Category Archives: Gastroenterology

Spice It Up! Curcumin for Ulcerative Colitis (2024)

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S Ben-Horin et al. Clin Gastroenterol Hepatol 2024; 22: 347-356. Open Access! Curcumin-QingDai Combination for Patients With Active Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Trial

This two part study involved a small open-label trial of combination curcumin-QingDai (CurQD) with 10 patients and a placebo-controlled trial with 42 patients with active ulcerative colitis (UC) over 8 weeks.

Background: “Curcumin and QingDai (QD, Indigo) are herbal compounds previously found to be effective in mild–moderate and moderate–severe ulcerative colitis (UC), respectively, but data on their use still are limited.” Curcumin has purported anti-inflammatory and antioxidant properties through downregulation of nuclear factor-kB, regulation the JAK/STAT pathways, and through its effects on the NLRP3 inflammasome. Qing Dai, also known as indigo naturalis, is a traditional Chinese medicine that has demonstrated efficacy in promoting recovery from colitis in animal models and prior human trials, potentially acting through activation of the aryl hydrocarbon receptor.

Methods: CurQD was administered as 3 capsules of 500 mg herbal extract dry powder QD (a total of 1.5 g) and 3 capsules of 500 mg dry powder curcumin (a total of 1.5 g)

Key findings:

  • Clinical response was observed in 85.7% vs 30.7% (P < .001), clinical remission in 14 of 28 (50%) vs 1 of 13 (8%; P = .01), a 50% calprotectin reduction in 46.4% vs 15.4% (P = .08), and endoscopic improvement in 75% vs 20% (P = .036) in the CurQD and placebo groups, respectively. 
  • In the maintenance arm, 11/15 responders in the CurQD arm maintained remission for an additional 8 weeks with just curcumin alone.

The editorial (pg 235 ) notes the following:

  • The number of patients in the study is small and safety and effectiveness of these agents is not certain. Qing Dai has been associated with a rare risk of pulmonary arterial hypertension (especially with long-term use). Thus, further studies are needed.
  • “Although it may be preferrable to use these agents in combination with therapies with established efficacy, should the patients’ choice be to use alternative therapy as sole agents for treatment, it is important for us to continue to maintain a trusting physician-patient relationship to ensure that our patients are achieving the treatment targets they need to maximize long-term favorable outcomes, irrespective of the therapeutic agent of choice.”

My take: Curcumin (with combination of Qing Dai for induction) was superior to placebo in achieving meaningful clinical outcomes including clinical response, remission, calprotectin improvement and endoscopic improvement. For future studies, I would favor an active comparator like mesalamine rather than placebo.

Related blog post: Spice It Up? Curcumin for Ulcerative Colitis (2015)

IBD Updates: How to Get Rid of Pesky Antibodies to Infliximab, Neoplasia in pouch, Vit D associated with improved IBD outcomes

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JZ Jagt et al. JPGN 2024; 78:57–67.Open Access! Effectiveness of strategies to suppress antibodies to infliximab in pediatric inflammatory bowel disease.

Anti‐infliximab antibodies were detected in 52/288 patients (18%)after a median of 15.3 months. Key findings:

  • Of the 49 studied patients, 19 had low titers and 30 had high titers
  • Of 19 low‐ATIs, 16 (84%) underwent treatment escalation with infliximab (IFX)
  • Among 30 patients with high‐ATIs, 17 (57%) continued with IFX; immunomodulators were started in seven patients
  • At 24 months of follow‐up, 73% of low‐ATI patients and 50% of high‐ATI patients could continue with IFX without steroids.
  • Interestingly, a large number of patients (3 of 17 in high titer group that continued IFX and 4 of 19 in the low titer group that continued IFX) did not have follow-up therapeutic drug monitoring (or availability of results)
  • ATIs were positively associated with infusion reactions
  • Overall, the authors conclude that dose optimization and/or use of an immunomodulator can help patients remain on infliximab (high and low titer)

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SA Urquhart et al. Inflammatory Bowel Diseases, Volume 30, Issue 2, February 2024, Pages 183–189. The Incidence of Pouch Neoplasia Following Ileal Pouch–Anal Anastomosis in Patients With Inflammatory Bowel Disease

Key findings: Out of 1319 patients, 10 (0.8%) developed neoplasia following IPAA (median follow-up of 8.6 yrs, mean age at time of IPAA was 36 years).  Presence of extensive colitis, primary sclerosing cholangitis, backwash ileitis, and rectal dysplasia at the time of IPAA were significantly associated with increased risk of pouch neoplasia. 

My take: The low rate of neoplasia along with risk factors should be considered in determining surveillance.

M Valvano et al. Inflammatory Bowel Diseases, Volume 30, Issue 2, February 2024, Pages 281–291. Effectiveness of Vitamin D Supplementation on Disease Course in Inflammatory Bowel Disease Patients: Systematic Review With Meta-Analysis

Methods: Randomized clinical trials (n=12) involving IBD patients treated with vitamin D supplementation, compared with placebo, that evaluated the risk of clinical relapse and disease activity were included

Key findings: The pooled risk ratio of clinical relapse was 0.64 (95% confidence interval, 0.46-0.89; I2 = 25%) among 458 IBD patients. (There were only 67 patients with ulcerative colitis in these studies)

Conclusion of authors: “This meta-analysis shows that vitamin D supplementation can reduce the risk of clinical relapse in IBD patients, especially in CD patients in clinical remission.” The dose and duration of vitamin D treatment to reduce the risk of relapse is unclear.

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A “Swell Diagnosis” (part 2)

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Recently, this blog post reviewed a case presentation of hereditary angioedema which often presents with bouts of severe abdominal pain: “A Swell Diagnosis”

Now, a study has shown how this can be effectively treated with CRISPR gene editing:

  • HJ Longhurst et al. N Engl J Med 2024; 390:432-441. CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

My take: Gene therapies have been very expensive. If this therapy is approved for hereditary angioedema it will be too. However, some of the current treatments for preventing hereditary angioedema are also quite costly.

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Irritable Bowel Syndrome Associated with Improved Survival

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F Li et al. AJG 2024; DOI: 10.14309/ajg.0000000000002675. The Time-Dependent Association between Irritable Bowel Syndrome and All-cause and Cause-specific Mortality: A Prospective Cohort Study within the UK Biobank

Key findings:

  • Having an IBS diagnosis was strongly associated with lower risks of all-cause (HR=0.70) and all cancer (HR=0.69) mortality in the first 5-years of follow-up. These associations were attenuated over follow-up, but even after 10 years of follow-up, associations remained inverse (all-cause: HR=0.89; all cancer: HR=0.87) after full adjustment.
  • Individuals with IBS had decreased risk of mortality from breast, prostate, and colorectal cancer in some of the follow-up time categories.

My take: Having IBS may cause suffering but appears to lower risk of death. The reason for this is not clear.

IBD Updates: Extending Mirkizumab Induction, Best Biologic, Fatigue in Pediatric IBD, Adalimumab Success in Patients with Abdominal Abscess

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  1. G D’Haens et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae004. Extended Induction and Prognostic Indicators of Response in Patients Treated with Mirikizumab with Moderately to Severely Active Ulcerative Colitis in the LUCENT Trials

Key findings:

  • Of patients not achieving clinical response during 12-week induction, 53.7% achieved response following extended induction (additional 3 doses of IV infusion every 4 weeks)
  • With “extended induction,” total of 80.3% mirikizumab-treated patients achieved clinical response by W24

2. S Schreiber et al. Inflamm Bowel Dis 2024; 30: S7. NETWORK META-ANALYSIS TO EVALUATE THE COMPARATIVE EFFICACY OF BIOLOGICS FOR MAINTENANCE TREATMENT OF ADULT PATIENTS WITH CROHN’S DISEASE

Methods: A network meta-analysis (NMA) was conducted to evaluate comparative efficacy of licensed biologics. Phase 3 randomized controlled-trials (RCTs) evaluating biologics approved by the European Medicines Agency or United States Food and Drug Administration as of 31 March 2023 for maintenance treatment of adult patients with moderate-to-severe CD were included, i.e. infliximab (IFX) intravenous (IV) and SC, adalimumab (ADL) SC, vedolizumab (VDZ) IV and SC, ustekinumab (UST) SC, and risankizumab (RZB) SC.

Key findings:

  • Among 8 comparator arms, IFX SC 120 mg every 2 weeks (Q2W) showed the highest odds ratio (95% credible interval) vs. PBO for clinical remission during the maintenance phase (3.52 [2.18–5.65]).

My take: This meta-analysis shows a favorable response for IFX SC; however, head-to-head trials are needed to really determine which biologic has the highest efficacy.

3. N Bevers et al. JPGN 2024; 2023; 77: 628-633. Fatigue and Physical Activity Patterns in Children With Inflammatory Bowel Disease

In this cross-sectional study with 104 children (24 with fatigue), biological parameters (CRP, fecal calprotectin) did not discriminate fatigued from non-fatigued patient

4. Y Bouhnik et al. Clin Gastroenterol Hepatol 2023; 21: 3365-3378. Adalimumab in Biologic-naïve Patients With Crohn’s Disease After Resolution of an Intra-abdominal Abscess: A Prospective Study From the GETAID

In this multicenter prospective study with 117 patients, the authors examined the success rate of adalimumab (ADA) in patients with CD with an intra-abdominal abscess resolved without surgery.

Key findings:

  • At W24, the survival rate without abscess recurrence or surgery was 74% (n=87)
  • Abscess drainage was significantly associated with ADA failure at W24 (odds ratio, 4.18)

My take (borrowed from authors): Provided that the abscess was carefully managed before initiating medical treatment, this study showed the high efficacy of ADA in the short and long term in biologic-naïve patients with CD complicated by an intra-abdominal abscess

Adjacent to Honeymoon Beach, St John

Predicting the Burden of IBD Until 2040

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R Patel et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae020.067. DECIPHERING THE BURDEN OF INFLAMMATORY BOWEL DISEASE LANDSCAPE (1990-2019) IN HIGH INCOME NORTH AMERICA: PROJECTIONS, TEMPORAL SHIFTS, AND A GLIMPSE BEYOND TO 2040 

Methods: “Utilizing Global Burden of DIsease tool, we estimated IBD prevalence, incidence, mortality, and Disability Adjusted Life Years (DALYs) of IBD in High-Income North America. Standardized statistical techniques facilitated comparisons by age, sex, year within this specific region. The DisMod-MR 2.1 tool was employed to estimate incidence and prevalence, while mortality rates were discerned using the Cause of Death Ensemble Model (CODEm). Additionally, we projected the deaths and Years of Life Lost (YLLs) up to 2040 using regression analysis.”

AGA Guideline on Pouchitis Management

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Key recommendations

  • AGA recommends metronidazole and/or ciprofloxacin as preferred treatment of pouchitis with duration of treatment 2-4 weeks.
  • For Crohn’s-like disease of the pouch, AGA guideline recommends using either ileal-release budesonide or advanced immunosuppressive agents (eg. Biological therapies and small molecule therapies)
  • “In patients with cuffitis, topical therapies should be the first-line therapy, such as mesalamine suppositories, corticosteroid suppositories, or corticosteroid ointment applied directly to the cuff. Biological therapies and small molecule therapies are recommended in refractory cases

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Cannabis Toxic Effects

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Two recent articles review cannabis-related disorders:

DA Gorelik. NEJM 2023; 389: 2267-2275. Cannabis-Related Disorders and Toxic Effects

Background: “In the United States, an estimated 52.4 million persons 12 years of age or older used cannabis in 2021, representing 18.7% of the community-dwelling population in that age group,5 and 16.2 million persons met the diagnostic criteria for cannabis use disorder, which has as its core feature the use of cannabis despite adverse consequences…Cannabis use poses a global disease burden, albeit substantially less than that posed by other psychoactive substances such as alcohol, tobacco (nicotine), opioids, and stimulants.10 The Global Burden of Disease project calculated that cannabis use in 2016 was responsible for an estimated 646,000 years of healthy life lost to disability.”

Key points:

  • “Cross-sectional surveys suggest that recent cannabis use increases the risk of motor vehicle crashes by 30 to 40%.26 By comparison, a blood alcohol concentration of 0.08% increases the risk of crashes by 250 to 300%.26“
  • “Cannabis use disorder, like other substance use disorders, is a chronic, relapsing condition.”
  • “A substantial reduction or a cessation of cannabis use after heavy or long-term use results in a withdrawal syndrome that is usually mild and self-limiting.39…Common psychological symptoms of cannabis withdrawal include depressed mood, anxiety, restlessness, irritability, decreased appetite, and sleep disturbance. Physical signs and symptoms are less common and include abdominal cramps, muscle aches, tremor, headache, sweating, chills, and weight loss. These signs and symptoms typically begin within 1 to 2 days, peak within 2 to 6 days, and last for several weeks…The prevalence of any withdrawal symptoms is almost 50% in persons who were using cannabis daily.”
  • Neonatal cannabis exposure: “Pregnant persons who use cannabis expose their neonates to cannabis. Such in utero exposure is associated with increased risk among newborns of having low birth weight, being small for gestational age, and being admitted to the neonatal intensive care unit.”
  • “Cannabinoid hyperemesis syndrome, a form of cyclic vomiting syndrome that is often accompanied by abdominal pain, occurs during or within 48 hours after frequent and heavy cannabis use.75 Cannabinoid hyperemesis syndrome is a major reason for cannabis-related visits to emergency departments, and it accounts for about 10% of patients with cyclic vomiting syndrome.76 Cannabinoid hyperemesis syndrome is distinguished from cyclic vomiting syndrome by its temporal association with cannabis use, relief with hot baths or showers, and resolution with extended abstinence from cannabis…The symptoms of cannabinoid hyperemesis syndrome are treated with benzodiazepines, haloperidol, and topical capsaicin. “
                 

M Camilleri, T Zheng. Clin Gastroenterol Hepatol 2023; 21: 3217-3229. Cannabinoids and the Gastrointestinal Tract This article focuses more on the GI tract effects of cannabinoids.

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Increased Risk of Suicide in Patients with IBD

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At a lot of IBD conferences, there is often a lot of focus on health maintenance including discussions on optimizing immunization levels and nutrition. It is often striking how, in comparison, so little attention is focused on emotional health which seems to cause a much greater health burden.

CS Tse et al. Inflamm Bowel Dis 2024; 30: 150-153. Increased Risks for Suicide, Self-Harm, Substance Use, and Psychiatric Disorders in Adults With Inflammatory Bowel Disease: A Nationwide Study in the United States From 2007 to 2017

Background: Patients with IBD are also at an increased risk for chronic opioid use, depression, anxiety, sleep disturbance, and disease-related disability (eg, unemployment), all known risk factors for suicide

Methods: This cross-sectional study uses the Nationwide Emergency Department Sample of the Healthcare Cost and Utilization Project (HCUP) as a public domain representing 80% of the U.S. population. This analysis included more than 260 million emergency department visits across the United States from 2007 to 2017.

Key findings:

  • Inflammatory bowel disease conferred >10-fold risk for suicide deaths, self-harm, substance use, and psychiatric disorders.
  • The absolute numbers of self-harm rates were low (<1% of all-cause inflammatory bowel disease emergency department visits; total 56 suicide deaths). This amounts to about 5 suicide deaths per year (compared to 0.5 per year for patients with celiac disease.
  • The risk of self-harm was higher in patients with Crohn’s disease than ulcerative colitis (RR, 3.3; 95% CI, 1.2-5.4), though the suicide risk was not statistically different (RR, 2.3; 95% CI, 0.8-4.5).
From Table 2: RR of self-harm, suicide, psychiatric disorders, and substance use of adults with inflammatory bowel disease compared with celiac disease in the United States from 2007 to 2017. 
The authors found that rates of self-harm and suicide were the same for patients with celiac disease as the general population (RR 1.0).

My take: Attention to mental health is important component of good care for patients with inflammatory bowel disease.

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Impressive Results for Risankizumab in Refractory Crohn’s Disease

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D Alsoud et al Inflamm Bowel Dis 2024; izad315, https://doi.org/10.1093/ibd/izad315. Real-world Effectiveness and Safety of Risankizumab in Patients with Moderate to Severe Multirefractory Crohn’s Disease: A Belgian Multicentric Cohort Study

Methods: Data from consecutive adult CD patients who started risankizumab before April 2023 were retrospectively collected at 6 Belgian centers. A total of 69 patients (56.5% female, median age 37.2 years, 85.5% exposed to ≥4 different advanced therapies and 98.6% to ustekinumab, 14 with an ostomy) were included.

Key findings:

  • At week 24, 61.8% (34 of 55) and 18.2% (10 of 55) of patients without an ostomy achieved steroid-free clinical response and remission, respectively.
  • At week 52, these numbers were 58.2% (32 of 55) and 27.3% (15 of 55), respectively. Endoscopic data were available in 32 patients, of whom 50.0% (16 of 32) reached endoscopic response within the first 52 weeks.
  • Results in patients with an ostomy were similar (steroid-free clinical response and remission, 42.9% and 14.3%, respectively).
  • 20.3% (14 of 69) of patients underwent CD-related intestinal resectionsand 18.8% (13 of 69) of patients discontinued risankizumab during followup (median 68 weeks).
  • Risankizumab was well tolerated with no safety issues.

Discussion points: “98.6% of patients in the current study were exposed to ustekinumab compared with less than 20% in the registration trials. This indicates that a previous lack or loss of response to the inhibition of the p40 subunit common to IL-12 and IL-23 does not preclude a potential response from subsequent selective inhibition of IL-23. “

My take: This study shows that risankizumab can be effective in refractory patients, even in those who have received similar type medications (eg. ustekinumab).

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