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

Ustekinumab Effectiveness for Ulcerative Colitis Over Two Years

R Pannacionne et al. AP&T. 2020; https://doi.org/10.1111/apt.16119. Full text link: Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy

Methods: Overall, 399 (adult) “responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long‐term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44”

Key Findings:

  • Symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively ((Intent-to-treat population).
  • At week 44 of maintenance, measures of UC disease activity (eg Mayo scores) were generally comparable among patients randomised to ustekinumab q12w and q8w with 46.1% and 52.4% in clinical remission and 56.7% and 61.5% with endoscopic improvement respectively
  • Among randomised patients treated in the long‐term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid‐free
  • No new safety signals were observed
Steroid-free Remission (Intent-to-treat population)

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

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.”

 

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.”

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:

 

IBD Briefs June 2020

SA Draiweesh et al. Safety of Combination Biologic and Antirejection Therapy Post-Liver Transplantation in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2020; 26: 949-59. In this case series of 19 patients, 14 who had liver transplantation for PSC, there was no increased risk of serious infections among patients receiving biologic therapy in combination with antirejection medications.

A Malian et al. Pedictors [sic] of Perianal Fistula Relapse in Crohn’s Disease. Inflamm Bowel Dis 2020; 26: 926-31. In this retrospective study with 137 patients, fistula relapse rates were not different in patients receiving infliximab or adalimumab (P = 0.66). In patients treated by anti-TNF at inclusion, discontinuation of anti-TNF therapy (odds ratio 3.49, P = 0.04), colonic location (OR 6.25, P = 0.01), and stricturing phenotype (odds ratio 4.39, P = 0.01) were independently associated with fistula relapse in multivariate analysis.

M-H Wang et al. Unique Phenotypic Characteristics and Clinical Course in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis: A Multicenter US Experience. Inflamm Bowel Dis 2020; 26: 774-81. Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001).  In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar.

B Barberio et al. Matrix Metalloproteinase 3 Predicts Therapeutic Response in Inflammatory Bowel Disease Patients Treated with Infliximab. Inflamm Bowel Dis 2020; 26: 756-62. Retrospectively, 73 IBD patients who had received IFX for at least 1 year were enrolled: 35 patients were responders and 38 were nonresponders at 52 weeks…The MMP3 levels were similar at baseline (19.83 vs 17.92 ng/mL), but at postinduction, patients who failed to respond at 1 year had significantly higher levels than patients who responded (26.09 vs 8.68 ng/mL, P < 0.001); the difference was confirmed at week 52 (29.56 vs 11.48 ng/mL, P < 0.001)…The MMP3 serum determination may represent an early marker of response to infliximab.

 

“No Solid Conclusions” for Alternative/Complementary Therapies for Inflammatory Bowel Disease

In this clinical review (N Chande et al Inflamm Bowel Dis 2020; 26: 843-51) assess evidence from Cochrane reviews of four popular nontraditional treatments for inflammatory bowel disease (IBD):

  • Fecal Microbiota Transplantation (FMT)
  • Nutritional Therapies including Enteral Nutrition (EN)
  • Naltrexone for Crohn’s Disease (CD)
  • Cannabis for IBD

So what does the literature have to say about these treatments:

  • FMT: FMT for mild to moderate ulcerative colitis (UC) increased the proportion of patients achieving clinical remission. “However, the number of included studies was small and the quality of evidence was low.”  Other problems included uncertainty regarding serious adverse events and short duration of followup.
  • “As a result, no solid conclusions [the authors did not indicate this as a pun] can be drawn at this time.”

  • Nutritional Therapies: For remission in CD, “EN may be more effective than corticosteroids in children, although the opposite was true in adults.”
  • “Exclusion diets did not promote clinical remission or reduce clinical relapse in UC”
  • “The overall certainty of evidence in these studies were generally very low, largely due to sparse data.”

  • Naltrexone for Crohn’s Disease (CD): “The paucity of data makes it impossible to draw any firm conclusions about the effectiveness and safety” of low dose naltrexone.

  • Cannabis for IBD: “The risk of adverse events was significantly higher in cannabis-treated patients”…though these events were generally mild (eg. sleepiness, confusion, nausea).
  • “The results of these studies suggest that cannabis is not effective for the treatment of IBD”  This conclusion is limited by the small number of patients in prior studies.  Cannabis may be helpful as an adjunct for some symptoms though this “warrants further study.”

Related blog posts:

 

 

Ionizing Radiation Exposure in Adults with Inflammatory Bowel Disease

From The Onion:


In the largest reported cohort to date, GC Nguyen et al (Inflamm Bowel Dis 2020; 26: 898-906) describe the ionization radiation exposure (IRE) in individuals (≥18 years) with inflammatory bowel disease (IBD).

Methods: N=72,933 with IBD,1994-2016. During 1st 5 yrs after diagnosis, IRE was estimated in a retrospective matched cohort in Ontario.

Key findings:

  • IBD patients were exposed to nearly 6-fold IRE due to abdominal imaging compared to controls: 18.6 mSv vs 2.9 mSv
  • Patients with CD had higher IRE than UC: 26 mSv vs 12 mSv (P<0.001).  CD patients were more likely to have >50 mSv exposure (15.6% vs 6.2%) and >100 mSv 5.0% vs 2.1%
  • Women were less likely to have high IRE compared to males
  • Residents in the poorest neighborhoods were 27% more likely to have IRE >100 mSv.  Socioeconomic status was an independent factor after accounting for comorbidities. The authors speculate that this could be related to increased use of emergency rooms where they may be more likely to receive a CT.
  • The use of CT scan began to decline after 2007…likely explained by the rise of MRE studies.

While strict guidelines on IRE are lacking, the International Commission on Radiological Protection has suggested that occupational exposure (eg. nuclear workers) should be limited to <100 mSv over 5 years and not more than 50 mSv in a single year.

My take: We need to continue efforts to reduce IRE due to concerns about subsequent secondary malignancies. This likely means avoiding CT for non-emergencies and working with our ED colleagues to think carefully about lifetime IRE in IBD patients.

Related blog posts:

Additional references:

  • -AJR 2001; 176: 289-96. Estimated risks of radiation-induced fatal cancer from pediatric CT
  • -Br J Radiol 2012; 85: 523-28.  Justification of CTs -some not needed
  • -AJR 2010; 194: 868-73.  Lower CT radiation doses in pediatric patients.  ‘Image gently’
  • -Arch Intern Med 2009; 169: 2078-86.

From LA Times:


 

Expert Guidance on Inflammatory Bowel Disease (Part 2)

A recent issue of Clinical Gastroenterology and Hepatology focused solely on the clinical features and management of inflammatory bowel disease. Even for those with expertise in IBD, there is a lot of useful information and concise reviews of what is known.

Here are some of my notes from this issue (part 2)

S Danese et al. Clinical Gastroenterol Hepatol: 2020; 18: 1280-90. Positioning Therapies in Ulcerative Colitis

This is a good article but recent AGA publications are probably better –there are some links below. One statement that was interesting: “the safety profile of vedolizumab seems even better than placebo in terms of risk of serious” adverse events. The authors favored infliximab in combination with azathioprine in those needing biologic therapy with moderate-severe UC.

Related blog posts:

S Vermeire et al. Clinical Gastroenterol Hepatol: 2020; 18: 1291-9. How, When, and for Whom Should We Perform Therapeutic Drug Monitoring?

“Although reactive TDM, testing at time of loss of response, is widely accepted in practice, especially for anti–tumor necrosis factor antibodies, there are less data for the other monoclonal antibodies belonging to other classes. Besides reactive testing, there is a movement toward proactively adjusting biologic dosing to prevent loss of response, in keeping with the tight control philosophy of inflammatory bowel disease care.” The authors favor proactive monitoring: “we are now beginning to see with well-powered proactive TDM studies” that proactive monitoring can maximize the benefits of TDM with “the potential to maximize durability of biologics and improve the outcomes of IBD patients.”

Related blog posts:

PS Dulai et al. Clinical Gastroenterol Hepatol: 2020; 18: 1300-8. How Do We Treat Inflammatory Bowel Diseases to Aim For Endoscopic Remission?

The initial part of this article reviews treatment targets -resolution of symptoms and resolution of endoscopic damage. The algorithm provides the authors’ suggested approach:

  • At initiation of therapy, patients should have a full assessment.  In addition to ileocolonoscopy, for patients with CD, the authors recommend cross-sectional imaging.
  • After treatment initiation, the authors recommend biomarker assessment every 3 months.  Mucosal assessment can occur 6-9 months after treatment initiation.
  • For UC, the authors note that fecal calprotectin (FC) “appears to be more stratightforward, and a cutoff of 250 mcg/g can be used reliably across all scenarios to make treatment adjustments.”  Though, they recommend endoscopic confirmation prior to transition to a biologic or small molecule therapy.
  • For CD, the authors suggest making treatment adjustments in those with FC >250 mcg/g and in those with lower values, followup colonoscopy is recommended.
  • The authors note that in the post-operative setting with CD, mucosal inflammation precedes symptomatic activity and “waiting for symptoms to emerge may unnecessary allow for disease progression.”
  • The authors suggest that tighter disease control will reduce disease-related complications, while acknowledging a lack of prospective clinical trials.
  • One thorny issue: :”For CD: it remains unclear what degree of residual mucosal healing is acceptable to impact important outcomes such as CD-related complications, hospitalizations, and surgeries.”

Related blog posts:

M Allocca et al. Clinical Gastroenterol Hepatol: 2020; 18: 1309-23. Use of Cross-Sectional Imaging for Tight Monitoring of Inflammatory Bowel Diseases

“Computed tomography is limited by the use of radiation, while the use of magnetic resonance enterography (MRE) is limited by its cost and access. There is growing interest in bowel ultrasound that represents a cost-effective, noninvasive, and well-tolerated modality in clinical practice, but it is operator dependent… Diffusion-weighted imaging (DWI) is a MR imaging technique that increasingly is used in both IBD and non-IBD conditions and has been shown to be a valuable and accurate tool for assessing and monitoring IBD activity.

L Beaugerie et al. Clinical Gastroenterol Hepatol: 2020; 18: 1324-35. Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases

The first part of this article reviews potential adverse effects from the medications used for IBD treatment, noting in Table 1 that there are not complications to monitor for with both vedolizumab and ustekinumab.

The article reviews infections, vaccination strategies and issues related to malignancy Some of the recommendations:

  • vaccine against pneumococcus should be given before patients begin immunosuppressive therapy
  • physicians should consider giving patients live vaccines against herpes zoster (in adults) before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment
  • sun protection and skin surveillance from the time of diagnosis are recommended
  • despite concerns about therapy, the authors note that “the extensive use of immunosuppressive therapy leads to a substantial decrease in the incidence of IBD complications, with a globally favorable benefit-risk ratio, which can be optimized further thanks to a good degree of awareness and knowledge of drug complications.”

It is interesting that this article (and the entire issue) does not address mental health concerns related to the diagnosis of IBD.  This likely creates more morbidity and complications than most of the other issues that are discussed.

Above: Why did the picture go to jail? Because it was framed.

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.