Tofacitinib Case Reports for Acute Severe UC and Pyoderma Gangrenosum

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Two recent case reports indicate that Tofacitinib may be useful in refractory cases of acute severe ulcerative colitis (ASUC) (JA Berinstein et al. Clin Gastroenterol Hepatol 2019; 17: 988-90) and for pyoderma gangrenosum (PG) (B Kochar et al. Clin Gastroenterol Hepatol 2019; 17: 991-93)

The case report for ASUC described 4 patients who received off-label high-intensity tofacitinib.  Initially dosing was 10 mg 3 times a day for 9 doses with subsequent transition to standard dosing.  All four patients had a rapid improvement, though one patient required a colectomy 6 months later and one patient required urgent colectomy after rapid return of symptoms when tofacitinib dose was reduced.

The case report for PG involved 3 patients -two healed with tofacitinib and one improved considerably; the latter patient required dose escalation to 10 mg twice a day.  To understand the mechanism of action further, the authors performed immunohistochemical staining from skin biopsy specimens from two patients and detected “strong staining of phosphorylated JAK-1, phosphorylated JAK-2, phosphorylated JAK-3…in the epidermis.”  Tofacitinib is an oral JAK-1/JAK-3 inhibitor.  In all of these patients, inflammatory arthritis was the indication for tofacitinib.

My take: Due to tofacitinib’s rapid onset of action as well as its rapid clearance, it is a promising agent for both acute severe ulcerative colitis and pyoderma gangrenosum.  More clinical trials are needed.

Related blog posts -Tofacitinib:

Related blog posts -ASUC:

Related blog posts -PG:

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.

Image below is from an unrelated tweet.

How Hepatitis C Therapy Affects Cardiovascular Outcomes

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Briefly noted: A recent retrospective study (AA Butt et al. Gastroenterol 2019; 156: 987-96) utilized a Veterans HCV database (n=242,680) and determined that HCV therapy improved cardiovascular outcomes.

Key finding: Treatment with a direct-acting antiviral regimen lowered the risk of cardiovascular events by more than 40% (hazard ratio of 0.57) compared to no treatment.

This finding is limited based on the reliance of a retrospective study and not being able to control for factors that may have led some patients to not receive treatment.

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Transient Exocrine Pancreatic Insufficiency or Misleading Tests?

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A recent retrospective study (J Garah et al. JPGN 2019; 68: 574-77) showed that many cases of exocrine pancreatic insufficiency, based on a low fecal elastase (<200), resolved over ~6 months.

Background:

  • 17 of 43 children had adequate data and no other recognized comorbidities which could explain low elastase levels
  • In these 17 children the median age was 3 years
  • Presenting symptoms were failure to thrive, or diarrhea. Children with known etiologies (eg. cystic fibrosis, Shwachman-Diamond, cholestatic liver disease) were excluded.
  • Median elastase at time of diagnosis was 71

Key findings:

  • Median time for normalization of elastase was 6 months. Patients received pancreatic supplements until elastase normalized.
  • 11 of the 17 had values of elastase <100, and an additional two had values of 105.
  • In all 17 children without identifiable underlying diseases, the pancreatic insufficiency was transient.
  • Only two children had fat soluble vitamin deficiency associated with pancreatic insufficiency

The article discusses the use of elastase for diagnosis of pancreatic insufficiency in comparison to more direct/invasive testing which can be difficult to perform.  It is important to recognize that elastase values are often unreliable in the presence of diarrhea or if diluted by urine.  Repeated assays may be needed to have confidence that elastase

My take: This report identifies “transient pancreatic insufficiency” as a frequent explanation for many children and may represent a postinfectious etiology. Thus, if no comorbidity is identified, the prognosis is favorable in most children.

Sculptured Cypress Trees in Retiro Park, Madrid

AGA Practice Guidelines for Celiac Disease

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AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease—Changing Utility of Serology and Histologic Measures: Expert Review (S Husby et al. Gastroenterol 2019; 156: 885-89)

Best Practice Advice 1: Serology is a crucial component of the detection and diagnosis of CD, particularly tissue transglutaminase–immunoglobulin A (TG2-IgA), IgA testing, and less frequently, endomysial IgA testing.

Best Practice Advice 2: Thorough histological analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry is important for diagnosis as well as for differential diagnosis.

Best Practice Advice 2a: TG2-IgA, at high levels (> ×10 upper normal limit) is a reliable and accurate test for diagnosing active CD. When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for CD is virtually 100%. In adults, esophagogastroduodenoscopy (EGD) and duodenal biopsies may then be performed for purposes of differential diagnosis.

Best Practice Advice 3: IgA deficiency is an infrequent but important explanation for why patients with CD may be negative on IgA isotype testing despite strong suspicion. Measuring total IgA levels, IgG deamidated gliadin antibody tests, and TG2-IgG testing in that circumstance is recommended.

Best Practice Advice 4: IgG isotype testing for TG2 antibody is not specific in the absence of IgA deficiency.

Best Practice Advice 5: In patients found to have CD first by intestinal biopsies, celiac-specific serology should be undertaken as a confirmatory test before initiation of a gluten-free diet (GFD).

Best Practice Advice 6: In patients in whom CD is strongly suspected in the face of negative biopsies, TG2-IgA should still be performed and, if positive, repeat biopsies might be considered either at that time or sometime in the future.

Best Practice Advice 7: Reduction or avoidance of gluten before diagnostic testing is discouraged, as it may reduce the sensitivity of both serology and biopsy testing.

Best Practice Advice 8: When patients have already started on a GFD before diagnosis, we suggest that the patient go back on a normal diet with 3 slices of wheat bread daily preferably for 1 to 3 months before repeat determination of TG2-IgA.

Best Practice Advice 9: Determination of HLA-DQ2/DQ8 has a limited role in the diagnosis of CD. Its value is largely related to its negative predictive value to rule out CD in patients who are seronegative in the face of histologic changes, in patients who did not have serologic confirmation at the time of diagnosis, and in those patients with a historic diagnosis of CD; especially as very young children before the introduction of celiac-specific serology.

Management

Best Practice Advice 10: Celiac serology has a guarded role in the detection of continued intestinal injury, in particular as to sensitivity, as negative serology in a treated patient does not guarantee that the intestinal mucosa has healed. Persistently positive serology usually indicates ongoing intestinal damage and gluten exposure. Follow-up serology should be performed 6 and 12 months after diagnosis, and yearly thereafter.

Best Practice Advice 11: Patients with persistent or relapsing symptoms, without other obvious explanations for those symptoms, should undergo endoscopic biopsies to determine healing even in the presence of negative TG2-IgA.

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Fountans by Manzanares River, Madrid. Royal Palace and Cathedral in background

Bad Diets –>High Mortality

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A recent article in Lancet (“Health effects of dietary risks in 195 countries, 1990–2017:
a systematic analysis for the Global Burden of Disease Study 2017″ -open access) estimated that bad diets lead to 11 million deaths per year. Thanks to Ana Ramirez for sending me this article. “High intake of sodium, low intake of whole grains, and low intake of fruits were the leading dietary risk factors for deaths and DALYs globally and in many countries.”

A summary of this study was reported on NPR: Bad Diets Are Responsible For More Deaths Than Smoking, Global Study Finds

An excerpt:

About 11 million deaths a year are linked to poor diet around the globe…

As part of a new study published in The Lancet, researchers analyzed the diets of people in 195 countries using survey data, as well as sales data and household expenditure data. Then they estimated the impact of poor diets on the risk of death from diseases including heart disease, certain cancers and diabetes. (They also calculated the number of deaths related to other risk factors, such as smoking and drug use, at the global level.)…

“Generally, the countries that have a diet close to the Mediterranean diet, which has higher intake of fruits, vegetables, nuts and healthy oils [including olive oil and omega-3 fatty acids from fish] are the countries where we see the lowest number of [diet-related] deaths,” …

What would happen if everyone around the globe began to eat a healthy diet, filling three-fourths of their plates with fruits, vegetables and whole grains? We’d run out…

Improving diets won’t be easy: A range of initiatives may be needed, including nutrition education and increased access to healthy foods, as well as rethinking agricultural production.

Related blog posts:

 

IBD Update April 2019

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Briefly noted:

Link (from KT Park’s twitter feed): What New Treatments for Crohn’s disease and Ulcerative Colitis Are Being Developed?

R Wittig et al. JPGN 2019; 68: 244-50. This study from Germany, using health insurance data, identified an overall pediatric inflammatory bowel disease (IBD) incidence of 17.41 per 100,000 in 2012 compared to 13.65/100,000 in 2009.  This is one of the highest incidence rates reported and agrees with other data suggesting increasing rates of IBD in pediatric populations.

B Christensen et al. Clin Gastroenterol Hepatol 2019; 17: 486-93.  This study provides data from 20 patients (CD =9, UC =11) who were treated with a combination of a calcineurin inhibitor and vedolizumab.  The calcineurin inhibitor was used as a ‘bridge’ treatment until the slower acting vedolizumab could be effective. After 52 weeks of treatment, 33% of the CD patients and 45% of the UC patients were in steroid-free clinical remission.  Three serious adverse events associated with calcineurin treatment.

G Pellet et al. Clin Gastroenterol Hepatol 2019; 17: 494-501. Retrospective study of calcineurin inhibitor induction with vedolizumab in 39 patients with refractory ulcerative colitis (36 had failed anti-TNF Rx).  11 patients (28%) required colectomy. week 14 response and remission noted in 56% and 38% respectively. Four serious adverse events were observed.

N Nalagatla et al. Clin Gastroenterol Hepatol 2019; 17: 494-501. In a retrospective study of 213 patients with steroid refractory acute severe ulcerative colitis, the authors did not find lower rates of colectomy in patients who received an accelerated infliximab dosing.  However, they were unable to control for confounding by disease severity. Patients who received an intial dose of 10 mg/kg had a lower colectomy rate than patients who received an initial dose of 5 mg/kg. Colectomy rates for accelerated vs standard infliximab dosing –in-hospital: 9% vs 8% respectively, at 3 months: 20% vs 14% respectively, at 12 months: 28% vs 27% respectively.

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Shenandoah National Park

Helicobacter Pylori 2019 Review

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A recent review (SE Crowe. NEJM 2019; 1158-65) provides a succinct summary of current H pylori management.

A couple of key points:

  • It is essential to test for cure after treatment 1 month afterwards
  • If retreatment is needed, use an alternative regimen
  • In the discussion of treatment, Dr. Crowe does NOT emphasize quadruple therapy except in individuals with a clarithromycin resistance probability of >25% (based on geographic incidence rates) or prior macrolide use.  She notes that in some populations that clarithromycin-based triple therapy had similar effectiveness as bismuth-based quadruple-based therapy.  Table 2 lists the 7 ACG approved treatment regimens.
  • It is noted that U.S. clarithromycin-resistance is between 21-30%.

Related blog posts:

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.

Celiac Hepatopathy 2019

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A recent retrospective study (E Benelli et al. JPGN 2019; 68: 547-51) examines a large cohort of patients (=700) who were diagnosed with celiac disease (CD) from 2010-2016 and had available liver transaminases.

Key findings:

  • ALT values >40 U/L were elevated in only 3.9% (27/700)
  • Younger age (<4.27 years) correlated with a higher risk of liver involvement with OR 3.73
  • Of these 27 patients with elevated ALT, 18 had adequate followup.  All but 3 patients normalized ALT values after at least 1 year; of these, 1 was diagnosed with sclerosing cholangitis. In the other two, one was thought to be nonadherent with gluten-free diet and one had dropped ALT to 47 U/L.
  • Thus, definitive autoimmune liver disease was identified in only one patient

My take: This study shows a lower rate of liver involvement than previous studies.

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Joshua Tree National Park

 

Liver Shorts April 2019

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CL Mack et al. JPGN 2019; 68: 495-501. This multicenter prospective open-label phase I/III trial of IVIG in biliary atresia patients status-post Kasai indicated that the infusions were tolerated.  However, though this study was not powered to detect efficacy, survival with native liver was LOWER among patients who had received IVIG (n=29): 58.6% compared to the comparison placebo group 70.5% (n=64).  Thus, despite the theoretical advantages of IVIG which targets aspects of the immune system and improvement in a murine model, in practice IVIG does not appear promising for biliary atresia.

D Kim et al. Hepatology 2019; 69: 1064-74. This study shows that despite improvements in hepatitis C mortality rates associated with newer treatments, there is an overall increase in mortality rates from cirrhosis and hepatocellular carcinoma.  This increase is driven by increasing prevalence and severity of both alcoholic liver disease and nonalchoholic fatty liver disease. The overall cirrhosis-related mortality increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3%. Similarly, the overall HCC-related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at annual increase of 2%. The editorial on page 931 (TG Cotter and MR Charlton) notes that each year there are more than 40,000 deaaths associated with chronic liver disease.

H Park et al. Hepatology 2019; 69: 1032-45. This study, using Truven Health MarketScan Cata, examined the outcomes of more than 26,000 patients with newly-diagnosed hepatitis C virus (HCV) infection.  Among the 30% who received oral direct-acting antiviral (DAA) therapy, there were improved outcomes in those with and without cirrhosis. In those with cirrhosis (n=2157), DAA was associated with a 72% and 62% lower incidences of HCC and DCC [decompensated cirrhosis] respectively. In noncirrhotic HCV patients (n=23,948), DAA was associated with a 57% and 58% lower incidence of HCC and DCC respectively.  In addition to improved health outcomes, DAA treatment resulted in decrease health care costs, especially for patients with cirrhosis.

Z Kuloglu et al. JPGN 2019; 68: 371-6.  In this multicenter Turkish study, the authors identified 810 children (median age 5.6 years) with unexplained transaminase elevation (62%),unexplained organomegaly (45%), obesity-unrelated liver steatosis (26%) and cryptogenic fibrosis or cirrhosis (6%).  LAL-D [lysosomal acid lipase deficiency] activity was deficient in 2 siblings (0.2%); both had LDL ~155.  Overall, even in at risk groups, LAL-D is rare.

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Joshua Tree National Park