Category Archives: Gastroenterology

REMSWITCH: Infliximab IV to SC Study

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A Buisson et al. Clin Gastroenterol Hepatol 2023; 21: 2338-2346. Open Access! Effectiveness of Switching From Intravenous to Subcutaneous Infliximab in Patients With Inflammatory Bowel Diseases: the REMSWITCH Study

In this study, 133 ot 184 patients in clinical remission agreed to switch to subcutaneous infliximab. Key findings:

  •  At visit 3, a relapse occurred in 10.2% (n = 6 of 59), 7.3% (n = 3 of 38), 16.7% (n = 3 of 18), and 66.7% (n = 10 of 15) (P < .001) of patients receiving 5 mg/kg every 8 weeks (5Q8W), 10Q8W, 10Q6W, and 10Q4W, respectively. 
  • Dose escalation to 240 mg every other week led to recapture clinical remission in 93.3% (n = 14 of 15).
  • Infliximab serum levels increased after the switch (P < .0001) except for patients receiving 10 mg/kg every 4 weeks.
  • Conclusion (borrowed from authors): Switching from intravenous to subcutaneous infliximab 120 mg every other week is safe and well accepted, leading to a low risk of relapse in IBD patients except for those receiving 10Q4W; these patients likely require 240 mg every other week

EV Loftus et al. Clin Gastroenterol Hepatol 2023; 21: 2193. Open Access! Therapeutic Drug Monitoring for Subcutaneous Infliximab? Too Early to Conclude (Editorial) This editorial provides a terrific analysis of the above-mentioned study. A few of the points:

  • Reduced (41.7%) or stable (36.8%) serum levels of IFX after the switch (difference: V1-V0) were associated with higher risk of relapse than increased serum levels (>1 μg/mL; 12.7%; P = .020 and P = .019, respectively)
  • Patients receiving IV infusion of IFX 10Q4W had a higher risk of relapse (odds ratio, 12.4; P = .017). In addition to having significantly higher serum levels than in other IFX IV regimens, this group of patients did not see a rise in IFX concentrations at V1, in contrast to other IFX regimens. 
  • Being overweight increases the clearance of CT-P13 SC, with an increase in clearance of 43.2% for a weight increase from 70 to 120 kg. The presence of antibodies to IFX also increases clearance by 39%. Finally, a decrease in serum albumin level (42 g/L vs 3.2 g/L) increases the clearance by 30.1%. 

My take:

  1. Monitoring IFX levels would be helpful in patients switching from IV to SC administration, especially in higher risk groups (eg. high baseline dosing, positive anti-drug antibodies, low serum albumin, overweight individuals)
  2. My experience with SC biologics has been that there is a much higher rate of non-adherence than with IV infusions. If/when SC biologics are used more often, I will need to implement more intensive followup to assure patients receive both the needed medication and the needed monitoring.

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Festive Street in Antibes, France

What We Are Learning from the “Blue Poop Challenge”

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8/21/23 Gastroenterology & Endoscopy News, Open Access! Gut Transit Time Varies by Country

The “Blue Poop Challenge,” (joinzoe.com/bluepoop), a citizen scientist project involving 21,541 volunteers in 17 countries on five continents, is evaluating whole gut transit time (WGTT).  “Findings were based on self-reported WGTT after volunteers consumed blue muffins (84.5 g per muffin x 2, each containing 0.75 g of blue food coloring paste). WGTT was defined as the time elapsing between muffin ingestion and first appearance of blue color in the stool…”

“The mean WGTT was 23.9 hours (range, 16.2- 32.0 hours), with country-specific differences, said Dr. Bulsiewicz, reporting the findings at Digestive Disease Week 2023 (abstract Su1612)“…

“Fast and slow WGTTs were significantly associated with less healthful diet quality compared with normal WGTT (P<0.001). ‘Lower intakes of plant-based foods were associated with abnormal transit times, which is consistent with the known effect of dietary fiber,‘”‘”

My take: Food-based transit studies are a lot easier to perform than Sitz marker studies. And, of course, who would not want to know if their transit time is faster than their friends?

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How Common is Bloating?

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JE Oh et al. Clin Gastroenterol Hepatol 2023; 21: 2370-2377. Open Access! Abdominal Bloating in the United States: Results of a Survey of 88,795 Americans Examining Prevalence and Healthcare Seeking

88,795 completed surveys detailing prevalence of bloating in preceding 7 days.

Key findings:

  • Nearly 1 in 7 (12,324 (13.9%) Americans have experienced bloating symptom in the past week; 58.5% never sought care for bloating—29% of whom were self-managing symptoms or were uncomfortable discussing symptoms with their providers
  • Women and those with comorbidities (eg, irritable bowel syndrome, chronic constipation, ulcerative colitis) and concomitant GI symptoms (eg, abdominal pain, excess gas) had higher odds for bloating (all P < .001) and severe bloating (all P < .001

My take: This study shows that a lot individuals have bloating.

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I saw this towel at a store. It’s pretty funny, but is someone really going to purchase it?

But How Well Does It Work in Theory and Eosinophilic Esophagitis Treatments

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C Mayerhofer et al. Clin Gastroenterol Hepatol 2023; 21: 2197-2210. Open Access! Efficacy of Elimination Diets in Eosinophilic Esophagitis: A Systematic Review and Meta-analysis

“That’s all well and good in practice… but how does it work in theory?” I saw this quote many years ago when I was visiting the University of Chicago.

This quote came to mind as I was reading this article which showed relatively little change in the efficacy between more and less stringent elimination diets for eosinophilic esophagitis. This meta-analysis included 915 children and 847 adults and assessed the efficacy rates of 4 major dietary treatment regimens in eosinophilic esophagitis: 6-food (SFED), 4-food (FFED), 1-food (OFED), and a targeted elimination diet (TED).

Key findings:

  • The overall rate of histologic remission was 53.8% and in the individual dietary groups was 61.3% for SFED, 49.4% for FFED, 51.4% for OFED, and 45.7% for TED.
  • The overall rate of clinical response was 80.8%, with response rates of 92.8% for SFED, 74.1% for FFED, 87.1% for OFED, and 69.0% for TED.
Percentage of food antigen triggers identified via endoscopic
and clinical evaluation after food re-introduction.

My take: It is clear to me that more restrictive diets can yield better response rates; however, in clinical practice they are difficult to maintain and this study shows that the improvement with more food restrictions may be quite limited.

Another reference on eosinophilic esophagitis: CJ Ketchem et al. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2252-2259. Open Access! Higher Body Mass Index Is Associated With Decreased Treatment Response to Topical Steroids in Eosinophilic Esophagitis. Key finding: Histologic response (n=296) to topic steroids was higher for those who were nonobese compared with obese at fewer than 15 eosinophils per high-power field (61% vs 47%; P = .049); in addition, nonobese patients had significantly greater endoscopic and symptomatic responses.

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Comparative Efficacy of Biologics for Crohn’s Disease

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S Singh et al. Clin Gastroenterol Hepatol 2023; 21: 2359-2369. Open Access! Comparative Safety and Effectiveness of Biologic Therapy for Crohn’s Disease: A CA-IBD Cohort Study

There is limited head-to-head data comparing the effectiveness of the biologics used for inflammatory bowel disease. In this study, the authors used a “series of propensity score (PS)-matched cohort studies comparing TNF-α antagonists vs vedolizumab vs ustekinumab in a large, diverse, multicenter, electronic health record (EHR)-based cohort.”

This graphical abstract summarizes the findings, though the first cohort (ustekinumab vs TNFalpha population is actually 1545 not 1030):

Key findings:

  • Ustekinumab-treated patients with CD (n = 515) experienced a lower risk of serious infections (hazard ratio [HR], 0.36), without any difference in the risk of hospitalization (HR, 0.99) or surgery (HR, 1.08) -compared to patients receiving TNF alpha antagonists (n=1030)
  • Ustekinumab-treated patients with CD (n = 221) experienced a lower risk of serious infections (HR, 0.20), without significant differences in risk of hospitalization (HR, 0.76) or surgery (HR, 1.42) -compared to vedolizumab-treated patients (n=221)
  • Compared with TNF-α antagonists (n = 442), vedolizumab-treated patients with CD (n = 221) had a similar risk of serious infections (HR, 1.53), hospitalization (HR, 1.32), and surgery (HR, 0.63).

The increase rate of infections with vedolizumab compared to ustekinumab could be an indication of lower efficacy with vedolizumab as the medication itself has a high safety profile.

In the discussion, the authors comment further on head-to-head studies and lack of these as well. “Biemans et al23 observed that ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (69 patients in each arm, vs vedolizumab; 46.4% vs 29.0%; P = .04) and biochemical remission (42.1% vs 13.2%; P = .01) at 12 months, although these rates were not significant at earlier time points.”

My take: This study provides further evidence that ustekinumab is a good option for Crohn’s disease with regard to both safety and efficacy.

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Infliximab Injections Coming Soon

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  1. L Gianolio et al JPGN 2023; 77(2):p 235-239, August 2023. Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy

Key findings: After switching from IV infliximab to SC 120 mg every other week, 6 of 7 patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). 

2. Gastroenterology & Endoscopy News (7/31/23) Safety, Efficacy of Subcutaneous Infliximab Supported by Trial

Excerpt:

In this multinational trial, called LIBERTY-CD, the median trough level was 16 mcg/mL, which is higher than that typically associated with IV dosing, according to Dr. Hanauer, who presented the results at Digestive Disease Week 2023 (abstract 1028)… “most professional societies to recommend a trough of 10 mcg/mL,” Dr. Hanauer said….

All patients received induction doses of infliximab by IV at weeks 0, 2 and 6. Those who achieved at least a 100-point reduction in the Crohn’s Disease Activity Index (CDAI), which accounted for 86% of the 396 patients initially enrolled, were randomized in a 2:1 ratio to receive 120 mg of subcutaneous infliximab (CT-P13) or placebo every two weeks.

The proportion of patients meeting the end point of clinical remission, defined on the basis of CDAI, was 62.3% for active therapy and 32.1% for placebo (P<0.0001). The proportion of patients in the active treatment arm achieving an endoscopic response was nearly three times higher than the proportion in the placebo arm (51.1% vs. 17.9%; P<0.0001).

My take: This study shows that SC infliximab (after IV induction) should be effective. A study showing that the SC product is not inferior to the IV dosing would be helpful. It is likely that vedolizumab will receive approval in U.S. for a similar IV induction followed by maintenance subcutaneous therapy in the next year.

Eze, France

Comparative Efficacy: Infliximab vs. Ustekinumab

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ECL Wong et al. Inflamm Bowel Dis 2023; 29: 1015-1023. Open Access! Comparative Efficacy of Infliximab vs Ustekinumab for Maintenance of Clinical Response in Biologic Naïve Crohn’s Disease

This post hoc analysis included data from separate trials examined the response of 220 biologic-naïve CD participants to either inflximab biosimilar or ustekinumab.

Key findings:

  • Clinical remission: One-year clinical remission (CR) and corticosteroid-free CR rates were similar between infliximab-treated and ustekinumab-treated patients (CR, 66 of 110 [60.0%] vs 63 of 110 [57.3%]; adjusted odds ratio [aOR], 1.15), corticosteroid-free CR, 11 of 28 (39.3%) vs 27 of 51 [52.9%]; aOR, 0.58)
  • Endoscopic response/remission:  infliximab-treated participants were more likely to achieve 1-year endoscopic response (43 of 92 [46.7%] vs 6 of 30 [20.0%], aOR, 3.59) and endoscopic remission (31 of 92 [33.7%] vs 4 of 30 [13.3%]; aOR, 3.35)

In the discussion, the authors note only 1 head-to-head study in CD with ustekinumab. “The SEAVUE trial (NCT03464136) compared adalimumab and ustekinumab among biologic-naïve CD patients. Ustekinumab demonstrated similar efficacy for the achievement of clinical and endoscopic outcomes compared with adalimumab.23 Similar rates of CR at 1 year were reported in SEAVUE (64.9% ustekinumab vs 61% adalimumab) as in our analysis (57.3% ustekinumab vs 60% infliximab)…ustekinumab demonstrated longer retention and lower immunogenicity and has practical advantages over adalimumab, including less frequent dosing intervals (every 8 weeks for ustekinumab vs every 2 weeks for adalimumab) while providing similar efficacy.”

My take: This study suggests that infliximab may be a little better than ustekimumab in biologic-naive patients due to the higher endoscopic response; however, the study was unpowered to provide a definitive answer. A prior study suggested similar endoscopic healing rates (P Riviere et al. Inflamm Bowel Dis 2023; 29: 923-931).

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Waters off the Cap d’Ail Trail (near Eze, France)

More Data: Upadacitinib “is Effective and Safe” Plus 2 in Kids

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S Friedberg et al. Clin Gastroenterol Hepatol 2023; 21: 1913-1923. Open Access! Upadacitinib Is Effective and Safe in Both Ulcerative Colitis and Crohn’s Disease: Prospective Real-World Experience

Methods: “We performed a prospective analysis of clinical outcomes on upadacitinib in patients with UC and CD using predetermined intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol.” 84 met inclusion criteria  (44 UC patients, 40 CD patients) -though complete data was available for only a fraction of these. All of the patients had received prior anti-TNF therapy and 89% had received 2 or more advanced therapies. 

Key findings:

  • Ulcerative colitis: At 4 and 8 weeks of treatment, 19 of 25 (76.0%) and 23 of 27 (85.2%) achieved clinical response and 18 of 26 (69.2%) and 22 of 27 (81.5%) achieved clinical remission, respectively. Of those who previously were tofacitinib-exposed, 7 of 9 (77.8%) achieved clinical remission by 8 weeks.
  • Crohn’s disease: In CD, 13 of 17 (76.5.%) achieved clinical response and 12 of 17 (70.6%) achieved clinical remission by 8 weeks. Of those with increased fecal calprotectin and C-reactive protein levels, 62% and 64% normalized by week 8, respectively. 
  • Results were seen as early as week 2 in both UC and CD, with clinical remission rates of 36% and 56.3.%,
  • Acne was the most commonly reported adverse event, occurring in 24 of 105 patients (22.9%) (Table 4). Six patients stopped upadacitinib due to adverse effects.

My take: “In this large real-world experience in medically resistant patients with UC or CD, we report that upadacitinib is rapidly effective and safe, including in those who had prior tofacitinib exposure.” In pediatrics, the effectiveness of this upadacitinib is a logical target for ImproveCareNow. More pediatric data will be needed to garner FDA approval.

Related articles:

LV Collen. Inflamm Bowel Dis 2023; 29: 1175-1176. Rapid Clinical Remission With Upadacitinib in a Pediatric Patient With Refractory Crohn’s Disease A pediatric patient with Crohn’s disease refractory to anti-tumor necrosis factor therapy, vedolizumab, ustekinumab, and 6-mercaptopurine achieved rapid clinical remission with upadacitinib.

A Bousvaros, BAR Schmidt, M Kurtz. Gastroenterology & Hepatology 2023; 19: 401-403. Open Access! “Treatment of Genital Crohn’s Disease with Upadacitinib in a Male Child: A Case Report”. This report describes the rapid response to upadacitinib in a 12 yo with refractory Crohn’s ileocolitis (x 5 yrs) with associated “granulomatous lymphangitis” affecting the penis and scrotum. It notes that “anti-TNF therapy was described as the most effective treatment, with either improvement or resolution of scrotal swelling in most patients. However, intermittent penile swelling persisted in a subset of the patients.18“…”Although data on the use of JAK inhibitors to treat pediatric IBD are limited, the fact that these are small molecules with wide systemic effects suggests that JAK inhibitors may be useful in the treatment of extraintestinal manifestations of IBD….[and]  that JAK inhibitors such as upadacitinib may play an important role in the treatment of such refractory patients.”

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On an adventurous day, we climbed the Nietzsche trail to get from the coast to the top of Eze, France.

AGA Guidance on Extraesophageal Gastroesophageal Reflux

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JW Chen et al. Clin Gastroenterol Hepatol 2023; 21: 1414-1421. Open Access! AGA Clinical Practice Update on the Diagnosis and Management of Extraesophageal Gastroesophageal Reflux Disease: Expert Review

Some the “best practice advice:”

  • #3 Currently, there is no single diagnostic tool that can conclusively identify GER as the cause of EER symptoms. Determination of the contribution of GER to EER symptoms should be based on the global clinical impression derived from patients’ symptoms, response to GER therapy, and results of endoscopy and reflux testing.
  • #4 Consideration should be given toward diagnostic testing for reflux before initiation of proton pump inhibitor (PPI) therapy in patients with potential extraesophageal manifestations of GERD, but without typical GERD symptoms. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable.
  • #6 In patients with suspected extraesophageal manifestation of GERD who have failed one trial (up to 12 weeks) of PPI therapy, one should consider objective testing for pathologic GER, because additional trials of different PPIs are low yield.
Proposed Diagnostic Algorithm by Authors

Related commentary: R Yadlapati, WW Chan. Clin Gastroenterol Hepatol 2023; 21: 1395-1398. Modern Day Approach to Extraesophageal Reflux: Clearing the Murky Lens

This commentary identifies huge gaps in our understanding of extraesophageal reflux (EER):

  • Clinical value of upper GI endoscopy
  • Diagnostic thresholds of reflux monitoring to use for EER (Is it the same as GERD?)
  • Significance of nonacidic or weakly acidic reflux
  • Whether focus should remain on distal esophageal reflux or proximal reflux

My take: If a patient has normal amounts of reflux, can they still have extraesophageal reflux symptoms? If so, how does one objectively gauge success?

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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.

Early Postoperative Anti-TNF Therapy

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JE Axelrad et al. Inflamm Bowel Dis 2023; 29: 888-897. Early Initiation of Antitumor Necrosis Factor Therapy Reduces Postoperative Recurrence of Crohn’s Disease Following Ileocecal Resection

This retrospective cohort study identified 1037 patients with Crohn’s disease who underwent ileocecal resection (ICR). Only 5.4% were younger than 18 yrs at the time of surgery. In this cohort, 278 (26%) received a biologic agent as prophylaxis to prevent recurrence with 80% receiving an anti-TNF agent. In those receiving an anti-TNF agent, 35% were started on therapy within 4 weeks of surgery and 65% were started between 4 and 12 weeks. Recurrence was defined by endoscopy (≥ i2b Rutgeerts score) or radiography (active inflammation in neoterminal ileum). Key findings:

  • After adjusting for factors associated with postoperative recurrence (POR), compared with no biologic prophylaxis, the initiation of an anti-TNF agent (n=223) within 4 weeks following an ICR was associated with a reduction in POR (adjusted hazard ratio, 0.61).
  • Prophylaxis after 4 weeks following an ICR or with vedolizumab or ustekinumab was not associated with a reduction in POR compared with those who did not receive prophylaxis –though sample size with vedolizumab (n=27) and ustekinumab (n=28) was very limited
  • Most patients receiving biologic prophylaxis had prior anti-TNF exposure including 73% of the anti-TNF group, 96% of the vedolizumab group, and 93% of the ustekinumab group.

In their discussion, the authors note that their findings reinforce previous studies which showed beneficial effects of anti-TNF therapy for POR, including the PREVENT trial. This randomized controlled trial with infliximab initiation within 45 days postoperatively in high risk individuals reduced endoscopic recurrence at 18 months (22.4% compared with 51% in placebo group).

My take: Anti-TNF therapy, even in those with prior exposure, likely improves outcomes in patients with Crohn’s disease following ileocecal resection. This study indicates that starting therapy within the first 4 weeks is more beneficial.

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Watersound, FL