Tag Archives: Crohn’s disease

NSAIDs and IBD Flares (2026)

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AS Mayer,et al. Arthritis Care Res. https://doi.org/10.1002/acr.80067. Open Access! Safety of Prescription Nonsteroidal Anti-inflammatory Drugs in Adults With Inflammatory Bowel Disease: Data From a Large Administrative Claims Cohort.

Methods:

  • “This retrospective cohort study included patients with IBD aged at least 18 years from Optum’s deidentified Clinformatics Data Mart Database (2000–2022). Patients with a new NSAID prescription fill were matched to those without an NSAID fill during the study period…Propensity score-based inverse probability of treatment-weighted Cox proportional hazards models evaluated the association between NSAID exposure and time to IBD-related hospitalization across IBD subtypes.”

Key findings:

Unweighted Kaplan-Meier curve for IBD-related hospitalization in patients
with Crohn disease (B).
Unweighted Kaplan-Meier curve for IBD-related hospitalization in patients
with ulcerative colitis (C).

Discussion:

  • “The use of IPTW [inverse probability of treatment weighting] to balance an extensive number of confounders associated with NSAID use optimizes the assessment of the association of NSAID exposure with IBD-related hospitalization and helps address recent concern of residual confounding in observational studies of NSAID risk in IBD.”
  • Besides the potential risk of an IBD flare, “NSAID use is associated with risk of hospitalization from several non-IBD–related entities such as acute kidney injury and adverse cardiac events…a large prospective multicenter observational study of more than 18,000 admitted patients in England found that NSAIDs were responsible for 29.6% of admissions related to adverse drug reactions, including gastrointestinal bleeding, stroke, and renal impairment.34“

My take: This study shows an association of increased hospitalization in patients with CD but not UC based on NSAID exposure. The absolute risk of this appears low and could be in fact related to residual confounders (despite use of IPTW) as this was not a prospective study. The risk of NSAIDs outside the GI tract are likely more significant for most patients. Nevertheless, there are limited options for pain management and NSAID benefits have to be weighed against other approaches.

Related blog post: Rethinking the Link between NSAIDs and IBD Flares

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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Reassuring Study of Infants Exposed to Biologics

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L Palomino et al. Clin Gastroenterol Hepatol 2026; 24: 1688-1701. Open Access! Psychomotor Development in Infants Following Maternal Exposure to Biologics: Results From the DUMBO Registry

Methods: DUMBO (NCT03894228) is an ongoing, prospective, multicenter, observational registry study supported by Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) which includes women with IBD whose pregnancy was known to the investigator before the 28th week of gestation. Psychomotor development of infants was assessed using the Spanish version of the Ages and Stages Questionnaire 3rd edition (ASQ-3) during the first year of life. 

Key findings:

  • Exposure to biologics in utero, had no impact on ASQ-3 scores at month 12.
  • Multivariate analysis revealed that preterm birth (odds ratio, 0.3; 95% confidence interval, 0.1–0.6) and maternal ulcerative colitis (odds ratio, 0.5; 95% confidence interval, 0.3–0.9) were associated with an increased risk of abnormal ASQ-3. 

Discussion Points:

  • “Active maternal inflammation during the periconception period and pregnancy has been associated with low birth weight, preterm delivery, small size for gestational age, spontaneous abortion, and stillbirths.3,4…Active maternal inflammation during the periconception period and pregnancy has been associated with low birth weight, preterm delivery, small size for gestational age, spontaneous abortion, and stillbirths.3,4“
  • “In infants born to mothers with IBD, exposure to biologics would be expected to reduce their exposure to inflammatory cytokines in utero, which could potentially mitigate the impact of maternal inflammation on psychomotor development… our study found no negative impact of biologics exposure on the psychomotor development of infants, either from exposure in utero or during breastfeeding. Furthermore, we observed higher ASQ-3 scores in the personal-social domain at 4 months and in the gross and fine motor domains at 12 months in biologics-exposed vs nonexposed children, possibly reflecting a beneficial effect of treatment in reducing maternal inflammation.”
  • “Data from the PIANO study further supports our findings. Mahadevan et al assessed psychomotor development in 206 children exposed to biologics (both anti-TNF and non-anti-TNF) in utero, and 92 controls, finding higher ASQ-3 scores in the exposed group.”

My take: Biologic exposure does not appear to impair psychomotor development in infants. While this study provides useful information, I am not impressed wtih with the Acronym DUMBO for this registry.

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Yesterday’s Peachtree Road Race Shirt

“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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Pediatric Experience with Subcutaneous Infliximab

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EH Boute et al. Inflamm Bowel Dis 2026; 32: 1086–1096. Open Access! Persistence and safety of subcutaneous infliximab up to 1 year after switching from intravenous infliximab in pediatric inflammatory bowel disease: a multicenter real-world cohort study

Methods: This was a retrospective multicenter study we identified pediatric IBD patients (n=66 including 41 with Crohn’s disease) who switched to SC-IFX. Median age 16.5 years. Pre-switch, the median IV-IFX maintenance dose was 10 mg/kg every 6 weeks. There were only 6 patients with a weight <40 kg.

Key findings:

  • The initial SC-IFX regimen was 120 mg every other week in 62/66 patients (94%).  4 patients (6%) were initiated on 120 mg every week
  • SC-IFX persistence was 78% at 12 months post-switch, with 89% of patients persisting on IFX, either intravenous (IV) or subcutaneous (SC), at the end of follow-up
  • 17% (n=11) of patients experienced relapses. 6 patients underwent dose intensification (3 regained response), 3 patients switched to a different advanced therapy, and 3 patients received concomitant therapy
  • 11 patients (17%) discontinued SC-IFX treatment after a median of 7.0 months
  • 6 patients underwent SC-IFX dose intensification, with 3 successfully regaining clinical response
  • Regarding anti-drug antibodies (ADA), 3 out of 4 patients who were ADA positive on IV-IFX resolved post-switch
  • Three patients (3/66, 5%) experienced serious AEs requiring hospitalization, namely IgA-mediated nephropathy, pyelonephritis requiring IV antibiotics, and perianal fistula requiring seton drainage

Discussion:

  • “Compared to IV-IFX, SC-IFX provides higher and more stable serum concentrations, avoiding peak-trough variability, potentially lowering immunogenicity and offering greater flexibility in TDM.”
  • “Careful monitoring by the IBD team remains essential to ensure treatment adherence during and after the switch. In our cohort, most discontinuations (64%) were related to difficulties with the SC route, highlighting the importance of identifying the most suitable candidates.”

My take: More pediatric studies are needed. This study suggests that the effectiveness of SC-IFX in children will be similar to the effectiveness in adults. As more patients receive SC therapy, it will be particularly important to work on adherence with scheduled dosing, lab monitoring, and careful followup visits; all of these can be more difficult with SC compared with IV infusions.

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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

Development of a Standardized Care Transfer Summary

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J Tung et al. J Pediatr Gastroenterol Nutr. 2026;82:1057–1061. Development and testing of a pediatric inflammatory bowel disease medical transfer summary

This article describes a “multidisciplinary development and testing of a standardized pediatric IBD medical transfer summary template (PIBD-MTS) as a tool to improve the handoff of patient care.”

The “succinct nature allows AGIs [adult GIs] to review information within 10 min, in contrast to typically sifting through copious disorganized notes that may be redundant, at times irrelevant or missing key information. Its comprehensive nature includes prompts for disease monitoring, health maintenance, nutrition as well as mental health and socioeconomic factors that may affect IBD care.”

My take: This is a good template for transitioning patients. Though the focus is on transfers to adult gastroenterologists as patients get older, this form would be applicable for many patients who see other pediatric gastroenterologists for location or second opinions. It would be a good idea for this form to be available on the ImproveCareNow website. (It may be there but I did not see it). In addition, many centers may want to incorporate this template into their EMRs (eg. EPIC letter).

Link: ImproveCareNow

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The transfer template is accessible as a word document (supplement 1) at the end of the report. Here is a screenshot:

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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Genetic Risk Impacts Severity of Inflammatory Bowel Disease

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MV Vestergaard et al. Gastroenterol 2026; 170: 721-734. Open Access! Genetic Risk of Inflammatory Bowel Disease Is Associated With Disease Course Severity

Methods: The authors calculated IBD polygenic scores (PGS) for 3732 Danish patients with Crohn’s disease (CD) and 4535 patients with ulcerative colitis (UC), and investigated their association with disease outcomes.

“The Danish National Biobank stores neonatal blood spots from almost all Danes born since 1982…The North Denmark IBD (NorDIBD) cohort is a population-based cohort of all patients from the North Denmark Region with a confirmed IBD diagnosis from 1978–2020.17 From this cohort, 940 patients with IBD and a further 973 blood donors with no IBD diagnosis were genotyped from whole blood…applied variant loadings for calculating PGS for CD and UC susceptibility generated by Middha et al19 to our dataset. These variant loadings were derived from summary statistics from the IIBDGC.” This cohort had a young age. Only 2% and 3% of CD and UC patients, respectively, were 40+.

Severe Disease Definitions:

  • For patients with CD, a severe disease course was defined as experiencing (1) 2 or more IBD-related hospitalizations exceeding 2 days, (2) 2 or more IBD-related major surgeries, (3) 1 IBD-related hospitalization and 1 IBD-related major surgery not overlapping in time, or (4) a total use of at least 5000 mg prednisolone-equivalent systemic corticosteroids within the first 3 years after diagnosis
  • For patients with UC the severity definition was modified to experiencing (1) 2 or more IBD-related hospitalizations exceeding 2 days, (2) 1 or more IBD-related major surgeries, or (3) a total use of at least 5000 mg prednisolone-equivalent systemic corticosteroids. 

Key findings:

  • Increased PGS was associated with higher fecal calprotectin and C-reactive protein levels, and decreased hemoglobin levels
  • When comparing the highest vs lowest PGS quintile, we observed a hazard ratio for major surgery of 2.74 in patients with CD and of 2.04 in UC
  • Patients with severe disease had higher PGS than patients with less severe disease (CD, odds ratio = 1.25; UC, odds ratio = 1.33)

The graphs below show the differences in hospitalization and surgery based on PGS for CD (A & B) and then for UC (C & D)

Discussion:

  • “Our results suggest that IBD susceptibility genetics only explain part of the severity of IBD, hence leaving room for other factors at play… This observation is promising, as it points toward the possibility of modulating the effects of genetic susceptibility through lifestyle interventions directed toward potential environmental factors that are yet to be uncovered.”

My take: It is intuitive that those with more genetic risk factors would be more likely to have severe disease. This study shows this assumption is correct in this cohort; in fact, there is a dose-response relationship. Those with higher PGS had more hospitalizations, major surgeries and medical treatments.

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Choosing Advanced Therapy for Crohn’s Disease Based on Disease Location

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Methods: In the study by Lee et al, the authors identified 14 randomized controlled trials in 3139 patients with moderate-to-severe CD who were treated with different advanced therapies vs placebo, and reported efficacy in inducing clinical remission, stratified by disease location (isolated colonic vs ileal disease, excluding ileocolonic disease). The authors did not identify any RCT of TNF antagonists that reported induction of remission by disease location.

Key findings:

  • All advanced therapies had better success with colonic disease rather than ileal disease
  • Anti-interleukins (eg. IL23 o rIL12/IL23 agents) worked best for ileal disease among these advanced therapies
  • JAK inhibitors did not work well for ileal disease, but performed well for colonic disease
  • Anti-integrins, like vedolizumab, had some efficacy for ileal disease but generally a lower clinical remission rate than other agents
  • Lmitations included the use of clinical remission as the primary outcome
  • While this study did not provide data on anti-TNF therapy, in the discussion the authors note that “TNF antagonists may have advantages in small bowel CD…infliximab demonstrated the highest rate of improvement in large ileal ulcers (>0.5 cm).” [ref#45] “Additionally, infliximab has been reported to reduce fibrostenosis-associated inflammation, [Ref#46] making it currently the most suitable therapeuctic option for small bowel CD.”

In the study by Sands et al, this post-hoc analysis included week (W) 10 responders (n=329) to intravenous IFX induction therapy who were randomized to receive IFX SC 120 mg every 2 weeks or placebo (PBO) during maintenance therapy.

Key findings:

My take: These two studies indicate that anti-TNF agents (particularly infliximab) and IL-23 type agents are most effective for Crohn’s disease affecting the ileum. JAK inhibitors are best for colonic disease.

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Graphic by Dr. Keith Siau