Tag Archives: inflammatory bowel disease

Vitamin D and IBD, More Data

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Another large study (Kabbani TA, et al. Am J Gastroenterol. 2016;doi:10.1038/ajg.2016.53) links low vitamin D status with worse outcomes in IBD.

An excerpt from summary from HealioGastro: (Low vitamin D linked to higher morbidity, disease severity in IBD)

Binion and colleagues identified 965 IBD patients (61.9% Crohn’s disease; 38.1% ulcerative colitis; 52.3% women; mean age, 44 years) with up to 5 years of follow-up data in University of Pittsburgh Medical Center’s longitudinal IBD natural history registry…

At enrollment, 8.9% of patients were vitamin D deficient and 33.1% had vitamin D insufficiency vs. 4.9% and 23.6%, respectively, at the conclusion of the study period. Among patients who received vitamin D supplements, 67.9% achieved normal levels by the end of the study…

Overall, patients with low vitamin D levels required significantly more steroids, biologics, narcotics, computed tomography scans, emergency department visits, hospital admissions and surgeries compared with those who had normal mean vitamin D levels (P < .05). They also had worse pain, disease activity scores and quality of life (P < .05).

“More importantly, correction of vitamin D deficiency was associated with overall improvement in clinical status,” Binion said.

My take: Vitamin D levels are often low when patients are acutely ill and can improve without supplements in many; this accounts for some of the association with worsened outcomes.  True vitamin D deficiency and insufficiency does have negative physiologic effects and should be treated.

Related blog posts:

Gibbs Gardens

Gibbs Gardens

 

Get Here If You Can: Improved Vitamin D Status

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“I don’t care how you get here
Just get here if you can”

–Oleta Adams, “Get Here”

A recent study (Kugathasan et al. JPGN 2016; 62: 252-8) reminded me of the aforementioned song lyrics. (Full lyrics: Get Here)

This randomized pilot study comparing two regimens for low Vitamin D levels (serum 25-OH Vit D <30 ng/mL). During a treatment period of 6 weeks, patients were randomized to treatment with Vitamin D3 (cholecalciferol) at 10,000 units or to 5,000 units per 10 kg per week.  The maximum weekly dose in the first group was 50,000 units (IU) and the maximum dose in the latter group was 25,000 IU.

Both treatments were associated with improvement; in the higher dose group the mean serum level reached 49.2 whereas it was 41.5 in the lower dose group.  Of note, this repletion effect was nearly lost by the 12-week followup.

Other points:

  • This study used Vitamin D3 (cholecalciferol) which has greater bioavailability than Vitamin D2 (ergocalciferol).
  • No serious adverse effects were noted.  The study monitored Calcium, and parathyroid hormone concentrations.
  • The authors did not report any correlation with CRP values.   This is important because other studies (Why Adding Vitamin D May Not Help IBD | gutsandgrowth)
    have shown improvement in Vitamin D levels without vitamin D supplementation when underlying inflammation has been treated.

My take: This study shows that supplementation with Vitamin D is associated with improved levels  –one can ‘get here’ with either regimen the authors studied.  In those with low levels (not due to inflammation), it is likely that maintenance Vitamin D supplementation will be needed.

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Michigan Union, Ann Arbor

Michigan Union, Ann Arbor

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.

CCFA Conference Notes 2016 (part 4) –Pregnancy and IBD

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Pregnancy and IBD –Dr. Doug Wolf

Dr. Wolf reviewed infertility, pregnancy issues, and PIANO registry. This topic has been covered elsewhere in this blog (IBD and Pregnancy | gutsandgrowth). Vedolizumab is a FDA category B; thus far, it is considered fairly safe. Thiopurines are category D but overall thought to be low risk.

This blog entry has abbreviated/summarized this terrific presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

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IBD and Pregnancy

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While managing inflammatory bowel disease during pregnancy is not within the scope of my practice as a pediatric gastroenterologist, it is helpful to have some familiarity with the issues.

Here’s a full-text link to AGA Guidelines: The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

From the abstract, an excerpt:

Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti–tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohn’s disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy.

Gastro March2016

More on Hidradenitis Suppurativa and Inflammatory Bowel Disease

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In a population-based inception cohort study (S Yada et al. Clin Gastroenterol Hepatol 2016; 14: 65-70) of 679 patients with inflammatory bowel disease (IBD) followed for a median of more than 19.8 years, it was determined that patients with IBD were ~9 times more likely to develop hidradenitis suppurativa (HS) compared with general population. 8 of 679 patients developed HS; only one had HS prior to IBD.

Other findings:

  • Most Crohn’s disease patients with HS had perianal disease.  Most ulcerative colitis patients developed HS after colectomy.
  • Female sex and obesity were risk factors for HS.

In a second retrospective study (N Kamal et al. Clin Gastroenterol Hepatol 2016; 14: 71-9), the authors identified 15 patients with CD and HS.  10 patients had perianal disease.  In this population, “both diseases were characterized by their severity, requirement of systemic medical therapies including anti-TNF and high operative rate.” this article contained some very helpful pictures.

Unrelated article: F Wang, JL Kaplan, BD Gold et al. Cell Reports; 2016: 14: 945-55.  This highly technical study used two independent cohorts of patients with Crohn’s disease and non-IBD controls.  One cohort, RISK, had over 700 patients and ~30,000 mean number of reads per sample; the other cohort, PIBD-CC, and 87 patients and ~3000 mean number of reads per sample.  Overall, the study showed associations between Crohn’s disease and bacteria in the lumen and the study helps provide an information-based method to depict dysbiosis.

Related blog post: Add it to the list

San Juan

San Juan

Guts and Valentines?

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I learned this week that the Crohn’s & Colitis Foundation of America (CCFA) was founded in part  based on a love story:

From CCFA: Irwin M. Rosenthal, one of the visionary co–founders of CCFA, and Suzanne were due to be married in a few months time when suddenly Suzanne became very ill. Motivated by her struggle with Crohn’s disease, Irwin, along with William and Shelby Modell, and Dr. Henry D. Janowitz, established the Foundation for Research in Ileitis, now known as the Crohn’s & Colitis Foundation of America.

To send an CCFA eValentine: CCFA Valentine E-card

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Value of Calprotectin

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A large study (WJ Sandborn et al Gastroenterol 2016; 150: 96-102) focuses on the question of how well calprotectin values correlate with clinical outcomes.  As part of a double-blind, placebo-controlled phase 2 trial of 194 patients who received various doses of tofacitinib or placebo, the authors obtained data on fecal calprotectin (FCP).  Here were the key findings:

  • Week 8 FCP levels were significantly lower in those with a clinical response: 156 vs 725 mg/kg, in clinical remission: 64 vs 617 mg/kg, in endoscopic remission: 44 vs 489 mg/kg and in mucosal healing: 127 vs. 753 mg/kg.
  • On an individual level, FCP showed only moderate agreement for these measures.

For clinical remission, FCP concentration:

  • At 50 mg/kg, the specificity was 0.91, sensitivity was 0.43
  • At 150 mg/kg, the specificity was 0.79, sensitivity was 0.68

For endoscopic remission, FCP concentration:

  • At 50 mg/kg, the specificity was 0.88, sensitivity was 0.52
  • At 150 mg/kg, the specificity was 0.75, sensitivity was 0.79

For mucosal healing, FCP concentration:

  • At 50 mg/kg, the specificity was 0.92, sensitivity was 0.29
  • At 150 mg/kg, the specificity was 0.85, sensitivity was 0.54

The authors speculate that the only fair to good accuracy of FCP in classifying clinical and endoscopic outcomes of individual patients could be related to day-to-day variability in FCP levels and due to residual microscopic inflammation.

My take: While a single normal calprotectin value is not entirely reassuring, I would not be surprised if these values outperform the PGA (physician global assessment).  It is likely that serial calprotectin values will be helpful in tracking clinical progress.

In brief:

Agardh et al. JPGN 2016; 62: 43-46.  Authors show that fecal calprotectin levels were markedly elevated (median 844 mg/kg) in 11 of 12 patients with juvenile polyps and that these levels normalized after polypectomy.  These levels were similar to their cohort (n=129) of children with active IBD (median values of 962 mg/kg).

Heida et al. JPGN 2016; 62: 47-49.  The investigators retrospectively examined 80 children who had endoscopy due to suspected inflammatory bowel disease.  In all 10 of the children with calprotectin levels less than 50 (mcg/g), IBD was excluded.

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Old Town, San Juan

Old Town, San Juan

Characteristics of Skin Lesions Associated with Anti-Tumor Necrosis Factor Therapy

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As noted in previous blog posts (see below), anti-tumor necrosis factor (anti-TNF) therapy has been associated with skin problems.  The following study/abstract elaborate on this issue further and indicate that while ~30% of patients with IBD may develop skin reactions, only 28 of 917 (3%) patients required anti-TNF therapy to be discontinued due to skin reactions.

I Cleynen et al. Ann Intern Med. Published online 8 December 2015 doi:10.7326/M15-0729  Characteristics of Skin Lesions Associated With Anti–Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study ONLINE FIRST

 Background: A subgroup of patients with inflammatory bowel disease (IBD) treated with anti–tumor necrosis factor (TNF) antibodies develop skin lesions, but the lesions and their clinical course are not well-characterized.

Objective: To describe patients treated with anti-TNF antibodies who did and did not develop skin lesions.

Design: Retrospective cohort.

Setting: Single IBD tertiary referral center.

Patients: 917 consecutive patients with IBD who initiated anti-TNF therapy.

Measurements: Skin lesions, patient demographic characteristics, treatments, clinical course, and serologic and genetic markers.

Results: During a median follow-up of 3.5 years (interquartile range [IQR], 0.5 to 7.4 years), skin lesions associated with the use of anti-TNF therapy developed in 264 of 917 (29%) patients (psoriasiform eczema, 30.6%; eczema, 23.5%; xerosis cutis, 10.6%; palmoplantar pustulosis, 5.3%; psoriasis, 3.8%; other, 26.1%). Lesions typically developed at flexural regions, genitalia, and the scalp, especially the psoriasiform lesions. Thirty-one percent of women and 26% of men developed lesions. Median cumulative doses (2864 mg/y [IQR, 2203 to 3819 mg/y] and 2927 mg/y [IQR, 2377 to 3667 mg/y]) and trough levels (4.2 µg/mL [IQR, 2.6 to 5.8 µg/mL] and 4.0 µg/mL [IQR, 1.6 to 5.9 µg/mL]) of infliximab were similar in patients with and without lesions. All but 28 patients (11%) were successfully managed without needing to stop therapy because of lesions.

Limitation: Retrospective nature and no matched control group of patients not receiving anti-TNF therapy.

Conclusion: Skin lesions occur frequently in association with anti-TNF therapy but rarely require discontinuation of therapy. Close surveillance and early referral to a dedicated dermatologist are recommended.

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Should Methotrexate Be Used For Ulcerative Colitis?

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A recent study (F Carbonnel et al. Gastroenterol http://dx.doi.org/10.1053/j.gastro.2015.10.050, article in press; thanks to KT Park twitter feed for reference) with 111 patients provides more questions than answers.  It appears that methotrexate improved clinical remission but the overall difference is fairly small; the abstract is below.

My initial impression: Immunomodulators (including methotrexate and thiopurines) have some efficacy as monotherapy agents in patients with inflammatory bowel disease. Their role as part of combination therapy (with anti-TNF agents) has been associated with improved outcomes but how long to use combination therapy and at what dosage is still being worked out.

Here’s the abstract and a link: Methotrexate is not Superior to Placebo in Inducing Steroid-free Remission, but Induces Steroid-free Clinical Remission in a Larger Proportion of Patients with Ulcerative Colitis

Background & Aims

Parenteral methotrexate is an effective treatment for patients with Crohn’s disease but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC.

Methods

We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/week) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe, from 2007 through 2013. Patients were given prednisone (10 to 40 mg/day) when the study began, and randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary endpoint was steroid-free remission (defined as a Mayo score ≤ 2 with no item > 1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤ 2 with no item > 1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24.

Results

Steroid-free remission at week 16 was achieved by 19/60 patients given methotrexate (31.7%) and 10/51 patients given placebo (19.6%)—a difference of 12.1% (95% confidence interval [CI], –4.0% to 28.1%; P=.15). The proportions of patients in steroid-free clinical remission at week 16 were 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI, 1.1%–35.2%; P=.04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group—a difference of 9.5% (95% CI, –7.5% to 26.5%; P=.28). No differences were observed in other secondary endpoints. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P=.03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P=.006).

Conclusions

In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC.

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Banning Mills

Banning Mills

Optimism for New Treatment in Inflammatory Bowel Disease: AJM300

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Yesterday’s post on “Eternal Nutrition” had a link to podcasts on enteral nutrition as therapy for Crohn’s disease.  I listened to the podcasts and they were helpful (Enteral Therapy as Primary Therapy for Crohn’s Disease Podcast).  A few points that were made included the following:

  1. Try to have the right person teach/place the nasogastric feeding tube.  If the first experience is bad, this may make further attempts quite difficult.  At CHOP, their facility has an education center and they schedule 3-hour learning session for enteral feeds.  Teaching the teen to place the NG tube is preferred.
  2. Many pediatric gastroenterologists in U.S. are not informing their patients that enteral feedings are a treatment option.
  3. In most parts of the world, induction with enteral nutrition involves virtually 100% of diet as enteral nutrition for ~8-12 weeks.  CHOP modification involves 80-90% of calories delivered enterally, typically over an overnight drip.  If someone is not responding to enteral feeds, CHOP may increase calories delivered enterally.
  4. For maintenance with CHOP modification, gradually reduction from 7 days per week to 5 days per week is attempted.  At CHOP, they prefer hydrolysate for enteral tube feedings and think more rapid gastric emptying could be helpful.  However, the podcast state that specific formulas have not been shown to be superior in trials to date.  At CHOP, if formula is taken orally, then an intact protein formula is selected.
  5. If someone uses enteral formula for maintenance, then consideration of a gastrostomy tube (after 3 months) is reasonable.  They have not had local issues at sites due to Crohn’s disease.
  6. Resources include the Oley.org website and the Crohn’s Survival Guide.
  7. Enteral therapy seems to work in small bowel as well as colonic disease, despite early reports suggesting less efficacy with colonic disease.

———————

A recent phase II study (N Yoshimura et al. Gastroenterol 2015; 149: 1775-83) indicates that an oral antagonist of α4 integrin may be quite useful for ulcerative colitis.

This double-blind, placebo-controlled trial with 102 patients found the following:

  • A clinical response rate at 8 weeks of 62.7% in the treatment group and 25.5% for placebo)
  • Rates of remission were 23.5% in the treatment group  compared with 3.9% in the placebo group.
  • Mucosal healing were 58.8%% in the treatment group  compared with 29.4% in the placebo group.
  • No serious adverse events were noted.

In the commentary by  BG Levesque and S Ghosh (pg 1669-72), it is noted that subsequent oral integrins will be compared to vedolizumab and similar safety concerns exist; that is making sure that there are no cases of progressive multifocal leukoencephalopathy (PML) which has been associated with natalizumab therapy.  For vedolizumab, the RAMP safety monitoring program has NOT identified PML in 2884 IBD patients.

The commentary (in blue) discusses several integrins as potential therapeutic targets and outlines future therapies.

Nontargeted therapies:

  • A) Induction: corticosteroids, 5- aminosalicylates, cyclosporin, and tacrolimus
  • B) Maintenance: thiopurines, methotrexate, 5-aminosalicylates, and tacrolimus.

Targeted therapies (those in development phase in italics)

  • A) Monoclonal antibodies (induction and maintenance): tumor necrosis factor inhibitors, vedolizumab, other integrin/adhesion molecule inhibitors, interleukin-12/23 inhibitors, and interleukin-6 inhibitors.
  • B) Oral synthetic (induction and maintenance or stop and start): Jakinibs, integrin blockers, sphingosine-1-phosphate (s1P) regulators, and SMAD7 antisense oligonucleotide.

“The results of AJM300 demonstrate feasibility of such an approach, and we anticipate a proliferation of such approaches given the robust evidence supporting integrins as a target, especially if the drug can be targeted or delivered in a gut-specific manner.”

My take: There are a number of therapies being developed that are likely to transform the treatment of inflammatory bowel disease; future treatments will be more precise, more effective and have many more options.

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Banning Mills

Banning Mills