Category Archives: inflammatory bowel disease

Spice It Up? Curcumin for Ulcerative Colitis

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This past week I’ve been on call and had not finished a few articles.  One article that was on the to do list: A Lang et al. Clinical Gastroenter Hepatol 2015; 13: 1444-9.

I’ve read it now.  However, even before finishing the article, I read a few good summaries of this article, including one from my colleague Stan Cohen/Nutrition4Kids: Curcumin Helps (A Lot) in Ulcerative Colitis

Here’s an excerpt:

The cover of a prestigious medical journal shows a pile of curcumin and over it, the announcement reads: Curcumin Helps Induce Remission in Mild-to-Moderate Ulcerative Colitis.  That’s big news for a lot of reasons: first, this Indian spice (derived from tumeric) is inexpensive and well-tolerated; second, in a well-designed scientific study, curcumin showed that it was more effective than some medicines; and third, it showed, again, that careful trials of long-used herbs can be done with important results being shown.  Again, because an earlier study (H Hanai, Clinical Gastroenterology 2006, pages 1502-6) had previously shown that curcumin can help keep ulcerative colitis (UC) patients from flaring for up to 12 months. 

This new study (A Lang, Clinical Gastroenterology 2015, pages 1444-9) compared curcumin to a placebo in patients who were not doing well on the standard therapy (mesalamine) for mild to moderate UC.  With a single daily dose of 3 grams of curcumin in capsule form, 65% responded (compared to 12% with a placebo) and 54% actually went into remission, having essentially no symptoms.  Perhaps even, more importantly, 38% of those taking the curcumin showed improvement in the intestinal tissue when a colonoscopy was performed.  That’s comparable or better than some of the medications that are being used.

A few other details: The researchers used a product called Cur-Cure from Bara Herbs Inc (Yokneam, Israel).  Also, the associated commentary in the same journal by CN Bernstein (pages 1450-52) suggests that the study may have targeted mild ulcerative colitis (rather than moderate ulcerative colitis). He comments that the increasing rates of ulcerative colitis among Indian immigrants could be related to including less curcumin in their now more westernized diets.  He also notes, as did Dr. Cohen, that there were previous promising studies dating back to 2006.  Why has it taken nine years for this report?

My Take: This is probably an article worth reading.  Although curcumin appears promising, I worry that a lack of financial incentive may hamper research efforts to better define its place as an agent for treatment of ulcerative colitis.

Related blog posts:

Curcumin

This has been a sad week in our office.  Here are links to two poems that come to mind:

Stress and IBD Flareups

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Over the years, I’ve had several experiences in which some patients had flareups of their inflammatory bowel disease (IBD) in relation to specific stresses (eg. going to away camp).  This was not just stomach pain but instead bloody diarrhea.  While this is very infrequent, I’ve come to believe that there may be some individuals who develop IBD flareups in response to stress. A recent study (Targownik LE, et al. AJG 2015; 110, 1001-1012 | doi:10.1038/ajg.2015.147) suggests that most of the time when individuals report a flareup in response to stress, that there is not objective evidence of increased inflammation.

The Relationship Among Perceived Stress, Symptoms, and Inflammation in Persons With Inflammatory Bowel Disease

From Abstract:

METHODS:

Participants were recruited from a population-based registry of individuals with known IBD. Symptomatic disease activity was assessed using validated clinical indices: the Manitoba IBD Index (MIBDI) and Harvey Bradshaw Index (HBI) for Crohn’s disease (CD), and Powell Tuck Index (PTI) for ulcerative colitis (UC). Perceived stress was measured using Cohen’s Perceived Stress Scale (CPSS). Intestinal inflammation was determined through measurement of fecal calprotectin (FCAL), with a level exceeding 250 μg/g indicating significant inflammation. Logistic regressions were used to evaluate the association between intestinal inflammation, perceived stress, and disease activity.

RESULTS:

Of the 478 participants with completed surveys and stool samples, perceived stress was associated with symptomatic activity (MIBDI) for both CD and UC (1.07 per 1-point increase on the CPSS, 95% confidence interval (CI) 1.03–1.10 and 1.03–1.11, respectively). There was no significant association between perceived stress and intestinal inflammation for either CD or UC. Active symptoms (MIBDI ≤3) were associated with intestinal inflammation in UC (odds ratio (OR) 3.94, 95% CI 1.65–9.43), but not in CD (OR 0.98, 95% CI 0.51–1.88).

CONCLUSIONS:

Symptomatic disease activity was unrelated to intestinal inflammation in CD and only weakly associated in UC. Although there was a strong relationship between perceived stress and gastrointestinal symptoms, perceived stress was unrelated to concurrent intestinal inflammation. Longitudinal investigation is required to determine the directionality of the relationship between perceived stress, inflammation, and symptoms in IBD.

Related blog posts:

For worried hikers in Yellowstone

For worried (“stressed”) hikers in Yellowstone

Is It Right? Anti-TNF Therapy Does Not Fix IBD-Related Anemia

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A surprising study (Koutroubakis, IE et al. Inflamm Bowel Dis 2015; 21: 1587-93) of prospectively-collected data from 430 patients with inflammatory bowel disease (IBD) showed that the rate of anemia did not change after 1 year in patients treated with anti-tumor necrosis factor (anti-TNF) therapy and oral iron.

The data was derived from 2010-2012 and included 324 patients with Crohn’s disease (51.6% females) with a median age of 41 years.  Anemia was defined as hemoglobin (Hb) <13 g/dL in men and <12 g/dL in women.  Patients with Hb <10 g/dL were considered to have severe anemia. Key findings:

  • Prevalence of anemia in IBD patients treated with anti-TNF was 38.1% at baseline and then 36.6% at 1 year.
  • Severe anemia was identified in 10% at baseline and 9.9% at 1 year.
  • A hematopoietic response with a Hb ≥2 g/dL was observed in 33.6% (n=45 of 134 anemic patients) and 14 (40%) of those with severe anemia.
  • There were 45 new anemic patients at 1 year; 64.4% were nonresponders to anti-TNF treatment.
  • Using multivariate logistic regression analysis, the author noted that use of immunomodulators was associated with an odds ratio of 2.56 of improvement in hemoglobin levels.

The authors state that anemia is the most common extra intestinal manifestation of IBD and remains underappreciated.  Anemia in IBD correlates with the extent of intestinal disease and activity.

Bottomline: “Use of anti-TNF therapy had only a modest effect on patients’ Hb level.”

From related post: IBD Update January 2015 (Part 2)

Inflamm Bowel Dis 2014; 20: 2266-70.  This study with 749 patients from Sweden showed that a large number of inflammatory bowel disease patients did not receive with iron supplementation: “Only 46% of patients with anemia were treated with iron supplementation or blood transfusion.”  This study showed frequent persistence of anemia one year after diagnosis, especially in children. At time of diagnosis, 55% of children and 27% of adults had anemia and 28% and 16% at one year followup, respectively.

My take: Treatment of the underlying IBD, often helps anemia.  However, in some patients treating the anemia with iron may help improve symptoms as much or more than other aspects of treatment.

Related blog post: Microcytic Anemia Review | gutsandgrowth

Sandy Springs, Georgia

Sandy Springs, Georgia

 

Ulcerative Colitis with Questionable Response to Fecal Transplant

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Fecal microbiota transplantation (FMT) is not going to be a “magic bullet” for most patients with inflammatory bowel disease. So far, it is unclear whether FMT works at all.  A recent study (full text link: Rossen NG et al. Gastroenterol 2015; 145: 110-8) with only 37 patients echo that experience. Here is the abstract:

Background & Aims

Several case series have reported the effects of fecal microbiota transplantation (FMT) for ulcerative colitis (UC). We assessed the efficacy and safety of FMT for patients with UC in a double-blind randomized trial.

Methods

Patients with mild to moderately active UC (n = 50) were assigned to groups that underwent FMT with feces from healthy donors or were given autologous fecal microbiota (control); each transplant was administered via nasoduodenal tube at the start of the study and 3 weeks later. The study was performed at the Academic Medical Center in Amsterdam from June 2011 through May 2014.

The composite primary end point was clinical remission (simple clinical colitis activity index scores ≤2) combined with ≥1-point decrease in the Mayo endoscopic score at week 12. Secondary end points were safety and microbiota composition by phylogenetic microarray in fecal samples.

Results

Thirty-seven patients completed the primary end point assessment. In the intention-to-treat analysis, 7 of 23 patients who received fecal transplants from healthy donors (30.4%) and 5 of 25 controls (20.0%) achieved the primary end point (P = .51). In the per-protocol analysis, 7 of 17 patients who received fecal transplants from healthy donors (41.2%) and 5 of 20 controls (25.0%) achieved the primary end point (P = .29). Serious adverse events occurred in 4 patients (2 in the FMT group), but these were not considered to be related to the FMT. At 12 weeks, the microbiota of responders in the FMT group was similar to that of their healthy donors; remission was associated with proportions of Clostridium clusters IV and XIVa.

Conclusions

In this phase 2 trial, there was no statistically significant difference in clinical and endoscopic remission between patients with UC who received fecal transplants from healthy donors and those who received their own fecal microbiota, which may be due to limited numbers. However, the microbiota of responders had distinct features from that of nonresponders, warranting further study. ClinicalTrials.gov Number: NCT01650038.

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Cumberland Island

Cumberland Island

 

Will Infliximab Worsen Flare-ups Associated with Cytomegalovirus Infection?

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Another look (Pillet S, et al. Inflamm Bowel Dis 2015; 21: 1580-86) at Cytomegalovirus (CMV) infection in patients with ulcerative colitis (UC) examines 109 flareups in 73 patients who were receiving maintenance therapy with anti-TNF therapy.

This was a single-center prospective observational study.  CMV load was determined with PCR based on a pair of biopsies. DNA load was either undetectable, mild (10-250 copies/mg of tissue) or high (>250 copies/mg of tissue). 69 patients with anti-TNF therapy were compared with 40 patients receiving azathioprine. Key findings:

  • CMV reactivation was noted in 35% of anti-TNF therapy patients and 38% in azathioprine patients.
  • Among 45 patients requiring infliximab optimization, clinical remission was not significantly impacted by the presence of CMV reactivation.
  • 17 of 20 who had repeat biopsies 8 weeks later had stable or decreased CMV load.

Bottomline: This prospective, small study shows that “in patients with moderate-to-severe UC, treatment with anti-TNF mab does not increase the risk of colonic CMV infection.”  In addition, “no adverse influence of CMV colonic infection was observed in patients with flare-up treated by anti-TNF mabs.”

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.

Zoo Atlanta

Zoo Atlanta

Utility of Antiviral Therapy for Cytomegalovirus in the Setting of Inflammatory Bowel Disease

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According to a recent study (Jones A et al. Clin Gastroenterol Hepatol 2015; 13: 949-55), the tissue density of cytomegalovirus (CMV) is an important determinant of antiviral response in patients with inflammatory bowel disease (IBD).

In this case-control study, the authors identified 68 samples from 1111 patients with IBD that were found to contain CMV.  Adequate data was available for 50, including 16 with high-grade CMV (all treated) and 34 with low-grade CMV (20 treated).  High-grade CMV was defined as biopsies with 5 or more inclusions.  Treatment included ganciclovir, valganciclovir or both; 33 of 36 treated patients received at least 21 days of therapy.

Key findings:

  • Patients with high-grade CMV showed significant benefit from treatment: they had the best outcomes with “only 33% undergoing surgery by 1 year after biopsy.”
  • All patients with low-grade CMV, treated or not, were more likely to undergo surgery than those with high-grade CMV, with HR of 2.13.  However, the treated low-grade CMV had a lower risk of surgery (HR 0.39) compared with the untreated group.  73% of the untreated low-grade CMV group had undergone resection by 1 year after biopsy.

The authors note the many limitations of the study.  Requests to rule out CMV were not done uniformly but “usually reflected refractoriness of steroids or failure to respond to escalation of therapy.”

Bottomline: In those with high-grade CMV, the likelihood of responding to antiviral therapy was much higher than in patients with low-grade CMV; however, treatment in all patients with CMV inclusions was associated with improved outcomes.

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.

Bird in Flowers

Immune-Mediated Reactions to Anti-TNFs and What to Do About Them

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Statue

A recent review article (Feuerstein JD et al. Inflamm Bowel Dis 2015; 21: 1176-86) serves as a useful reference regarding immune-mediated reactions to anti-tumor necrosis factor (anti-TNF) medications used in inflammatory bowel disease (IBD).

Background:

  • All anti-TNF agents induce antidrug antibodies (ADAs).
  • With regard to infliximab (IFX) which has the most literature, it is well-recognized that combination therapy with an immunomodulator reduces the risk of antibodies to infliximab (ATIs).  For example, in the SONIC study, ATIs were noted in 0.9% of those with combination therapy compared with 14.6% of those receiving monotherapy with IFX.  With the UC-SUCCESS, the rates were 19% and 3% respectively.

Acute Infusion Reactions -Key points:

  • Acute infusion reactions (IRs) are more common in patients with ADAs.  IRs can be categorized as acute (w/in 24h) and chronic (2-14 d after infusion).
  • Acute IRs can be mild (dizziness, flushing, nausea, palpitation), moderate (chest pain, hypertension [SBP increase of more than 20], hypotension, fevers urticaria, mild dyspnea, chills, rash) or severe (severe hypertensions [SBP increase of more than 40] , severe hypotension, significant dyspnea with brochospasm, stridor, and rigors)
  • The authors provide a treatment algorithm (Figure 1) based on severity of acute IR.  All reactions are initially treated by stopping infusion, but many can be restarted at a low rate after administration of acetaminophen (mild & moderate), normal saline (mild & moderate), diphenhydramine (moderate), and possibly hydrocortisone (if needed in moderate cases).  While the algorithm suggests the possibility of restarting infusion reaction in severe cases without anaphylaxis, if this is considered, it may be worthwhile to attempt in a hospital setting.
  • Typically if infusions are restarted, the rates are 10 mL/hr x 15 minutes –>20 mL/hr x 15 minutes–> 40 mL/hr x 15 minutes –>80 mL/hr x 15 minutes –>100 mL/hr x 15 minutes–>125 mL/hr until completion.
  • Following an IR, the authors recommend checking for ATIs and for IFX level.
  • Prophylaxis for mild IRs includes the use of acetaminophen and antihistamines (2nd generation antihistamine daily for 5 days prior or first generation antihistamine an hour prior to infusion).  In addition, the infusion should be started at 10 mL/hr
  • Prophylaxis for moderate IRs includes the use of acetaminophen and antihistamines and steroids (prednisone 50 mg q12 hr x 3 doses prior or hydrocortisone 100 mg (or equivalent) 20 minutes prior to infusion).  In addition, the infusion should be started at 10 mL/hr
  • The authors recommend against premedication in those who have not had IRs. Use of premedication may cause a paradoxical increase in IRs due to symptoms induced by the antihistamine.

Autoimmune Complications:

  • Autoantibodies: anti-nuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), anti-cardiolipin antibody, antihistone antibody
  • Drug-Induced Lupus Erythematosus (DILE) -“the most frequently presenting symptoms, seen in 90% of cases, is symmetric arthralgias.”  Systemic involvement of the kidneys or central nervous system is rare. Treatment is cessation of the offending medication.
  • Vasculitis -likely due to the development of circulating immune complexes that deposits into smaller capillaries–>result in a type III hypersensitivity reaction.  The most common manifestation would be palpable purpura due to a leukocytoclastic vasculitis.
  • While autoimmune complications can be a class effect, many patients have been able to switch to a different anti-TNF.

Dermatologic Complications:

The authors review both anti-TNF induced psoriasis and eczema.  Treatment should be in conjunction with dermatology.  For psoriasis that involves >5% of body surface area, this could require changing to a different anti-TNF or a different drug class.  For severe cases, “anti-TNF therapy should be discontinued.”

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.

Sunflowers

Stopping Infliximab –What Happens Next?

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A recent retrospective single-center study (Papmichael K et al. Clin Gastroenterol Hepatol 2015; 13: 1103-10) of 100 patients with Crohn’s disease examined what happens to patients who discontinued infliximab therapy upon clinical remission.  The study used a medical database in Belgium.  The authors defined sustained clinical remission (SCR) as “maintenance of disease remission, without escalation in medical therapy or CD-related surgeries, until the end of the follow-up period, which was a median period of approximately 10 years.” 84 patients continued on immunomodulator therapy.

Key findings:

  • 52 (52%) had SCR.
  • Complete mucosal healing, lower infliximab trough concentrations, and serum positivity for vascular cell adhesion molecule-1 were factors associated with SCR.

Limitations: SCR was based on physician global assessment which may underestimate relapse rates and endoscopic data at the time of infliximab discontinuation was available in only a small subgroup.

Bottomline: In this small study, half of the patients did well clinically for a long time after stopping infliximab (most remained on immunomodulator therapy).  However, given the insidious nature of Crohn’s disease, careful monitoring before and after stopping infliximab is worthwhile.  In addition, other studies have demonstrated higher relapse rates.

Related blog posts:

 

Optimal Dose of Thiopurine When Used for Combination Therapy

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To improve long-term outcomes and response in patients with inflammatory bowel disease, many experts advocate the use of combination therapy (thiopurine with anti-tumor necrosis factor).  Thiopurine cotherapy resulted in higher response rates in pivotal studies (eg. SONIC, UC Success), likely due to lower rates of antidrug antibody (ADA) and higher serum levels of biologic agents (e.g. infliximab).  To achieve these advantages, it is not clear whether a lower dose of a thiopurine may be similarly effective as a higher dose.  If a lower dose could result in a similar effect, it would likely result in fewer adverse effects.

A recent study (Yarur AJ, et al. Clin Gastroenterol Hepatol 2015; 13: 1118-24) provide some data to address the issue of optimal dosing of thiopurines.  The authors performed a cross-sectional study of 72 patients receiving infliximab (IFX) and a thiopurine.

Key findings:

  • The thiopurine metabolite 6-thioguanine (6-TG) that “best predicted a higher level of infliximab was 125 pmol/8 x 10 to the 8th RBCs.”
  • Only 8 patients (11%) had detectable antibodies to infliximab (ATI)
  • Patients with 6-TG <125 were more likely to have ATI (OR 1.3)
  • Higher 6-TG levels did not confer additional benefit

This study had many limitations including the small number of patients and the cross sectional design.  In addition, the patients may not be representative of typical patients; more than 50% were in endoscopic remission. A randomized controlled trial with larger number of patients is needed for a more definitive answer.

Take-home message: (from authors); “6-TGN metabolite levels rather than weight-based dosing may assist clinicians in optimizing treatment when using thiopurines in combination with IFX…lower target 6-TGN levels (125-176 pmol/8 x 10 to the 8th RBCs) may be adequate to maximize IFX levels and reduce immunogenicity while potentially minimizing toxicity.”

Briefly noted:

Ananthakrishnan AN et al. Clin Gastroenterol Hepatol 2015; 13: 1197-1200.  In this prospective study with 1659 patients with Crohn’s disease (CD) and 946 patients with ulcerative colitis, the authors found wide variation among the 7 participating academic centers, particularly with regard to CD treatment.  Comparing the site with the lowest usage to the highest usage, for CD:

  • Oral mesalamine 13% vs. 46%
  • Immunomodulator use 16% vs. 56%
  • Anti-TNF use 31% vs 60%
  • Combination therapy 8% vs 32%
  • Immunomodulator-naive anti-TNF use 10% vs. 17%
  • Surgery 32% vs 55%

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Cumberland Island

Cumberland Island

New Target Drug Levels in Inflammatory Bowel Disease

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According to a recent review (Vaughn BP, Sandborn WJ, Cheifetz AS. Inflamm Bowel Dis 2015; 21: 1435-42), higher target levels of infliximab should be considered.

After reviewing the relevant studies which are summarized in Table 1, the authors state that in their experience infliximab (IFX) levels of 5 to 10 mcg/mL are desirable.  Using this standard, they note in a retrospective review that proactive testing identifies only 29% of patients in this range.

Similarly, the TAXIT study (Casteele NV et al. Gastroenterol 2015; 148: 1320-29) identified 44% of patients with a trough concentration of 3-7 mcg/mL at baseline screening.  In this study, after achieving an adequate trough concentration, they found that patients had ~70% clinical remission at 1 year.  TAXIT acronym = the Trough Concentration Adapted Infliximab Treatment trial.  The TAXIT study was a 1-year randomized control trial with 263 adults (178 with CD and 85 with UC).

Recommendations from this review:

  • When therapeutic drug monitoring is used to react to symptomatic patients (Figure 1), if they test negative for antibodies to infliximab (ATIs) and have a low IFX level, then increasing the dose is recommended.  In those with therapeutic IFX and negative ATIs, then consider change in drug class or surgery (rather than dose escalation).
  • When therapeutic drug monitoring is used to react to symptomatic patients, if they test positive for ATIs, if there is a low level ATI (<15 mcg/mL for the referenced assay), then increasing the dose is recommended, otherwise consider change in drug class or surgery (rather than dose escalation).
  • For proactive monitoring, if negative ATI, and IFX trough level is >10 mcg/mL consider extending interval.  If the IFX level is low, increase dose.  If IFX is therapeutic, continue same dose and consider re-check in 6-12 months.
  • For proactive monitoring (Figure 3), if positive ATI, the authors recommend increasing dose if faced with low level ATI and consider change in drug class or surgery (rather than dose escalation). [If someone is doing well, I would not agree with this recommendation.  I would not stop a therapy based on a single blood test.]

One more useful point:

The authors note that combination therapy improves IFX levels and lessens the likelihood of ATIs.  “Current evidence suggests that combination of an anti-TNF with an immunomodulator is the most efficacious treatment for new-onset IBD.”  They speculate that proactive monitoring may allow IFX monotherapy without the need for combination therapy or allow de-escalation of combination therapy.

Bottomline: Consider a higher infliximab target level (5-10 mcg/mL) and using proactive monitoring to achieve higher remission rates.

Related blog posts:

Cumberland Island

Cumberland Island

Briefly noted:

Casen C, et al. Aliment Pharmacol There 2015; 42: 71-83. (Thanks to Ben Gold for this reference). After studying the stool of 165 healthy controls, the authors used 54 DNA probes targeting >300 bacteria.  This genetic analysis-map dysbiosis test, subsequently analyzed 330 more patients; it confirmed dysbiosis in 73% of IBS patients, 70% of treatment-naive IBD patients and 80% of IBD patients in remission compared with 16% of healthy individuals.  Take-home point: Ultimately stool analysis could lead to more accurate evaluation and monitoring of individuals with suspected IBS or IBD.

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.