Tag Archives: Crohn’s disease

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

CHOOSE TNF TRIAL

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While most physicians consider drug efficacy as the most important factor in choosing therapy, this is not always the determinant factor in patient choice.

The “CHOOSE TNF TRIAL” (Inflamm Bowel Dis 2012; 18: 1523-30) was a prospective survey of 100 adult patients with Crohn’s disease who were naive to anti-TNF therapy (infliximab, adalimumab, certolizumab).

Most important to patients:

  • Ease of use 69%
  • Time for therapy 34%
  • Time between applications 31%
  • Evidence for efficacy 19%
  • Fear of syringes 10%

Patient choice: Adalimumab preferred in 36%, certolizumab in 28%, and infliximab in 25%

While patient concerns need to be considered, others have shown that physician opinion is an important factor for patient decisions (J Rhemumatol 2008; 35: 618-24).  The discussion notes that “three anti-TNF drugs used in inflammatory bowel disease treatment have not been compared side-by-side in clinical trials.”  Thus far in pediatrics, infliximab is the only TNF approved for clinical use; as such, the other anti-TNF agents have been used primarily when infliximab loses effectiveness.

One drawback with injectable medications has been reduced adherence; up to 50% of patients fail to maintain regular injection interval; in addition, in patients who have had intravenous infusions (rather than patients who are naive) it is preferred over injections (Jay Popp, medical director of Janssen pharmaceuticals–personal communication).

As such, when patients receive infusions (eg. infliximab), closer followup and better adherence are more likely in comparison to injections.  This certainly improves efficacy.

Related blog entries:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression

How sensitive is Calprotectin?

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A recent article suggests that fecal calprotectin, while good, is not as good as endoscopy at detecting mucosal disease in pediatric Crohn’s disease (Inflamm Bowel Dis 2012; 18: 1493-97).

In this study, 60 consecutive children with new onset untreated Crohn’s disease (diagnosis based on Porto criteria -JPGN 2005; 41: 1-7) were enrolled in ESPGHAN growth study.  The data for this study was collected prospectively (21 investigators from multiple sites).  The calprotectin values were obtained prior to treatment.

Median fecal calprotectin values were 2198 μg/g in patients with isolated small bowel disease; this did not differ significantly from the value of 2400 μg/g in patients with colonic disease (with or without small bowel disease).

Fecal calprotectin was elevated in 95% of patients; this outperformed CRP (86%) and ESR (83%) as a marker for Crohn’s disease.  In the three children with normal calprotectin values, the serum inflammatory markers were normal in all three and two had minimal endoscopic findings.  The histology findings for these three children were not reported.

In my experience, fecal calprotectin has been very useful as a marker for Crohn’s disease and has helped identify some atypical cases by increasing my clinical suspicion.  I have had two patients with high calprotectin values who had normal-appearing mucosa with panendoscopy; they both had small bowel (jejunal) Crohn’s disease; one of these patients did have granulomas identified histologically.

While I realize that no test is perfect, I think additional studies are warranted to determine the actual sensitivity of this test for Crohn’s disease.  The sensitivity of calprotectin may yet be higher than the 95% reported in this study.

Related posts:

Biomarkers identify patients who benefit and how  Multiple additional calprotectin references with this link

Abatacept for IBD?

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Doesn’t work (Gastroenterology 2012; 143: 62-69).  While this study indicates that Abatacept was not effect for either Crohn’s disease (CD) or ulcerative colitis (UC), it was useful nevertheless.

In brief, the study examined four placebo-controlled trials of abatacept for induction and maintenance therapy in both CD and UC.  The induction studies included 451 CD patients and 490 UC patients.  The maintenance studies had 90 CD and 131 UC patients.

Results for induction:

  • CD: Clinical response: 17%, 10%, 15% for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 14%
  • UC: 21%, 19%, 20%  for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 29.5%

Results for maintenance:

  • CD: 24% abatacept vs 11% placebo
  • UC: 12.5% vs 14% placebo

The premise of this study was that T-cell activation requires co-stimulatory signaling via T cell CD28 and CD80 or CD86 on the antigen-presenting cell.  Abatacept (CTLA4-Ig) which is effective for psoriasis, rheumatoid arthritis, and juvenile idiopathic arthritis was thought to have potential; it blocks costimulation pathways involved in T-cell activation which was shown to be helpful in animal model of colitis.

So why did it not work?  The editorial in the same volume (pages 13-16) suggests the following possibilities:

  • Abatacept would be more likely to work when naive T cells are actively recruited into inflammation rather than memory T cells which are predominant in IBD
  • CD28-related pathways may not be important in IBD pathogenesis
  • Abatacept may have impeded Treg function in addition to preventing T-cell activation (explained in Fig 1D)
  • Blockade of CD28 pathways could have resulted in unfavorable changes in cytokine profiles from T-cell differentiation (Th1 vs Th2)

The implication of this study is that not all T-cell mediated inflammatory disease respond to the same treatment approaches.  The complexity of intestinal immune responses necessitates ongoing clinical studies to determine which promising therapies will be useful.

What is the GRADE of GM-CSF in IBD?

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I was not familiar with the acronym “GRADE” which refers to an analysis by Cochrane review:

Grading of Recommendations Assessment, Development and Evaluation.

With regard to Sargramostim (GM-CSF), GRADE analysis indicates that GM-CSF does not appear more effective than placebo for Crohn’s disease (Inflamm Bowel Dis 2012; 18: 1333-39).

Three randomized studies were examined with 537 patients.  Clinical remission was achieved in 25.3% of GM-CSF patients compared with 17.5% of placebo-treated patients (p=0.17).  Clinical response (100-point CDAI score drop) was noted in 38.3% of GM-CSF group compared with 24.8% of placebo group (p=0.06).  Adverse effects were not statistically different either.

In my view, there are probably populations of IBD patients who will be benefit from GM-CSF.  The difficulty is identifying which groups.

Additional references:

  • -Gastroenterology 2011; 141: 28, 208.  GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -NEJM 2005; 352: 2193. Leukine decreased Crohn’s dz severity: 48% c decrease in CDAI of >100 (vs 26% placebo). injection & bone pain -common; 3 pts (n=81 in leukine group) c serious rxns- migraine, weakness/lethargy, R-sided weakness (?demyelinating d/o)
  • -Lancet 2002; 360: 1478-1481. use of GM-CSF for Crohn’s.

More on IBD medicine risks

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As noted in a recent post (Assessing and discussing risk of lymphoma in IBD), diagrams can be useful to convey the absolute risks for IBD medicines; this risk is often poorly understood by patients and their families. Two articles add additional insight that may help with counseling. (Thanks to Ben Gold for forwarding these articles.)

  • Am J Gastroenterol 2012; 107: 964-70.
  • Am J Gastroenterol 2012; 107: 1051-63.

The first article reviews the risk of lymphoma with regard to inflammatory bowel disease treatment decisions.  Important points in this article include the following:

1. Relative risks may appear large while absolute risk may be quite low.  The estimate for absolute risk for lymphoma:

  • For azathioprine or 6-mercaptopurine: 1 additional case for every 4357 persons treated
  • For anti-TNF (infliximab, adalimumab, certolizumab): 1 additional case for every 2380 persons treated between ages 20-29.

2. Framing the discussion with regards to risk of continued active disease, continued exposure to steroids, and potential need for surgery can be helpful:

  • “It would take only three patients discontinuing their azathioprine to cause one additional relapse of IBD per year”
  • Seven patients stopping anti-TNF therapy would result in an additional hospitalization each year and 14 patients stopping anti-TNF therapy would result in an additional abdominal surgery each year
  • While the ‘relative risks of lymphoma associated with these medications may sound inappropriately large…A more appropriate comparison is the absolute risk of lymphoma versus the absolute risk of active/untreated disease or corticosteroid therapy.’  An example: if 2000 patients with IBD took one of these medications (eg. anti-TNF agent), probably one patient will develop a lymphoma; however, if none of those patients took an anti-TNF agent, it would result in more than 100 hospitalizations and nearly 60 surgeries.

3. “Patients can also be very sensitive to numerators and pay relatively insufficient attention to denominators.” This has been called “anchoring and adjustment” or “base-rate neglect.”  This issue has to do with “numeracy;” this is defined as the basic math skill needed for health-related activities. To help families, consider the following:

  • avoid labels such as “very low” when describing risk
  • use absolute risk data
  • use similar denominators when comparing risks
  • use visual aids

The second study cited is a pooled analysis of infections, malignancy, and mortality risks associated with infliximab and immunomodulator treatment in adult IBD patients.  This study collected safety data from 10 previous trials.  Five of these trials were randomized, controlled studies.  Table 3 and Table 4 detail extensive safety data for immunomodulators (eg. azathioprine) and for infliximab respectively.

With regard to immunomodulators, the combined studies enrolled 947 on immunomodulators in comparison to 1170 without immunomodulators.  With ulcerative colitis (UC) patients but not with Crohn’s disease (CD), immunomodulator use increased the risk of infections (120/100 patient years versus 92.5 among placebo-treated patients).  CD patients, but not UC patients, had an increased risk of malignancy with immunomodulator use (1.84/100 patient years compared with 0/100 patient years in the control group).  With the exception of the SONIC study, use of immunomodulator was not randomly assigned.  So, some of the increased risk in these patients could be due to having more severe IBD rather than due to the medication.

With regard to infliximab, and in contradiction to the previous article’s estimated risks, infliximab treatment did not appear to affect the incidence of infection, mortality, or malignancy.  This study and several others have not demonstrated an increased risk of malignancy with infliximab. This could be that even with this pooled data it is difficult to detect a rare adverse outcome.  More prospective studies and more long-term followup will be needed to truly determine the risk.

While it is known that these agents may increase the risk of some infections, the limited increase in infections which was detected only with immunomodulator use in UC is likely due to a lowered risk of infection when active inflammatory bowel disease is controlled.  A much bigger risk factor for infection is the use of corticosteroids.  When effective IBD medications are administered, this helps control inflammation and allows tapering of corticosteroids.

Related posts:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression

Delays in diagnosing Crohn’s disease

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Delayed diagnosis remains a problem in Crohn’s disease (Inflamm Bowel Dis 2012; 18: 496-505).  This study included a total of 1591 IBD patients (932 CD, 625 UC, 34 indeterminate colitis) from the Swiss IBD cohort study (SIBDCS).

  • Diagnostic delay in CD patients was significantly longer compared to UC patients (median 9 versus 4 months, P < 0.001).
  • 75% of CD patients were diagnosed within 24 months compared to 12 months for UC and 6 months for IC patients.
  •  Independent risk factors for long diagnostic delay in CD (>24 months)  included age <40 years at diagnosis (odds ratio [OR] 2.15, P = 0.010) and ileal disease (OR 1.69, P = 0.025)
  • In UC patients, nonsteroidal antiinflammatory drug (NSAID intake (OR 1.75, P = 0.093) and male gender (OR 0.59, P = 0.079) were associated with long diagnostic delay (>12 months)

Diagnostic delay has been a problem for quite a long time; in children, delays can worsen growth failure.  In 1988, Kanof et al reported that decreased height velocity preceded the diagnosis of CD in 88% of their patients (pediatric cohort). In addition, 42% of their population had a reduction in height velocity before intestinal symptoms were noted.

Especially when there is not a lot of colonic disease, a high degree of suspicion needs to be maintained.  This is not difficult for pediatric gastroenterologists.  For pediatricians and family physicians, the increased availability of biomarkers (Biomarkers identify patients who benefit and how) should be helpful in reducing diagnostic delays.

Additional blog entries and references:

  • Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology.1988; 95 :1523– 1527.
  • Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America.  North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Colitis Foundation of America, Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, et al.J Pediatr Gastroenterol Nutr. 2007 May; 44(5):653-74.

Upper endoscopy useful for identifying Crohn’s disease

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In a large pediatric study, the value of upper endoscopy in detecting Crohn’s disease (CD) is evident (JPGN 2012: 54: 753-57).

While the majority of pediatric patients with suspected inflammatory bowel disease probably undergo both upper endoscopy and colonoscopy, the added value of upper endoscopy remains unclear.  In this retrospective study with 171 pediatric patients (70 with CD, 33 with UC, 68 Non-IBD), 11% of children with CD had the diagnosis established based “solely” on the finding of granulomatous inflammation in upper intestinal tract (along with clinical symptoms).

Other key findings:

  • Presence of histologic gastric inflammation in CD patients compared to control patients was significantly higher (p<0.0001) but not significantly higher compared to UC patients (p=0.19).
  • Duodenal inflammation was highly suggestive of CD compared with both UC and non-IBD patients.  This occurred in 19% of CD patients compared with 0% and 1% in the other groups respectively.
  • 21 children (30%) had granulomas identified in upper GI tract (19 in stomach).  In 8 (11%), the diagnosis was changed based on this finding.  Prior to histology, the tenative diagnosis: 2 UC, 4 IC, 2 non-IBD.
One curious finding was a the presence of “perianal abscess/fistula” with similar frequency in CD patients and UC patients based on their Table 2 Patient Characteristics.
Additional references:
  • -IBD 2009; 15: 1101-4.  Presence of UGI disease in IBD.
  • -JPGN 2007; 44: 653.  NASPGHAN report on discriminating/labelling UC vs. Crohn’s.
  • -JPGN 2002; 35: 636-40. Advocates panendoscopy for all new IBD.  Granulomas in 28% of EGDs & 71% of UC pts c some abnl on EGD; 82% Crohn’s c abnl EGD.
  • -JPGN 2005; 41: abstract 181 (page 549).  UGI identified granulomas in 15% that were not identified elsewhere.
  • -JPGN 2004; 39: 257-61. Diagnostic role of EGD for pediatric IBD.
  • Magnetic resonance enterography for Crohn’s disease

Quantifying Risk of PML with Natalizumab

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Given the limited number of treatment options for inflammatory bowel disease, when Natalizumab became available, there was a great deal of enthusiasm.  This quickly diminished as reports of progressive multifocal leukoencephalopathy (PML) emerged.  So far, I have not prescribed this agent.

Due to its efficacy for multiple sclerosis and IBD, there has been continued interest in understanding the risk for PML (NEJM 2012; 366: 1870-80, editorial pg 1938-39).

Key findings:

  • 212 cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000)
  • Three main risk factors: positive JC-virus antibody, previous use of immunosuppressants, and receiving natalizumab more than 2 years

Patients who were negative for anti-JC virus antibodies had an incidence of 0.09 cases or less per 1000 patients.  Among patients who test positive for anti-JC virus antibodies, the risk remained <1 per 1000 patients if no use of immunosuppressants and 2 per 1000 if prior use of immunosuppressants during the first two years of therapy.  The risks were five-fold higher after 2 years in both groups.

While the risks are becoming more clear, the benefits of natalizumab are fairly well-established for multiple sclerosis.  Natalizumab decreased the annualized rate of relapse among patients with relapsing–remitting multiple sclerosis by 68%.

Additional references:

  • -NEJM 2009; 361: 1067, 1075, 1081.  Asymptomatic detection of JC virus common in urine noted in patients Rx’d with natalizumab (19% baseline to 63% on Rx); actual leukoencephalopathy ~1/1000 patients.
  • -Gastroenterol 2007; 132: 1672.  ENCORE trial.
  • -JPGN 2007; 44: 185. n=31 children/adolescents.  55% response, 29% remission; dosed at 3mg/kg.
  • -IBD 2007; 13: 2.  n=79.  Trial of combination natalizumab & infliximab.
  • -NEJM 2006; 354: 899, 911, 924.  Natalizumab slows progression of MS.  Risk of PML due to JC virus 1:1000 in 18 months of Rx.
  • -NEJM 2005; 353: 1912/1965.  Natalizumab not significantly effective for Crohn’s in this study
  • -NEJM 2005; 353: 362, 369, 375, 414.  3 cases of PML associated with Natalizumab
  • -JPGN 2004; 39: S49 [abstract 0107].  Natalizumab in 38 adolescents was effective (Hyams et al).
  • -Gastroenterol 2004; 126: 1574-81. review.  Natalizumab benefitted subjects with elevated CRP. (dosing 300mg every 4 weeks.)
  • -NEJM 2003; 24-32 & 68.  Natalizumab improved response rates in pts c Crohn’s dz (similar to infliximab).  Drug blocks alpha4 integrins which are required for lymphocytes to enter the intestine.
  • -Gastroenterol 2001; 121: 268-74. Infusion of 3mg/kg decreases CDAI in Crohn’s dz.