Tag Archives: Ulcerative colitis

Clostridium difficile in IBD

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A useful review of Clostridium difficile infection (CDI) in the inflammatory bowel disease population has been published and makes several useful points (Inflamm Bowel Dis 2013; 19: 194-204). (Thanks to Ben Gold for suggesting this reference.)

Key points:

  • The incidence of CDI in IBD patients is increasing (faster than general population).  The prevalence of CDI in IBD was nearly eight times greater than non-iBD gastrointestinal patients in a recent population-based study (37.3 cases vs. 4.8 cases per 1000 discharges).
  • Though there is some conflicting data, CDI appears to worsen both short- and long-term outcomes in IBD patients.
  • Carriage (asymptomatic) rates in outpatient IBD patients is higher than the general population (8.2% vs. 1%) according to a recent study.
  • Endoscopic appearance of CDI is rarely classic in the setting of IBD.  Only 13% of hospitalized IBD patients with CDI had pseudomembranes (J Crohns Colitis 2010; 4: 194-98).  Thus, endoscopy has little utility in helping to distinguish IBD flare from superimposed infection.
  • Unique IBD risk factors for CDI: colonic disease and steroid use.
  • The review has a thorough discussion of the available testing and recommends testing only patients with unformed stools unless an ileus is present.
  • For recurrent disease, the authors suggest prolonged tapered vancomycin in adults: 125 mg QID for 10-14 days, then 125 mg BID x 1 week, then 125 mg QD x 1 week, then 125 mg QOD for 2-8 weeks.  Alternative approaches could included fidaxomicin, IVIG/antibody therapy, and fecal transplantation.

Related blog posts:

Data on Allopurinol

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Given the limited number of therapeutic options for inflammatory bowel disease (IBD), it is important to optimize each individual treatment.  Allopurinol can increase the effectiveness of thiopurines and if used properly can be safe (Inflamm Bowel Dis 2013; 19: 363-69).

The referenced study took place between 2004-2011 and examined 77 patients who failed monotherapy with a thiopurine due to “skewed” metabolism.  The average age of study participant was 38 years (28-45).  23% had previous surgery. Cotreatment with an anti-TNF occurred in 7 patients and with an 5-ASA i 17 patients.

Results:

  • Median 6-thioguanine (6-TGN) levels increased from 145 to 271 pmol/8 x10-to-the-8th. 6-methyl mercaptopurine (6-MMP) concentrations decreased from 10,110 to 265 pmol/8 x10-to-the-8th.
  • Leukopenia occurred in 16%, necessitating dose reductions.
  • Liver tests normalized in 81% with the addition of allopurinol
  • The median azathioprine dose while on combination therapy was 0.64 mg/kg/day and the median 6-mercaptopurine dose was 0.39 mg/kg/day.  While on mono therapy, median values were 2.05 mg/kg/day and 1.23 mg/kg/day respectively.
  • 21% had to discontinue combination therapy.
  • Combination therapy was continued at 6, 12, 24, and 60 months in 87%, 85%, 76%, and 65%.

Take-home Message:

Allopurinol can salvage failed thiopurine monotherapy, but only in a minority of these patients.  Allopurinol should be considered for patients unable to achieve therapeutic 6-TGN levels who have liver toxicity/elevated 6-MMP levels.  Careful attention to dose reduction of the thiopurine is essential to avoid life-threatening bone marrow suppression.

Related blog entry:

Thiopurine Metabolite Testing -NASPGHAN … – gutsandgrowth

Additional references:

  • -Aliment Pharmacol Ther 2010; 31: 640-47. use of allopurinol.
  • -Gastro & Hep 2008; 4: 505. use of allopurinol. Consider if pts unable to enter steroid-free remission AND on adequate AZA/6MP dose. ONLY in those who preferentially metabolize towards 6-MMP (~15% of population); thus subtherapeutic 6-TG levels and increased 6-MMP (>5700). Need adequate WBC >4.5 at start since this will decrease. Check labs every week x 4 at start, then qoweek x 4, then per routine.
  • -IBD 2008; 14: 1678. Experience with allopurinol in children -dose 100mg of allopurinol if >30kg and 50mg if < 30kg. AZA dose decreased to 25% of previous dose. n=13.
  • -Clin Gastro & Hep 2007; 5: 170 (editorial) & 209.  Use of allopurinol (100mg/day) in 20 adults.  Dose of 6-MP reduced 25-50% concomitantly.  Improved disease control w/o hepatotoxicity.  Important to follow counts closely for first 2 months.

How effective are aminosalicylates for pediatric UC?

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In a prospective, multicenter, inception cohort study (JPGN 2013; 56: 12-18) with 213 newly diagnosed ulcerative colitis (UC) patients, oral aminosalicylate (5-ASA) therapy was effective in 86 (40%).  That is, 40% were considered to be in corticosteroid-free remission at 1 year using 5-ASA as primary maintenance therapy.

This study took place between 2002-2010.  Of 1669 children enrolled in the registry from 32 sites, 440 (26%) were diagnosed with UC.  Of this group, 353 had followup >1 year and 213 met inclusion/exclusion criteria; all patients had to be treated with only 5-ASA or corticosteroids in the initial 30 days following diagnosis.  Most of those excluded had other therapies.  Among those with primary oral 5-ASA treatment, only 98 started treatment without a steroid induction.

Some interesting aspects of the study group:

  • 82% had pancolitis
  • 62% had moderate/severe disease at diagnosis based on physician global assessment
  • No laboratory or clinical features were associated with a higher likelihood of response
  • Mean daily dosage of 5-ASA was 52 mg/kg/day; 23% had a dose >60 mg/kg/day

The authors note that improved patient adherence and possibly higher 5-ASA dosing schedules may improve response to 5-ASA treatment.

Related blog entry:

Once daily Mesalamine | gutsandgrowth

A-OK for Accutane

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Another article has reaffirmed that isotretinoin (Accutane) does not increase the risk of IBD (JAMA Dermatol 2013; 149: 216-20).  Thanks to Mike Hart for this reference. However, this data will not reverse the millions of dollars that have been lost in litigation (Isotretinoin – Wikipedia, the free encyclopedia).

Using a large U.S. health claims database (68 million patients), the authors examined women ages 18-46 years who had received at least one oral contraceptive prescription between 2001-2009.  For each patient with IBD, 20 controls were identified in a nested case-control study design.

In total, 2159 IBD cases (1056 UC, 1103 CD) were matched with 43,180 controls.  Only 10 patients with IBD were exposed to isotretinoin compared with 191 controls.  The adjusted relative risk (RR) for IBD was 0.99; for ulcerative colitis the RR was 1.1 (confidence intervals 0.44-2.7) and for Crohn’s disease the RR was 0.91 (confidence interval 0.91).  For the meta-analysis which was a secondary part of this study, the RR for IBD with 5 studies was 0.94.

Conclusion: The study results do not suggest an increase risk of IBD with isotretinoin use.

Why did previous studies suggest a link between IBD and isotretinoin? The authors note that this is the first study to adjust for two main confounders, mainly a diagnosis of acne and use of oral tetracycline antibiotics.  Oral antibiotics, including tetracyclines, have been associated with IBD previously.  In addition, the design limits the confounding of contraceptive usage.

Limitations of this study:

  • Only women were studied; however, there are no known biologic factors that would make isotretinoin more problematic for males.
  • Other risk factors were not examined: smoking, ethnicity, diet, IBD family history

Additional references:

  • -Am J Gastroenterol 2009; 104: 2774-78.  Population-based study in Winnipeg, <40yrs.  n=1960 cases and 19,419 controls.  No differences in the proportions of IBD cases taking isotretinoin vs controls.  1.2% of IBD cases received isotretinoin prior to IBD diagnosis (n=25) compared with 1.1% of controls (n=213).  Mean # of days prior to IBD dx was 1102.  Thus, isotretinoin unlikely to be causally-associated with idiopathic IBD.
  • -IBD 2009; 12: Supplement -abstract O -0002  Increased risk of UC after isotretinoin.  OR 4.36 for developing UC
  • -Am J Gastroenterol 2009; 104: 2387-93.  7 country study found no causal association between isotretinoin & colitis.

Mortality from IBD

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A large Danish cohort provides useful information on the mortality effects of having inflammatory bowel disease (IBD) and how this has changed over the last three decades (Clin Gastroenterol Hepatol 2013; 11: 43-48).

Using a national cohort of all individuals living in Denmark between 1982-2010 (on average 5.3 million), the authors studied 36,080 patients with ulcerative colitis (UC) and 15,361 with Crohn’s disease (CD) in comparison to data from 2,858,096 matched controls (50 controls from each IBD patient) from the general population.  For UC, the median age was 45.2 years and for CD 36.3 years.

Findings:

  • With UC, the first year of diagnosis carried a higher risk of dying (HR 2.43) then rapidly declined to around HR 1.1 after 2 years.  Overall, long-term mortality was increased 10% among UC patients.  Mortality from UC decreased from 1982 to 2010 due to decreased mortalities from gastrointestinal disorders, including colorectal cancer.
  • Mortality was higher among patients diagnosed at younger ages.  Patients diagnosed with UC in childhood or adolescence had a 2.15-fold higher relative mortality than patients diagnosed with UC at 60-79 years.
  • Cause-Specific Mortality: during the first year after UC diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 13.3) and infection (HR 9.17).  These areas were most prominent at 10+ years, but the HR ratios had decreased to 1.95 and 1.64 respectively at that time.
  • For CD, mortality was markedly increased in the first year with HR 3.69 and declined to HR 1.53 during years 2-4; HR was 1.49 at 10+ years following diagnosis.  Overall, long-term mortality was increased 50% among CD patients.  Unlike UC, no improvement in mortality rate occurred during the study.
  • Cause-Specific Mortality: during the first year after CD diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 23.02) and infection (HR 10.19). These areas were most prominent at 10+ years, but the HR ratios had decreased to 3.67 and 2.70 respectively at that time.  Infections were not increased in the most recent decade, indicating that thiopurines and biologics have not increased the overall risk of fatal infections.
  • While the relative risk of cardiovascular disease was only slightly increased (HR 1.11 for both CD and UC), this is important given the overall frequency of cardiovascular disease in the population.  Presumably, systemic inflammation contributes to the formation of atherosclerosis.
  • Suicide was also increased, especially in the first year after diagnosis (HR 2.05 for UC and HR 1.37 for CD)

Strengths of study: since Denmark has free access to health care and all citizens have a unique 10-digit personal identification, this enables capture of virtually all patients with IBD.  Previous studies have validated the database to be accurate and that the IBD diagnoses have been validated.

Related blog entries:

More frequent pediatric IBD

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Using a national cohort of prospective and retrospective data on pediatric inflammatory bowel diagnosis, (PIBD) a recent report indicates a rising incidence of PIBD in Scotland (Inflamm Bowel Dis 2012; 18: 999-1005).

Key findings:

  • Between 2003-2008, 436 patients were diagnosed with PIBD; this equates to 7.82/100,000; Crohn’s was 4.75 and UC 2.06 per 100,000 respectively
  • Between 1990-1995, 260 patients were diagnosed with PIBD; this equates to 4.45/100,000; Crohn’s was 2.86 and UC 1.59 per 100,000 respectively
  • Mean age of diagnosis in more recent cohort was younger: 12.7 years compared with 11.9 years

Currently, a data-base coordinated in a single center along with collaboration with regional networks enables the capture of all new IBD diagnosis (since 1999).  Prior cohort was determined by “exhaustive examination” of previous IBD records.

How new therapies impact colectomy in UC patients

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Has the need for colectomy changed with the increasing use of more potent medical therapies for ulcerative colitis (UC)?  One article gives some insight into this question (Inflamm Bowel Dis 2012; 18: 1641-46).

This French study followed 151 patients with newly diagnosed UC from 2000-2008; median followup was 58 months. During this time, 21 patients (14%) underwent colectomy.  1.3% required colectomy in the first year following diagnosis.

Looking closer at their study, 55% of patients had pancolitis.  Cyclosporin usage, typically given in refractory cases, was the only medication determined to be a predictive factor for surgery.

Medication usage during study period:

  • 68% oral mesalamine products
  • 72% systemic corticosteroids
  • 7% methotrexate
  • 49% azathioprine
  • 9% cyclosporin
  • 30% had received at least one anti-TNF agent

The authors concede several limitations, including the evolving nature of UC treatment.  Yet, they conclude that colectomy still is frequently needed and the use of IBD medications, including anti-TNF, “does not appear to reduce the long-term need for surgery in UC.”

I take issue with the last sentence.  Whether anti-TNF agents prove to be a disease-modifying treatment over the long-term is not known.  In this particular cohort, only 30% were even exposed to these agents.  My conclusion: we need a study designed to answer the question.  This would require larger numbers of patients followed prospectively for many years.

Related blog entries:

According to the study which you would never qualify for…

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When I give patients advice on treatment, I rely on well-designed studies to help select the medications/treatments that are most likely to be effective.  It is interesting to ponder how applicable these studies are and how closely they reflect the patient population that I’m seeing.  A recent article indicates that in a tertiary referral center for inflammatory bowel disease, the majority of patients would be excluded from participation in these studies (Clin Gastroenterol Hepatol 2012; 10: 1002-07).

These authors performed a retrospective cohort study of patients presenting to the Mount Sinai Medical Center between January 2008 and June 2009.  For Crohn’s disease (CD) patients, the authors selected 7 published randomized control trials of biological therapy for patients with moderate-severe disease (ACCENT 1, CLASSIC 1, CHARM, PRECISE 1, ENCORE, ENACT, and SONIC).  For Ulcerative Colitis (UC), they selected ACT 1 and ACT 2 trials for moderate-severe UC.

Only 31.1% of 206 patients with IBD would have been eligible to participate in any of the selected RCTs.  The average age of their patients was about 35 and did not differ significantly among patients who would qualify compared to those who would not.

Among the CD patients, the inflammatory phenotype was most likely to qualify; 37 patients with inflammatory disease behavior would have been eligible.  While only 54% (37 of 68) of the inflammatory phenotype would have qualified, this accounted for 86% of the total population who would have qualified (only 34% of the entire CD cohort would have been eligible for study participation).

Among the UC patients, there were no disease characteristics or demographics associated with eligibility; that is, there was a similar distribution of disease extents, Mayo scores, disease duration, gender, and age among the patients who qualified and those who did not.

Reasons for exclusion: stricturing or penetrating disease, steroid dosing, comorbities, concomitant therapies, or prior exposure to biologics.

The authors note that the results from this study mirror that from similar studies with other chronic diseases including rheumatoid arthritis, chronic obstructive pulmonary diseases, and congestive heart failure.

When the authors looked at the trial-ineligible patients, 60% had a response to biological therapy. The response rates for ineligible patients (compared to eligible patients) were lower for CD patients but not for UC patients (Figure 2 in study).

While stringent criteria for eligibility limit the external validity of the study results, these criteria are in place for multiple reasons.  Less rigid selection criteria would require larger study populations, longer duration studies, and greater costs.

The issue of study applicability is even a bigger problem in pediatrics.  This is primarily due to fewer high quality studies in children. As such, many clinical judgements require extrapolation from adult studies.

Related blog post:

Interpreting industry-funded studies

What is the risk of colon cancer in IBD?

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Some recent studies have shown that colorectal cancer complicating IBD may not be as common as previously thought or may be decreasing in incidence (Gastroenterology 2012; 143: 375-81 & Gastroenterology 2012; 143: 382-89 ).

The first study used a nationwide cohort of 47,374 Danish patients with IBD over a 30-year period.  During a 178 million person-years of follow-up evaluation, 268 patients with ulcerative colitis (UC) and 70 patients with Crohn’s disease (CD) developed colorectal cancer (CRC).  The risk was comparable to the general population (RR 1.07)!  Furthermore, the relative risk for CRC decreased over sequential time periods: 1.34  (1979-88) to 0.57 (1999-2008).

Increased risk:

  • UC diagnosed in childhood or adolescence
  • longer disease duration
  • patients with primary sclerosing cholangitis

Their conclusion, ‘the overall risk of CRC in patients with UC has decreased markedly over time and no longer exceeds that of the general population, at least in the first decade after diagnosis.”  And, based on their data, patients with Crohn’s disease are not at increased risk for CRC.

The second study from California used a large Kaiser Permanente database from 1998-June 2010.  29 cancers were identified in CD (n=5603) and 53 in UC (n=10,895) patients.  The incidence per 100,000 for CRC was 75 for CD, 76 for UC, and 47 for general population.

These authors conclude that there is an increased risk of CRC in a community-based IBD population between 1998-2010 despite advances in medical treatment.

To understand the discrepancy of these reports, the same issue provides an editorial (page 288).  My take is that the current incidence of CRC is lower than in previous reports but that the risk factors identified in the Danish cohort (see above) likely remain important.

Additional references:

  • -Gastroenterol 2009; 136: 718. 22% of cancers occurred before recommended surveillance in adults (only 9% if exclusion of patients who had IBD and cancers diagnosed at same time).
  • Colon Cancer Survival Calculator http://www.mayoclinic.com/calcs-Gastro 2010; 138: 207-2177 (entire issue)
  • -JAMA 2009; 302: 649. Aspirin use likely increases survival after dx of colon cancer. Commentary-Gastro 2010;138: 2012.
  • -NEJM 2009; 361: 2449. molecular basis of colorectal cancer
  • -Gut 2008; 57: 1246. IBD and colon cancer
  • -IBD 2007; 4: 367. 5ASA Rx did not reduce rate of cancer in large study of UC/CD -review of 18,000 colorectal cancer cases. IBD increased risk of CRC 6-7-fold..
  • -Clin Gastro & Hep 2006; 4: 1346. aminosalicylates reduce CRC.
  • -Gastroenterol 2006; 130: 1030, 1039, 1350. 600 patients followed for 35 yrs: CRC by colitis duration: 2.5% @ 20yrs, 7.6% @ 30yrs, 10.8% @ 40yrs. 5 year survival was 73% among those with cancer. 2nd study showed main CRC risk in UC pts is among those with extensive colitis.
  • -Clin Gastro & Hepatol 2004; 2: 1088. Lower cancer risk in this cohort, n=1460. CRC 0.4 @10yrs, 1.1% @ 20yrs, 2.1% @ 30yrs. Lower CRC may be due to more surgery in Rx failures & use of 5-ASA.
  • -Clinical perspectives in Gastro 1999; 2: 9 & 25. (review) surveillance/ overview take 4 bx q10cm. start p 8yrs in pancolitis & 15yrs for left-sided dz. Cancer risk: ~5% at 20yrs + 1%/yr p 20yrs in pancolitis.
  • -Gastroenterol 2003; 125: 1311. Advancement of dysplasia to cancer in UC.

Vedolizumab -another new IBD treatment

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Occasionally a parent will express concern that their child may run out of effective treatments for inflammatory bowel.  At this time, there are a limited number of effective therapies. If a patient develops reactions or antibodies to medications and/or does not have a clinical response, then the options become quite limited.

Against this backdrop, it is encouraging that new medical treatments are being tested, including Vedolizumab (Inflamm Bowel Dis 2012; 18: 1470-79).

The cited study reports the experience of using Vedolizumab in a randomized controlled phase 2 dose-ranging study in 46 patients (9 placebo, 37 vedolizumab).

Vedolizumab is “a gut-selective monoclonal antibody that antagonizes α4β7 integrin on select subsets of leukocytes binding to MAdCAM-1 on gut vascular endothelium.”  Many have considered vedolizumab to be similar to natalizumab, except it is considered  gut-specific and therefore should not increase the risk of progressive multifocal leukoencephalopathy (PML).  By altering the immune surveillance/lymphocyte tracking of the GI tract and not the brain, theoretically there should not be an increased risk of PML.

Another previous limitation of vedolizumab in small studies was the development of human antihuman antibodies (HAHA) –no joke!  HAHA occurred in up to 44% of patients in previous studies and were associated with reduced efficacy.  As a consequence, a new formulation of vedolizumab has been developed with presumably reduced  immunogenicity.

In the cited study, patients between 18-70 were recruited to receive one to three doses of vedolizumab (2, 6, or 10 mg/kg) or placebo.

Results:

  • Over 50% of vedolizumab-treated patients maintained a clinical response between days 29-253 whereas placebo response ranged between 22-33%.
  • This study was not powered for efficacy; however, the treated patients did have reduced fecal calprotectin.  At baseline, the calprotectin in the treatment groups averaged 405 μg/g and by day 113 had reduced to 54 μg/g.  In contrast, placebo group started with calprotectin of 310 μg/g and dropped to 192 μg/g during same time period.
  • HAHA were detected in 4 (11%)

According to a presentation at DDW (GEMINI I trial), more than 2500 patients have been treated in trials with vedolizumab.  None has developed PML. Encouraging results for efficacy (dosing 300mg IV q4weeks) were also noted; 1 year clinical remission noted in 45% of treated patients compared with 14% of placebo group. Digestive Disease Week 2012 – Vedolizumab Scores on Safety …)

Results of vedolizumab for Crohn’s disease are expected soon as well.

Related blog entries:

Quantifying Risk of PML with Natalizumab

Tofacitinib –a JAK Inhibitor for UC