Category Archives: inflammatory bowel disease

When To Perform Genetic Testing In The Setting Of Inflammatory Bowel Disease

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HH Uhilg et al. JPGN 2021; 72: 45-473. Free Full Text: Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition

  • This is a very useful article. Table 3 lists many of the features of some monogenic inflammatory bowel disease (IBD). Table 4 details potential immune workup tests. Table 5 lists 75 genes that should be included when testing for monogenic IBD.
  • Box 2 (see below) provides a list of conditions that should prompt consideration of genetic testing. Figure 1 provides an algorithm for testing.
  • Table 6 provides a summary of statements
    • #3:”Genetic screening for monogenic IBD is recommended in all patients with infantile-onset IBD (<2 years) and should be considered in patients with very early-onset IBD (<6 years), in particular, in those patients with relevant comorbidity, extraintestinal manifestations, and/or family history”
    • #5: “Routine genetic screening for all IBD patients is not recommended since a monogenic cause of IBD in patients with IBD onset over 6 year of age, especially those with adolescent or adult age onset of IBD is exceptional in the absence of relevant comorbidity”
  • There is also some advice on variants of unknown significance: “Databases, such as Clinvar, ClinGen, or The Human Gene Mutation Database can help to assess variant phenotype relations”

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From The Onion:

From The Onion

Paradoxical Chronic Recurrent Multifocal Osteomyelitis (CRMO)

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A recent case series (A Cordesse et al. JPGN Reports; 2020. November 2020 – Volume 1 – Issue 2 – p e007doi: 10.1097/PG9.0000000000000007. Chronic Recurrent Multifocal Osteomyelitis in Pediatric Crohn Disease, A Paradoxical Effect to Antitumor Necrosis Factor Alpha) reported on paradoxical Chronic Recurrent Multifocal Osteomyelitis (CRMO) which I have seen in one of my patients as well.

Key points:

  • In patients receiving anti-TNF agents which are usually effective for CRMO, CRMO may develop paradoxically and may be associated with a psoriaform reaction.
  • At the time of diagnosis of paradoxical reaction, all patients were in remission due to anti-TNFα efficiency. Trough levels of anti-TNFα were in the expected range, and there were no anti–anti-TNFα antibodies.
  • All patients recovered after discontinuation of infliximab (n = 2) or adalimumab (n = 1). 

My take: This study describes a rare adverse effect of anti-TNFα agents. If CRMO develops while on one of these agents, an alternative treatment is needed.

Hellebores

Stratifying Risk of Clots in Inflammatory Bowel Disease

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T Naito et al. Gastroenterol 2021; 160: 771-780. Full text: Prevalence and Effect of Genetic Risk of Thromboembolic Disease in Inflammatory Bowel Disease

Background: 10% of healthy subjects are genetically at high risk for thromboembolic disease (TED). For adults with inflammatory bowel disease, TED is “largest cause of mortality in
patients”

Key findings:

  • In total, this retrospective study had 792 IBD patients who had both whole-exome sequencing and genotyping data to identify thrombophilia pathogenic variants. 122 of 792 IBD patients (15.4%) as genetically high risk for TED.
  • Genetic TED risk was significantly associated with increased TED event (odds ratio,2.5; P ¼ .0036).
  • Patients with high TED genetic risk more frequently had thrombosis at multiple sites (78% vs 42%, odds ratio, 3.96; P ¼ .048)

“Our analyses demonstrate that approximately 1 in 7 patients with IBD have odds 2.5 times higher than nongenetically high-risk patients with IBD for experiencing TED.” The risk of TED in IBD is generally 3- to 4-fold higher than the general population

My take: In children, the risk of clots is much lower than in adults. Thus, the potential to identify those at highest risk would be useful in order to target interventions. Also, patients at higher risk for TED may affect choice of treatment (eg. avoiding JAK inhibitors).

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From The Onion:

From The Onion

Ustekinumab Escalation in Patients with Crohn’s Disease & Healthy Lifestyle Choices for IBD Patients

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JE Ollech et al. Clin Gastroenterol Hepatol 2021; 19: 104-110. Effectiveness of Ustekinumab Dose Escalation in Patients With Crohn’s Disease

In patients with Crohn’s disease, dose escalation of biologic therapy (eg. anti-TNF agents, vedolizumab) has been shown to be helpful in recapturing response to treatment. In a retrospective study with 110 patients, Ollech et al explore the outcomes in those who had their subcutaneous ustekinumab interval shortened to 4 weeks (from every 8 weeks).

Key findings:

  • Following dose interval shortening, the patients’ median Harvey Bradshaw Index (HBI) decreased from 4.5 to 3 ( P = .002), the median level of CRP decreased from 8 mg/L to 3 mg/L ( P = .031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g ( P = .57).
  •  Among patients with active disease (HBI >4, CRP ≥/=5mg/dL, fecal calprotectin >250ug/g, or endoscopic evidence for disease activity), dose interval shortening was associated with a 28% clinical remission (an HBI score ≤4), and 50% had reduced levels of fecal calprotectin; 36% achieved endoscopic remission.
  • The authors did not identify serious adverse events with dose shortening.

My take: Prospective studies are needed. This study indicates that more frequent dosing improves outcomes in a significant fraction of those with active disease.

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Unrelated article: C-H Lo et al. Clin Gastroenterol Hepatol 2021; 19: 87-95. Healthy Lifestyle Is Associated With Reduced Mortality in Patients With Inflammatory Bowel Diseases In this study, using data from three large cohort studies, the authors assessed the impact of 5 healthy lifestyle factors: never smoking, body mass index 18.5–24.9 kg/m 2, vigorous physical activity in the highest 50% with non-zero value, alternate Mediterranean diet score ≥4, and light drinking [0.1–5.0 g/d]. Key finding:

  • Compared to patients with IBD with no healthy lifestyle factors, patients with IBD with 3–5 healthy lifestyle factors had a significant reduction in all-cause mortality (hazard ratio [HR], 0.29; 95% CI, 0.16–0.52; Ptrend < .0001). 

My take: Like the general population, healthy lifestyle choices are important in individuals with IBD; this study provides some data on the effects on outcomes.

A New FDA Warning for Tofacitinib

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2/4/21: FDA: Initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib)

“The U.S. Food and Drug Administration (FDA) is alerting the public that preliminary results from a safety clinical trial show an increased risk of serious heart-related problems and cancer with the arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib) compared to another type of medicine called tumor necrosis factor (TNF) inhibitors. FDA required the safety trial, which also investigated other potential risks including blood clots in the lungs and death. Those final results are not yet available….

Patients should not stop taking tofacitinib without first consulting with your health care professionals, as doing so may worsen your condition. Talk to your health care professionals if you have any questions or concerns.”

Related blog post: FDA Warning on Tofacitinib (July 2019)

Growth in Inflammatory Bowel Disease: Better Late Than Never

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Briefly noted: N Gupta et al. Inflamm Bowel Dis 2020; 26: 1880-1889. Continued Statural Growth in Older Adolescents and Young Adults With Crohn’s Disease and Ulcerative Colitis Beyond the Time of Expected Growth Plate Closure

In this retrospective observational longitudinal cohort study with 3007 patients with IBD from the ImproveCareNow Network, the authors found a high rate of continued linear growth after expected growth plate closure (15 years in females, 17 years in males).

Key findings:

  • 80% manifested continued growth beyond the time of expected growth plate closure, more commonly in CD (81%) than UC (75%; P = 0.0002)
  • Median height gain was greater in males with CD (1.6 cm) than in males with UC (1.3 cm; P = 0.0004), and in females with CD (1.8 cm) than in females with UC (1.5 cm; P = 0.025)

My take: This study provides additional information about delayed skeletal maturation in the pediatric population with inflammatory bowel disease. Interestingly, the rate of continued growth with ulcerative colitis was nearly as high as with Crohn’s disease.

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STRIDE II -Updated Crohn’s Disease Target Goals

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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.

Vaccination Recommendations for IBD Patients

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From COVID-19 Memorial in Washington D.C. 1/19/21

Siegel CA, Melmed GY, McGovern DP, et al. Full text link: SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting Gut  Published Online First: 20 January 2021. doi: 10.1136/gutjnl-2020-324000

From David Rubin’s Twitter Feed

In the article, they note “the exception is for any live-attenuated virus vaccines or replication-competent viral vector vaccines that come to market.” Currently, all of the vaccines are inactivated (not live-attenuated).

These recommendations apply to approved populations which currently do not include pediatric patients or patients who are pregnant.

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From Children’s Healthcare of Atlanta:

Getting Lost in the Pathophysiology of Inflammatory Bowel Disease

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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.

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Converting to Monotherapy for Children with Inflammatory Bowel Disease

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W El-Matary et al. JPGN 2020; 71: 740-743. Discontinuation of Immunosuppressive Medications in Children With Inflammatory Bowel Disease on Combination Therapy

This study looked at 105 patients receiving combination therapy; the a median duration of combination therapy was 2.1 years, with infliximab and either methotrexate  (53) or azathioprine (52). 89 patients had Crohn’s disease.

Key findings:

  • 11 (10.5%) patients experienced a clinical relapse over a median duration of follow-up of 12.0 months after stopping the immunomodulator.
  • In the patients who did not relapse, the median IFX trough level at IM discontinuation was 6.2; the IFX trough level was 3.8 μg/mL in those who relapsed.

In their discussion, the authors urge caution in discontinuation of immunomodulators in those with clinically-severe Crohn’s disease and those with low infliximab levels.

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Tons of shells on Picnic Island, Tampa Bay

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