Pregabalin Helpful for Functional Dyspepsia in Small Study

I Kotikula et al. AP&T 2021; 54: 1026-1032. https://doi.org/10.1111/apt.16588. Randomised clinical trial: the effects of pregabalin vs placebo on functional dyspepsia

Key findings (8 week, randomized placebo-controlled study)

  • The self-reported adequate relief rates in the pregabalin and placebo groups were 70.6% and 42.1% at week 4 (P = 0.02), and 70.6% and 44.7% at week 8 (P = 0.03), respectively
  • Pregabalin improved the overall quality of life (P = 0.03)
  • The most common adverse event with pregabalin was dizziness, occurring in 51.6% of patients

My take: In this study, pregabalin led to significant alleviation of dyspeptic symptoms, especially in patients with predominant epigastric pain.

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.

Unpacking the Pivotal Ozanimod (True North) Trial

WJ Sandborn et al. NEJM 2021; 385: 1280-1291. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis

This study led to FDA approval of ozanimod (Zeposia) in May 2021 for ulcerative colitis.

Mechanism of Action: Ozanimod is a selective sphingosine-1-phosphate receptor modulator which leads to internalization of S1P1 receptors in lymphocytes and the prevention of lymphocyte mobilization to inflammatory sites.

Design: There were two initial cohorts of adults with moderately to severely active ulcerative colitis. The first cohort (n=645) of this 52-week multicenter, randomized, double-blind, placebo-controlled trial (285 sites, 30 countries) of ozanimod as induction and maintenance therapy received either 1 mg of ozanimod hydrochloride once a day or placebo. A second cohort (n=457) received open-label ozanimod and was designed to assure that there would be adequate numbers of patients for the maintenance phase. The design allowed up to 30% of the first cohort to have received prior anti-TNF therapy and up to 50% of the second cohort to have received prior anti-TNF therapy. Ozanimod-treated patients with a clinical response during the 10-week induction were randomized again to a treatment group (n=230) or a placebo group for maintenance (n=227). Placebo-treated patients with a clinical response continued to receive placebo.

Approximately 97% of both cohorts had received prior aminosalicylate treatment and ~20% had received prior vedolizumab therapy.

As a safety measure (due to concerns of bradycardia), there was a 7-day period at the start of treatment with dose escalation, starting at 0.25 mg on days 1-4, 0.5 mg on days 5-7, then to 1 mg thereafter.

Key findings:

  • The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). 
  • The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001).
  • Histologic remission during induction, ozanimod vs placebo: 15.% vs 5.8%.
  • A post hoc analysis showed decreases in the rectal-bleeding and stool-frequency subscores by week 2 (1 week after the completion of dose adjustment).
From NEJM Twitter Feed

Safety Concerns:

  • Serious adverse events attributed to ozanimod or placebo occurred in 4 (0.5%) and 2 (0.9%) during induction respectively and none and 1 (0.4%) respectively during maintenance.
  • Overall all adverse events during induction occurred in 40% of ozanimod-treated patients and 38% of placebo recipients; during maintenance, adverse events were 49% and 37% respectively.
  • Absolute lymphocyte count (ALC) decreased by a mean of ~54% from baseline to week 10 in ozanimod-treated patients; ALC was <200 in 1.1% (both cohorts) in induction and 17 patients during maintenance. None of the patients with ALC <200 experienced a serious or opportunistic infection.
  • Serious infections associated wtih ozanimod or placebo occurred in 10 (1.3%) and 1 (0.5%) during induction respectively and 2 (0.9%) and 4 (1.8%%) respectively during maintenance.
  • Common infections like nasopharyngitis and upper respiratory tract infections in 3-4% of ozanimod-treated patients compared to ~2% of placebo-treated patients
  • Cancer: during induction there was one ozanimod-treated patient who had a basal cell carcinoma and during maintenance there was one ozanimod-treated patient who had a basal cell carcinoma. In the placebo group, during maintenance there was one patient who developed adenocarcinoma of the colon and one who developed breast cancer.
  • Among ozanimod-treated patients, bradycardia was evident in 5 (~0.6%) during induction and none during maintenance. (Patients with significant cardiovascular history were excluded from trial)
  • Among ozanimod-treated patients, hypertension occurred in 13 (~1.6%) during induction and 4 (1.7%); in the placebo group, none in the induction period and three (1.3%) in the maintenance had hypertension.
  • Prior to entry, the trial required documented varicella zoster IgG antibody or completion of vaccination. Still, HSV occurred in 3 during induction (~0.5%) and 5 (2.2%) during maintenance (only 1 placebo patient (0.4%) had an HSV infection during maintenance.
  • Elevated liver tests associated wtih ozanimod or placebo occurred in 42 (5.3%) and 2 (0.9%) during induction respectively and 32 (13.9%) and 1 (5.3%%) respectively during maintenance.
  • Macular edema was noted in 2 ozanimod-treated patients during induction and 1 during maintenance.

My take: This study shows that ozanimod was more effective than placebo in adults with moderately to severely active ulcerative colitis. It will probably be years before we have adequate pediatric data.

From NEJM Twitter Feed

Vedolizumab vs Adalimumab: Histology Outcomes from Varsity Trial

L Peyrin-Biroulet et al. Gastroenterol 2021; Open Access DOI:https://doi.org/10.1053/j.gastro.2021.06.015. Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY)

In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52.

Key findings:

Vedolizumab induced greater histologic remission than adalimumab:

  • week 14: Geboes: 16.7% vs 7.3%, RHI: 25.6% vs 16.1%
  • week 52: Geboes: 29.2% vs 8.3%, RHI: 37.6% vs 19.9%
  • Histologic outcomes were generally better in anti–TNF-naïve vs -failure patients

My take: This study shows that histologic outcomes with vedolizumab, similar to clinical outcomes, were better than with adalimumab. Some of this difference could be due to the trail design which did not allow optimization of adalimumab dosing.

Related posts:

Pseudomelanosis -Blue-Black Staining of Colon

The image below is from a 57 yo woman with Crohn’s disease who was taking a supplement, indigo naturalis (Qing-Dai). “Higher magnification disclosed bluish, needle-like crystals in the cytoplasm of these histiocytes. In light of the presence of pigment-laden histiocytes, we called the lesions indigo naturalis-related pseudomelanosis. Unlike melanosis coli, which typically shows continuous homogeneous brown or black discoloration of colon mucosa (snake-skin appearance or starry sky appearance), indigo naturalis-related pseudomelanosis exhibits a haphazard distribution of black discoloration reminiscent of the skin markings of Holstein Friesian cattle…It remains to be seen whether deposition of indigo naturalis has any long-term adverse effect, although histologically the mucosa with indigo deposition was not accompanied by significant inflammatory activity.”

Link: P-H Le et al. Gastroenterol 2021; 161: e10-e11. Colonic Bluish–Black Patches in a 57-Year-Old Woman with Crohn’s Disease

Oral Treatment of Celiac Disease & Research Optimist

A long time ago I heard a joke from a mentor about how can you tell if a person is an optimist.  An optimist is a person who finds a pile of manure under the tree on Christmas morning and declares: ‘Oh boy, I’m getting a pony.’

Researchers who are trying to identify oral treatments for celiac disease are probably true optimists. Yet, despite my skepticism, a recent study (D Schuppan et al. NEJM 2021; 385: 35-45. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease) provides the best proof yet that an oral treatment may be helpful.

In this 6-week randomized, double-blind, placebo-controlled study with 159 participants, treatment with ZED1227, a selective oral transglutaminiase 2 inhibitor reduced histologic injury compared to placebo; all patients were receiving a diet with 3 grams of daily gluten. Key findings:

  • Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001)
  • The estimated differences from placebo in the change in intraepithelial lymphocyte density were −2.7 cells per 100 epithelial cells (95% CI, −7.6 to 2.2) in the 10-mg group, −4.2 cells per 100 epithelial cells (95% CI, −8.9 to 0.6) in the 50-mg group, and −9.6 cells per 100 epithelial cells (95% CI, −14.4 to −4.8) in the 100-mg group
  • Adverse events were similar to placebo; 3 (8%) patients in the 100 mg group developed a rash

The need for a treatment besides a gluten-free diet is significant; among adults, 40-50% do not achieve mucosal healing/recovery despite GFD institution; in addition, the diet is difficult and costly.

My take: I think it is still a long journey to find an effective & safe oral treatment for celiac disease.

Related blog posts:

How Likely/Persistent is Eosinophilic Esophagitis with Peanut Oral Immunotherapy

BL Wright et al. Clin Gastroenterol Hepatol 2021; 19: 1151-1159. Gastrointestinal Eosinophil Responses in a Longitudinal, Randomized Trial of Peanut Oral Immunotherapy

Background: “The incidence of EoE during OIT has been estimated at 2.7%.” (AJ Lucendo et al. Ann Allergy Asthma Immunol 2014; 113: 624-629)

Methods: Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5) in this prospective study. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks)

Key findings:

  • At baseline: 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS)
  • At 52 weeks: OIT induced or exacerbated esophageal eosinophilia (EoE) at 52 weeks with peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%] who did not have EoE at baseline. EoE did not develop in patients receiving placebo
  • At 104 weeks: In 4 of 6 participants (67%), OIT-induced EoE and gastrointestinal eosinophilia resolved by the end of the maintenance phase
  • One patient developed a clinical diagnosis of EoE.

The discussion notes overlap between EoE and IgE-mediated food allergy. The risk of EoE in patients with IgE-mediated food allergy is 118 times that of the general population (4.7% vs 0.04%) (J Allergy Clin Immunol Pract 2017; 5: 369-375). Also, the authors note that in this study all of the peanut allergic subjects had evidence of epithelial barrier dsyfunction.

My take: This small study shows, that for most adult patients, the development of EoE during OIT is often transitory.

Related blog posts:

2021 AGA Guidelines For Crohn’s Disease

A series of articles details the 2021 AGA Guidelines for Crohn’s disease (CD) including a clinical practice guideline (pg 2496-2508), a clinical decision support tool (2509-2510), a spotlight summary (pg 2511), a technical review (2512-2557), and a review of the recommendations (pg 2557-2262). I will highlight the first article.

JD Feuerstein et al. Gastroenterol 2021; 160: 2496-2508. Full text: AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease

Full text: Spotlight

For me the most important of their recommendations was #7:

  • In adult outpatients with moderate to severe CD, the AGA suggests early introduction with a biologic with or without an immunomodulator rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.

Other points:

From Spotlight:

Radiomic Imaging in Crohn’s Disease

X Li et al. Gastroenterol 2021; 160: 2303-2316. Development and Validation of a Novel Computed-Tomography Enterography Radiomic Approach for Characterization of Intestinal Fibrosis in Crohn’s Disease

Methods: This article describes the development a computed-tomography enterography (CTE)–based radiomic model (RM). This retrospective multicenter study included 167 CD patients who underwent preoperative CTE and bowel resection. 1454 radiomic features were extracted from venous-phase CTE and a machine learning–based RM was developed based on the reproducible features using logistic regression. The RM was validated in an independent external test cohort recruited from 3 centers.

Key findings:

  • In the training cohort, the area under the ROC curve (AUC) of RM for distinguishing moderate–severe from none–mild intestinal fibrosis was 0.888.
  • In the test cohort, the RM had an AUC of 0.816.
  • RM was more accurate than visual interpretations by either radiologist (radiologist 1, AUC = 0.554; radiologist 2, AUC = 0.598; both, P < .001) in the test cohort

My take: This CT approach with RM allowed for accurate characterization of intestinal fibrosis in CD. The images look pretty cool too.

Looking at the Mycobiome to Distinguish Clostridium difficile Infection vs. Carriage

Y Cao et al. Gastroenterol 2021; 160: 2328-2339. Fecal Mycobiota Combined With Host Immune Factors Distinguish Clostridioides difficile Infection From Asymptomatic Carriage

Key findings:

  • The ratio of Ascomycota to Basidiomycota was dramatically higher in patients with CDI than in Carrier and Control (P < .05).
  • Using 4 fungal operational taxonomic units combined with 6 host immune markers in the random forest classifier can achieve very high performance (area under the curve ∼92.38%) in distinguishing patients with CDI from Carrier.

My take: It is interesting that fecal fungal diversity (mycobiome), in addition to bacterial diversity, is reduced in those with Clostridium difficile infection (CDI) compared to both control groups and those with Clostridium difficile asymptomatic carriage.

Related blog posts:

Another reason to get vaccinated

Persistent Villous Atrophy in Celiac Disease Despite a Gluten-Free Diet

A recent study (F Fernandez-Banares et al. Am J Gastroenterol 2021; 116: 1036-1043. Persistent Villous Atrophy in De Novo Adult Patients With Celiac Disease and Strict Control of Gluten-Free Diet Adherence: A Multicenter Prospective Study (CADER Study) shows that there is a high likelihood of persistent villous atrophy among adults with celiac disease (CD) despite adherence with a gluten-free diet (GFD). Thanks to Ben Gold for showing me this paper.

Key findings:

  • Among 76 patients (median age 36.5 years) who were prospectively followed for 2 years, persistent villous atrophy was observed in 40 (53%). In this group, 72.5% were asymptomatic (based on Likert scales) and 75% had negative serology
  • Detectable fecal gluten immunogenic peptides (f-GIPs) were present in at least one sample in 69% of patients. (Two samples obtained at f/u visits which were ~every 6 months during study)
  • Excellent or good adherence to GFD was demonstrated in 68.4% of patients based on dietetic evaluations. Only 6 (8%) were clearly nonadherent
  • “There were no significant differences in the rate of clinical and serological remission between patients with villous atrophy and those with mucosal recovery”
  • The authors did not find potentially modifiable predictive factors

Discussion:

  • The authors note that serology is “not useful for monitoring patients on a GFD.” Anti-TTG2 and EMA, in a recent meta-analysis, had a pooled sensitivity of around 50%.
  • “Adults are significantly less likely than children to normalize their duodenal histology.”

Editorial:

  • The associated editorial by Rej et al (pg 946-948) outline a personalized approach for dealing with persistent villous atrophy:
    • In those with persistent symptoms/positive GIPs/elevated serology/micronutrient deficiency, the first step is careful dietetic assessment. After this, endoscopy could be considered to confirm presence or absence of mucosal healing.
    • In those with no symptoms and no abnormalities, use of monitoring endoscopy needs to be weighed against the costs as well as potential complications.
    • Other points in the editorial: 1. GIPs have poor concordance with mucosal healing and 2. causes of poor mucosal healing include the following: natural slow healing process, super sensitive to gluten, ongoing gluten exposure, and refractory celiac disease.

My take: This study shows that there is ongoing gluten exposure in the majority of patients even in those with excellent or good adherence to a GFD; in addition, it shows that clinical/serological markers are NOT effective in predicting mucosal healing in adults. Nevertheless, it is not clear that followup endoscopy is beneficial.

Related blog posts:

Forbes (7/1/21): 99.5% Of People Killed By Covid In Last 6 Months Were Unvaccinated, Data Suggests

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