Crohn’s Disease Anastomotic Ulcerations

A recent retrospective study (RP Hirten et al. Inflamm Bowel Dis 2020; 26: 1050-1058Anastomotic Ulcers After Ileocolic Resection for Crohn’s Disease Are Common and Predict Recurrence) showed that anastomotic ulcers occur in over half of Crohn’s disease patients after ileocolic resection and are associated with Crohn’s disease recurrence and are persistent.

Key findings:

  • Anastomotic ulcers were present in 95 (52.2%) subjects. No factors were associated with anastomotic ulcer development.
  • Anastomotic ulcers were associated with disease recurrence (adjusted hazard ratio [aHR] 3.64)

The associated editorial by Philllip Fleshner (pg 1059) identifies are a number of methodologic flaws, noting that less than 20% of all ileocolonic resections were included and marked variability in postoperative assessment (from 29 days to 2897 days).

My take: (borrowed from the editorial) the “findings should convince us that anastomotic ulcers do not represent ischemic changes but are rather a reflection of disease progression.”  Prospective studies with standardized surveillance would be helpful.

 

IBD Update -September 2020

EM Kim et al. Inflamm Bowel Dis 2020; 26: 1232-38. Mucosal Eosinophilia Is an Independent Predictor of Vedolizumab Efficacy in Inflammatory Bowel Diseases n=65 patients. In IBD cohort, colonic eosinophilia (340 +/- 156 vs 236 +/- 124) was associated with clinical non-response to vedolizumab (as was prior anti-TNF treatment). In those with ulcerative colitis, mean eosinophil count was 438 in nonresponders compared to 299 in responders. In those with Crohn’s disease, colonic biopsies showed a non-significant increase in eosinophil count in non-responders compared to responders: 352 vs. 232.

MA Sofia et al. Inflamm Bowel Dis 2020; 26: 1251-9. Poor Sleep Quality in Crohn’s Disease Is Associated With Disease Activity and Risk for Hospitalization or Surgery

  • Ninety-two CD and 82 control subjects
  • Crohn’s disease subjects with Pittsburgh Sleep Quality Index (PSQI) >5 more often had inflammatory phenotypes and reported increased benzodiazepine and psychiatric medication use. Crohn’s disease subjects with PSQI >5 also reported more night awakenings due to pain and bathroom use.
  • The PSQI correlated with HBI
  • PSQI >8 was predictive of surgery or hospitalization (hazards ratio 5.37; 95% confidence interval, 1.39-27.54).

My take: This study indicates that poor sleep is a marker for increased adverse outcomes/disease activity.  It may be that sleep disturbance is due to increased disease activity or this may be a bidirectional issue in which poor sleep triggers more disease activity as well.

A Ricciuto et al. Clin Gastroenterol Hepatol 2020; 18: 1509-1517. Primary Sclerosing Cholangitis in Children With Inflammatory Bowel Diseases Is Associated With Milder Clinical Activity But More Frequent Subclinical Inflammation and Growth Impairment

This retrospective study provides additional information on the observation that children with PSC often have subclinical disease; it is similar to a prospective study by the same group in 2018 (n=37):  (prior blog post: Active Colitis More Likely in Children in Clinical Remission Who Have IBD and PSC) Key finding: Higher proportions of children with PSC-IBD had backwash ileitis, pancolitis, and rectal sparing, and more severe right-sided disease, than controls (P < .05). Conclusions: “Despite the mild clinical activity of IBD in patients with PSC, lack of symptoms does not always indicate lack of mucosal inflammation. Children with PSC-IBD have greater growth impairments compared with children with ulcerative colitis or IBD-unclassified.”

Which Crohn’s Disease Ulcerations Are Harder to Treat — Small Bowel or Colon?

K Takenaka et al. Clin Gastroenterol Hepatol 2020; 18: 1545-1552. Small Bowel Healing Detected by Endoscopy in Patients With Crohn’s Disease After Treatment With Antibodies Against Tumor Necrosis Factor

Methods: This was a post-hoc analysis of data from a clinical trial from 116 patients with CD (46 with ileal and 70 with ileocolonic type) who received induction and then maintenance therapy with anti-TNF agents (2013-18). Median age 29 years.

Key findings (based on findings from balloon-assisted enteroscopy )

  • Before treatment, small bowel ulcerations were present in 114 patients (98%); 42 patients (60%) with ileocolonic disease had colon ulcerations.
  • During maintenance therapy, 41/114 patients (36%) had small bowel endoscopic healing; all the patients with small bowel endoscopic healing also had colonic endoscopic healing.
  • Failure to achieve small bowel endoscopic healing was significantly associated with stricturing or penetrating disease (P = .014), lack of concomitant treatment with immunomodulators (P = .015), and having received previous treatment with an anti-TNF agents (P = .018).
  • The authors found that endoscopic healing was only 35% (36% for small bowel and 79% for colonic inflammation)

My take: Small bowel inflammation did not respond to treatment as well as colonic inflammation.  The implication of this study is that even in patients who are doing well clinically with treatment, disease progression especially in the small bowel may be ongoing.

Briefly noted: M Kayal et al. Inflamm Bowel Dis 2020; 26: 1079-1086.  Inflammatory Pouch Conditions Are Common After Ileal Pouch Anal Anastomosis in Ulcerative Colitis Patients.

  • In this retrospective study of adults with ulcerative colitis who had undergone total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA). Acute pouchitis occurred in 205 patients (53%), 60 of whom (30%) progressed to chronic pouchitis.
  • Cuffitis and Crohn’s disease-like condition (CDLC) of the pouch occurred in 119 (30%) patients and 46 (12%) patients
  • Pouch failure was noted in 6.7%
  • Only one-third of patients with chronic pouchitiis, cuffitis and CDLC responded to biologic therapy

Related blog posts:

Intestinal Barrier Function and Risk of Crohn’s Disease

Several recent studies have examined biomarkers to predict Crohn’s disease.  A recent prospective study (W Turpin et al. Gastroenterol 2020; DOI: https://doi.org/10.1053/j.gastro.2020.08.005Increased Intestinal Permeability is Associated with Later Development of Crohn’s Disease) sought to determine whether increased intestinal permeability, as measured by urinary fractional excretion of lactulose to mannitol ratio (LMR), is associated with future development of CD.

Methods: 1420 asymptomatic first-degree relatives (6–35 years old) of patients with CD (collected from 2008 through 2015) had LMR measured and were then followed for a diagnosis of CD from 2008 to 2017, with a median follow up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017

Key findings:

  • An abnormal LMR (> 0.03) was associated with diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64–5.63; P=3.97×10 -4).
  • This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62, 95% CI, 1.051–2.50; P=.029).

My take:  It remains unclear whether abnormal barrier function primarily precedes or follows CD development.  The authors state that these findings support a model in which altered intestinal barrier function contributes to pathogenesis.

Does a Low Vitamin D Level Increase the Risk of Crohn’s Disease? And Other Biomarkers

A recent study (BN Limketkai et al. Clin Gastroenterol Hepatol 2020; 18: 1769-76Levels of Vitamin D Are Low After Crohn’s Disease Is Established But Not Before) takes advantage of stored serum from U.S. military personnel.

Key finding: By examining 240 with Crohn’s disease (CD) along with 240 control patients, the authors show that vitamin D levels prior to CD diagnosis are not associated with the development of CD up to 8 years preceding the diagnosis.

Two other articles on predictive biomarkers for CD and an associated editorial:

  • N Nair et al. Gastroenterol 2020; 159: 383-5. Association Between Early-life Exposures and Inflammatory Bowel Diseases, Based on Analyses of Deciduous Teeth
  • J Torres, F Petralia et al. Gastroenterol 2020; 159: 96-104Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis
  • New Biomarkers for Crohn’s Disease (editorial) C Bernstein. Gastroenterol 2020; 159: 30-32. Key points from editorial:
    • “In the article by Nair et al, the authors relate the presence of heavy metals in baby teeth to the later development of Crohn’s disease…The finding of metals that can be tracked to the in utero state suggests that the offspring who will ultimately present with IBD and have high values of these metals are likely acquiring these metals from their mothers.”
    • “In the study by Torres et al, a serum bank of Department of Defense recruits was accessed to study for microbial antibodies and immune-inflammatory markers for ≤5 years antedating diagnoses of either Crohn’s disease or ulcerative colitis. Anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease…The authors have convincingly showed that these microbial antibodies and immune-inflammatory mediators are present years before the first clinical manifestation of Crohn’s disease. These phenomena very likely are early biological manifestations of Crohn’s disease. They may not be risk factors that Crohn’s disease is coming, but rather that it is already present.”

My take: Stored tissue/blood eventually may help predict who will develop CD.  Given a lack of current treatment options in those at risk, the importance of these predictive markers is unclear.

Briefly Noted: How to Approach Crohn’s Disease Complicated by an Intra-abdominal Abscess

A recent review (T Qazi, M Regueiro. Practical Gastroenterology 2020: June Issue, 10-18. Full PDF Link: Crohn’s Disease Complicated by an Intra-abdominal Abscess: Poke, Prod, or Cut?)

The article is a good review & the algorithm below provides some good guidance -if difficult to visualize, then it may be worthwhile to look at source article.

The authors propose initial management with antibiotics, minimization of steroids, nutritional support and drainage.

Medical treatment is favored after initial management:

  • Newly diagnosed Crohn’s disease
  • Extensive disease
  • No fibrostenoting disease
  • Active perianal disease

Surgical treatment is favored after initial management:

  • Long-standing disease
  • Stricture with dilatation
  • Abscess >6 cm in size
  • Prior surgical intervention

The authors note that “recent studies have suggested that roughly 30% of patients
treated with PD are able to avoid future surgical resection.”

Related blog posts:

 

IBD Update -August 2020

S Jansson et al JPGN 2020; 71: 40-5. This retrospective study (1998-2008) showed that pediatric patients with extraintestinal manifestations (EIM) had more severe IBD course than patients with IBD without an EIM.  EIM often had a temporal relationship with a relapse of IBD as well. Of 333 patients, 14 had an EIM at diagnosis and 47 had an EIM develop during followup.

PA Olivera, JS Lasa et al. Gastroenterol 2020; 158: 1554-73. This systematic review and meta-analysis ultimately included 82 studies with 66,159 patients (including those with IBD and other immune-mediated diseases) exposed to a JAK inhibitor; two-thirds of studies were randomized controlled trials.  Key findings:

  • Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81, 2.67, 0.89, and 0.48 per 100 person year respectively. After meta-analysis, the authors conclude that there is an increased risk of herpes zoster (RR 1.57), but all other adverse events were not increased among patients treated with JAK inhibitors
  • Mortality was not increased in those receiving JAK inhibitors compared to placebo

Loebenstein, JD Schulberg. Gastroenterol 2020; 158: 2069-71.  This case report describes a successful alternative anti-TNF rechallenge after infliximab induced Lupus in Crohn’s disease.  The authors note that in a previous study, 14 of 20 IBD patents with drug-induced lupus secondary to an anti-TNF agent were rechallenged with an alternative anti-TNF agent and 13/14 tolerated rechallenge without recurrent lupus (Inflamm Bowel Dise 2013; 19: 2778-86).

These images show active disease prior to intervention. The article provides f/u images showing endoscopic remission after re-starting a different anti-TNF agent.

Ustekinumab Over Vedolizumab as 2nd Line Agent for Crohn’s Disease

A recent study: Ustekinumab is associated with superior effectiveness
outcomes compared to vedolizumab in Crohn’s disease patients with prior failure to anti-TNF treatment. VBC Biemans et al. Aliment Pharmacol Ther 2020; 52: 123-134.  Thanks to Ben Gold for this reference.

Methods: Crohn´s disease patients, who failed anti-TNF treatment and started
vedolizumab or ustekinumab in standard care as second-line biological, were
identified in the observational prospective Dutch Initiative on Crohn and
Colitis Registry.  128 vedolizumab- and 85 ustekinumab-treated patients fulfilled
the inclusion criteria. Median age in the cohorts were 37 and 39 respectively.

Key findings (at 52 weeks):

  • After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (odds ratio [OR]: 2.58, 95% CI: 1.36-4.90, P = 0.004), biochemical remission (OR: 2.34, 95% CI: 1.10-4.96, P = 0.027), and combined corticosteroid-free clinical and biochemical remission (OR: 2.74, 95% CI: 1.23-6.09, P = 0.014).
  • Safety outcomes (infections: OR: 1.26, 95% CI: 0.63-2.54, P = 0.517; adverse events: OR: 1.33, 95% CI: 0.62-2.81, P = 0.464; hospitalisations: OR: 0.67, 95% CI: 0.32-1.39, P = 0.282) were comparable between the two groups

My take: This study indicates that ustekinumab is likely a more effective 2nd line agent for Crohn’s disease.

Related blog posts:

Curcumin Was NOT Effective For Post-operative Crohn’s Disease, Goldman Sachs Take on Masks

NBC/NY Link: Goldman Sachs Says National Mask Mandate Could Slash Infections, Save Economy From 5% Hit


Briefly noted: G Bommelear et al. Clin Gastroenterol Hepatol; 2020; 18: 1553-60. Oral Curcumin No More Effective Than Placebo in Preventing Recurrence of Crohn’s Disease After Surgery in a Randomized Controlled Trial

Methods:

  • Double-blind randomized controlled trial at 8 referral centers in France, from October 2014 through January 2018, with 62 consecutive patients with CD undergoing bowel resection.
  • Patients received azathioprine (2.5 mg/kg) and were randomly assigned to groups given oral curcumin (3 g/day; n = 31) or an identical placebo (n = 31) for 6 months, and were then evaluated by colonoscopy.
  • The primary endpoint: postoperative recurrence of CD in each group (Rutgeerts’ index score ≥i2) at month 6

Key findings:

  • Postoperative recurrence at 6 months: (Rutgeerts’ index score ≥i2): 58% receiving curcumin vs 68% receiving placebo (P = .60).
  • Severe recurrence: 55% receiving Curcumin 55%vs 26% receiving placebo –had a severe recurrence of CD (Rutgeerts’ index score ≥i3) (P = .034).
  • Clinical recurrence of CD (CD activity index score >150) at 6 months: 30% with curcumin compared with 45%  receiving placebo (P = .80)

My take: Curcumin was ineffective in preventing recurrent post-operative Crohn’s disease

Related blog posts:

 

Can Microscopic Colitis Lead to Crohn’s Disease or Ulcerative Colitis?


A recent prospective cohort “ESPRESSO” study (H Khalili et al. Gastroenterol 2020; 158: 1574-83) from 1990-2017 examined the risk of incident inflammatory bowel disease (IBD) in subjects with microscopic colitis, n=13,957 (& each matched with 5 controls). ESPRESSO = Epidemiology Strengthened by histoPathology Reports in Sweden.

Key findings:

  • In the microscopic colitis group, there were 323 incident cases of ulcerative colitis (UC) and 108 cases of Crohn’s disease (CD)
  • Mean times to diagnosis were 3.2 years for UC and 3.3 years for CD
  • Microscopic colitis was associated with an aHR of 12.6 for CD and 17.3 fo rUC
  • The absolute excess risk compared to matched control over a 10-year period were 2.6% for UC and 0.9% for CD

My take: Individuals with microscopic colitis are at increased risk of developing UC and CD.

Related blog post/related article: