Tag Archives: Ulcerative colitis

Comparing Biologics for Ulcerative Colitis

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A recent study has reviewed biologic therapies for ulcerative colitis (Ann Intern Med. 2014;160(10):704-711). Here’s the abstract link: bit.ly/1o5PpRX.

Data Synthesis: ..There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo.

Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials.

Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.

Related blog posts:

 

How Long Will Infliximab Work?

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Given the limited therapeutic options, the question of infliximab (IFX) durability in pediatrics is quite important.  One center has published its 10-year retrospective experience (Inflamm Bowel Dis 2014; 20: 606-13).

Inclusion criteria for the 188 patients included initiating IFX prior to age 21 years and patients who had a minimum of 1-year followup.

Demographics: Median age at diagnosis was 11 years for Crohn’s disease (CD) and 12 years for ulcerative colitis (UC). Indication for IFX due to steroid refractory disease was present in 42% of UC patients compared with 14% of CD patients.  Monotherapy was more common in UC patients, 65%, compared to 35% of CD patients.

Methotrexate was administered in 69 (44%) of CD patients at time of IFX with the majority (n=56) as oral treatment (low-dose <10 mg every week).  In addition, MTX was initiated after IFX induction in another 38 (24%).  Only 36 (23%) remained on IFX mono therapy throughout the duration of treatment in CD patients.

Key findings:

  • 88% of CD patients remained on IFX at 1 year, 80% at 2 years, and 72% at 5 years.
  • Only 7 of 157 CD patients were primary nonresponders.
  • 65 of 89 CD patients who did not achieve a sustained durable remission underwent dose escalation. 40 of 65 responded to dose escalation.
  • Of those who lost response to IFX, the majority were transitioned to adalimumab (ADA) and among this group, 82% remained on ADA treatment at last followup.
  • Among UC patients (n=31), 9 were primary nonresponders. At last followup, 41% (9) remained in a durable sustained response at last followup.
  • While the authors used MTX due to favorable effects on IFX pharmacokinetics (Arthritis Rheum 1998; 41: 1552-63), there was “not a significant difference in IFX durability or efficacy between this group and patients with CD on IFX monotherapy”
  • Availability of antibodies to infliximab (ATIs) and IFX trough levels were only assessed in a subset.  However, “we did see a significant difference in those that responded to dose intensification when ATIs were undetectable.”

Bottomline: The majority of CD patients can remain on IFX for >5 years.  Among those who lose response, adalimumab was a durable alternative.  A much lower durable response was evident with the subset of patients with UC.

Related blog post:

Also noted:

Inflamm Bowel Dis 2014; 20: 614-21. In this study of 78 youth with IBD, depressive symptoms warranting additional evaluation were present in 13% which was lower than in the community comparison group.  Disease severity was noted to be inactive in 63% and mild in another 18%.

Inflamm Bowel Dis 2014; 20: 495-501. This study showed that 25 children exposed to anti-TNFs prenatally for maternal IBD seemed to show good safety.  Immunologic investigation undertaken in 17 of the children was normal.  No control group limited the ability to determine if increased infections were present.

And, here’s a link to Mar-April Circle Newsletter from ImproveCareNow -topics include group medical appointments, parent working group, dieting with IBD, and includes link to self management handbook.

 

 

The Search for a Dietary Culprit in IBD

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Uniformly, patients diagnosed with inflammatory bowel disease (IBD), both ulcerative colitis and Crohn disease, are interested in whether there is a dietary culprit which triggered their IBD and what modifications in their diet can help improve their IBD.  A really good summary of what we know has been published (Inflamm Bowel Dis 2014; 20: 732-41).

A summary of the key points:

Traditional dietary recommendations:  These diets may help decrease symptoms but are not thought to improve disease control.

  • Low-residue: <10-15 g/d of fiver. Potential deficiencies: folate, vitamin A, vitamin C, and potassium.  Overall, this diet is poorly studied.  “One small randomized controlled trial showed that low-residue diet made no difference in symptoms, need for hospitalization, need for surgery…when compared with an unrestricted diet.”
  • Lactose-free: potential deficiencies: calcium, vitamin D

Carbohydrate-restrictive:  Potential deficiencies with all carbohydrate restriction: folate, thiamine, vitamin B6

  • Specific carbodydrate diet: allows only monosaccharides.  Restricts complex sugars, starches, grains and legumes.  This diet was popularized by Elaine Gottschall in 1994 (Breaking the Vicious Cycle) but was developed by Dr. Sidney Haas in 1924.  The premise of SCD is that “complex carbohydrates and legumes are poorly absorbed in gastrointestinal disease…they promote bacterial overgrowth and fermentation.  By-products from bacterial dysbiossis are postulated to contribute to gut inflammation.”  Nevertheless, it “has been poorly studied.”
  • Low FODMAPs (see numerous previous posts).  “A small restrospective study…showed that the low FODMAPs diet resulted in improvement in functional symptoms present in patients with IBD who were in remission.”  This diet is difficult for long-term adherence.
  • Gluten-free: not truly a carbohydrate-restrictive diet, but breads/cereals contain large amounts of carbs. “No evidence that a gluten-free diet has any effect on disease activity in IBD.”

Fat-modified diets

  • Fat-restrictive diets: “On a cellular level, multiple animal studies have shown that prolonged feeding of a high-fat diet seems to promote colitis/ileitis and to perturb barrier function…shifts in microbiome composition…Despite some biologic plausibility, there is a paucity of data evaluating efficacy of fat-restrictive diet for IBD management.”
  • Vegetarian/semi-vegetarian: Potential deficiencies: iron, vitamin B12 (vegans), calcium, vitamin D, ω-3 fatty acids.   A small study of 22 patients with Crohn’s disease who adhered to a semi-vegetarian diet, had lower rate of relapse.  “There does not seem to be sufficient evidence at this time to recommend eliminating meat to patients with IBD as a means to control their disease.”
  • Modified ratio of ω-3/ω-6 polyunsaturated fat: “The efficacy of dietary interventions with ω-3 PUFA has been disappointing..recently, 2 large multicenter clinical trials demonstrated that ω-3 PUFA (fish oil) at a dose of 4 g/day was not significantly better than placebo at maintaining remission in CD.”

Restriction of Multiple food groups

  • Paleolithic: based on the “premise that human genetics have scarcely changed over the past 3000 years, and thus modern humans are genetically adapted to the diet of their Paleolithic ancestors (i.e. Stone Age)…daily calories should come from plant sources (50-65%) and from animal sources (35-45%) with fish preferred over meat.  Most of the restricted foods are carbohydrates..refined salt, and refined oils as well as any “processed foods.”  However, there are “no data that this diet has any effect in IBD.”  Previous reports of improvement in IBD are mainly testimonials (anecdotal evidence).
  • Exclusive enteral nutrition (EEN)/Elemental/Semielemental: In pediatric CD, “EEN has been shown to be as effective as corticosteroids in inducing remission (70-90%)..EEN does not seem to be effective in UC.”  High rate of relapse when diet is stopped.  Formula type does not seem to be very important.

Take-home message: “Clinical trials in all dietary strategies (with possible exception of EEN in pediatric patients) are lacking and further study is needed.” “From the current evidence available, a low FODMAPS or gluten-free diet may be the most helpful in controlling diarrheal and bloating symptoms…However, …symptom improvement does not equate to remission or objective evidence of disease regression.”

Related Blog Posts:

ImproveCareNow has published information on IBD and Nutrition as well.  Here’s an excerpt from their Circle eNewsletter:(initially published April 2013, Stacie Townsend, MS, RD, LDN, CSP)

Diet is an important part of your IBD treatment plan and should be used in conjunction with medications. Proper nutrition plays a critical role in managing IBD. Eating healthfully and in appropriate amounts will improve IBD symptoms, contribute to age-appropriate growth, and decrease risk of anemia, poor bone density, and vitamin/mineral deficiencies. It can also increase effectiveness of IBD medications.

No one diet has been proven to prevent IBD or to prevent flare ups, although several diet books and plans have claimed to “cure IBD”. Unfortunately, there is little scientific evidence to prove that these diet plans, such as the Specific Carbohydrate Diet (still being studied) and the Guts and Glory Program, are effective, and most of these plans avoid entire food groups, which can then lead to vitamin and mineral deficiencies and poor weight gain.

Nutritionists frequently get asked what foods are safe for people with IBD, and creating a diet plan for you is often trial and error… The best diet plan is one that includes all food groups (proteins, grains, fruits, vegetables, dairy, and oils) and in appropriate portions for your age, weight, and physical activity level… If gas, bloating, and diarrhea are among your symptoms, lactose free dairy products may be better tolerated.

So what IS the most appropriate diet for IBD? The United States Department of Agriculture’s food guidance system, MyPlate, is the appropriate diet plan for you… and the SuperTracker within the MyPlate website can help you track what you eat each day, and how your diet measures up to the recommended diet plan for you.

General nutrition guidelines for individuals with IBD include:

  • choose foods from all food groups
  • limit fried/fatty foods, caffeine and spicy foods, especially if these foods worsen symptoms of IBD
  • drink fluids at each meal to maintain hydration
  • consume a multivitamin daily to aid nutrient absorption
  • consume small frequent meals (eat every 2-3 hours while awake) if volume of foods at a meal is an issue

…If you want additional help with your diet, make an appointment to see our nutritionist.

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.

 

Second-Guessing Aggressive Medical Treatment in Pediatrics

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An excerpt of a review of a recent study (Inflamm Bowel Dis. 2014;20:291-300.) from Healio Gastro, http://bit.ly/1njexRZ.  This study was briefly referenced at the bottom of a previous blog post (UC SUCCESS | gutsandgrowth).

Mortality and malignancy, the most serious complications of pediatric inflammatory bowel disease, were relatively rare and linked most commonly with aggressive treatment rather than the condition itself, according to recent study data.

In a multinational retrospective study, researchers surveyed all pediatric gastroenterologists in 20 European countries and Israel on cancer and/or mortality among their pediatric patients with inflammatory bowel disease (PIBD) from 2006 to 2011.

Among 44 children diagnosed with IBD (median age at diagnosis, 10 years; 26 boys), 18 cases of cancer were identified and/or 31 patients died. Twelve cancer patients had Crohn’s disease, and 19 patients who died had ulcerative colitis (UC). The most common cancers were hematopoietic tumors (n=11). Mortality was attributed to infections (n=14) and other causes, including cancer (n=5), uncontrollable disease activity related to IBD (n=4) and procedural complications (n=3).

“Cancer and mortality in PIBD are rare, but cumulative rates are not insignificant,” the researchers wrote. “…. At least six lymphomas were likely treatment-associated by virtue of their phenotype.”

Researchers said that aggressive therapy with immunosuppressants and biologics has become common among PIBD patients because their disease is often more severe than that found in adults with IBD…

“Nine out of 19 patients with UC died because of an infectious complication. These fatalities may have been prevented by earlier surgical intervention when intensified medical treatment is ineffective.”

Bottomline: Making a colectomy decision is quite difficult when medical therapies may be effective.  Recent guidelines using PUCAI scores may assist physicians in identifying medical failures more quickly.

 

CCFA Conference Notes 2014 (part 2)

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Yesterday’s notes highlighted the most useful discussion at this year’s meeting regarding mucosal healing (MH) in inflammatory bowel disease.

Many points were intriguing but often at odds. For example, the speakers noted that symptoms and scoring systems like CDAI are unreliable in establishing remission.  It was noted that the FDA is mandating more objective measures (like endoscopic improvement) in future studies. Yet, the studies cited for their arguments often were derived from studies which did not use objective endpoints. Similarly, some of the arguments were based on small studies and yet experts often caution to use evidence-based medicine.

Bo Shen (Cleveland Clinic) “Surgerical Options in IBD”

  • 50-71% of CD patients require some type of surgery within 10 years of diagnosis
  • End-ileostomy may be a cure for some CD patients,  For UC, end-ileostomy 98% are cured.  2% develop enteritis.
  • Can use infliximab after surgery.  Immune system different after surgery and may work even
  • ‘Don’t operate until a CD patient develops a complication. But, don’t wait until further complications develop.’

Different type strictures –web-like strictures are suitable for dilatation, others are more difficult: spindle-like (longer) , ulcerated stricture, and anastomotic.

  • Classification: Gast Endosc 2013; 78: 8181-35.
  • Etiology: primary, secondary (anastomotic), benign, malignant
  • Short-long: Length (<4cm) if dilating
  • Degree: high-grade, low-grade
  • Number: single, multiple
  • Associated conditions: abscess, others

Determining resection margin –does not depends on absence of histologic activity (Ann Surg 1996; 224: 563-71).  Try to save as much bowel as possible, often based on how thick bowel is rather than histologic margins.

Save the gut –stricturoplasty.  1st surgery –usually is a resection rather than stricture plasty.  Heineke-Mikulicz (most common) <10 cm for short , Finney for strictures 10-20 cm, Michelassi >20 cm (sid-to-side isoperistaltic). (Dis Colon Rectum 2007) Stricturoplasty –best for mid small bowel, minimum inflammation, no fistula

Fistula –Hollow-organ to hollow-organ fistula –treat surgically. Whereas if fistula is perianal, start with medical treatment. Perianal fistulas often treated with seton; seton often kept in place for a long time (“forever if not bothering patient”).

Abscess—avoid surgical drainage if possible.  Delineate anatomy and consider elective surgery later.  If less than 3 cm, could aspirate and not leave in drain. If >3 cm, start with interventional radiology

Post-op management –Ruttgerts score.  Rescope 6 months post-op to determine if needs more aggressive treatment.

UC Surgery: issues: preoperative biologics, 2- or 3-stage operations, what type of pouch

  • There may be increased risk with biologics (studies have not shown this consistently) –depends on type of surgery.  If very sick, use 3-stage rather than 2-stage operation.  Don’t do pouch at time of 1st operation if very sick DCR 2013; 56: 1243-52).
  • J-pouch now standard.  Kock pouch –catheterize pouch/no ostomy.  S-pouch –problemswith mechanical obstruction.
  • Even with mucosectomy (vs. stapler/no mucosectomy)–can still develop cuffitis and malignancy.  Mucosectomy may increase risk of incontinence.

Edward Loftus (Mayo Clinic) “Optimizing Biologic Therapy: Maximizing Benefit and Minimizing Risk”

Is azathioprine an effective drug? Should we be using biologics sooner?

Key points:

  • ACT1 and ACT2 were pivotal studies for infliximab approval for UC.  1/3rd chance of going into full remission, 1/3rd chance of response, 1/3rd chance of not responding.  Infliximab lowers risk of colectomy.  Favorable studies of other anti-TNFs as well: adalimumab (Gastroenterol 2012; 142: 257-65) and golimumab (Gastroenterol 2014; 46: 85-95 & 96-109). No head-to-head anti-TNF trials.
  • Crohn disease:  5-ASA products don’t work for Crohn disease.  Reviewed pivotal trials of anti-TNF agents (infliximab, adalimumab, certolizumab)-30% in remission.
  • Natalizumab (anti-alpha 4 integrin) for refractory disease was discussed (NEJM 2005; 353: 1912-25).  Takes longer to work then anti-TNFs but maintenance data look good. PML risk: 395 cases among 118,100 patients treated as of August 2013.  Lots of paperwork and physicians have to be certified.  If you are JC virus serology is negative, “your risk is about 1 in one million in the next year. If you are positive, about a 1% risk in the following year.”
  • Azathioprine (AZA) not very effective (Gastroenterol 2013; 145: 766-74 & 758-65).  Prospective double-blind Spanish study (n=131) –no statitistical benefit.  2nd reference is French study. N=132. No significant difference at 36 months in patients with added AZA.  In U.S., most “thought leaders” going straight to anti-TNFs.
  • Combination therapy works best in adults (SONIC study for Crohn disease, UC Success for UC).  UC Success only studied 16 weeks, no maintenance therapy trial.  However, methotrexate (MTX) with anti-TNFs combination has not been proven to be effective (Gastroenterol 2014; 146: 681-8).  Reason this was a negative study, per lead author, may have been related to steroid use.

Other pointers:

  • Don’t rely on symptoms alone.  Symptoms/CDAI do not correlate with CDEIS (endoscopic improvement).  FDA mandating all future trials have an endoscopic endpoint and not rely on use of CDAI alone. Other factors cause symptoms including IBS, infections, and bacterial overgrowth. Take-home point: Need to look (endoscopy) if someone is not doing well.
  • In the SONIC trial –if there was inflammation on endoscopy, there was an impressive 30% delta in response to treatment (with combination therapy compared with AZA monotherapy). Whereas if you have no lesions, combination therapy no more effective than either monotherapy agent.  Patients whose complaints are due to irritable bowel rather than inflammation do not respond well to treatment.
  • OLD paradigm –treat based on symptoms.  NEW paradigm–treat based on biologic/radiographic markers or endoscopic findings.  “Treat to target” has been approach used by Dr. Sandborn. Target mucosal healing and then assess mucosal healing every 6 months until target achieved, then less frequently.  Yet mucosal healing cannot be achieved in many/most patients.
  • Therapeutic drug monitoring.  For example, 6-TGN >235 associated with better response to AZA (OR 5.0)
  • Pharmacokinetics of anti-TNFs: lower clearance if concomitant use of immunomodulators, increased clearance if high CRP, higher BMI
  • New drugs: Ustekinumab –three phase 3 trials underway.  Should be available in about 2 yrs for Crohn disease. Vedolizumab –under FDA review (NEJM 2013; 369: 699-710).  Infusion (similar to remicade frequency). Blocks lymphocyte homing in the gut. UC data much more robust than with CD, but probably will be approved for both.  Rate of adverse events were low. Etrolizumab—similar to Vedolizumab, but SC administered. Currently, this drug is in phase 2 studies.

Eva Szigethy (Pittsburgh Pediatrics) “Psychological evaluation and assessment in IBD”

Key points:

  • Anxiety/depression ~25-40% of pediatric IBD.  Occurs in both active and inactive disease.
  • IBD effects on brain: inflammation, drugs (steroids, biologics)–both have direct effects on brain.
  • 15% of kids and 25% of adults are having thoughts of death on screening tools. Pain is frequent trigger for suicidal thoughts.
  • Simple depression screen: Mood, Energy, Sleep, Suicide/Self-esteem, Anhedonia (lack of pleaure), Guilt, Eating (change in appetite)
  • We should not ignore adjustment disorders.  We may be able to prevent a full-blown psychiatric disorder.  Each time we let problems like anxiety or depression go untreated, this can leave long-term changes in brain.
  • Anxiety screen: Tense, Tired, Recurrent worries/fear, Restless, Avoidance, Poor sleep/nightmares, Poor concentration
  • Important to look at patient perspective of their disease: identity (what they see as their symptoms), cause/etiology, timeline (how long the patient believes that the illness will last), consequences, cure/control.
  • Catastrophizing –more persistent pain and increased visceral hyperalgesia.  Abnormal brain activation. Poor coping drives development of depression and anxiety.
  • With adult IBD, 20% of patients consume up to 80% of medical costs.  Chronic pain and depression are key factors (Binion et al 2010).
  • Management of anxiety/depression: Cognitive Behavioral therapy –changing behaviors and thinking, problem-solving. ACT –activities, calm (relaxation, guided imagery, hypnosis), think positive (cognitive reframing). Antidepressants: TCA, SSRI, SNRI.  SSRI/SNRI –few side effects or drug interactions.  Overdose risk is highest with TCA (but typically using low doses of these agents).  No pediatric studies in IBD and only small studies in adults. If inactive IBD, SSRI often 1st line. If active IBD, Bupropion often used as 1st line.
  • For anxiety, most likely use SSRI if comorbid anxiety
  • For pain, most likely use SNRI  or low dose TCA
  • Opiates are problematic due to psychological/physical dependence, increased mortality/infection risk, narcotic bowel
  • Sleep –don’t go to bed if not tired, aim for consistency, if not asleep in 20 minutes, then do something else.  1st line pharmacology: consider antihistamines or melatonin.

Sachin Kunde (Michigan State University, Helen DeVos Children’s Hospital) “FMT for IBD”

Key points:

  • Microbial diversity altered in IBD –can we modulate dysbiosis to treat IBD?
  • Issues with cause and effect.  Is dysbiosis due to IBD or causing IBD.
  • FMT –“the ultimate probiotic.” Application of FMT.  For recurrent C difficile, cure rate nearly 90% –?better with lower GI route. For any indication besides C difficile infection (CDI), can only be given through clinical trials (FDA IND).  Currently 9 ongoing trials for IBD (1 pediatric, 3 in U.S).

FMT in IBD: Studies:

  1. -Anderson et al.  Aliment Phar Ther 2012: 13/18 without CDI had some resolution of IBD symptoms.
  2. -Kunde et al JPGN 2013: n=10. PUCAI decrease by 15 indicated response found in 78% (7/9) at 1 week, and 67% (6/9) at 1 month, 3 (33%) went into remission.
  3. -Kump et al IBD 2013: n=6. FMT for UC was not effective.  Transient improvement in 2/6 patients, 1/6 improved on Mayo sub score.

Bottomline for FMT & IBD: More questions than answers: efficacy, route of administration, # of infusions needed, fresh vs. frozen, adverse effects, best donor, etc.

For today’s post today and yesterday’s post, I may have made some transcription errors and these notes were not reviewed with the speakers.  Also, due to brevity, some useful information was not included.  Thus, the disclaimer with these posts is particularly important.

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.

Related blog posts:

CCFA Conference Notes 2014 (part 1)

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Each year our local CCFA chapter holds a one day seminar with separate lectures for health care providers and families.  Overall, it is a good opportunity to hear ‘cutting edge’ material.  I did not pick up as much at this year’s seminar as in previous years, but will highlight what I thought was most important.

Key points:

  1. Symptoms are not accurate at determining effectiveness of IBD therapy.
  2. More frequent use of objective markers are needed to optimize treatment.  Mucosal healing is starting to be a target in clinical practice, but limited by number of medications available.
  3. Stricture classification and operative techniques were reviewed.
  4. IBD frequently results in psychological problems: anxiety, depression, pain, sleep. 15% of kids and 25% of adults are having thoughts of death on screening tool intake.
  5. Fecal microbiota transplantation (FMT) –not enough data to recommend for IBD.  Clinical trials ongoing.

Debate: What should be the End Points in Therapy? 

  • Tanvi Dhere (Emory): Goal: clinical symptoms
  • Cary Sauer (Emory Pediatrics): Goal: mucosal healing and normal bloodwork

In my opinion, this was the most thought-provoking and best presentation

Mucosal healing (MH) consensus definition –normal mucosa after previously abnormal with complete absence of ulceration, macroscopic and histologic signs of inflammation.  In practice MH = absence of ulcerations.

Reasons why mucosal healing as a target is problematic:

  • Problems with MH –not validated.  No long-term data utilizing endoscopic scoring indices of MH.
  • MH relies on a binomial endpoint –Yes or no, but there may be intermediate endpoints.
  • How likely is MH (different definitions in these studies)?  SONIC –MH in 43.9% of combination Rx (30.1% in those with infliximab monotherapy); EXTEND (Adalimumab) 27% and 24.2% 12/52 weeks; MUSIC (certolizumab at 10/54 weeks) 11.5% and 18.9%.

In practice, Mayo Score 0-1 both considered to have MH.

MayoScore Visual

Images above online at www.nature.com

In small study, MH at 1 year were not associated with improved outcomes at 5 years.  Risks of MH: more procedures, more costs of treatment, and potential for more complications.

Dr. Sauer’s reply.  Three simple questions –why should I try to target MH, is it possible, what is needed to get this done?

  1. If the goal were only an asymptomatic patient – why do screening colonoscopy in the general population, much less in IBD?
  2. In IBD, long-term evolution of IBD (Cosnes J et al. Inflamm Bowel Dis. 2002 Jul;8(4):244-50) is toward structuring and penetrating disease. CD Evolution This needs to be modified if possible.

Why MH? Improved symptoms, better quality of life, less likely to develop colon cancer, and it is an objective measure of treatment response.

  • In MH patients, less steroids and fewer flares over 2 year period.
  • MH healing patients have sustained clinical benefit over 96 months.
  • With MH, there is a decreased colectomy in UC.  In one study, there was a lower  colectomy rate at 8 years if colonic CD (62% vs 8%), decreased steroids in CD, decreased hospitalizations, & decreased fistulae.

Is MH possible in clinical practice?  The accuracy of CDAI to detect endoscopic healing is low in patients with CD. (Bouguen G et al Clin Gastrohep 2014).  More frequent adjustments in medical therapy –could lead to MH in up to 80% over 80 week study period.  Same story in UC (Bouguen G et al IBD 2014).

What do I need to do to obtain MH? Endoscopy (or MRE), maximize medications (checking levels), change medications, and most important –set a target. “Adjusting infliximab dose alone could lead to MH in up to 60%.”

When to assess for MH?  Consider endoscopy at 6 months into treatment if symptoms and at 12 months if in clinical remission.

Other viewpoints on MH from panel:

Dr. Loftus –“I think of this like oncology.” He agreed with using the best evaluating tool 6 months into treatment.  Cross-sectional imaging is often more helpful, but may need more than one tool.

Dr. Long—“Are we going to check every 6 months?” No.  She stated that she does not do this and tries to avoid repeated endoscopic procedures if this will not change treatment.  Goal is to make sure patient is headed in right direction, often after starting therapy.  Dr. Long stated that stool biomarkers most useful for colonic disease.

Dr. Dhere—documenting MH is important for deescalating treatment.

Millie Long  “Quality of Care in IBD”

  • 75% of Crohn disease patients will need surgery, 10% in 1st year
  • “One way to gauge quality of care is to examine the degree of consistency in care”
  • High variability in care in IBD (Aliment Pham Ther 2007; 26: 1005-18)
  • “Over half of institutions with worst quality have mortality in normal range.” Outcomes may not occur until several years after treatment, thus more useful to measure process measures

PQRS IBD Quality Measures in Adults: 10 Measures

  • #1 Establishing/documenting IBD type, anatomic location, and activity
  • #2 Preventive care: corticosteroid sparing.  Steroids associated with mortality (OR 2.1 in TREAT registry)
  • #3 Preventive care:  Preventing bone loss.  Limiting steroid use.  Recommend weight-bearing exercise, Quit Smoking, Measure DEXA, added Calicum/Vit D/Bisphosphonates
  • #4: Vaccination –pneumococcal vaccine.  Avoid live virus vaccines
  • #5 Vaccination –influenza vaccine, zoster vaccine
  • #6 Testing for latent TB prior to anti-TNF
  • #7 Testing for hepatitis B virus
  • #8 Testing for C diff with patients hospitalized with IBD
  • #9 VTE prophylaxis in adult IBD patients.  Risk assessment on admission to hospital is recommended.  IBD patients have 1.5-3.5-fold higher risk of VTE àwhich can increase mortality risk
  • #10 Screening for tobacco.  Tobacco use after surgery increases recurrence by 2.5-fold.  It also increases risk for reoperation.

Last year’s notes:

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.

UC SUCCESS

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The results of the “UC SUCCESS” trial show that combination therapy with infliximab and azathioprine is more effective than either medication as monotherapy in ulcerative colitis (UC) (Gastroenterol 2014; 146: 392-400). This study findings are similar to the SONIC trial in Crohn’s disease (CD).

Study Design: randomized, double-blind trial with evaluation at 16 weeks with a total of 239 patients.  In patients assigned to infliximab (IFX) alone, they were given daily oral placebo pills. In patients with azathioprine monotherapy (AZA), dosed at 2.5 mg/kg/day, they also received placebo infusions.  Patients had moderate to severe UC as defined by Mayo scores at baseline and had not responded adequately to a course of corticosteroids.  All patients were naive to tumor necrosis factor α antagonists (anti-TNFα).  Mean age was approximately 40 years.

Results:

  • IFX/AZA had a 39.7% corticosteroid-free remission at week 16 compared with 22.1% with IFX monotherapy and 23.8% with AZA monotherapy.
  • Mucosal healing at week 16 was evident in 62.8% of combination group compared with 54.6% IFX monotherapy and 36.8% with AZA monotherapy.
  • Serious adverse events were noted more frequently in the AZA monotherapy group, though this did not reach statistical significance.
  • A subset of patients had antibodies to infliximab (ATIs) measured.  ATI-positivity was more common with IFX monotherapy (19%, 7 of 37) than for IFX/AZA combination (3%, 1 of 31)

While this study indicates that for moderate to severe UC combination therapy with IFX/AZA was superior in this age group, there were several limitations.  Given the slow onset of action of azathioprine, more patients may have responded to this therapy if longer treatment duration was studied.

Take-home message: Combination therapy for UC, like CD, is more effective.  In this small study population, the adverse events were not increased. In the pediatric population, particularly males, the concern for malignancy in patients (especially males) treated with combination therapy may limit the frequency of combination therapy.

Related blog posts:

Other recent IBD articles of interest:

Inflamm Bowel Dis 2014; 20: 291-300. “Malignancy and Mortality in Pediatric Patients with Inflammatory Bowel Disease”  This article presented the results of a survey of 20 European countries and Israel.  Key finding: 18 cases of cancer and 31 deaths in 44 children. 5 of the deaths were due to cancer; the most common cause of mortality was infectious (n=14).  In this cohort, all HSTCL or EBV-positive lymphomas were treated with thiopurine monotherapy.

Inflamm Bowel Dis 2014; 20: 196-212.  “Opportunistic Infections Due to Inflammatory Bowel Disease Therapy”  This review article covers a broad range of pathogens and includes recommendations for prophylaxis and treatment (Table 3).  In addition the authors  provide suggestions for checking for several infections prior to treatment and vaccinations.

Does Sun Exposure Lower the Risk of Crohn Disease?

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An intriguing recent study suggests that individuals who spend more time outside are less likely to develop Crohn disease (CD) (Inflamm Bowel Dis 2014; 20: 75-81).

In this prospective cohort study from France, 123 cases of inflammatory bowel disease (45 CD, 71 ulcerative colitis, and 7 indeterminant colitis)  developed among the 91,870 women in the study.  The study period had a mean followup of 13.1 years and followed women between 40 and 65 years. The authors estimated residential sun exposure by utilizing a database (derived from satellite collection) containing the mean daily ultraviolet radiation dose for each French county.

Key findings:

  • Higher levels of sun exposure were associated with a decreased risk of Crohn disease with a Hazard Ratio (HR) of 0.49.
  • Sun exposure did not affect the likelihood of developing UC (HR 1.21).
  • In women with information about dietary vitamin D intake, higher sun exposure had a HR of 0.29 for developing CD.  That being said, the authors note a low dietary vitamin D intake in their population.

Despite the large cohort, this study has a number of limitations. The absolute number of IBD patients can lead to a Type 1 error (false-positive conclusion).  In addition, the age of the study population and the lack of data regarding individual sun exposure limit the conclusions as well.  Besides these factors, there may be confounders such as changes in diet and soil exposure which are not accounted for.

At the same time, there have been other studies which have shown a latitude effect.  As with this study, those living in sunny areas had a lower incidence of CD.

Bottomline: This study suggests that additional sun exposure is associated with a lower risk of developing Crohn disease.  Whether this lower risk is directly through better vitamin D levels or simply an epiphenomenon is unclear.

Other recent unrelated studies:

Gut 2013; 62: 1122-30.  A randomized phase 1 study of etrolizumab (rhuMAb β-7) in moderate to severe ulcerative colitis.  Etrolizumab is an adhesion cell molecular blocker.

Inflamm Bowel Dis 2014; 20: 21-35.  Meta-analysis of 23 randomized controlled trials of probiotics for UC, Pouchitis, and CD.  Probiotics, in particular VSL#3, increased UC remission rates and helped maintain remission in patients with pouchitis.

Inflamm Bowel Dis 2014; 20: 213-27. Review article of cutaneous manifestations of inflammatory bowel disease.  Good pictures of multiple problems including metastatic Crohn disease, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, aseptic abscess syndrome, and epidermolysis bullosa acquisita.

Inflamm Bowel Dis 2013; 19: 1753-63.  Review on hair loss associated with inflammatory bowel disease. Remember telogen effluvium?

Related posts:

For those who read from the top to the very bottom, here’s a tangential question: Do you know what a “sun dog” is?   Sun dog – Wikipedia, the free encyclopedia

In PURSUIT of Better Treatment for Ulcerative Colitis

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Patient education materials:

#1  Ulcerative Colitis For Dummies | UC Patient Resource This link connects to a free educational book promoted by Salix pharmaceuticals.  In order to receive a free download, you have to register and include your email.  I have not read this book but other similar books (eg. Colonoscopy for Dummies) by Salix have been well-written.

#2 This link, ow.ly/sPX95, is to the ImproveCareNow visit planner website.  It poses of ~ 8 questions and a text box  for “my list of things I’m concerned about and questions that I have.”  Families that use this planner may help themselves achieve more comprehensive care.

Anyone who follows this blog knows that I really enjoy a good study acronym.  The Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) is responsible for two papers in the most recent Gastroenterology issue:

  • Gastroenterol 2014; 146: 85-95
  • Gastroenterol 2014; 146: 96-109

PURSUIT is composed of >200 sites from around the world.  The first study was a combined phase 2 and phase 3 study. It enrolled 1064 adults with moderate to severe ulcerative colitis (UC) who were randomly assigned to either placebo, 200/100 mg or 400/200 mg of SC golimumab at 0 and 2 weeks.  All patients were naive to previous anti-TNF therapies. The average duration of disease was 6 years among the participants. The primary endpoint of the phase 3 part of this study was the clinical response at 6 weeks.  Clinical response was at least a 30% improvement and a ≥3-point improvement in the Mayo score. At baseline, the average Mayo score was 8.

  • The golimumab groups had response rates of 51.8% and 55.0% respectively compared to 29.7% for placebo.
  • Approximately 18% of patients achieved a clinical remission with treatment compared with 6% of placebo patients.
  • Approximately 10% had healed mucosa compared with ~4% in the placebo group.
  • Adverse events: Rates of serious infection were 1.8% for the active treatment group compared with 0.5% for placebo-treated patients.  In the 400/200 mg dosing group, there was 1 death attributed to peritonitis and sepsis after multiple procedures for ischiorectal abscess repair.  In addition, a single case of demyelination was noted in this group.

The second study, a phase 3 double-blind trial, evaluated the efficacy of maintenance treatment of 50 mg or 100 mg SC every 4 weeks in those with a successful induction (n=464).  This study took place at 251 centers between 2007-2011. At 54 weeks, the actively-treated gourds had maintained a clinical response, using the Mayo score, in 47.1% and 50.6% respectively compared to 31.4% for placebo.  Antibodies to golimumab developed in 2.9%, two-thirds of these antibodies were neutralizing.  Antibody formation was lower in those receiving concomitant immunomodulators. 4 cases of tuberculosis were noted from endemic regions despite previous screening.  Overall, infections occurred in 28% of those treated with placebo compared with 39% of those treated with golimumab.

During the course of the study, three deaths were reported, all in the 100 mg golimumab maintenance group.  The causes were malnutrition/sepsis, cardiac failure/thrombosis, and disseminated tuberculosis (patient was receiving isoniazid). After the study, another 6 deaths were reported, including two in the placebo group.  Three malignancies were reported through week 54 in patients receiving golimumab maintenance, two of these presented in the induction period while receiving placebo rectal cancer and thyroid cancer) and one (lung adenocarcinoma) occurred in a patient with a 40-year smoking history who received golimumab for induction and maintenance.

Taken together, about 25% of patients randomized to and maintained on golimumab achieved a clinical response lasting >1 year; similarly, about 17% had clinical remission at 1 year.

In the commentary (page 13-15), Stephen Hanauer notes that better response was noted with higher serum levels and there remains “a strong possibility that optimal dosing was not achieved.”  He and the authors comment on the observation that less-severe patients had a better response, indicating that  “greater disease severity may be correlated with more rapid clearance.”

Bottomline: These studies demonstrate that golimumab is an effective treatment for UC with a similar risk of adverse reactions as other anti-TNF agents.  The published studies are complicated and take some time to analyze.

Plus more references:

Gastroenterol 2014; 146: 110-18. “Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis.” Data for this studies was derived from ULTRA1 and ULTRA2 trials with 963 patients.  Risk for hospitalization, whether due to UC or all-causes, was reduced between 40-50% compared to placebo within the first 8 weeks of adalimumab administration.

Clin Gastroenterol Hepatol 2013; 11: 1538-49.  Excellent review on pouchitis. Figure 5 (pg 1545) provides a nice treatment algorithm.  Initial approach is antibiotics (metronidazole or ciprofloxacin); in those responsive, either prn therapy or chronic treatment.  In those not responsive, look for pathogens (eg. CMV and C difficile) or determine it is immune-mediated (PSC-associated, IgG4-associated, or autoimmune).  The immune-mediated may respond to 5-ASA/budesonide or immunomodulators.

Clin Gastroenterol Hepatol 2013; 11: 1601-08. This case-control study with 141 UC controls and 59 patients who developed colorectal neoplasia found that increased inflammation was associated with colorectal neoplasia.  Use of immune modulators reduced the risk of colorectal neoplasia.

Related blog post:

Simponi (Golimumab) Approved for Ulcerative Colitis | gutsandgrowth

Population-Based Outcomes for Primary Sclerosing Cholangitis

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A study from the Netherlands examined the outcomes for Primary Sclerosing Cholangitis (PSC) (Hepatology 2013; 2045-55). Using four independent hospital databases with 44 hospitals, allowed the investigators to identify 590 PSC patients from a population of almost 8 million. Median followup was 92 months. Mean age at diagnosis was 38.9 years.  A second comparison cohort of 450 patients was identified from three Dutch transplantation centers outside the study area.  134 (30%) of this cohort were present in the population-based cohort.  An IBD comparison group of 722 cases was identified as well from a population of 271,000 patients.

Results:

  • Prevalence: 6 per 100,000.  This is significantly lower than previous estimates.  The authors emphasize the problem with previous epidemiology studies and the need for population-based studies with rigorous case-finding.
  • Survival, estimated at 21.3 years for the entire cohort following diagnosis, was better than previous studies and this may indicate less selection bias than tertiary referral center studies.  It could also reflect diagnosis of milder cases with newer imaging techniques.
  • 402 (68%) of PSC patients were diagnosed with inflammatory bowel disease.
  • 23 (4%) had autoimmune hepatitis overlap.
  • Colorectal cancer was 10-fold increased compared to ulcerative colitis controls and developed at a younger age (39 years compared with 59 years).
  • Cholangiocarcinoma (CCA) was nearly 400-fold increased risk.  The cumulative risk of CCA was estimated at 20% after 30 years following PSC diagnosis.
  • During followup, there were 97 deaths; 73 (75%) were PSC-related.

Related blog posts: