Category Archives: inflammatory bowel disease

Intestinal Barrier Function and Risk of Crohn’s Disease

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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.2020.08.005. Increased 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.

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

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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.”

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Comparative Efficacy: Vedolizumab vs Anti-TNF Agents

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M Bohm et al. AP&T: 2020; July 2020 https://doi.org/10.1111/apt.15921 Full text: Comparative safety and effectiveness of vedolizumab to tumour necrosis factor antagonist therapy for Crohn’s disease

Thanks to Ben Gold for this reference.

Methods: Retrospective observational cohort (May 2014–December 2017) propensity score‐weighted comparison of vedolizumab vs TNF‐antagonist therapy (infliximab, adalimumab, certolizumab) in CD.  This study included 1266 patients (n = 659 vedolizumab).

Key findings:

  • Rates of non‐infectious serious adverse events (odds ratio [OR] 0.072, 95% confidence interval [CI] 0.012‐0.242) were significantly lower with vedolizumab vs TNF‐antagonist therapy.
    • These events included severe arthralgias in 3 vedolizumab-treated patients.  For anti-TNF recipients, events included hypersensitivity or infusion reactions (n = 6), drug‐induced psoriasis (n = 6), drug‐induced lupus (n = 5), severe liver function test abnormalities (n = 3), skin rash (n = 2), lung cancer (n = 1) and jaw or hip necrosis (n = 2).
  • Rates of serious infections (OR 1.183, 95% CI 0.786‐1.795), were NOT significantly lower with vedolizumab vs TNF‐antagonist therapy.
    • “The risk of serious infections with biologic therapy is largely driven by disease activity and concomitant use of immunosuppressive agents…. the higher concomitant use of steroids among the vedolizumab‐treated patients in our cohort may therefore help to explain the lack of observed difference in risk for serious infections between agents.”
  • No significant difference was observed between vedolizumab and TNF‐antagonist therapy for clinical remission (hazard ratio [HR] 0.932, 95% CI 0.707‐1.228), steroid‐free clinical remission (HR 1.250, 95% CI 0.677‐2.310) or endoscopic remission (HR 0.827, 95% CI 0.595‐1.151).
    • “Our observational cohort study was not designed to be a noninferiority study, and the safety and effectiveness comparisons were exploratory in nature.”
  • The efficacy of vedolizumab in this study is more impressive given that 91% of the patients had prior anti-TNF therapy.
    • “Exploratory subgroup analyses suggested that vedolizumab might be superior to subcutaneous TNF‐antagonist therapy for the achievement of clinical remission and steroid‐free clinical remission in TNF‐antagonist–naïve patients.”
  • TNF‐antagonist therapy was associated with higher treatment persistence compared with vedolizumab.

My take: This article shows that clinical experience with vedolizumab is quite good and compares favorably with anti-TNF agents.  Randomized head-to-head studies are needed, though, to truly determine efficacy in similar populations.

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The Downside of Home Infusion of Biologics

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N Giese-Kim et al. Am J Gastroenterol: July 22, 2020 – Volume Publish Ahead of Print – Issue – doi: 10.14309/ajg.0000000000000750. Link to abstract:  Home Infliximab Infusions Are Associated With Suboptimal Outcomes Without Cost Savings in Inflammatory Bowel Diseases

In this study, there were 27,396 patients with IBD (1,839 pediatric patients). Overall, 5.7% of patients used home infliximab infusions.

Results:

  • Those with home infusions:
    •  more likely to be nonadherent compared with both office-based (22.2% vs 19.8%; P = .044) and hospital-based infusions (22.2% vs 21.2%; P < .001).
    • more likely to discontinue infliximab compared with office-based (44.7% vs 33.7%; P < .001) or hospital-based (44.7% vs 33.4%; P < .001) infusions.
  • On Kaplan-Meier analysis, the probabilities of remaining on infliximab by day 200 of therapy were 64.4%, 74.2%, and 79.3% for home-, hospital-, and office-based infusions, respectively (P < .001)
  • Home infusions did not decrease overall annual care costs compared with office infusions ($49,149 vs $43,466, P < .001)

My take: In my experience, office-based infusions can be provided safely and in a cost-effective manner.  From the authors: “home infliximab infusions for patients with IBD were associated with suboptimal outcomes including higher rates of nonadherence and discontinuation of infliximab. Home infusions did not result in significant cost savings compared with office infusions.”

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IBD Update -August 2020

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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.

More Iron Infusions, Less Blood Transfusions in Kids with Inflammatory Bowel Disease; COVID-19 Transmission in Children

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Briefly noted: AE Jacobson-Kelly et al. J Pediatr 2020; 222: 141-5. In this retrospective multicenter cohort study (2012-2018), the authors used the Pediatric Health Information System administrative database (n= 8007 with 28 260 admissions, <21 yrs of age). Key findings:

  • Anemia was documented in 29.8% of admissions.  IV iron was given in 6.3% of admissions and blood transfusions in 7.4%
  • A steady increase in the proportion of IBD admissions received IV iron, from 3.5% in 2012 to 10.4% in 2018 ( P < .0001), and the proportion of admissions with red cell transfusions decreased over time from 9.4% to 4.4% ( P < .0001).

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Adjustment of azathioprine dose in NUDT15 intermediate metabolizers, COVID-19 in Georgia & COVID-19 Phase 1 Vaccine Study

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LA Jackson et al. NEJM 2020; DOI: 10.1056/NEJMoa2022483. Link:  An mRNA Vaccine against SARS-CoV-2 — Preliminary Report  The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants (n=45), and no trial-limiting safety concerns were identified.

______________________________________________________________________

COVID-19 in Georgia (Data from 7/13/20):

B Kang et al. AP&T 2020; https://doi.org/10.1111/apt.15810. Thanks to Ben Gold for this reference. Full text: Adjustment of azathioprine dose should be based on a lower 6‐TGN target level to avoid leucopenia in NUDT15 intermediate metabolizers

Background: “In addition to TPMT polymorphisms, a recent genome‐wide association study reported that a missense variant of nudix hydrolase 15 (NUDT15 ), which encodes a novel thiopurine‐metabolizing enzyme, was strongly associated with thiopurine‐induced leucopenia especially in Asians”

Key findings:

  • Among the 167 pediatric patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolizers respectively (P  < 0.001)
  • There was a positive association between 6‐TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolizers
  • In order to reduce the development of thiopurine‐induced leucopenia (<15%) in NUDT15 intermediate metabolizers, adjustment of azathioprine doses should be based on a lower 6‐TGN target level (<167.1 pmol/8 × 108 RBC)

Limitations: single-center, retrospective study and possible selection bias

My take: While 6-TGN levels between 235-400 are typically considered therapeutic, individuals with intermediate metabolism are at increased risk for leukopenia and may respond at lower levels.  This study indicates that careful dosing and close monitoring is needed for NUDT15 intermediate metabolizers

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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

What Our Office Is Recommending: School and Pediatric IBD Patients

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We are getting a lot of calls from families trying to figure out what they should be doing for their children with inflammatory bowel disease in regards to school attendance.  Here is what our ICN team has developed:

School guidance during Covid pandemic:

With the flood of information in the lay and scientific media, GI Care for Kids wanted to assure that our patients and families who had children with inflammatory bowel disease (IBD), Crohn’s or ulcerative colitis, had some guidance in making important decisions about beginning the 2020-2021 school year.  Currently, research shows that just having IBD, DOES NOT put a person more at risk for acquiring (i.e. catching) coronavirus (COVID-19) infection.  In addition, research suggests that biologics (e.g. Remicade, Humira) DO NOT seem to increase the risk for more severe Covid related illnesses.

However, steroids, thiopurines (e.g. 6-MP; azathioprine, immuran) and prograf DO appear to have a larger effect on increasing risk for more severe coronavirus infection and COVID-19 disease.  Additional research is being carried out with oldest patients (e.g. > 65 years of age) who appear to be at increased risk for infection and COVID-related disease, and, other co-morbid conditions (e.g. obesity, diabetes, cardiovascular disease) being at highest risk for COVID-19 disease as well.

All patients should practice good hand hygiene, wear masks at all times outside of the house, and observe social distancing.  If your family does not feel that return to a traditional school building is in your child’s best interest, please let us know, and we will help make sure we support you from a medical standpoint. 

For further information on the status of coronavirus in people with IBD world-wide, young or old, please go to: www.covidibd.org.

Additional information about the status of COVID-19 can be found at the following websites:

Also, this:

Facebook link (1:22 min): This is what happens when a Special Effects guy stays at home with his son during lockdown

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

Emerging IBD Treatment: Selective Jak Inhibitor, Upadacitinib

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Two recent large studies examined the use of Upadacitinib, an oral JAK1 inhibitor, for Crohn’s disease and for Ulcerative Colitis.

The first study, “CELEST,” (n=220) is the “first to evaluate the efficacy, safety, pharmacokinetics, and dose-response of upadacitinib immediate-release formulation in patients with moderate to severe CD and refractory to TNF antagonist therapy using PRO-based clinical and endoscopic endpoints… Nearly half of the patients enrolled in CELEST (44% [96/220]) were taking oral corticosteroids at baseline and underwent a mandatory taper starting at week 2.” The key findings are noted in the graphical abstract (below). A couple of additional points:

  • During the induction period, the 24-mg twice-daily dose exhibited the most consistent association with meaningful improvements for multiple clinical and endoscopic endpoints at week 12 or 16
  • Clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib
    twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo.
  • Endoscopic remission was achieved by 10% (in 3 mg group) (P < .1 vs placebo), 8% (in 6 mg and 12 mg groups) (P < .1 vs placebo), 22% (in 24 mg BID group) (P < .01 vs placebo), and 14% (in 24 mg QD group) (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo
  • Upadacitinib was also associated with improvements in quality of life, based on IBDQ, observed as early as week 8
  • AEs reported in this study were consistent with those previously observed in clinical trials with JAK inhibitors. Two patients had myocardial infarction events and 1 patient had a mesenteric vein thrombosis.
  • Limitations: sample size, lack of placebo control during maintenance

The second study, “U-ACHIEVE,” for ulcerative colitis (n=250) notes that in cellular assays upadacitinib is up to 60-fold selective for JAK1 over JAK2 and >100-fold selective over JAK3.  The study incorporated a new definition for the primary endpoint of clinical remission using the adapted Mayo score with a more stringent criterion than previous studies. A consistent dose-response relationship with upadacitinib for this primary endpoint was observed. Other points:

  • Upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active ulcerative colitis
  • The onset of action was rapid, as shown by improvement in the partial
    Mayo score at week 2
  • Endoscopic improvement at week 8, defined as endoscopic subscore of 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P ¼ .033, P < .001, P < .001, and P < .001 compared with placebo, respectively)
  • Histologic improvement was demonstrated in all treatment arms
  • The types of AEs reported in this study were similar to those previously observed in clinical trials with JAK inhibitors. In the 45 mg daily arm, one patient developed herpes zoster and one participant developed deep venous thrombosis/pulmonary embolism (26 days after discontinuation of study medication)

My take: Upadacitinib looks quite promising for ulcerative colitis and is likely to be helpful in a smaller subset of patients with Crohn’s disease.  HIgher doses appear to be more effective but are likely to be associated with higher rates of adverse events. Further studies, including pediatric trials, are needed.

 

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

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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.

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