STRIDE II -Updated Crohn’s Disease Target Goals

From Tauseef Ali’s Twitter Feed — a summary slide of Crohn’s disease targets for both pediatric and adult patients and a slide showing typical response/remission/healing times to medications.

From the following article: D Turner et al. Gastroenterology (12/31/20, Online Ahead of Print): DOI: 10.1053/j.gastro.2020.12.031 STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD

Recommendations were based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in two surveys and two voting rounds.

Getting Lost in the Pathophysiology of Inflammatory Bowel Disease

A recent review (JT Chang. NEJM 2020; 383: 2652-2664. Pathophysiology of Inflammatory Bowel Diseases) provides an in-depth description of the pathophysiology of inflammatory bowel disease (IBD). Digesting the article is akin to putting together a 1000 piece puzzle due to the complex interactions.

Some of the Key Points:

  • Based on genomewide association studies, there are “more than 240 risk variants that affect intracellular pathways recognizing microbial products (eg. NOD2); the autophagy pathway, which facilitates recycling intracellular organelles and removal of intracellular microorganisms (eg. ATG16L1); genes regulating epithelial barrier function (eg. ECM1); and pathways regulating innate and adaptive immunity (eg. IL23R and IL10).”
  • In this article, Figure 1 and 2 describe the intestinal mucosal immune system in health and disease. At baseline, this system promotes an antiinflammatory state “by virtue of active down-regulation of immune responses. For example, unlike macrophages in other parts of the body, intestinal macrophages do not produce inflammatory cytokines” after exposure to bacteria.

Other points:

  • Dysbiosis is present with IBD; however, studies have been “unable to infer causal relationships.”
  • Germ-free mice, when given fecal material from patients with IBD have increased susceptibility to colitis as compared to those who received fecal material from a healthy person.
    • Thus, this leads to potential for mitigating intestinal inflammation by modulation of the microbiome.
    • However, the authors note that humans are colonized by trillions of viral, fungal, bacterial, and eukaryotic microbes.
  • Other components of IBD pathophysiology: reduced mucus layer, increased microbial adherence, dysregulation of tight junctions/increased permeability, dysfunctional Paneth cells, TNF, IL23, IL12, IL6, IL 17A, IL17F, IL22, Interferon-gamma, integrins, JAK inhibitors, T-cells

My take: This article is a useful reference detailing the complexity of IBD pathophysiology and tries to summarize a whole textbook of information into 12 pages.

Related blog posts:

Disease Activity, Not Medications, Linked to Neonatal Outcomes Among Women with IBD

U Mahadevan at el. Gastroenterology; 2020: (in press) DOI:https://doi.org/10.1053/j.gastro.2020.11.038. Pregnancy and Neonatal Outcomes after Fetal Exposure To Biologics and Thiopurines among Women with Inflammatory Bowel Disease

Methods: Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States (PIANO registry). 

Key findings:

  • Exposure was to thiopurines (242), biologics (642) or both (227) versus unexposed (379)
  • Medication exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, LBW, and infections over the first year of life
  • Higher disease activity was associated with risk of spontaneous abortion (HR 3.41, 95% CI 1.51-7.69) and preterm birth with increased infant infection (OR 1.73, 95% CI 1.19-2.51)

My take: This study provides some reassurance that treatments for IBD are unlikely to affect neonatal outcomes; however, increased IBD activity does affect outcomes

Related blog post: IBD and Pregnancy

Histologic Healing and IBD Outcomes

Several recent studies recently evaluated outcomes based on histologic healing compared to endoscopic remission.

RK Pai et al. Clin Gastroenterol Hepatol 2020; 18: 2510-2517. Full text link: Complete Resolution of Mucosal Neutrophils Associates With Improved Long-Term Clinical Outcomes of Patients With Ulcerative Colitis n=281.Key findings:

  • “We found histologic evidence of UC activity (Geboes score ≥ 2B.1) in biopsies from 182 patients (65%) and endoscopic evidence of UC activity in 149 patients (53%) (substantial agreement, κ = 0.60).”
  • “Histologic features of UC activity were associated with increased rates of systemic corticosteroid use, colectomy, and hospitalization in the entire cohort (P < .05 for all) and associated with increased rates of systemic corticosteroid use in an analysis limited to patients in endoscopic remission (P < .001).”

B Christensen et al. Clin Gastroenterol Hepatol 2020; 18: 2518-2525. Full text link: Histologic Healing Is More Strongly Associated with Clinical Outcomes in Ileal Crohn’s Disease than Endoscopic Healing This was a a retrospective study of 101 patients with CD (52% male) isolated to the terminal ileum. Key findings:

  • At ileo-colonoscopy, 63% of patients had endoscopic healing and 55% had histologic evidence of healing. The level of agreement between endoscopic and histologic activity was fair (62%, K = 0.2250, P = .0064)
  • On multivariate analysis, only histologic healing was associated with decreased risk of clinical relapse (hazard ratio [HR], 2.05; 95% CI, 1.07–3.94; P = .031), medication escalation (HR, 2.17; 95% CI, 1.2–3.96; P = .011), and corticosteroid use (HR, 2.44; 95% CI, 1.17–5.09; P = .018).
Kaplan-Meier analysis of effect of endoscopic and histologic activity on (A) clinical relapse-free survival versus histologic healing, (B) clinical relapse-free survival versus endoscopic healing

D Kevans et al. Inflamm Bowel Dis 2020; 26: 1722-1729. Histological Markers of Clinical Relapse in Endoscopically Quiescent Ulcerative Colitis Key finding: In endoscopically quiescent UC (n=76), active histological inflammation …[is] adjunctive histological marker associated with increased likelihood of disease relapse. The associated editorial (1730-32 by Asher Kornbluth) quotes Voltaire: “A wise Italian says that the best is the enemy of the good.” He notes that there is “a very real risk of abandoning an effective drug while chasing the goal of some yet to be universally defined histologic remission.” Currently organizational guidelines (ACG, AGA, ECCO, IOIBD) do NOT suggest the use of histologic normalization as an endpoint at this point.

My take: These studies show that histologic healing in ileal Crohn’s disease and in ulcerative colitis are associated with better outcomes that endoscopic appearance. However, there are a lot questions because many patients, possibly a majority, will not achieve histologic healing despite aggressive treatment. Related technical issues include how many biopsies are needed to assess histology and having a validated histologic assessment.

Related blog posts:

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.

In Case You Missed It: IBD Year in Review (Eric Benchimol)

I did not have the opportunity to hear this #NASPGHAN20 lecture but Dr. Benchimol has shared his slides. Link to Dropbox Slides: IBD Clinical Science: Year in Review

Some of the key points on slides (links to articles below):

Some screenshots:

Links to many of the referenced papers:


Related links:

Outcomes Associated with Delayed Diagnosis in Pediatric Crohn’s Disease

A Ricciuto et al. Journal of Crohn’s and Colitis; 2020. jjaa197, https://doi.org/10.1093/ecco-jcc/jjaa197 Link: Diagnostic Delay Is Associated with Complicated Disease and Growth Impairment in Paediatric Crohn’s Disease

Methods: “We conducted a national, prospective multi-centre IBD inception cohort study, including 1399 children. Diagnostic delay was defined as time from symptom onset to diagnosis >75 th percentile.”

Key findings:

  • In CD, diagnostic delay was associated with a 2.5-times higher rate of strictures/internal fistulae (HR 2.53, 95% CI 1.41-4.56)
  • Every additional month of diagnostic delay was associated with a decrease in height-for-age z-score of 0.13 standard deviations
  • Diagnostic delay was more common in CD, particularly small bowel CD

My take: Delays in diagnosis in this study were associated with stricturing/internal fistulising complications and growth impairment in paediatric CD.  It is likely that inadequate treatment would increase the risk of these problems as well.

Related blog posts:

Shared Genetic Risk of Celiac Disease, Crohn’s Disease, Ulcerative Colitis, and Collagenous Colitis

E Stahl et al. Gastroenterol 2020; DOI:https://doi.org/10.1053/j.gastro.2020.04.063 Link: Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases

“In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC.”

 

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: