Tag Archives: refractory

Phase 2 Trial of Tulisokibart for Ulcerative Colitis

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Yesterday’s pumpkin -please no snide remarks about how I can now retire and become a sculptor:

BE Sands et al. N Engl J Med 2024;391:1119-1129. Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis

Background: “Several studies have implicated human tumor necrosis factor–like cytokine 1A (TL1A) in the pathogenesis of inflammatory bowel disease…Tulisokibart (formerly PRA023) is a humanized IgG1 kappa monoclonal antibody that binds to the membrane-bound and soluble forms of TL1A with high affinity and specificity. Tulisokibart prevents the interaction of TL1A and DR3, thereby suppressing type 1 and type 17 helper T-cell responses, increasing regulatory T-cell activity, and decreasing profibrotic pathways.”

Methods: (ARTEMIS-UC trial) The authors “randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.”

“The inclusion of an integrated assessment of a panel of genetic markers as a diagnostic assay was based on the notion that patients with a propensity to overexpress TL1A might be more likely to have a response to tulisokibart than an unselected population.”

Key findings:

  • In the first cohort, a significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%), endoscopic healing (31% vs. 4%), endoscopic improvement (37% vs 6%) and clinical response (66% vs 22%)
  • “Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%).”
  • Improvement in CRP and Calprotectin were noted as early as 2 weeks and 6 weeks respectively
  • The incidence of adverse events was similar in the tulisokibart and placebo groups

My take: Tulisokibart was effective in a group of patients with moderately to severely active ulcerative colitis who were refractory to advanced therapies.

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What to Do with Refractory Autoimmune Hepatitis: Case Report

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N Hadzic et al. NEJM 2024; 390: 284-286.JAK Inhibition in STAT1 Gain-of-Function–Mediated Treatment-Resistant Autoimmune Hepatitis

In this case report, the authors describe a 21 month old who presented with jaundice and abnormal liver tests. Diagnostic evaluation identified high titers of LKM antibodies (1:10,520) along with liver biopsy findings consistent with type 2 autoimmune hepatitis (AIH). After 6 months of treatment with steroids and subsequently azathioprine, the patient continued with severe biochemical relapses and a liver biopsy showed only a partial response.

Subsequently, “genetic testing found the patient had a heterozygous c.821G→A p.(Arg274Gln) pathogenic variant in the gene encoding signal transducer and activator of transcription 1 (STAT1)… Functional assays in the patient repeatedly showed abnormally high STAT1 phosphorylation as compared with healthy controls; this confirmed an autosomal dominant STAT1 gain-of-function defect.”

Treatment with “baricitinib, an inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2), was started. Within weeks, the patient’s aminotransferase levels normalized. ..A liver-biopsy sample that was obtained 4 months after the initiation of baricitinib therapy showed an absence of appreciable inflammation with residual mild fibrosis…She was weaned off mycophenolate and is continuing to receive daily baricitinib (8 mg) and prednisolone (2.5 mg) along with fluconazole and azithromycin for infection prophylaxis.”

My take: In children with refractory autoimmune hepatitis, genetic testing is worthwhile and may allow targeted therapy.

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Tyre Palm on St. John

Celiac Disease: “Ten Things That Every Gastroenterologist Should Know”

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Turns out that a recent review (AS Oxentenko, JA Murray. Clin Gastroenterol Hepatol 2015; 13: 1396-1404) is a succinct summary on celiac disease with questions focused on diagnosis, endoscopy, genetics/HLA typing, at risk groups, management, adherence, non responsive celiac patient, and refractory patients.  Most of these topics have been addressed previously on this blog.

However, here are a few pointers:

  • “Histologic improvement is slow in adults…Mucosal recovery, defined by a villous:crypt ratio of 3:1, was present in 34% at 2 years and 66% at 5 years, with healing complete in 90% by 9 years.”
  • “Mucosal recovery is faster and more complete in children, with 95% recovery in 2 years and 100% recovery long-term in children following a GFD.”
  • With nonresponsive celiac disease, “defined as a lack of response to 6 months on a GFD or a recurrence of celiac-related features despite compliance,” the authors recommend reviewing serology and biopsies.  Other etiologies to consider include bacterial overgrowth, autoimmune enteropathy, tropical sprue, Crohn’s disease, combined variable immunodeficiency, collagenous sprue, and eosinophilic gastroenteritis.
  • For refractory celiac disease with ongoing villous atrophy, this “should prompt immunophenotyping and T-cell rearrangement studies” of duodenal biopsies.

Briefly noted: ET Jensen et al. Clin Gastroenterol Hepatol 2015; 13: 1426-31.  The authors examined 88,517 patients who had undergone both esophageal and duodenal biopsies.  “Odds of EoE (eosinophilic esophagitis) were 26% higher in patients with celiac disease than in patients without celiac disease” (adjusted odds ratio 1.26).

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From the High Line, NYC

From the High Line, NYC