Category Archives: inflammatory bowel disease

Why the Genetics of Inflammatory Bowel Diseases Matter Now

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A terrific update on the genetics of inflammatory bowel diseases (DPB McGovern, S Kugathasan, JH Cho. Gastroenterol 2015; 149: 1163-76) explains why and how this information matters right now.  The article is a little difficult to read due to its review of highly technical material.

Here’s what I think were the key points:

  • Big advances in understanding the genetics started with the first genome-wide association studies (GWAS) using genome-wide single nucleotide polymorphisms (SNP) chips in 2005.  “The conceptual basis of GWAS is that most complex (ie, not single-gene Mendelian) genetic disorders are polygenic, being driven by multiple common genetic polymorphisms.”
  • “Early GWAS identified the most significant loci.”  Now, more than 200 loci associated with IBD have been identified with GWAS and Immunochip data. Table 1 lists these loci over 4 pages.  About 2/3rds of these are associated with Crohn’s disease (CD) and ulcerative colitis (UC) whereas the remaining 1/3rd are unique to either CD or UC.
  • These loci provide insight into disease mechanisms. NOD2 mutations result in “impaired activation of NF-κB” This supported “the general concept that deficiencies of innate immune cell function represent a central factor in Crohn’s disease, distinguishing it from ulcerative colitis.”
  • ATG16L1 gene mutation “establish the fact that the CD risk allele is correlated with impaired autophagy.”  This is leading directly into treatment efforts.
  • IL23R.  “The most significant association is Arg381Gln…confers a 2- to 3-fold protection against development of IBD.”  The protective effect is thought to be due to “decreased numbers of interleukin (IL)-23 dependent CD4+ Th17 and CD8+ Tc17 cells…decreasing IL-23 signaling, such as through monoclonal antibody blockade of anti-p40 or anit-p19 may be beneficial.”
  • FUT2 mutations.  These mutations affect the mucus layer in Crohn’s disease.
  • Studies in non-Caucasians highlight other susceptibility regions.
  • “Currently, sequencing of the whole exome has become not only a practical method but also a cost-effective option to identify functionally relevant variants in the protein encoding regions of the genome.”

Very Early Onset IBD:

  • Whole exome sequencing (WES) identified XIAP (X-linked inhibitor of apoptosis) in a case of boy with very early onset (VEO) IBD.  XIAP is a positive regulator of NOD2 function.  WES has also identified FOXP3, and IL10RB genes.
  • “The VEO group experiences a more severe disease course and more frequently shows a positive family history for IBD in support of higher genetic load.”  Table 2 lists ~40 genes associated with VEO.  These genes are involved in epithelial barrier function, neutropenia/defects in phagocyte function, hype-and autoinflammation, and  regulatory T cells and immune regulation.

Genetic Testing Will Impact Current Therapies and Help Explain Extraintestinal Manifestations:

  • Currently testing for TPMT variations is recommended prior to use of thiopurines due to concerns of toxicity in individuals with decreased metabolism of these medications.  However, genetic testing can identify other individuals with propensity to leukopenia (eg. NUDT15 polymorphism) and those with increase risk for pancreatitis (eg. HAL-DQA1-HLA-DRB1)
  • Primary Sclerosing Cholangitis (PSC) is associated with numerous genetic loci as well. PSC “genetically is more similar to UC than to CD.” Most other extraintestinal manifestation studies have been underpowered.
  • IBD share more genetic similarity to spondyloarthropathy (SpA) than any other immune-mediated diseases.  “The vast majority of shared susceptibility loci are concordant between IBD and SpA.”
  • With regard to psoriasis, the genetic relationship to IBD is complex.  Anti-TNF agents can cause psoriaform lesions in IBD patients.  In addition, anti-IL17a therapy, “so successful in psoriasis, appears to worsen Crohn’s disease” but not in those with a TNFSF15 variant.  Specific genotyping may help identify which patients with CD are susceptible to psoriaform lesions and those who may improve with therapy typically given for psoriasis.

My take: This article shows how understanding genetics of IBD is providing insight into pathophysiology and more personalized treatment approaches.

Briefly noted: EM Stoffel, CR Boland. Gastroenterol 2015; 149: 1191-1203. Excellent review of the genetics and genetic testing for Hereditary Colorectal Cancer.  The review includes polyposis syndromes and Lynch syndrome.

Atlanta Botanical Gardens

Atlanta Botanical Gardens

Single High-Dose Oral Vitamin D Therapy (Stoss) for Children with Inflammatory Bowel Disease

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A retrospective study (D Shepherd et al. JPGN 2015; 61: 411-14) shows that a single high-dose oral vitamin D3 therapy can be effective for 6 months.  This study involved treatment of 76 children between 2006-2010.

Stoss vitamin D dosing used in this study:

  • < 3 yrs 200,000 IU
  • 3-12 yrs 400,000 IU
  • >12 800,000 IU

Followup levels of Vitamin D (25-OH) and calcium were checked at 1 week, 4 weeks, 3 months and 6 months..

Key finding:

  • 25-OHD >50 nmol/L (=20 ng/mL) was seen in 96.6% at 3 months and 76.4% at 6 months.  63% had a level >75 nmol/L (=30 ng/mL) at 1 month.

Bottomline: Authors noted: “Stoss therapy safely and effectively achieved and maintained a level of 25OHD > 50 nmol/L during 6 months in these children with IBD.”

Related blog posts:

Atlanta Botanical Gardens

Atlanta Botanical Gardens

Be Aggressive! Treating Anemia Associated with Inflammatory Bowel Disease

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A number of recent publications have made the point that anemia is a biomarker for severe inflammatory bowel disease and undertreatment affects quality of life. Reading one of the more recent studies (IE Koutroubakis et al. Clin Gastroenterol Hepatol 2015; 13: 1760-66) brought to mind the high school football cheer: Be Aggressive!

This particular retrospective study involved 410 patients (245 with Crohn’s disease, 165 with ulcerative colitis) from 2009-2013.  This study is from the same group that published data on a somewhat smaller cohort and showed that IBD treatment alone often will not resolve anemia (Koutroubakis, IE et al. Inflamm Bowel Dis 2015; 21: 1587-93–see previous blog links).

Key findings:

  • Prevalence of anemia: 37.2% in 2009 and 33.2% in 2013
  • Anemia was associated with increased hospitalizations (P<.01), clinic visits (P<.001), telephone calls (P<.004), surgeries for IBD (P=.001), and lower quality of life scores (P<.03)

The associated editorial (pgs 1767-69) suggests that IBD-related anemia, if mild (w/in 1 g/L below normal) to treat with oral iron replacement and if moderate-to-severe, then to replace intravenously (using Ganzoni’s formula calculator). In addition, if anemia is not improving, looking for alternative explanations (e.g. vitamin B12 or folate deficiency) is recommended.

Ganzoni Equation: Total Iron Deficit = Weight {kg} x (Target Hb – Actual Hb) {g/l} x 2.4 + Iron stores {mg}.   Iron stores: { 500 if W > 35kg } & { 15 mg/kg if W < 35kg }

My take: Anemia is a biomarker for severe disease.  While treating the underlying inflammatory bowel disease, don’t forget to make sure the patient’s anemia is addressed.

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.

Central Park

Central Park

Should All Pediatric Patients with Crohn’s Disease Continue Combination Therapy?

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Among patients/families who are not in denial about their inflammatory bowel disease, especially Crohn’s disease, an important discussion is the use of combination therapy.  This has been discussed on this blog before (see some links below).  More data on this subject has been published and again favors the use of combination therapy (V Grossi, T Lerer, et al. Clin Gastroenterol Hepatol 2015; 13: 1748-56).

This study collected data from 2002-2014 on 502 children who participated in a prospective multicenter study. This data was derived from an observational registry rather than a randomized trial, but likely reflects real-world experience with regard to newly diagnosed patients. The authors excluded those with prior biologic therapy and prior resectional surgery.

KEY FINDINGS:

  • Children receiving combination immunomodulator (IM) treatment were more likely to have durable infliximab therapy at 1 year, 3 years, and 5 years.
  • Greater length of concomitant IMs was associated with better durability.
  • For patients who had IM > 6 months after starting infliximab (n=194), durability was 0.70 at 5 years compared with 0.55 for patients with IM <6 months (n=144), and 0.48 for those who did not receive IMs (n=135).
  • In boys, methotrexate appeared to be superior to thiopurines (P<.01): 0.98 at 5 yrs compared with 0.58.  However, there were 60 males receiving methotrexate.  In the study, only 21 females received methotrexate which limited any conclusions.

Among patients who stopped IFX, the reasons included loss of response (n=61, 43%), hypersensitivity reaction (n=41, 29%), elective (n=25, 18%), lost to f/u (n=5, 3%), and other causes (10, 7%).

The “right” dose of methotrexate as a combination agent remains unclear.  There was a wide range of dosing schedules in this study.  It is worth observing that the COMMIT study in adults found no significant difference in adults who received methotrexate in addition to infliximab compared with those receiving infliximab monotherapy.

Take-home message: In this large pediatric observational study, the use of immunomodulators increased the likely durability of infliximab.  Given prior conflicting data (particularly with regard to methotrexate), even more studies are needed to determine exactly how useful combination therapy is and when monotherapy will suffice.  From my viewpoint, I worry much more about loss of efficacy to infliximab than I worry about medication adverse effects.  As such, I will continue to inform families that combination therapy appears to improve infliximab durability.

Related blog posts:

Mount Washburn, Yellowstone

Mount Washburn, Yellowstone

ER Evaluations of Visits Related to Inflammatory Bowel Disease

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A short communication (C Pant et al. JPGN 2015; 61: 282-84, ed 267-8) provides some insight into what is happening in the ER when patient with inflammatory bowel disease are evaluated.

The authors analyzed a national database, the Healthcare Cost and Utilizationa Porject Nationwide Emergency Department Sample (NEDS), from 2006-2010.

Key findings:

  • ED visits for children 5-19 years of age increased from 14,527 (2006) –>18,193 (2010)
  • Frequency of computerized tomography (CT) imaging increased 80.43% (P<0.01) for Crohn’s disease and 59.26% (P<0.01) for ulcerative colitis
  • Overall rate of hospital admissions decreased by 14.32% (P<0.01)

The associated editorial by Jennifer Dotson and Michael Kappelman explain the limitations of relying on data that are derived mainly for billing rather than research and comment on the “alarming increase” in CT  usage due to the risk of radiation exposure and the potential alternatives (eg. ultrasound, MRE).  With regard to limitations, they likely included inaccurate and incomplete entries.  In addition, the database included 950 hospitals, but may have under-sampled large freestanding children’s hospitals.  This could skew the data.  Finally, the data uses “visit-level” data rather than “patient-level” data; thus, one ‘cannot distinguish between a single patient who is seen on three separate visits or three unique patients.’

My take:  There has been increasing use of ER visits and CT scanning for pediatric patients with IBD.  One of my colleagues in town (Cary Sauer) has a humorous slide of a CT scanner as the entrance door to the ER.  The message from this study indicates that we should be working on changing practice by working with our ER colleagues along with radiologists to minimize CT scans in favor of more gently imaging.

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Atlanta Botanical Gardens, Bruce Munro exhibit

Atlanta Botanical Gardens, Bruce Munro exhibit

Desperate Measures in Refractory IBD

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The often cited, ‘desperate times call for desperate measures,’ resonates in the setting of refractory inflammatory bowel disease (IBD).  [Of course, this saying could be used to justify about anything you want to do.]  For IBD, two recent studies point out potential remedies:

  • SA Merkley, et al. Inflamm Bowel Dis 2015; 21: 1854-59.
  • M Lazzerini, et al. Inflamm Bowel Dis 2015; 21: 1739-49, with editorial by A Bousvaros (1750-51)

In the first study, the authors retrospectively analyzed date from 24 IBD patients who were treated with intravenous immunoglobulin (IVIG) at a dose of 0.4 g/kg/day for 3 days, then 0.4 g/kg once a month. Key findings: 16 (67%) had a response and 3 (12.5%) obtained remission. Measures of improvement included CRP, ESR, Simple Endoscopic Score for Crohn’s disease, and the Harvery-Bradshaw Index. The researchers speculate that IVIG has anti-inflammatory and immunomodulator effects.  In addition, they note that IVIG can be given with concurrent infections.

In the second study, the authors studied thalidomide(1.5-2.5 mg/kg/day) in a double-blind, placebo-controlled randomized pediatric clinical trial in children with refractory active ulcerative colitis. Key findings: at week 8, clinical remission was achieved in 10/12 (83%) of thalidomide arm compared with 2/11 (19%) of control patients.  Then, among control patients who were switched, 8 of 11 (72%) reached remission as well. Peripheral neuropathy and amenorrhea were reported adverse effects. In the accompanying editorial, Dr. Bousvaros notes that there has been some data to suggest thalidomide efficacy in ulcerative colitis since 1979.  However, due to widespread bad publicity related to thalidomide-induced teratogenicity (eg. phocomelia) and side effects including neuropathy, it has not been used with much frequency. He notes that this study, as well, requires replication and speculates that “the primary focus on drug development will focus on newer small molecules and biologics, and this potentially useful medication may be left on the sidelines.” It is worth noting that the authors response (pg 1752) to this editorial was that the stigma of thalidomide is unwarranted and that teratogenicity can be avoided. “No case was observed out of 124,000 patients enrolled in the thalidomide distribution risk management program for more than 6 years.”

Bottomline: Both thalidomide and IVIG may be beneficial to desperate patients (and desperate doctors).  While small trials appear promising, larger trials are needed.  Don’t hold your breath waiting … will they ever happen?

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Another Look at “Step-up” IBD Therapy

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Whether and how long to continue immunomodulators in patients who have undergone a “step-up” treatment to anti-tumor necrosis factor (anti-TNF) therapy remains murky.  This is due to conflicting data from different patient cohorts, changing treatment trends, (e.g. use of drug monitoring to enhance anti-TNF therapy), and different endpoints. With regard to the latter, dual therapy has been clearly more effective in some landmark studies (eg. SONIC, UC SUCCESS); however, there have been ongoing concerns regarding long-term outcomes and adverse effects.

Will more studies help resolve this question? Perhaps, but not today.

A recent study (MT Osterman et al. Clin Gastroenterol Hepatol 2015; 13: 1293-1301) examined a retrospective cohort of new users of anti-TNF therapy for Crohn’s disease in Medicare recipients.  The authors matched 381 combination with infliximab (ie. dual therapy) with 912 users of monotherapy. In addition, the authors did the same with adalimumab with 196 combination users and 505 monotherapy users. In their cohort, combination therapy occurred primarily as a “step-up” treatment after institution of thiopurine therapy.

Results:

  • Key outcome measures were unchanged: rates of surgery (hazard ratio [HR] 1.2, hospitalization HR 0.82, discontinuation of anti-TNF therapy or surgery HR 1.09, and serious infection HR 0.93
  • Opportunistic infections were increased in combination therapy with HR 2.64 and herpes zoster infection was increased with HR 3.16

Take-home message: This study suggests, at least in this elderly population, that once remission is achieved with anti-TNF therapy, discontinuation of thiopurine therapy or use of an alternative immunomodulator therapy may be worthwhile.  At the same time, definitive answers to these type of questions await carefully designed randomized trials.

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1000th Tweet: GI Symptoms Preceding IBD Diagnosis

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Another milestone for this blog: since 2012, the blog has been publicized on twitter; this is the 1000th tweet. It is also 1314th blog post over nearly 4 years.

A recent study (H Singh et al. Clin Gastroenterol Hepatol 2015; 13: 1302-09) indicates that children with inflammatory bowel disease (IBD) were more likely to have gastrointestinal symptoms in each of the 4 years before the diagnosis of IBD than children without IBD.

In this study, the researchers identified all children with IBD from a population-based Manitoba database; Manitoba had a population of 1.27 million in 2012.  651 children were matched with 5950 controls without IBD.  The study’s Table 1 & 2 indicates that children with IBD had increased clinic visits prior to diagnosis:

  • 54-66 months prior: standardized rate ratio for number of ambulatory visits 1.15; & for ≥1 visit due to GI symptoms odds ratio 1.44
  • 42-54 months prior: standardized rate ratio for number of ambulatory visits  1.22; & for ≥1 visit due to GI symptoms odds ratio 2.05
  • 30-42 months prior: standardized rate ratiofor number of ambulatory visits 1.19; & for ≥1 visit due to GI symptoms odds ratio 2.16
  • 18-30 months prior: standardized rate ratio for number of ambulatory visits 1.23; & for ≥1 visit due to GI symptoms odds ratio 2.93
  • 6-18 months prior: standardized rate ratio for number of ambulatory visits  1.15; & for ≥1 visit due to GI symptoms odds ratio 5.23

There was not a clear trend in increased symptoms between those who developed Crohn’s disease compared with Ulcerative Colitis. In addition, the study noted a trend towards decreased colectomy and resective surgery in Crohn’s in the time period 2002-2010 compared with 1987-2001.  One limitation of this study is the few number of pediatric gastroenterologists in Manitoba (only 1 before 2003); the lack of pediatric gastroenterology availability could impact timely diagnosis.

My take: This data shows that GI symptoms still predate diagnosis in many children and indicate a potential for diagnosis delay. The authors note that noninvasive tools like stool calprotectin have not been widely adopted (at least in Manitoba) and could be helpful in reducing diagnostic delays.

Estes Park, Colorado

Estes Park, Colorado

Higher Stool Infliximab Correlates with Poor Response in Severe Ulcerative Colitis

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A recent study (full text link: “Loss of Infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis” Gastroenterol 2015; 149; 350-55.e2) provides information about patients with ulcerative colitis who do not respond well to infliximab therapy.

In this study, the authors obtained fecal samples from 30 consecutive patients with moderate to severe UC during the 1st 2 weeks of therapy.  In addition, they obtained serum infliximab levels as well as assessed clinical and endoscopic response at 2 weeks, 8 weeks, and 3 months after treatment began.

Key findings:

  • Fecal infliximab was detected in 129 of 195 (66%) samples.  The greatest loss was observed approximately 2 days after infusion. Low serum albumin was associated with greater infliximab levels in the stool.
  • Clinical nonresponders at week 2 had significantly higher fecal infliximab
  • The authors did not observe a correlation between fecal and serum infliximab concentrations.  However, it is possible that stool losses could indicate lower mucosal concentrations of infliximab.
From AGA twitter account

From AGA twitter account

From AGA twitter account

From AGA twitter account

From AGA twitter feed

From AGA twitter feed

Bottomline: It is not clear whether stool losses of infliximab directly contribute to drug failure or whether the loss is another biomarker of disease activity/high-risk patients.

The study authors note that “intestinal loss of IFX in moderate to severely active UC is associated with a diminished response to this treatment.  Patients with severe disease can, therefore, benefit from more intensive dosing regiments. This strategy warrants a prospective clinical trial.”

Related blog posts:

Head-to-Head: Nutritional Therapy versus Biological Therapy in Pediatric Crohn’s Disease

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The best data to date: D Lee et al. Inflamm Bowel Dis 2015; 21: 1786-93. In this prospective study, the authors studied treatment initiation in children (N=90), comparing partial enteral nutrition (PEN, n=16), exclusive enteral nutrition (EEN, n=22), and anti-TNF therapy (n=52).

Results:

  • Clinical response, defined by PCDAI reduction ≤15 or final PCDAI ≤10, was achieved by 64% PEN, 88% EEN, and 84% anti-TNF.
  • Fecal calprotectin ≤250 noted in 14% PEN, 45% EEN, and 62% anti-TNF

Because of the discrepancy between EEN and PEN, the authors speculate that the “efficacy of EEN may be a consequence of elimination of table food rather than providing a uniquely therapeutic method of delivering nutrients.”  They note that “choice of formula has not impacted the efficacy of enteral nutrition.”

More extensive information on this subject: D Lee et al. Gastroenterol 2015; 148: 1087-1106.

Bottomline: Anti-TNF therapy was as effective or more effective than EEN. And, “for patients who prefer treatment with a nutrition-based therapy, EEN seems superior to PEN.”

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Street Art, NYC

Street Art, NYC