High Relapse Rates with Anti-TNF Withdrawal Even with Endoscopic Remission

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R Mahmoud et al. Clin Gastroenterol Hepatol 2023; 21: 750-760. Open Access! Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease

This was a prospective observational study (n=81). In order to participate, patients (all adults) had to be in confirmed baseline steroid-free clinical remission (for at least 6 months) and endoscopic healing;  endoscopic healing was defined as endoscopic Mayo score <2 or Simple Endoscopic Score for CD (SES-CD) <5 without large ulcers. Endoscopic healing was subclassified as complete endoscopic healing (Mayo 0/SES-CD 0–2) versus partial endoscopic healing (Mayo 1/SES-CD 3–4).

Key findings:

  • At 12 months, 70% (7 of 10) versus 35% (25 of 71) of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43–7.50)
  • Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01–0.67)
  • Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months.

The authors highlight the lower relapse rate between those with complete endoscopic healing and those with partial healing. They acknowledge that those eligible for anti-TNF de-escalation are highly selected (~7% in a prior study) and “few patients with an unfavorable IBD phenotype, such as stricturing or penetrating CD, anti-TNF for perianal fistulizing CD, young age at diagnosis, or prior biological failure, were included in this study. Therefore, our findings may not be generalizable to patients with a more severe IBD phenotype.

My take: Even in those with complete endoscopic healing, there is a high rate of relapse. In addition, stopping anti-TNF therapy likely increases risk of not responding to anti-TNF therapy when it is restarted. This study does show that transitioning from anti-TNF therapy to mesalamine therapy in those with ulcerative colitis (or IBDU) could be a reasonable consideration.

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Targeting Calprotectin Levels Below 80 for Ulcerative Colitis Plus Obesity Medication Pushback

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K Kawashima et al. Inflamm Bowel Dis 2023; 29: 359-366. Low Fecal Calprotectin Predicts Histological Healing in Patients with Ulcerative Colitis with Endoscopic Remission and Leads to Prolonged Clinical Remission

In this prospective study (n=76), patients with UC in clinical and endoscopic remission, defined as a partial Mayo score (PMS) ≤ 2 points and a Mayo endoscopic subscore 0–1, were enrolled and followed for 2 years or until relapse, defined as a PMS > 2 or medication escalation.

Key findings:

  • The median fecal calprotectin (FC) value in patients with histologic healing (HH) (n = 40) was 56.2 µg/g, significantly lower than that in those with histological activity (118.1 µg/g; P < .01)
  • The optimal FC cutoff value to predict prolonged CR was 84.6 µg/g (72% sensitivity; 85% specificity; P < .01)

My take: Even among ulcerative colitis in clinical & endoscopic remission, fecal calprotectin levels are an objective way to identify histologic healing and to stratifying likelihood of prolonged remission.

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Sendero Esperanza Trail, Saguaro National Park, Tucson AZ

It is good to see some skepticism regarding the new obesity medications. 4/2/23 USA Today: Why experts worry the ‘magic’ in new weight loss medications carries a dark side

Good Bowel Sound Podcasts: Cow’s Milk Intolerance and Hirschspurng Disease

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Two recent bowel sound podcasts had some useful clinical insights. Some of my summation below could be off a bit as I tend to listen to these while driving. So, it may be a good idea to hear the podcasts for yourself.

Victoria Martin discussed cow milk intolerance/allergic proctocolitis.

Listen now: http://buzzsprout.com/581062/12503492

Dr. Martin emphasized the importance of challenging children with these diagnoses; in many, the disorder is transient. A challenge is typically done 1 month after resolution of symptoms. In those with confirmed reactions, rechallenge 6 months later is typical. The reasons for doing this:

  1. This is in keeping with international guidelines
  2. Many children do not need to stay on expensive formulas or dietary restrictions (if breastfed)
  3. This is likely to reduce the risk of developing lifelong food allergies
  4. Other pointers: generally it is not helpful to follow stool heme testing (high number of normal infants with heme-positivity). Stool calprotectin is not helpful (wide variability in infants). Flexible sigmoidoscopy is rarely needed. In those with mild symptoms, it may be reasonable to watch without intervention, especially in breastfed infants.

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Jacob Langer discussed Hirschsprung disease

Listen now: https://buzzsprout.com/581062/12359851

In terms of diagnosis, Dr. Langer recommended use of rectal suction biopsy as 1st step in smaller kids (less than 1 yr of age) and rectal manometry as 1st step in those older than 1 yr of age. He reviewed the three main operations:

  • Swenson -pulldown to anus
  • Duhamel -pouch: with an end-to-side anastomosis is performed with the remaining rectum
  • Soave -cuff: strip mucosa and leave a muscular cuff

He noted that he prefers Soave but that there is not clear superiority of one operation.

Other pointers:

  • Enterocolitis is #1 cause of mortality. If someone is coming in sick, worthwhile to start an in-and-out irrigation promptly. Irrigation information can be found on YouTube. From Colorado Children’s: Rectal Irrigations for Hirschsprung
  • He pioneered the use of Anal Botox for children post-operatively. Many children with obstructive symptoms related to sphincter malfunction will improve with time and this often allows a child to avoid a myectomy
  • He described workup for post-operative soiling and potential pathophysiology: muscle issues (manometry), sensory issues, functional retention with overflow, and hypermotility (sigmoid propelling stool rapidly which may improve with imodium)
  • Dr. Langer is also a musician — you can listen to his music here.

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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.

When to Reinsert a GJ Tube After Intussusception

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AT Abebe et al. JPGN 2023; 76: 379-384. Length of Bowel Rest Does Not Predict Gastrojejunostomy Tube-Associated Intussusception Recurrence

In this retrospective study, 46 GJ intussusceptions were identified; patients had a median age of 2.8 years. Key findings:

  • There were 7 recurrences (15.2%).
  • There was no difference in recurrence based on time of bowel rest (5 days in those without vs 6 days in those with, P = 0.30) nor a difference in recurrence with <72 hours of bowel rest compared to >72 hours (1/15, 6.7% vs 6/31, 19.3%)
  • In 15 patients who had a smaller GJ tube replaced, there were no recurrences compared with 7 recurrences among 29 (24%) that had the same caliber GJ tube replaced (P=0.08)

My take: This study indicates that prolonged removal of GJ is not needed with GJ intussusception and if feasible, consider replacement with a smaller (or shorter) GJ tube.

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Image from JPGN Twitter

How to Get More Active Kids

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J Pedersen et al. JAMA Pediatr 2022; 176: 741-749. Effects of Limiting Recreational Screen Media Use on Physical Activity and Sleep in Families With Children

Key finding: In this cluster randomized controlled trial (n=181, ages 6-10 years), screen media reduction in the treatment group resulted in an increase of 45.8 minutes per day of physical activity compare to the usual routine group.

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Current Practice in Hepatitis B and Long-term Prospects

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D Yardeni et al. Gastroenterol 2023; 164: 42-60. Open Access! Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure

This is a very helpful review. Table 1 lists treatment indications by group. For example, AASLD recommendations:

  • Table 3 compares the effectiveness of current treatments
  • Table 4 describes the large number (~50) of antiviral agents in development and their mechanism of action
  • The authors recommend HCC surveillance in those with cirrhosis every 6 months with ultrasound with or without serum AFP
  • “Although current therapy is associated with improved clinical outcome, it is not curative because of a lack of effect on cccDNA and integrated HBV DNA. Stopping therapy in the absence of HBsAg loss usually leads to relapse to active disease in most patients and thus treatment must be administered long term.”
  • “Many challenges remain, the sheer breadth of therapeutic approaches in development holds great promise for curing and eliminating chronic HBV infection”

My take: While it is likely that newer medications will help many with chronic hepatitis B, the best hope for eliminating HBV continues to be with prevention and vaccination.

Related article: J-F Wu et al. Clin Gastroenterol Hepatol 2023; 21: 663-669. Baseline Hepatitis B Virus Surface Antigen Titers in Childhood Predict the Risk of Advanced Liver Fibrosis in Adulthood

Key finding: In this study with more than 30 years of prospective followup (n=214): n a multivariate analysis, both an HBsAg titer >4.44 log10 IU/mL at 15 years of age and HBV genotype C were predictors of advanced fibrosis (odds ratios, 15.43 and 4.77; P = .01 and P = .02, respectively).

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Life Expectancy Dropping in U.S.

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NPR 3/25/23: ‘Live free and die’? The sad state of U.S. life expectancy

Life expectancy around the world decreased in 2020 due to COVID-19.
Most peer countries rebounded by 2021, while the U.S. continued to decline.

An excerpt:

  • Just before Christmas, federal health officials confirmed life expectancy in America had dropped for a nearly unprecedented second year in a row – down to 76 years. While countries all over the world saw life expectancy rebound during the second year of the pandemic after the arrival of vaccines, the U.S. did not….American life expectancy is lower than that of Cuba, Lebanon, and Czechia.
  • Then, last week, more bad news: Maternal mortality in the U.S. reached a high in 2021. Also, a paper in the Journal of the American Medical Association found rising mortality rates among U.S. children and adolescents…
  • The panel looked at American life and death in terms of the public health and medical care system, individual behaviors like diet and tobacco use, social factors like poverty and inequality, the physical environment, and public policies and values. “In every one of those five buckets, we found problems that distinguish the United States from other countries.”
  • Yes, Americans eat more calories and lack universal access to health care. But there’s also higher child poverty, racial segregation, social isolation, and more. Even the way cities are designed makes access to good food more difficult.
  • “Two years difference in life expectancy probably comes from the fact that firearms are so available in the United States,” Crimmins says. “There’s the opioid epidemic, which is clearly ours – that was our drug companies and other countries didn’t have that because those drugs were more controlled. Some of the difference comes from the fact that we are more likely to drive more miles. We have more cars,” and ultimately, more fatal crashes.

My take (from authors): “the focus should… be on the fact that every other rich country has been able to figure out how to help people live longer, healthier lives. That means that Americans could do it too.” Meanwhile, lawmakers across the country are protecting kids from harm by stopping drag shows, banning books, and preventing care for transgender kids.

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Radiographs and Constipation -Bad Practice and Good Study

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A really good study, in my view, is one that provides useful data and 100% backs up what I want it to find.

N Yallanki et al JPGN 2023; 76: 295-299. Inter and Intraobserver Variation in Interpretation of Fecal Loading on Abdominal Radiographs

Methods: Electronic records of 100 children seen in the emergency room for gastrointestinal symptoms who had an abdominal radiograph performed were included. Four physicians from each specialty including gastroenterology, radiology, and emergency medicine interpreted the radiographs independently.

Key findings:

  • Overall agreement among all providers: 40.8%. Fixed margin kappa 0.18
  • Intradepartmental agreement: 41.5% for Peds GI, 36.7% for Peds EM, and 47.3% for Peds Radiology.

My takes:

  1. The only surprising finding was the low intradepartmental agreement for Peds EM; many of my colleagues have insisted that all Peds EM think everyone has a high fecal burden (so there should have been uniform agreement)
  2. This study reinforces expert guidance to avoid reliance on AXRs for the diagnosis of constipation

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IBD Update: MMR Vaccine and Lower Rates of IBD, Humira Biosimilar Data, Oral Health Associated with IBD Activity, Low Chance of Reconnection After Fecal Diversion

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C Kim et al. Inflamm Bowel Dis 2023; 29: 430-436. Vaccination Against Measles, Mumps, Rubella and Incident Inflammatory Bowel Disease in a National Cohort of Privately Insured Children

This retrospective cohort study (n = 1 365 447) using de-identified claims data from a national private payer (Optum Clinformatics Data Mart), between 2001 and 2018 found that receipt of at least 1 dose of MMR had lower risk for IBD than children who did not (hazard ratio, 0.71; 95% confidence interval, 0.59-0.85). This association persisted after adjustment for potential confounding factors.

My take: This study provides reassurance to encourage MMR vaccination

A Tursi et al. Inflamm Bowel Dis 2023; 29: 376-383. Comparison of Performances of Adalimumab Biosimilars SB5, ABP501, GP2017, and MSB11022 in Treating Patients with Inflammatory Bowel Diseases: A Real-Life, Multicenter, Observational Study

In this retrospective study (n=533), compare the efficacy and safety of ADA biosimilars SB5, ABP501, GP2017, and MSB11022 in treating IBD outpatients in a real-life Italian setting. Key findings:

  • Clinical remission was obtained in 79.6% of patients new to biologics and 59.2% of patients new to ADA but not to other biologics
  • Clinical remission was maintained in 81.0% of patients switched from the originator
  • No difference in efficacy and safety was found between ADA biosimilars.

My take: This study suggests that these biosimilars are equally effective; however, the fact that nearly 20% failed to maintain remission after switching from the originator ADA indicates more comparative (prospective) studies are needed

Related blog post: Adalimumab Biosimilars on the Horizon (Finally) Plus Two Studies

GR Madsen et al. Inflamm Bowel Dis 2023; 29: 396-404. The Impact of Periodontitis on Inflammatory Bowel Disease Activity

Key finding: In this questionnaire-based study among 1093 patients with inflammatory bowel disease (IBD), periodontitis and tooth loss were significantly associated with increased IBD-related disability and more disease activity in the preceding 12 month. This type of study does not allow one to draw conclusions about causality but does provide a good rationale to encourage regular attention to oral health/dentistry.

G Kassim et al. Inflamm Bowel Dis 2023; 29: 417-422. Long-Term Outcomes of the Excluded Rectum in Crohn’s Disease: A Multicenter International Study

Methods: In this retrospective study (n=197) reviewed all CD patients between 1990 and 2014 who had undergone diversionary surgery with retention of the excluded rectum for at least 6 months and who had at least 2 years of postoperative follow-up.

Key findings:

  • 92 (47%) of 197 patients ultimately underwent subsequent proctectomy; only 20 (10%) remained symptom-free with excluded rectums.
  • Only 28 (14.2%) of 197, and only 4 (5.9%) of 66 with initial perianal disease, were able to achieve reanastomosis without further problems

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Is There An Increased Risk of Infections with Anti-TNF Therapy?

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J Holmgren et al. Inflamm Bowel Dis 2023; 29: 339-348. Open Access! The Risk of Serious Infections Before and After Anti-TNF Therapy in Inflammatory Bowel Disease: A Retrospective Cohort Study 

Methods: Retrospective study with 980 patients at 5 centers participating in the Swedish IBD Quality Register. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated.

A decline in the incidence rate can first be seen beyond 1 year of treatment with anti-TNF, with an incidence rate of 1.22 (95% CI, 0.90-1.66) events per 100 person year compared with 2.19 (95% CI, 1.43-3.36) events per 100 person year the year before treatment. This is a significant reduction of infections, with an incidence rate ratio of 0.56 (95% CI, 0.33-0.95; P = .030).

Key findings:

  • A 72.0% reduction in the incidence rate of perianal abscesses and intra-abdominal abscesses during treatment with anti-TNF was found compared with before treatment.
  • Figures 2 & 3 show than most infection rates decreased with treatment. CMV infection did not change significantly with 0.10 per 100 person-years prior to treatment and 0.14 per 100 person-years after starting anti-TNF therapy
  • ” In the current study, patients younger than 20 years old experienced a substantial decrease of infection incidence rate ratio (0.11) with the introduction of anti-TNF treatment. The results could be explained by the fact that young patients have a more active disease with increased risk of infection before treatment with anti-TNF.”
  • “The most common type of infection after anti-TNF treatment was pneumonia. The high incidence of pneumonia confirms earlier data.9,36,37” However, the authors show that the rate of pneumonia dropped from 0.51 to 0.27 per 100 person-years after starting anti-TNF therapy.

The authors note that a prior study by “Zabana et al showed that patients with IBD had an increased risk for serious infection after starting immunosuppressive treatment compared with before treatment (median follow-up 3 years before and 5 years after)… the discrepancy in the result may be explained by selection bias. We included all patients starting anti-TNF treatment. However, Zabana et al included only patients who suffered from infections during immunosuppressive treatment and retrospectively examined the risk of infection before start of treatment.24“

Limitations of study: several other important factors affecting infections were not captured in this study including steroid exposure and nutritional status.

My take (from authors): “The incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.”

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