More Data, More Nuance with MMP-7: Best Biliary Atresia Biomarker

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As noted by my previous blog (New Way to Diagnose Biliary Atresia), I am enthusiastic about the development of MMP-7 (Serum Matrix Metalloproteinase-7) as a biomarker for biliary atresia.

A new study (Wu J-F , Jeng Y-M, Chen H-L, Ni Y-H, Hsu H-Y, Chang M-H. Quantification of serum matrix metallopeptide 7 levels may assist the diagnosis and outcome prediction for biliary atresia. J Pediatr. 2019;208:30–7) and associated editorial provide additional data and nuance.

Key points:

  • “Wu et … studied 100 cholestatic infants presenting consecutively to their institution over a 10-year period, including 36 eventually diagnosed with biliary atresia. Median serum MMP-7 levels were significantly higher in biliary atresia at the time of diagnosis, with an optimal serum MMP-7 level of >1.43 ng/mL for predicting biliary atresia.  In comparison, similarly high MMP-7 levels were found in only 1 infant who was cholestatic without biliary atresia.”
  • “The authors found that serum MMP-7 levels were significantly lower in the 14 infants ≤30 days old diagnosed with biliary atresia, compared with the 22 infants >30 days old at diagnosis. In some cases, serum MMP-7 levels in younger infants with biliary atresia overlapped with those from infants with other liver diseases, such as neonatal hepatitis.”
  • After Kasai portoenterostomy: “Serum MMP-7 levels were significantly higher 6 months post-Kasai portoenterostomy in infants who later required liver transplant, with a serum MMP-7 level of >10.30 mg/dL optimally predicting transplant 3-4 years after Kasai portoenterostomy … serum MMP-7 levels are still high even in patients who do not need liver transplant.”
  • The authors “highlight 1 complication with using serum MMP-7 levels: values can vary widely among different enzyme-linked immunosorbent assay kits used.”

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Sagrada Familia -work in progress.  Amazing.

 

Surprising Findings in Prospective Budesonide-Eosinophilic Esophagitis Study

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A recent study (ES Dellon et al Clin Gastroenterol Hepatol 2019; 17: 666-73) prospectively followed patients in a 24 week open-label extension of a randomized, double-blind, placebo-controlled trial of budesonide oral suspension (BOS) for eosinophilic esophagitis (EoE). The authors defined histologic response as ≤6 eos/hpf. During the extension, the dosage of BOS was reduced from 2 mg twice daily to 2 mg once a day.

Key findings:

  • No new safety signals. One patient in placebo/BOS arm (n=37) developed oral candidiasis and one patient in the BOS/BOS arm (n=45) did as well. In addition, four patients in placebo/BOS developed esophageal candidiasis. No clinically relevant changes in morning serum cortisol levels were identified.
  • Histologic response was observed in 49% (16/33) in placebo/BOS arm and 23% (9/39) of BOS/BOS arm. 58% of placebo/BOS and 28% of BOS/BOS patients had ≤15 eos/hpf.
  • Mean peak eosinophil count decreased in placebo/BOS arm from 119 to 29 and increased in BOS/BOS arm from 38 to 72.
  • Overall, only 42% of patients who responded to BOS during double-blind 12 week study maintained a histologic response.

While this study shows that BOS is effective for many patients with EoE, it also shows that many lose a response.  In addition, most patients who “did not respond to treatment during the double-blind phase did not gain a histologic or endoscopic response with longer-term treatment.”  Only 1 of 26 patients (4%) gained a response. This has several important implications:

  • Some patients may develop corticosteroid resistance
  • In patients who respond to induction, it may be prudent to continue with the same induction dose rather than reducing the dosage
  • In patients who do not respond to induction, further treatment is not beneficial

My take: Though the response to BOS was not very high in this study, the population studied was highly symptomatic and had histologically-severe EoE.  Thus, in a more typical population of patients with EoE, the response rate is likely to be more favorable. Also, many patients will not maintain a response to BOS at a lowered dose.

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Boqureia Market, Barcelona

 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

Getting In the Shower for Emetic Symptoms

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A recent study (I Aziz et al. Clin Gastroenterol Hepatol 2019; 17: 878-86) examined the epidemiology and clinical characteristics of Rome IV functional nausea and vomiting disorders (FNVDs) in adults.  The study used internet cross-sectional health surveys from 5931 adults in 2015.

Key findings:

  • 2.2% of the population (n=131) fulfilled criteria for Rome IV FNVDs
  • Hot water bathing, which has been reported in cannaboid hyperemesis syndrome, was also noted  in patients with cyclic vomiting syndrome (CVS) in 44%.  “This behavior was independent of cannabis but augmented by its use.”

My take: FNVDs are common and hot water bathing is not pathognomonic for cannaboid hyperemesis syndrome.

Related references:

  1. Moon AM, Buckley SA, Mark NM. Successful treatment of cannabinoid hyperemesis syndrome with topical capsaicin. ACG Case Rep J. 2018 Jan 3;5:e3.
  2. Graham J, Barberio M, Wang GS. Capsaicin cream for treatment of cannabinoid hyperemesis syndrome in adolescents: A case series. 2017 Dec;140(6): e20163795.

Hotel in Barcelona

Measles Outbreak

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704 Measles cases for this year were reported on April 30th. It is likely to climb much higher. More than 40,000 cases were reported in Europe in the first 6 months of 2018.

Related article: NY Times: Should Adults Get a Measles Booster Shot?

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IBD Briefs: May 2019 (Part 2)

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KP Quinn et la. Inflamm Bowel Dis 2019; 25: 460-71.  This is a terrific review of evaluation and management of pouch disorders.

A Armuzzi et al. Inflamm Bowel Dis 2019; 25: 568-79. This prospective cohort study examined infliximab biosimilar in 810 patients (PROSIT cohort).  This included 459 patients naive to anti-TNF therapy (group a) , 196 with previous exposure (group b), and 155 who were switched while on original infliximab (group c).  At 12 months, patients without a loss of response were 71%, 64%, and 82% respectively in these three groups.

S Coward et al Gastroenterol 2019; 156: 1345-53. This study from Canada used population-based health administrative data from multiple provinces and then applied autoregressive integrated moving average regression to predict prevalence of IBD in 2030. Key point: “In 2018, 267,983 Canadians were estimated to be living with IBD, which was forecasted to increase to 402,853 by 2030.” This is approximately 1% of the population (981 per 100,000).

F Castiglione et al. Aliment Pharm Ther 2019; 49: 1026-39. This observational longitudinal study with 218 patients with Crohn’s disease who completed 2-years of anti-TNF treatment examined transmural healing via ultrasonography (≤3 mm bowel wall thickness).  “Transmural healing was associated with a higher rate of steroid-free clinical remission (95.6%), lower rates of hospitalization (8.8%) and need for surgery 0%).”  The authors conclude that transmural healing is associated with better long-term clinical outcomes than mucosal healing.

“Magic Fountain” Barcelona

 

IBD Briefs: May 2019 (Part 1)

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H Khalili et al. Clin Gastroenterol Hepatol 2019; 17: 123-29.  Using data from two prospective Swedish cohort sutdies with 83,042 participants (age 44-83 yrs), the authors determined that there was “no evidence for association between consumption of sweetened beverages and later risk of” Crohn’s disease or Ulcerative Colitis.

WJ Sandborn et al. Gastroenterol 2019; 156: 946-57.  This study published data from 354 patients who received subcutaneous abrilumab, an anti-alpha4beta7 antibody as a treatment for moderate-to-severe colitis. This 8 week treatment increased the odds of remission compared with placebo.

B Wynne et al. Gastroenterol 2019; 156: 935-45. This study showed that a psychological intervention termed “acceptance and commitment therapy (ACT)” was effective in a randomized controlled trial in reducing stress and depression in patients with quiescent or mildly-active IBD (n=122). With ACT, the “primary aim is to encourage subjects to adopt positive life values and to accept adverse experiences, including thoughts, feelings and sensations that are an inevitable consequence of life.”  All program materials are available in article supplement: Full text and supplement: https://doi.org/10.1053/j.gastro.2018.11.030

D Duricova et al. Inflamm Bowel Dis 2019; 25:789-96. This study included 72 consecutive children born to mothers with IBD treated with anti-TNF therapy during pregnancy (2007-16) along with 69 unexposed controls.  Key findings: Anti-TNF therapy exposure in utero was NOT associated with a negative impact on postnatal complications, including infections, allergy, growth, or psychomotor development. Findings are limited by the small number of participants.

AW Gridnal et al. Inflamm Bowel Dis 2019; 25:642-45.  The authors examined the frequency of financial conflicts of interest (FCOI) among authors of 11 relevant clinical practice guidelines for IBD in the US,  the UK, Canada, and Europe. Key finding: FCOI were frequently present with 19% prevalence among US authors, 56% in UK, 84% in Canada, and 94% in Europe.

KN Weaver et al. Inflamm Bowel Dis 2019; 25:767-74. This retrospective study examined the efficacy of ustekinumab for Crohn’s disease of the pouch in 56 patients; 73% had previously been treated with anti-TNF therapy, vedolizumab or both. Key finding: 83% demonstrated a clinical response 6 months and 60% with endoscopic improvement after induction with ustekinumab. Clinical response was defined as “any improvement in symptoms …including a decrease in bowel movements, pain, or fistula drainage.”

Retiro Park, Madrid
Thanks to Jennifer

 

How Quickly Does Tofacitinib Work for Ulcerative Colitis?

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The second study reference yesterday:

A recent study (S Hanauer et al. Clin Gastroenterol Hepatol 2019; 17: 139-47) shows that tofacitinib can work quickly to reduce symptoms in ulcerative colitis.

In a post-hoc analyses of data from OCTAVE induction 1 and 2 (n=905 patients, n=234 placebo), the authors determined that tofacitinib reduces symptoms within 3 days.

Key findings:

  • By day 3, there was a reduction in stool frequency (-1.06 vs. -0.27 for placebo) and a reduction in rectal bleeding subscore (-0.30 vs -0.14 for placebo)
  • 28.8% of tofacitinib-treated patients had a reduction in stool frequency subscore by >1 point compared to 17.9% for placebo.  For rectal bleeding subscore, tofacitinib-treated patients had a reduction by >1 point in 32% compared to 17.9% for placebo 20.1%.

My take: This study reinforces the impression that tofacitinib works rapidly.

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La Boqueria, Barcelona

How Quickly Does Vedolizumab Work?

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Two recent studies highlight more rapid onset of action for vedolizumab and tofacitinib than previous reports.

In the first study (BG Feagan et al. Clin Gastroenterol Hepatol 2019; 17: 130-8), the authors performed a post-hoc analysis of data from phase 3, randomized controlled trials of vedolizumab vs placebo in adult patients (UC, N=374; CD, N=784).

Key findings:

  • In patients with UC, 19.1% overall and 22.3% of anti-TNF naive achieved a composite score of rectal bleeding of 0 and stool frequency of ≤1 at week 2 compared to 10% and 6.6% respectively in the placebo group. By 6 weeks, this response rate was 40.8% among anti-TNF naive patients.
  • In patients with CD, 15.0% of anti-TNF naive patients achieved a composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 compared to 7.9% of placebo; at 4 weeks, the vedolizumab group, the rate was 23.8% compared to 10.3% with placebo.

My take: This study shows that a substantial portion of patients respond fairly quickly to vedolizumab, especially among patients who are naive to anti-TNF therapy.  This is in contrast to the impression that vedolizumab is slow-acting and needs closer to 14 weeks to see clinical effects.

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Jardines de Cecilio Rodríguez; Retiro Park, Madrid

Favorable “Break”through Data for Proton Pump Inhibitors and Bone Density

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Franklin Roosevelt’s secretary of state, Cordell Hull, wrote: “A lie will gallop halfway round the world before the truth has time to pull its breeches on.”

This saying came to my mind as I read a recent study (KE Hansen et al. Gastroenterol 2019; 156: 926-34) titled: “Dexlansoprazole and esomeprazole do not affect bone homeostasis in healthy postmenopausal women.”

In this study, the authors performed a prospective double-blind study with 115 healthy postmenopausal women who were treated with one of these two PPIs or placebo daily for 26 weeks.

Key findings:

  • PPI therapy did not reduce true fractional calcium absorption
  • There were no significant difference between groups in serum or urine levels of minerals, bone mineral density, or parathyroid hormone

Previous studies have found conflicting results of PPIs on bone density.  Studies suggesting that PPIs could affect bone density have been questioned due to “low odds ratios (<2), lack of dose response, biological implausibility, and uncontrolled potential confounders.”  The authors note that they chose bone turnover rather than changes in BMD as a primary outcome as bone turnover precede changes in BMD and should serve as an early marker of adverse effects.

My take: This study, while short in duration and with limited numbers of participants found no harmful effects of PPIs on skeletal health.

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Tajo River, Toledo Spain