Category Archives: inflammatory bowel disease

Interleukin-10 Autoantibodies and Development of IBD Plus One

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N Gharahdaghi et al. N Engl J Med 2026;394: 2212-2222. Interleukin-10 Autoantibodies and HLA-DRB1*01:03 in Inflammatory Bowel Disease

Background: “The allele HLA-DRB1*01:03 is the strongest genetic risk factor not only for susceptibility to ulcerative colitis but also for complicated phenotypes, including acute severe ulcerative colitis and an increased likelihood of surgical resection.2-5 However, the underlying pathogenic mechanism linking this HLA allele to disease remains unclear.”

“Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD)…In one child, anti–interleukin-10 titers and disease activity responded to B-cell–depleting anti-CD20 therapy.12“

Methods:

Key findings:

  • Interleukin-10–neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%) and in none of 1006 controls (P<0.001)
  • High anti–interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response
  • Anti–interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0), the U.K. IBD BioResource cohort (odds ratio, 24.7), and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5)

Discussion Points:

  • “The genetic association between HLA-DRB1*01:03 and anti–interleukin-10 autoreactivity provides mechanistic insight into one of the strongest known genetic susceptibility factors for IBD, with possible diagnostic, prognostic, and therapeutic implications.”
  • “Monogenic interleukin-10–signaling defects tend to manifest during infancy with colonic and penetrating disease, poor response to IBD therapies, high inflammatory activity with notably elevated C-reactive protein levels, and a high incidence of postoperative complications.27 It will be informative to establish the extent to which anti–interleukin-10 seropositivity associates with a similar disease pattern.”
  • “Our data highlight the need for research into therapeutic maneuvers to reduce anti–interleukin-10 titers — for example, by means of B-cell and plasma-cell depletion (e.g., anti-CD19, anti-CD20, anti-CD38, or CD19 chimeric antigen receptor [CAR] T-cell therapy),29-31 plasma exchange, or blockade of the neonatal Fc receptor.32“

My take: Historically, in younger patients (6 or younger) and those with more severe inflammatory bowel disease, it has been common to evaluate for monogenetic diseases which may require different treatment approaches. For similar reasons, assessing for neutralizing autoantibodies against interleukin-10 is likely to become part of routine care.

Related study: Q Zhang Q, Shakweh E, Sharip M et al. The Lancet Gastroenterology & Hepatology, 2026; 0. Open Access! HLA-DRB1*01:03 in patients with inflammatory bowel disease: a genotype–phenotype association study Key findings:

  • Among 43,762 patients with IBD (21 839 with Crohn’s disease and 21 923 with ulcerative colitis or IBD unclassified), HLA-DRB1*01:03 carriage was observed in 2009 (4·6%) patients with IBD and associated with multiple severe outcomes …including colonic resection in patients with Crohn’s disease (odds ratio 1·35), colectomy in patients with ulcerative colitis or IBD unclassified (1·99), and perianal disease in both patients with Crohn’s disease (1·65) and patients with ulcerative colitis or IBD unclassified (1·70)

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“Real-World” Impact of Vitamin D for Patients with Inflammatory Bowel Disease

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JA Sninsky et al. Clin Gastroenterol Hepatol 2026; 24: 1666-1674. Open Access! The Real-World Impact of Vitamin D Supplementation on Inflammatory Bowel Disease Clinical Outcomes

Methods: This was a retrospective cohort study of adult patients (n=5021) with IBD seen in the national Veterans Health Administration system from 2000 to 2023. The researchers used 3 different methods to try to determine causality of improved outcomes with supplementation of Vitamin D.

  1. “Difference-in-differences (DiD) approach to compare changes in clinical outcomes before and after vitamin D testing between patients who did and did not receive supplementation”
  2. “The regression discontinuity design leveraged the clinical threshold of 30 ng/mL serum 25-hydroxyvitamin D, comparing outcomes in patients just lower than and just higher than this cutoff, who are assumed to be otherwise similar”
  3. “The inverse probability weighting method adjusted for confounding by weighting patients based on their likelihood (propensity) of receiving vitamin D15“

Key findings:

  • The median 25-hydroxyvitamin D level was 23 ng/mL, and 41% received vitamin D supplementation
  • Vitamin D supplementation was associated with reduction in IBD-related emergency department visits by 2.17% (34.4% relative risk reduction; P = .007), hospitalizations by 2.64% (53.18% relative risk reduction; P = .003), and corticosteroid prescriptions by 1.29% (25.13% relative risk reduction; P = .066)

Discussion:

  • “Collectively, our data strongly suggest that vitamin D supplementation reduces the risk of IBD flare, underscoring its promise as an effective adjunctive therapy in clinical practice.”
  • “Vitamin D deficiency is prevalent among patients with IBD and is strongly linked to poor clinical outcomes, including higher rates of hospitalization and surgery. Patients with IBD are 64% more likely to be vitamin D deficient compared with healthy control subjects.29“
  • “Vitamin D deficiency is prevalent among patients with IBD and is strongly linked to poor clinical outcomes, including higher rates of hospitalization and surgery. Patients with IBD are 64% more likely to be vitamin D deficient compared with healthy control subjects.29“
  • “Although these findings support a strong association between vitamin D deficiency and worse clinical outcomes, they do not address whether supplementation itself mitigates the risk of adverse events, because disease severity confounds this relationship.33 Our study fills this knowledge gap and provides rigorous real-world data to support the effectiveness of vitamin D supplementation.”

My take: There have been large studies (eg. VITAL) study showing that Vitamin D supplementation does not help most people in the general population. In addition, many individuals with IBD who have low Vitamin D levels may see improvement in Vitamin D status by treating the IBD (without Vitamin D supplement). Yet, studies like this one by Sninsky indicate that Vitamin D supplementation is associated with improved outcomes in this retrospective cohort; the study methods likely indicate a causal effect of supplementation; however, a prospective randomized controlled study would be more definitive.

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Oral Vancomycin For Pediatric Inflammatory Bowel Disease

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S Ancona et al. J Pediatr Gastroenterol Nutr. 2026;82:1416–1426. Effectiveness and safety of oral vancomycin in non-primary sclerosing cholangitis paediatric inflammatory bowel disease

Background: “Oral vancomycin (OV) has limited usage in paediatric inflammatory bowel disease (PIBD) with reported efficacy in primary sclerosing cholangitis (PSC-PIBD), acute severe colitis as part of quadruple-antibiotic regimen, and very early-onset IBD. This study evaluates OV effectiveness and safety as a single-agent in non-PSC PIBD.”

Methods: Retrospective, single center study with 31 children (median age 15.1); the presence of PSC and C diff were exclusion criteria. There were  23 ulcerative colitis (UC), 4 IBD-unclassified (IBDU) and 4 Crohn’s disease. OV was started at 250 mg for patients ≥30 kg or 125 mg for those <30 kg and administered four times daily (QDS) or three times daily (TDS). The majority were receiving concomitant medications: steroids in 16%, biologics in 32%, 5-ASA in 74%, and thiopurines in 42%.

Key findings:

  • Clinical and biochemical remission was achieved or maintained in 17/31 (55%), with 15/17 reducing/stopping other treatments and two remaining on OV monotherapy
  • At 1-month faecal calprotectin dropped from 686 to 60 μg/g in responders (p = 0.001) but remained high in nonresponders
  • Responders (Group 1) continued OV for a median of 7.0 months (IQR 2.5–23.5), maintaining consistently low PUCAI and FC levels throughout a median follow‐up of 19.0 months. After discontinuation, three relapsed and restarted OV,recapturing remission in 2/3.
  • Responders had lower baseline clinical disease activity
  • No serious adverse events occurred. No vancomycin-resistant enterococcus (VRE) colonization was seen

My take: This study’s vancomycin responders (55%) had significant improvement within four weeks. This is in agreement with other studies indicating that antimicrobial regimens may be helpful in a significant subset of children with inflammatory bowel disease. Larger prospective studies are warranted.

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Island Ford in Sandy Springs

Real-life Study of Ustekinumab for Pediatric Crohn’s Disease (REALITI Study)

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SJ Steiner et al. J Pediatr Gastroenterol Nutr. 2026;82:1242–1250. Open Access! Effectiveness and safety of ustekinumab in pediatric Crohn’s disease: Results of the REALITI study

This retrospective study used prospectively-collected data from the ImproveCareNow (ICN) registry for pediatric patients. Overall, 479 patients with CD were treated with ustekinumab, 348 pediatric patients and 131 young adults; most were biologic-exposed (pediatric, 98.9%; young adult, 95.4%).

Key findings:

  • At week 52, clinical remission was achieved by 47.3% (125/264) of pediatric patients and 44.8% (39/87) of young adults, and CF (corticosteroid-free) clinical remission by 41.3% (109/264) and 39.1% (34/87), respectively
  • At Week 52 (observed case), among patients with moderately-to-severely active CD, clinical remission was achieved by 36.9% (41/111) of pediatric patients and 34.3% (12/35) of young adults, and CF clinical remission by 31.5% (35/111) and 28.6% (10/35), respectively.
  • Ustekinumab was well tolerated, with no new safety signals identified; however, a majority (89.4%) of the pediatric patients were 12–17 years old and most (76.5%) weighed ≥40 kg. Thus, further evaluations of ustekinumab in younger pediatric patients with CD and in those weighing <40 kg are still needed.
Observed case analysis of clinical effectiveness endpoints at Week 52 in (A) all patients with CD treated with ustekinumab, and (B) patients with moderately-to-severely active CD treated with ustekinumab.

My take: Studies indicate that newer selective IL-23 agents like risanizumab outperform ustekinumab. However, ustekinumab has FDA approval* for patients 2 years and older. In addition, there are several generic versions of ustekinumab which are less expensive than the newer agents. As such, I anticipate it will continue to be used.

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*There has been recent approval recent of Stelara (ustekinumab) for the treatment of pediatric patients 2 years and older with moderately to severely active Crohn’s disease. Here’s a link: Johnson & Johnson (JNJ) Gains FDA Approval for Pediatric Crohn’s Disease Treatment

Appendectomy for Refractory Ulcerative Colitis: 2026 COSTA Study

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Visser E, Reijntjes M, Heuthorst L et al.The Lancet Gastroenterology & Hepatology, 2026; 11, 190-203. Appendicectomy versus switching to a JAK inhibitor in inducing remission in patients with active ulcerative colitis after biologic therapy failure (COSTA): 1-year results of a multicentre, prospective, cohort study

Last year, the ACCURE Trial (see blog post link below), showed that laparoscopic appendicectomy, in addition to standard medical therapy, significantly reduced the relapse rates for ulcerative colitis (UC) within 1 year. Most patients were treated with mesalamine.

The COSTA study examined adult patients (n=125) who were not responding to advanced therapy. Patients were offered one of three treatments: laparoscopic appendicectomy while continuing their existing advanced therapy at a stable dose; switching their advanced therapy to a JAK inhibitor; or colectomy. 116 patients were included in the modified intention-to-treat-analysis (67 received appendicectomy and 49 received JAK inhibitor (primarily tofacitinib).

Key findings:

  • 22 (32.8%) of 67 patients in the appendicectomy group were in clinical remission without therapy failure at 12 months compared with six (12.2%) of 49 patients in the JAK inhibitor group (p=0.016)
  • At 12 months, corticosteroid-free clinical remission without therapy failure was attained in 22 (32.8%) of 67 patients in the appendicectomy group compared with six (12.2%) of 49 patients in the JAK inhibitor group  (p=0.010). Clinical response in 49 (73.1%) of 67 patients compared with 26 (53.1%) of 49 patients (p=0·025), and endoscopic response in 31 (48.4%) of 64 patients compared with 11 (25.6%) of 43 patients (p=0·018)

My take (borrowed in part from the authors): “Appendicectomy as an adjunct to advanced therapy in biologic-exposed patients with active ulcerative colitis was associated with higher clinical remission rates at 12 months compared with switching to a JAK inhibitor.” We don’t know how appendectomy would influence disease course in pediatric patients. We also don’t know how this information will be incorporated into adult guidelines.

Interestingly, there have been studies (two cited below) indicating that appendectomy lowers the risk of developing inflammatory bowel disease:

Related blog post: ACCURE Trial: Appendectomy As an Adjunct Ulcerative Colitis Treatment Plus One

Kiawah Island at Sunrise

    Proactive Therapeutic Drug Monitoring is Routine Part of Pediatric IBD Care Plus SNL Humor

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    RJ Colman et al. Crohn’s & Colitis 360, Volume 7, Issue 3, July 2025, otaf050. https://doi.org/10.1093/crocol/otaf050. Open Access! Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease: A Nationwide Survey of Anti-TNF Therapy Practices, Attitudes, and Barriers 

    Methods: A 28-item survey of therapeutic drug monitoring (TDM) was deployed through the ImproveCareNow Learning Health System Network between February and June 2023.

    Key findings:

    • Among 380 invitees, 256 (77%) completed the questionnaire. Among respondents, 67% (171) were academic-affiliates
    • In contrast to the adult literature, most pediatric gastroenterologists report undertaking proactive TDM for anti-TNF agents in IBD management
    • TDM: All 256 respondents reported using TDM for infliximab, while 252 (98%) used TDM for adalimumab (ADL)
    • Proactive TDM: Proactive TDM was more common for infliximab 98% (205/256) compared to ADL 92% (232/252; P = .0007)
    • Overall, 61% (156/255) of respondents reported that they experienced barriers in undertaking TDM. Insurance denial (50%) and cost (31%) were the 2 most commonly reported barriers
    Frequency of therapeutic drug monitoring use stratified by anti-TNF agent.

    Limitation: Only surveyed practitioners in ICN. However, “approximately 65% of US pediatric gastroenterologists practice within ICN-affiliated institutions, [thus] our findings likely reflect national trends.”

    My take (borrowed from authors): “Proactive TDM, is a widely practiced strategy, and represents the current standard of care among pediatric gastroenterologists in the United States.” 

    How to explain a complication with Will Ferrell, YouTube Link: SNL Post-Op (5 minutes)

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    Mirikizumab for Pediatric Ulcerative Colitis

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    K Jimbo et al. Inflammatory Bowel Diseases 2026; 32: 711-720. Real-World Effectiveness of and Optimization Strategies for Mirikizumab in Pediatric Ulcerative Colitis: A Prospective, Observational Study

    Methods: This prospective cohort study included Japanese children (n=28) with UC receiving intravenous mirikizumab (300 mg at weeks 0, 4, 8), followed by subcutaneous maintenance (200 mg every 4 weeks). The cohort had a median age 13 years (50% female) with a median PUCAI 67.5; 67.4% were biologics-naive. In those with clinical remission at 12 weeks, sucutaneous injections were started; otherwise, IV infusions (prolonged induction, n=11) continued every 4 weeks. Complete remission was defined as PUCAI<10 and colonic wall thickness on IUS <3.0 mm with no detectable color Doppler flow signal throughout the colon.

    Key findings:

    • The median time to complete remission (CR) was 10 weeks. All patients ultimately achieved CR
    • Durable CR was achieved in 27/28 (96%).
    • SF-CR generally increased over time: 17/28 (61%) at week 12, 28/28 (100%) at week 24, and 27/28 (96%) at wek 52
    • No serious adverse events were noted. 6 children developed self-limiting flu-like symptoms

    Limitations included relatively small number of patients at a single center. Also, the majority of patients had not received prior advanced therapies.

    My take: It is encouraging to see favorable pediatric data. Though, the complete remission rate of 100% will likely be an outlier as more data become available.

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    ImmunogenicityTable by Tauseef Ali IBD Library

    Dr. Bonney Reed: Optimizing Quality of Life in IBD

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    We had a terrific lecture given to our group by Dr. Bonney Reed. She is a pediatric psychologist with a clinical and research focus on children with inflammatory bowel disease. Our group has worked closely with Dr. Reed for many years. Many of her slides are included below along with my notes; my notes may contain errors in transcription and in omission.

    • GI symptoms may begin as the result of organic disease (e.g., IBD). Anxiety and chronic activation of the stress response system may lead to alterations in the brain, spinal cord, and gut increasing the load of GI symptoms. In turn, distress associated with GI symptoms may contribute to anxiety or depressed mood, creating a cycle of worsening GI symptoms and overall psychological distress.
    • Consistent with a brain-gut axis model, individuals with IBD, compared to healthy controls, demonstrate dysfunction of the ANS indicative of a chronic stress response which is characterized by increased sympathetic nervous system (SNS) activity and reduced parasympathetic nervous system (PNS) activity
    • Psychological factors are the key factor for pediatric patients with IBD when self-rating their global health
    • Factors that contribute to an individual’s current QoL: symptom exacerbation, psychological functioning including stress, and family support.
    • Health-related quality of life factors: major life transitions (eg. graduating high school and needing to manage IBD at college), fatigue ( persists despite controlled inflammation), poor body image (especially with weight changing rapidly), a diminished self-perception or seeing oneself as less capable, comorbid functional abdominal pain (about a quarter of youth with IBD), and food restrictions that can interfere with daily quality of life.
    • Stress plays important role influencing (bidirectional) disorders of brain gut interaction (DBGI)
    • Dr. Reed’s research includes a longitudinal cohort of newly-diagnosed (w/in 45 days) pediatric patients with IBD. This cohort undergoes psychosocial assessment along with ANS assessment
    • Emotional reactivity indicates individuals with a ‘short fuse’ who take longer to return to normal.  Those with emotional reactivity are at increased risk for anxiety/depression.
    • Skin conductance response (SCR) can help determine autonomic nervous system (ANS) dysfunction.  It is a measure of sympathetic arousal and stress
    • Stressful life events increase the rates of depression and correlate with skin conductance at medium and high levels
    • Within this model, Dr. Reed’s research focuses on the hypothesis that autonomic dysfunction is indicative of a chronic stress response. This, in turn, contributes to increased sympathetic nerve activity and decreased parasympathetic activity. This contributes to symptoms of anxiety and depression as well as GI clinical symptoms, all of which lead to impairments in QoL. Addressing autonomic dysfunction may provide a mechanism by which to address all of these QoL drivers
    • ANS dysfunction (which is also seen in cyclic vomiting syndrome) can improve with biofeedback focused heart rate variability (HRV). HRV, in turn, is associated with increase inflammation
    • Preliminary data from breath pacer intervention has shown in improvement in multiple variables

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    Upadacitinib for Pediatric Ulcerative Colitis

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    A Yerushalmy-Feler A et al. Clinical Gastroenterology and Hepatology, 2026 (In press); Upadacitinib Maintenance Therapy in Pediatric Ulcerative Colitis: 52-Week Multicenter Study From the Porto Group of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition

    Background/Methods: There is limited data on the use of upadacitinib for pediatric inflammatory bowel disease. This retrospective data from 35 European centers analyzed its effectiveness in 105 children (95 with UC and 10 with IBD-U).  Prior to upadacitinib, 103 of 105 children (98%) were treated with biologic therapies and 79 (75%) with ≥2 biologics. The induction dose was 45 mg in 86% of cohort; the maintenance dose was 30 mg in 87% (only 2 patients received 45 mg maintenance). Mean age at IBD diagnosis was 11.3 yrs and mean age at start of upadacitinib was 14.6 yrs. 65% of study participants had a pancolitis.

    Key findings:

    • Clinical remission and corticosteroid-free clinical remission (CFR) were observed after 8 weeks in 61 (58%) and 53 (51%) children, respectively
    • By week 52, 75 children (71%) achieved clinical remission, 73 (70%) achieved CFR, and sustained CFR in 63 (60%); CFR with FC <150 mcg/g was reached 30 of 80 (38%) (29% of the ITT group)
    • Adverse effects: There were two serious AEs: an appendiceal neuroendocrine tumor and cytomegalovirus colitis. The most frequent AEs were hyperlipidemia (n = 20), infections (n = 18), and acne (n = 14)

    Predictors of response: “The baseline variables that were associated with achieving sustained CFR were prior failure of fewer biologic agents (≤2 vs >2), a lower PUCAI score, absence of corticosteroid therapy, and higher serum hemoglobin and albumin levels.”

    Age: “Our findings suggest that upadacitinib provides comparable effectiveness in younger children weighing <40 kg, supporting its therapeutic potential across a broader pediatric age and weight range.”

    My take: Upadacitinib is an important therapy for ulcerative colitis in the pediatric age range and in adults. It is effective in all age groups. Also, young children can now be prescribed a liquid version (Rinvoq LQ) which requires twice daily dosing (rather than once a day). Some patients who do not respond adequately or lose response may benefit from higher dosing.

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    Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

    Case Report: Car-T for Refractory Ulcerative Colitis

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     F Muller et al. NEJM 2025;393:1239-1241. CD19 CAR T-Cell Therapy in Multidrug-Resistant Ulcerative Colitis

    This case study involved the use of “autologous chimeric antigen receptor (CAR) T cells targeting CD19 in a 21-year-old woman with severe multidrug-resistant ulcerative colitis, who had declined colectomy. Previous treatments with prednisolone, mesalamine, infliximab, ustekinumab, ozanimod, filgotinib, vedolizumab, upadacitinib, and cyclosporine combined with mirikizumab had not induced clinical remission.”

    “Clinical and biochemical remission occurred and were maintained over the 14-week follow-up period… without the use of concomitant therapy. Endoscopic, histologic, and ultrasonographic assessments showed signs of mucosal healing over time….These data suggest the possibility that CD19 CAR T-cell therapy can induce rapid drug-free remission in refractory ulcerative colitis, a disease that was previously thought to be largely B-cell–independent, given that rituximab treatment showed no efficacy..”

    My take: This is only a single case report. However, it shows that modulation of the immune system could potentially cure ulcerative colitis. At the same time, long term adverse effects of CAR-T therapy will need to be monitored.

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