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
“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).”
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.
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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):
Lots of data on COVID-19 and IBD. Steroids and Thiopurines are associated with more severe disease whereas anti-TNF agents are not
Lower intestinal barrier function is associated with increased risk for development of Crohn’s disease
More greenspace associated with lower rates of development of IBD
Exome sequencing has shown ~3% of pIBD with genetic mutations linked to monogenetic IBD & 1% with mutations which could benefit from HSCT. Identifying specific defects may lead to other treatments as well (eg. Leflunomide for TTC7A deficiency). Related blog posts:
Early biologic therapy associated with better long-term outcomes in adult and pediatric IBD
Reviewed data on adalimumab showing improvement in growth and relationship between good titers and clinical response (related post: IBD Update -September 2020)
Also, there will be a webinar for both patients and health care providers on November 19 with the SECURE-IBD steering committee as guests to go over the new data.
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.
CCFA: Updates in IBD (2017) -Dr. Kugathasan lecture discussed the RISK study and reported that there is likely a window of opportunity to more favorably affect natural history of the disease
“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.”
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.
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.
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.
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.”
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.
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
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.
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:
“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.
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