnancies. One-in-five women initiated JAKi in pregnancy (n=8, 18.6%). Abortion occurred in 8 cases, at a median gestational age (GA) of 8.5 weeks (range 3-16). Of these, 3 (7.0%) were spontaneous and 5 (11.6%) induced, with two terminations due to concerns about potential adverse effects of JAKi treatment. Of the remaining 35 pregnancies 26 (74.3%) were exposed to TOFA (5 mg BID (n=9), 10 mg BID (n=17)), 8 (22.9%) to UPA (30 mg daily (n=2), 45 mg daily (n=6)) and one (2.9%) to FILGO (200 mg daily). The majority received JAKi treatment throughout pregnancy (n=24, 68.6%). Discontinuation of JAKi during the 1^st or 2^nd trimester was followed by disease activity in 7 of 11 cases (63.6%). Maternal complication risk was low: no cases of DVT or (pre)eclampsia; premature rupture of membranes (GA 34–37) occurred in 3 cases, and 4 women required hospitalization due to infection or other complications. Among 35 live births, one infant (2.9%) was preterm (GA 34), three (8.6%) were small for gestational age, one (2.9%) had an Apgar score <7 at 5 minutes, and no congenital abnormalities were reported. Follow-up infant data are shown in table 1. One-third of breastfeeding women continued JAKi treatment. A high adherence rate to the national immunization schedule was seen. Three (8.6%) skipped the live rotavirus vaccine due to in uteroJAKi exposure. No adverse effects were reported following live attenuated or inactivated vaccines, and no malignancies were observed.

Conclusion

In this global multicenter study of JAKi exposure during pregnancy in women with IBD, maternal complication rates were low, and no increased risk of adverse pregnancy outcome were observed among live births. While disease activity was common, particularly following early discontinuation of JAKi, infant outcomes - including development, infection risk, and vaccine response - were reassuring. These findings provide important preliminary safety data to guide decision-making regarding the use of JAKi in pregnancy, though further prospective studies are needed to confirm long-term safety.

References

1. Fein KC, Arral ML, Kim JS, et al. Placental drug transport and fetal exposure during pregnancy is determined by drug molecular size, chemistry, and conformation. J Control Release 2023;361:29-39.
2. Torres J, Chaparro M, Julsgaard M, et al. European Crohn's and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. J Crohns Colitis 2023;17:1-27.

Disclosure

M. Julsgaard: Advisory board for AbbVie. G. Santana: Speaker and advisory board for pfizer.

Introduction

Although anti-TNF therapy is a cornerstone treatment for moderate to severe ulcerative colitis (UC)¹, up to 40% of patients are primary non-responders². The molecular basis for non-response in colonic mucosa remains poorly understood.

Aims & Methods

We aimed to identify compartment-specific molecular signatures in colonic epithelium and lamina propria that distinguish anti-TNF non-responders from responders with similar disease activity before treatment. UC patients with unambiguous endoscopic response (n = 6) or non-response (n = 6) after 6 months anti-TNF therapy were included. Pre-treatment inflamed and uninflamed colonic histological biopsies were laser microdissected into epithelial and lamina propria samples for total RNA sequencing. We analysed differentially expressed genes (DEGs), gene enrichment and weighted gene co-expression networks (WGCNA). Cellular deconvolution and pseudobulk validation were performed using a publicly available single-cell atlas³, and findings were further validated by immunohistochemistry.

Results

Inflammation elicited mucosal compartment-specific transcriptional changes, with more alteration in the epithelium (2,654 DEGs, log2 fold change (FC) > 0.3, padj < 0.05) enriched for interferon signaling and antigen presentation, compared to heightened cell-cycle and adaptive immune responses in the lamina propria (1,525 DEGs). We found no underlying differences in treatment response in either uninflamed or inflamed epithelium, nor in gene expression of TNF and its receptors in any compartment. The main difference between non-responders and responders was in uninflamed lamina propria where we identified distinct inflammatory signatures more overlapping with inflamed tissue (395 DEGs vs 1,112 in responders) and with high expression of cell cycle genes (e.g. TOP2A, MKI67, CDC20, CDKN1A, FZR1). A co-expression gene network enriched for humoral activity (log2 FC > 0.3, padj < 0.01) correlated strongly with non-response (r = 0.6, padj = 0.06) and contained numerous immunoglobulin genes (IGHA2, JCHAIN), including antigen-binding variable segments of heavy (IGHV4-34, IGHV3-7, IGHV3-73) and light chains (IGKV1-6, IGKV1D-17, IGLV2-11, IGLV2-14), in addition to other B cell-associated genes (BMI1, POU2AF1, TPD52). The cell cycle and humoral genes were systematically expressed higher in uninflamed lamina propria of non-responders compared to responders, with the differences disappearing in inflamed lamina propria. Cellular deconvolution³, showed that the humoral gene network was expressed in plasma cell populations (mainly IgA), which were confirmed increased in non-responder uninflamed lamina propria through tissue staining and gene expression. Pseudobulk analyses of uninflamed lamina propria samples from UC non-responders (n = 6) and responders (n = 3) filtered form the independent single-cell dataset³, validated the association of both cell cycle (14 of 18) and humoral (50 of 61) genes with uninflamed lamina propria in non-responders. Also, DEGs in uninflamed lamina propria IgA plasma cells from non-responders compared to responders in the validation dataset, were confirmed (15 of 18) in our data.

Conclusion

Our findings suggest that anti-TNF non-response in UC involves pre-existing humoral immune activation in macroscopically uninflamed colon mucosa. This spatially resolved signature offers a potential biomarker for treatment stratification and highlights the need for personalized therapeutic approaches in UC.

References

1 Raine, T. et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohn's Colitis 16, 2-17 (2021). https://doi.org/10.1093/ecco-jcc/jjab178
2 Ben-Horin, S., Kopylov, U. & Chowers, Y. Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmunity Reviews 13, 24-30 (2014). https://doi.org/https://doi.org/10.1016/j.autrev.2013.06.002
3 Thomas, T. et al. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. Nature Immunology 25, 1-14 (2024). https://doi.org/10.1038/s41590-024-01994-8