Tag Archives: Crohn’s disease

Don’t Fix What’s Not Broken

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A recent study provides information about elective switching from infliximab (IFX) to adalimumab (ADA) in stable Crohn’s disease (CD) (Inflamm Bowel Dis 2013; 19: 761-66).  As a practical matter, patients and families inquire about switching therapy due to potential convenience and flexibility.  Thus far, there is little data to guide clinicians.  As such, the authors explored this question by designing an open-label study which would allow enrollment of any patients who had stable disease for >6 months (Harvey-Bradshaw Index ≤ 8) on IFX therapy.

In total, 29 patients with CD were enrolled with an average age of 39.  Twelve had previous resections.

Key results:

  • 21 patients (72%) were able to remain on ADA at 54 weeks.  8 patients discontinued ADA due to disease activity (n=3), side effects (n=4), or other symptoms (n=1).
  • 4 patients were restarted on IFX therapy; 1 required dose intensification.
  • At 54 weeks, 13 patients indicated a preference for IFX due to efficacy (n=9) or safety profile (n=4).  12 patients indicated a preference for ADA.  4 patients had no preference.

The authors state that a recommendation to avoid elective switching.  In their study, 28% were not able to be maintained on ADA therapy, more patients preferred IFX after experiencing both therapies, and switching back to IFX has been associated (in some) with reduced efficacy.  The main concern with an elective switch is the potential loss of response with very limited therapeutic alternatives.

The authors note that their study showed better results with an elective change than a previous study (the SWITCH trial, n=73).  In the SWITCH trial, “elective switch from IFX to ADA in patients with stable CD led to 47% of patients requiring dose intensification or interruption of treatment” in the ADA arm compared with 16% of patients who continued IFX therapy.  (Adalimumab in Crohn’s Disease Controlled by Infliximab)

The better outcomes in the current trial may have been due to selection of patients with milder disease and the more frequent use of concomitant immunosuppression.  In the current trial, 52% had concomitant immunosuppression (48% thiopurine, 4% methotrexate); in contrast, only 17% received concomitant immunosuppression in the SWITCH trial.  Another important difference was that the patients in the current trial received 160-80 loading doses rather than 80-40 induction.  Also, the trial designs were different.  The current trial enrolled patients without randomization; in contrast, the SWITCH trial randomized some patients to continue IFX and others to change to ADA therapy.

Related reference:

  • -Gut 2012; 61: 229-34. SWITCH trial.

Related blog references:

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.

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:

Where is the Journal Editor?

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A recent article is titled “Determination of Bone Age in Pediatric Patients with Crohn’s Disease Should Become Part of Routine Care” (Inflamm Bowel Dis 2013; 19: 61-65). (Thanks to Ben Gold for suggesting this reference.)

Does the study merit the authors’ conclusion that ‘determination of bone age (BA) should become the standard of care in pediatric Crohn’s disease (CD) patients, allowing clinically meaningful interpretation of growth…leading to improved treatment recommendations?’

No.  This small study (n=49, 84% Caucasian) simply showed that a lot of pediatric CD patients have a delayed bone age.  This is not a novel finding.

Specifically, the mean BA Z score was -1.40 ± 1.5 in this population and 41% had a BA Z score of < -2.0.  This cross-sectional study was conducted between 2007-2009.  Patients were consecutively approached for enrollment during this time period.

Clinical factors associated with delayed bone age included Caucasian race, Tanner stage 1-3, history of steroid exposure, colonic disease location, azathioprine/6-mercaptopurine usage, and female sex.  Interestingly, these variables are not entirely consistent with prior studies in which male sex was associated with delayed bone age.

The reason why the conclusion is a far-reach is that there is no data in the study showing how bone age influences any clinical decision-making in these patients.  There is no information on cost-effectiveness of their proposed “standard of care.”  There is no longitudinal data to suggest that the delayed BA or the recognition of a delayed BA  resulted in a different outcome.

My conclusion:

Many pediatric patients with CD have delayed BA and some may benefit from a BA determination.  I think extrapolating a much broader conclusion from this study is not warranted.

Vitamin D deficiency and metabolism in pediatric Crohn’s disease

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As noted in previous blog posts (see links below), vitamin D has received a great deal of attention with a number of chronic diseases.  In this latest study from CHOP, the incidence and mechanisms of vitamin D deficiency in pediatric Crohn’s disease are explored (Inflamm Bowel Dis 2013; 19: 45-33).

At diagnosis (2002-2005), Crohn’s disease (CD) participants (n=78) had their serum vitamin D assays and parathyroid hormone (PTH) levels checked.  Then, these values were sequentially followed at 6 months, 12 months, and a median of 43 months later (n=52). The average age of the CD patients was 12.7 years.

Key findings:

  • 42% of CD participants were 25-OH D deficient (<20 ng/mL) with an odds ratio of 2.1 compared with controls.
  • Among patients with 25-OH D <30 ng/mL, CD patients had a lower PTH than controls.
  • At final visit, 3% remained 25-OH D deficient and PTH levels corrected.
  • Risk factors, besides CD, for vitamin D deficiency: black race (OR 10.4), visit in winter (OR 2.4), age 12 to <15 (OR 2.7), age >15 (OR 3.2).  Greater disease activity was associated with lower vitamin D levels at baseline.

Implications of this study:

  1. Vitamin D deficiency normally causes secondary hyperparathyroidism.  With newly-diagnosed CD, there was a relative hypoparathyroidism that resolved with therapy.  “It is conceivable that proinflammatory cytokines associated with CD …prevent an appropriate PTH response.”
  2. The authors state that ‘vitamin D deficiency likely contributes to the pathogenesis of CD through effects on T and B lymphocyte, macrophage, and dendritic cell regulation.”  Correcting vitamin D deficiency may improve CD treatment response in addition to potential improvements in bone health.

Related posts:

Best strategy for dose escalation of infliximab

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At least 50% of patients with long-term infliximab therapy require dose escalation.  However, dose escalation can mean doubling the dose or shortening the infusion interval.  So which strategy is best?  A recent article provides some insight into this question (Inflamm Bowel Dis 2012; 18: 2026-33).

In this multicenter retrospective study of 168 Crohn’s disease (CD) patients, the outcome of patients who had dose-doubling (n=112) to 10 mg/kg/dose/8 weeks was compared with patients whose infusion intervals were halved to 5 mg/kg/dose/4 weeks (n=56).  The entire cohort had a mean age of 25 years and a mean disease duration of 12 years.  39% had a history of previous intestinal surgery.  Concurrent use of thiopurines was noted in 68% and concurrent use of methotrexate in 4%.

Sustained response at 1 year to dose-doubling strategy was 50% compared with 39% in the interval-halving group.  Favorable factors included nonsmoking status, normal C-reactive protein, and CD diagnosis between 16-40 years of age.

It is noted that a subsequent dose escalation was experienced by 28 of the 87 patients who had loss of response after first dose escalation.  Regained response occurred in 9 (32%) of this cohort.

The authors indicate that increasing the dose to 10 mg/kg/8 weeks is likely preferable due to convenience and cost.  At the same time, it is apparent that shortening the infusion interval is not likely to be more effective than dose doubling.

Related blog entries:

More “Survivin” in Crohn’s disease

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Survivin is a member of the inhibitors of apoptosis family.  It helps regulate cell division and prevents cell death.  (Gastroenterology 2012; 143: 1017-26).  While survivin has been shown to be important in cancer, it appears to be important in inflammatory and autoimmune disorders.

In the referenced study, lamina propria T cells (LPT) were isolated from mucosal samples of patients with Crohn’s disease (CD), ulcerative colitis (UC), and controls.  Expression of survivin was assessed by immunohistochemistry, confocal microscopy, and immunoblotting.

LPTs from patients with Crohn’s disease had increased survivin levels; this was not seen in control patients or UC patients.  Furthermore, the investigators showed that the survivin (bound to heat shock protein) was resistant to proteasome degradation.

Implications of this study: 

Survivin may have crucial consequences for CD and other inflammatory/autoimmune diseases; cell proliferation and apoptosis alteration may be important in the pathogenesis of  in these disorders.

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