Is First Line Therapy for Autoimmune Hepatitis Changing? CAMARO Study Results

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RJ Snijders et al. J Hepatol 2024; 80: 576-585. Open Access! An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis

Methods: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients (mean age 57.9 years) with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission (BR) defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment.

Treatment dosing in study (Table S2):

Key findings:

  • 56.4% of the MMF group and 29.0% of the azathioprine group achieved BR
  • No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034)

Excerpts from the discussion:

  • “The evidence for the current standard induction therapy in AIH with azathioprine and prednisolone is limited and stems from the early seventies of the last century.”
  • “Patients assigned to azathioprine were significantly more prone to discontinuing treatment because of intolerance or SAEs, with nausea and vomiting as the main reasons for cessation of treatment.”
  • “MMF exhibits high teratogenicity. MMF should not be used during pregnancy and may only be used with strict contraceptive measures in women of childbearing age and men planning to father a child, as its use is absolutely contraindicated during pregnancy.”
  • “In addition, MMF must be administered twice daily, while azathioprine is given as a single dose daily…relevant for a disease that requires lifelong treatment.”

My take: This study needs to be replicated in the pediatric age group. Though many patients have some frequent side effects with MMF, the overall safety (and possibly effectiveness) appears improved with MMF compared with azathioprine.

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.

More Data Supporting Dietary Treatment for Irritable Bowel

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S Nybacka et al. The Lancet Gastroenterol Hepatol 2024; DOI: https://doi.org/10.1016/S2468-1253(24)00045-1. A low FODMAP diet plus traditional dietary advice versus a low-carbohydrate diet versus pharmacological treatment in irritable bowel syndrome (CARBIS): a single-centre, single-blind, randomised controlled trial

In this Swedish study with 294 randomized participants who had with moderate to severe I.B.S, 96 assigned to the LFTD (low FODMAPs with IBS advice) diet, 97 to the low-carbohydrate diet, and 101 to optimised medical treatment. Response was defined as a reduction of 50 or more in IBS-SSS compared with baseline.

Key findings:

  • Response rate after 4 weeks: 73 (76%) of 96 participants in the LFTD diet group, 69 (71%) of 97 participants in the low-carbohydrate diet group, and 59 (58%) of 101 participants in the optimised medical treatment group

The findings of this study were included in a recent NY Times Article (4/18/24): What’s the Best Way to Treat I.B.S.?

An excerpt:
“A new study suggests that certain dietary changes may be more effective than medication.. When she checked on the participants during the trial, one from the low-FODMAP group cried when she described how much better she felt on the diet. Another in the low-carbohydrate group said she “never in her life had felt so good in her stomach,” Dr. Nybacka said…

Dr. Chey said the study was well done and provided “real data” to support what many doctors have observed: That “diet therapy is at least as good and probably better” than medication.

My take: Dietary therapies and psychological therapies are underutilized in the management of IBS. For those using dietary therapies, counseling with a nutritionist is a good idea.

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Grand Canyon (from Seth Hochman)

AGA Guidance: GLP-1 Receptor Agonists Prior to Endoscopy

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JG Hashash et al. Clin Gastroenterol Hepatol 2024; 22: 705-707. Open Access! AGA Rapid Clinical Practice Update on the Management of Patients Taking GLP-1 Receptor Agonists Prior to Endoscopy: Communication

“GLP-1 RAs (eg, semaglutide, tirzepatide, exenatide, liraglutide, albiglutide, dulaglutide, and lixisneatide) mimic incretins, which are hormones released after eating that prompt glucose-dependent insulin release from the pancreatic islets, stimulate satiety centers, inhibit glucagon release, and result in diminished gastric emptying.”

Because GLP-1 RAs diminish gastric emptying, they can increase the risk of residual gastric contents prior to surgery and endoscopy.

AGA Recommendations:

  • “If patients taking GLP-1 RAs solely for weight loss can be identified beforehand, a dose of the medication could be withheld before endoscopy with likely little harm, although this should not be considered mandatory or evidence-based. Nevertheless, it is unclear
    if withholding the medication for only one dose would be reliably adequate for an individual’s gastric motility to return to normal. ..there is insufficient evidence to suggest this practice be performed for patients taking these medications to treat diabetes”
  • “Generally, in patients on GLP-1 RAs who have followed standard perioperative procedures (typically an 8-hour solid-food fast and a 2-hour liquid fast) and who do not have symptoms of nausea, vomiting, dyspepsia, or abdominal distention, we advise proceeding with upper
    and/or lower endoscopy.”
  • “When possible, placing patients on a liquid diet the day before sedated procedures may be a more acceptable strategy, in lieu of stopping GLP-1 RAs.”

My take: This guidance provides useful advice given the increasing use of GLP-1 RAs. If these medications are being used for obesity, holding a dose prior to endoscopy is a good idea.

Related article: S Sen et al. JAMA Surgery 2024;  doi:10.1001/jamasurg.2024.0111. Glucagon-Like Peptide-1 Receptor Agonist Use and Residual Gastric Content Before Anesthesia Key finding:  Use of a GLP-1 RA was independently associated with increased residual gastric content (1.5 mL/kg of clear liquids on gastric ultrasonography) on preprocedural gastric ultrasonography: 56% (35 of 62) in patients with GLP-1 RA use (exposure group) compared with 19% (12 of 62) in patients who were not taking a GLP-1 RA drug (control group).

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This is at the entrance to the Westside Reservoir Park.
I had the chance to go there as part of a Westside Beltline Tour in Atlanta.

This reservoir is as deep as the Statue of Liberty is tall and
can hold 2.4 billion gallons of water for the city of Atlanta

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.

Prokinetics Have Little Benefit for Gastroparesis

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WL Hasler et al. Clin Gastroenterol Hepatol 2024; 22: 867-877. Open Access! Benefits of Prokinetics, Gastroparesis Diet, or Neuromodulators Alone or in Combination for Symptoms of Gastroparesis

Methods: In this prospective study of patients (n=129) with suspected gastroparesis, the authors examined longitudinal outcomes focusing on responses to prokinetics and other therapies. This included gastroparesis diets and neuromodulators. Patients underwent validated gastric emptying testing (wireless motility capsule and gastric emptying scan) before recommending new treatments.

Prokinetics included dopamine antagonists, motilin agonists, acetylcholinesterase
inhibitors, and pyloric botulinum toxin injection.

Key findings:

  • “Initiating prokinetics as solo new therapy had little benefit for patients with symptoms of
    gastroparesis.”
  • “Neuromodulators as the only new therapy decreased symptoms other than
    nausea and vomiting”
  • Combination therapy of a prokinetic with a neuromodulator appeared to be the most effective
  • Neuromodulators were mainly effective in those without delayed gastric emptying times

My take: Our therapies for gastroparesis are not very good. And, neuromodulators are likely to be more helpful than prokinetics.

Example of a gastroparesis diet: Cleveland Clinic Gastroparesis Diet (7 pages). Part of the diet recommendations are shown below.

Related blog posts:

Fundamentals for Ostomy Management

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K Mullin, RM Rentea, M Appleby, PT Reeves. Pediatrics in Review 2024; 45: 210-224. Gastrointestinal Ostomies in Children: A Primer for the Pediatrician

Like yesterday’s article on GTs, this is another terrific review with plenty of helpful images and advice regarding ostomy management.

  • Background: “There are upwards of 1 million people living with ostomies (ostomates) in the United States.” “Approximately 75% of all ostomies in the pediatric population are created in the neonatal or infant patient.”
  • Table 1 lists the purposes and types of ostomies including gastrostomy, jejunostomy, ileostomy, appendicostomy (Malone), cecostomy, colostomy and urinary diversions (eg. Mitrofanoff).
  • Surgical considerations are reviewed including optimizing nutrition preoperatively and minimizing corticosteroids. Biologics: “The most recent evidence does not support a delay in gastrointestinal surgery for children with IBD receiving biological therapy…[and] typically, biological therapy can be resumed 14 to 28 days after the operation.” For oral small molecules (with short half-lives), these may be restarted sooner if indicated.
  • Table 2 provides pictures of the lower ostomies. For example:
  • Postoperative care is discussed including healing times, need for wound ostomy nurse input, and addressing self-image. Patients with motility disorders are “more likely to experience postoperative complications”
  • Table 4 details the products for pouch care including pouching systems, skin barriers, pouch liner, gas vent, pouch lubricant, pouch covers, and adhesive remover.
  • Table 5 summarized ostomy-related complications and treatments. Complications include stomal necrosis, stomal bleeding, stomal retraction, mucocutaneous separation, parastomal hernia, stoma prolapse (can apply cool compresses, apply osmotic agent (sugar) or manually reduce), stoma stenosis, and dermatitis.
  • Table 6 addresses medical management issues like odor, blockage, diarrhea, and constipation. This table also provides recipes for antegrade enemas (see below) and links including a very useful bowel management guide for families (28 pg from Boston Children’s) and enema ingredients and supplies (2 pg from Seattle Children’s); the latter has some overlapping information with the former.
  • At the conclusion of the article, there is further discussion of systemic and ostomy-related complications (much of which is summarized in Table 5). The article references the Ostomy Skin Tool as a metric to follow the clinical state of the ostomy. The United Ostomy Associations of America (ostomy.org) is listed as a good resource (which it is!).

My take: This is a very useful resource. Even a quick read will make clinicians appreciative of having the assistance wound ostomy nurses.

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.

Fundamentals of Gastrostomy Tubes

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I Novak, NK Velazco. Pediatrics in Review; 2024: 45: 175-187. Gastrostomy Tubes: Indications, Types, and Care

Thanks to Patrick Reeves for sharing this reference. While reading this article, I was reminded of Debbie Mason RN. She worked mainly for Colin Rudolph when I was a fellow at Cincinnati. She would teach the fellows the ‘ins and outs’ regarding gastrostomy tubes (GTs).

Some of the points from this article:

  • Background: In one large study, 25% of hospitalized pediatric patients in 63 U.S. hospitals required a temporary NG tube. GTs “preferred for longer-term access due to being less prone to accidental dislodgement, blockage, and interruption of feeds. They are also more durable, discrete, and avoid nasal trauma.” They are probably safer too for longer-term use. (An omission in the article: AMT bridles can help maintain NGs.)
  • Indications: Reviews the extensive list of reasons for GT placement, most related to inadequate nutritional intake (related to many chronic disease processes)
  • Contraindications are reviewed. “Absolute contraindications include active sepsis or peritonitis, massive ascites, uncorrectable coagulopathy, portal hypertension with significant varices, and history of total gastrectomy.” Transoral PEG tube is contraindicated, as well, if pharyngeal or esophageal obstruction, malrotation, or colonic interposition.
  • Preprocedural evaluation is described. Some have recommended UGI prior to placement in those with congenital anomalies. Others have stated that “even congenital anomalies should not mandate an upper GI series given how rare malrotation is in general.” Many children benefit from NG feeding trials prior to GT placement which can also improve nutritional status preoperatively.
  • The placement methods and types of GTs are reviewed. “As of now, there is no clearly identified optimal technique” (eg. laparoscopic GT vs PEG). The others note a meta-analysis of 22 studies (n >5000) found a higher rate of major complications with PEG placement. The authors recommend T-fasteners if GT balloon is used for initial placement.
  • Examples of bolster-type (non-balloon) GTs:
  • GT complications are discussed including infection, peritonitis, bleeding (rare to need a transfusion), injury to adjacent organs, pneumoperitoneum (usually benign and transient), hypergranulation, cellulitis (often treated with a first-generation cephalosporin or topical mupirocin), dislodgement, tube migration, and buried bumper syndrome. For early dislodgement (especially first 4-6 weeks after placement), blind reinsertion should be avoided.
  • GT care: The authors recommend starting feeds “not more than 3 to 6 hours” after placement to monitor for immediate postoperative complications, and cleaning site with warm water, saline or soap. Once the site has healed showering and bathing can resume; swimming can be permitted a few weeks after placement. Medications should be given via gastric port (if GJ) for better absorption of medications and lessen risk of tube clogging.
  • Troubleshooting: This is the most useful part of this article. Advice on peristomal leakage: “Placing larger tubes should be avoided because this will only enlarge the stoma tract…removal of the tube for a few hours can be considered because this permits the tract to start closing.” Leakage is often due to issues with balloon volume, poor fit, gastric pressure (eg dysmotility, gastroparesis) and poor wound healing. Clogging: “Carbonated beverages, juices, and meat tenderizer…studies have not shown these to be effective.” Lukewarm water, left to stand 20 minutes, is the first line agent for declogging. Other options include commercial enzymatic decloggers, and mechanical decloggers.
  • GT removal is discussed and I disagree with the authors that “persistent gastrocutaneous fistulas are rare after removal” (though the majority will close with conservative management). The authors do not recommend cutting GT bolsters due to risk of obstruction and note that endoscopic removal is often necessary.

My take: This article would be well-positioned as part of any GI fellows’ required curriculum and has a bunch of pointers for experienced clinicians as well. It could easily be used for material for ABP questions too. The article is much more detailed than the summary I have provided.

Also, another relevant resource (not discussed in article): Oley Foundation (oley.org). This foundation aims to help those living with home IV nutrition or tube feeding through advocacy, education, community and innovation.

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Dr. Joel Rosh: Positioning Therapies for Pediatric Ulcerative Colitis

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Dr. Joel Rosh gave our group an excellent update on sequencing therapy for ulcerative colitis (UC).  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of his slides.

  • There are only two FDA-approved biologics in pediatric Ulcerative Colitis. It typically takes 8-10 years for a medication with approval in adults to receive FDA approval in children
  • The concept of IBD as two diseases, Crohn’s disease and UC, is flawed; there are more than 200 susceptibility genes for inflammatory bowel disease
  • There has been an increasing incidence and prevalence of IBD. Some of this increase is likely due to our diet and its effects on the microbiome
  • Ultrasound is a nice tool to see what is going on in real time and shows that UC is really a transmural disease.  UC changes in the bowel can result in fibrosis
  • Consider cytokine-basis for disease as a way to conceptualize disease presentation compared to organ-based disease. Many autoimmune diseases (eg. JIA, RA, Psoriasis) are different manifestations related to cytokine-based autoimmunity
  • Almost all pediatric IBD can be considered higher risk based on known risk factors including disease extent (>80% of pediatric UC is pancolitis) and disease age of onset
  • Mesalamine steroid-free clinical remission rates are about 1/3rd after 1 year of treatment
  • Overall, there has been an improvement in colectomy rates since 2001; there still appears to be a bump in the colectomy rate after having UC for more than 10 years
  • Elevated CRP is less common in patients with UC, compared to Crohn’s disease, and is a marker for more severe disease activity
  • Dr. Rosh prefers to avoid some terms including biologic-naive and steroid failure; he favors biologic-unexposed for the former. For the latter, he tries to make it clear that the patient was not a steroid failure. Steroids failed the patient rather than the patient failing the steroids
  • Therapeutic drug monitoring (TDM) is mainly beneficial for anti-TNF agents at this time. Use of TDM can help monotherapy achieve similar results as combination therapy. For infliximab, Dr. Rosh’s ‘rule of thumb’ is 28-18-8 for 2 week trough, 6 week trough, and maintenance trough. Therapeutic levels will meet or exceed these trough levels.
  • Combination therapy has not been shown to improve pharmacokinetics for vedolizumab or ustekinumab
  • Generally, a washout period is not needed when changing biologic therapies. In fact, having some overlap in the medications may have some therapeutic benefit
  • Upadacitinib (Rinvoq) appears to be the most effective JAK for IBD. It is labelled for use as a 2nd-line agent but may be superior for some sicker patients. Rinvoq could be considered as a ‘bridge’ medication in patients with acute severe ulcerative colitis with transition to another biologic like vedolizumab
  • It is important for families to be informed that there is a black box warning for the use of JAK inhibitors. However, major cardiac adverse events (MACE) do not appear to be increased in patients without preexisting cardiac disease risk factors

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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.

The Naismiths of Endoscopy

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The pioneers of endoscopy are discussed in the following article:

AR Schulman, JD Howell. Clin Gastroenterol Hepatol 2024; 22: 684-688.Open Access! From Hirschowitz to 2023: Modern Endoscopy and Beyond

A few excerpts:

  • “In 1868, the German physician Adolph Kussmaul looked inside the stomach of a human being. He chose to peruse the stomach of a professional sword-swallower, someone who was able to tolerate, although probably not to enjoy, a straight, 47-cm long metal tube with a diameter of 13 mm.1 This marked the beginning of the first era of endoscopy, the era of rigid endoscopy…encountered 2 fundamental problems. One, although a metal tube is straight, the gastrointestinal tract is not. And, two, the inside of the human body is dark.”
  • “Rudolf Schindler, working in Munich, realized that the rigid gastroscope “never could be routinely used.”2 In 1932 he designed a semiflexible endoscope, an invention that marked the beginning of the second era of endoscopy…[after surviving Dachau concentration camp], he settled at the University of Chicago.3“
  • “In 1954, [Basil] Hirschowitz learned that it might be possible to create a device that could transmit optical images along a flexible axis. Working with 2 colleagues from the University of Michigan Physics Department, which was located not far from the Medical School, he created a prototype device for looking into the stomach.”

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Do We Need Documented Consent to Do a Rectal Exam for a Pediatric Patient?

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AGA 4/10/24: New NHS Guidance on Informed Consent consent impacts GIs

My take: This guidance likely was derived from patients having sensitive exams without permission while under anesthesia. While this guidance is directed at hospital settings and hospital-based outpatient clinics where written consent is now needed, practitioners in the outpatient setting likely will need to better document permission prior to rectal examination and assure appropriate use of chaperones.

Resources:

Related blog post: Don’t Let the Chief of Staff Review This Constipation Study

Proactive Monitoring Associated with Higher Rates of Transmural Healing

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SR Fernades et al. Inflammatory Bowel Diseases, izad272, https://doi.org/10.1093/ibd/izad272 Proactive Infliximab Monitoring Improves the Rates of Transmural Remission in Crohn’s Disease: A Propensity Score–Matched Analysis 

Methods: Retrospective cohort study (n=195) including consecutive CD patients starting treatment with IFX. Rates of transmural remission were compared between patients with and without therapeutic drug monitoring (target level: 5-7 µg/mL).

Key findings:

  • The rates of transmural remission were higher in patients under proactive therapeutic drug monitoring (37.2% vs 18.3%; P = .004) with similar results in the propensity score–matched analysis (34.2% vs 17.1%; P = .025). 
  • In multivariate analysis, proactive therapeutic drug monitoring was independently associated with transmural remission (odds ratio, 2.95)

My take: Proactive therapeutic monitoring is beneficial in improving outcomes in patients with Crohn’s disease. Higher drug levels are likely to be particularly important to achieve adequate tissue penetration in transmural Crohn’s disease.

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Ram Head Trail, St John