Latiglutenase Not Effective for Celiac Disease, Plus One

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A recent study (JA Murray et al. Gastroenterol 2017; 152: 787-98) examined the effectiveness of  latiglutenase for celiac disease.  Latiglutenase (aka ALV003) is an oral medicine which is a mixture of two recombinant gluten-targeting proteases.

The concept of latigluenase is that a medicine that degrades the gluten protein could obviate the need for a gluten free diet.  Unfortunately, in this study with 494 patients with celiac disease for at least 1 year, the medicine at various doses for 12 to 24 weeks was ineffective. There was no difference between the medicine and placebo with regard to villous height:crypt depth ratio, number of intraepithelial lymphocytes or serologic markers of celiac disease.  Symptom scores increased in both the active treatment group and the placebo group.  While this was a negative study, the authors did note some effect on symptom domains on higher dosing regimens. “This observation suggests that treatment with latiglutenase may affect symptoms before showing clinically meaningful effects on serologic and histologic end points.

A second study (RS Choung et al. Gastroenterol 2017; 152: 830-9) examined prevalence and morbidity of undiagnosed celiac disease in Olmstead County. After excluding patients with celiac disease, sera from 30,425 adults and 830 children were tested for tissue transglutaminase IgA antibody (tTG)  and endomysial antibody (EMA).  Case definition: patients were considered to have celiac serologically if tTG titer was 2.0 U/mL or greater with a positive EMA. The prevalence of celiac disease was 1.1% in adults and 1.0% in children. The majority of patients with celiac disease (>80%) have not received the diagnosis.  By comparing those with positive celiac serology to matched controls (2 controls for each positive), the authors determined that undiagnosed celiac disease was associated with increased rates of hypothyroidism (OR 2.2) but no other significant morbidities.  Median followup period was 6.3 years.

My take: A promising new therapy for celiac disease, latiglutenase, looks like it will not be effective and there are a lot of individuals with celiac disease who are unaware of their diagnosis.

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

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What Happens When Patients With ‘Gluten Sensitivity’ Are Challenged with Gluten?

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A recent review of double-blind, placebo-controlled trials (n=10) (J Molina-Infante, A Carroccio. Clin Gastroenterol Hepatol 2017; 15: 339-48) showed that most individuals who consider themselves to have nonceliac gluten sensitivity (NCGS) do not show gluten-specific symptoms.  Only 16% (38 of 231) showed symptoms specific to gluten ingestion.  In addition, the authors describe a 40% nocebo response (similar or increased symptoms in response to placebo).

My take: Due to the absence of a reliable test for NCGS, there are a lot of people who avoid gluten when gluten is not the main culprit for their symptoms.

On a related topic –NPR reports on colleges developing a New Niche -Gluten-free Dining Rooms.  An excerpt:

An estimated 5 to 10 percent of college students have celiac disease or other gluten-related disorders, according to Dr. Alessio Fasano, director of the Center for Celiac Research and Treatment in Boston…

There’s also a marketing angle in responding to the rising rate of gluten-related diagnoses. “Families tell us that Kent has become a top contender because this option exists

Also from NPR –For People With Celiac Disease -Could a Viral Infection Be a Trigger?

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USPSTF Takes Neutral Stance on Celiac Disease Screening in Asymptomatic Individuals

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Full Text: JAMA. 2017;317(12):1252-1257. doi:10.1001/jama.2017.1462

From Abstract:

Objective  To issue a new US Preventive Services Task Force (USPSTF) recommendation on screening for celiac disease.

Evidence Review  The USPSTF reviewed the evidence on the accuracy of screening in asymptomatic adults, adolescents, and children; the potential benefits and harms of screening vs not screening and targeted vs universal screening; and the benefits and harms of treatment of screen-detected celiac disease. The USPSTF also reviewed contextual information on the prevalence of celiac disease among patients without obvious symptoms and the natural history of subclinical celiac disease.

Findings  The USPSTF found inadequate evidence on the accuracy of screening for celiac disease, the potential benefits and harms of screening vs not screening or targeted vs universal screening, and the potential benefits and harms of treatment of screen-detected celiac disease.

Conclusions and Recommendation  The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for celiac disease in asymptomatic persons. (I statement)

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FDA Approval of HCV Medications for Children, 12-17 years

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4/7/17:  FDA Okays Two Hepatitis C Drugs for Our Pediatric Patients

An excerpt:

The US Food and Drug Administration (FDA) today granted approval for supplemental applications for sofosbuvir (Sovaldi) and ledipasvir and sofosbuvir (Harvoni) to treat hepatitis C virus (HCV) in children ages 12 to 17…

Sovaldi, combined with ribavirin, is indicated to treat pediatric patients 12 years older or weighing at least 77 pounds (35 kilograms) with genotype 2 or 3 HCV infection without cirrhosis or with mild cirrhosis.   Harvoni is indicated for the treatment of pediatric patients 12 years and older or weighing at least 77 pounds (35 kilograms) with HCV genotype 1, 4, 5 or 6 infection without cirrhosis (liver disease) or with mild cirrhosis.   The approval for the new indication was based on an open-label, multicenter clinical trial including 100 pediatric patients 12 years and older looking at the safety, pharmacokinetics, and efficacy of Harvoni to treat HCV genotype 1 infection…

health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Harvoni or Sovaldi.

Celiac Titers and Likelihood of Celiac Disease

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A recent study (A Ermarth et al. Clin Gastroenterol Hepato 2017; 15: 396-402) retrospectively examined serology from 3555 pediatric patients who had intestinal biopsies, including 517 with celiac disease from a total of 30,413 with serologic testing These patients had their testing at a commercial lab (ARUP laboratiories). The authors note their regional prevalence of celiac disease was 1.7% of screened patients.

Table 1 lists the PPV, NPV, Sens, Spec based on the degree of elevation of the TTG IgA value.

Some examples:

  • If TTG IgA at 1-fold ULN, then PPV 61%, NPV 98%, Sens 90%, Spec 90%
  • If TTG IgA at 2-fold ULN, then PPV 79%, NPV 97%, Sens 82%, Spec 96%
  • If TTG IgA at 5-fold ULN, then PPV 93%, NPV 94%, Sens 62%, Spec 99%
  • If TTG IgA at 7-fold ULN, then PPV 96%, NPV 91%, Sens 41%, Spec 100%

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Liver Briefs -April 2017

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JA Flemming et al. Hepatology 2017; 65: 804-12.  This cohort study (2003-2015) of 47,591 adults wait-listed for liver transplantation, using the SRTR registry, showed that the era of direct-acting antivirals for hepatitis C was associated with a drop of 32% for HCV patients who were listed compared to the numbers listed during the interferon era.

AG Feldman et al. J Pediatr 2017; 182: 217-22. This retrospective study showed that elevated lactate levels (≥2.5 mmol/L) and elevated lactate to pyruvate ratio (≥25) were NOT predictive of mitochondrial diseases in pediatric patients who presented with acute liver failure.

AG Feldman et al. J Pediatr 2017; 182: 232-38. This retrospective cohort study showed a high rate of vaccine preventable illnesses (VPIs) following liver transplantation (n=2554), occurring in 1 of 6 liver transplant recipients. Most common infections was RSV; most common VPIs: rotavirus and influenza

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What Works for Itching?

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Two recent articles delve into the issue of pruritus associated with cholestasis:

  • JE Squires et al. JPGN 2017; 64: 425-430.
  • Thebaut et al. JPGN 2017; 64: 431-35.

In the first study, a single-center retrospective review of 8 patients with FIC1 disease who underwent partial exernal biliary diversion (PEBD) showed that all patients had resolution of chronic cholestasis (T bili <2 mg/dL) but 7 of 8 experience episodic cholestatic events. Pruritus improved but did not resolve.  PEBD did not obviate the need for aggressive fat-soluble vitamin supplements.

In the second study, the authors added sertraline to patients who had ongoing pruritus despite ursodeoxycholic acid and rifampin therapy.  Patients had either Alagille syndrome or PFIC (progressive familial intrahepatic cholestasis). Two patients had undergone PEBD. Sertraline was started at 1 mg/kg/day and increased as needed every two weeks to max of 4 mg/kg/day (median daily dose 2.2 mg/kg/day).  6 patients had adverse effects, including agitation (2), skin reactions (2), alopecia (1) and vomiting (1). Key finding:

  • 14 of 20 children had improved “itching score” from 8/10 to 5/10.  This correlated with improved sleep and less skin scratch marks.

 

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.

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How Slow Do Objective Markers of Celiac Change After Treatment?

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In a recent study (D Gidrewicz et al. JPGN 2017; 64: 362-7) with 228 consecutive, newly diagnosed children with biopsy-proven celiac disease, the authors followed improvement in serology.  Patients were divided into tertiles based on the degree of TTG IgA/EMA abnormalities. For example, Group A had the most abnormal serology: TTG >10 times ULN and EMA ≥1:80.

My take: This data confirms the fact that it takes a long time for resolution of celiac serology, particularly in those with the most severe disease.

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

FDA Warning: Anesthesia and Developing Brains

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A good review on the issue of anesthesia and the developing brain: DB Andropoulos, MF Greene. NEJM 2017; 376: 905-7.

The authors from Texas Children’s Hospital comment on the prior studies and how their approach has changed since the FDA on December 14, 2016 issued a “Drug Safety Communication” (www.fda.gov/Drugs/DrugSafety/ucm532356.htm).  The FDa warning targets anesthesia in children less than 3 yrs of age and pregnant women in the 3rd trimester who undergo anesthesia for >3 hrs.

At Texas Children’s, the authors state that the FDA warning is now discussed with parents of all children younger than 3 yrs receiving an anesthetic. The authors, however, worry that the “FDA warning will cause delays for necessary surgical and diagnostic procedures.”

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