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Background: Pediatric ulcerative colitis (UC) is typically more extensive and severe at diagnosis compared with adult disease. Tofacitinib, a Janus kinase inhibitor, has been used since 2018 to induce and maintain remission in UC. There are limited pediatric data regarding its use, either as a monotherapy or in combination with other treatments. Objectives: To determine the real-world experience and outcomes of tofacitinib therapy in the Irish national cohort with pediatric UC. Methods: A retrospective study of tofacitinib outcomes was undertaken at Ireland's single national center for pediatric inflammatory bowel disease. All patients commenced on tofacitinib since its availability in 2019 were included. Baseline and follow-up clinical characteristics, phenotype, Pediatric Ulcerative Colitis Activity Index (PUCAI) scores, and treatments before and after tofacitinib commenced were recorded. The primary outcome was remission by 8 weeks, with other clinical outcomes being recorded to maximal available follow-up. Results: Between November 1, 2019 and June 30, 2022, 15 children (M:F 1:2) were prescribed tofacitinib, 5 as monotherapy. Thirteen had baseline pancolitis at diagnosis and all patients had prior infliximab exposure. The mean time from diagnosis to starting tofacitinib was 381 days (±SD 265). Dual therapy included 5 with infliximab, 4 with vedolizumab, and 1 with adalimumab. The average length of treatment on tofacitinib was 232 days (±SD 170) with 2 patients transitioning to adult services while in remission on tofacitinib therapy. The mean PUCAI score was 48.7 (±SD 14.1) pre-tofacitinib, 16.7 (±SD 15.6) at week 8, and 22.5 (±SD 29.6) by week 16, with a significant reduction in PUCAI by week 16 (P = 0.0004). Eight patients (3 monotherapy) achieved clinical remission, with 4 of the 5 dual therapy patients on infliximab. There were no significant outcome differences between those on mono- or dual therapy. Three patients with combined vedolizumab therapy did not achieve remission, 2 of whom required colectomy by week 24. There were no malignancies, 1 patient developed shingles and another developed herpangina post-tofacitinib. Failure to achieve clinical remission by week 16 was seen in all children who progressed to colectomy (n = 4). Conclusion: Combining tofacitinib with other biologics is effective in select children with refractory UC. Early responders were more likely to achieve a sustained response at week 16. Failure to achieve remission by week 16 of tofacitinib therapy was strongly associated with progression to colectomy.
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We carried out a yeast two-hybrid screen using a BRCA1 bait composed of amino acids 1 to 1142 and identified BRD7 as a novel binding partner of BRCA1. This interaction was confirmed by coimmunoprecipitation of endogenous BRCA1 and BRD7 in T47D and HEK-293 cells. BRD7 is a bromodomain containing protein, which is a subunit of PBAF-specific Swi/Snf chromatin remodeling complexes. To determine the functional consequences of the BRCA1-BRD7 interaction, we investigated the role of BRD7 in BRCA1-dependent transcription using microarray-based expression profiling. We found that a variety of targets were coordinately regulated by BRCA1 and BRD7, such as estrogen receptor alpha (ERalpha). Depletion of BRD7 or BRCA1 in either T47D or MCF7 cells resulted in loss of expression of ERalpha at both the mRNA and protein level, and this loss of ERalpha was reflected in resistance to the antiestrogen drug fulvestrant. We show that BRD7 is present, along with BRCA1 and Oct-1, on the ESR1 promoter (the gene which encodes ERalpha). Depletion of BRD7 prevented the recruitment of BRCA1 and Oct-1 to the ESR1 promoter; however, it had no effect on the recruitment of the other Swi/Snf subunits BRG1, BAF155, and BAF57 or on RNA polymerase II recruitment. These results support a model whereby the regulation of ERalpha transcription by BRD7 is mediated by its recruitment of BRCA1 and Oct-1 to the ESR1 promoter.