Category Archives: inflammatory bowel disease

Simponi (Golimumab) Approved for Ulcerative Colitis

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The U.S. Food and Drug Administration on 5/15/13 approved a new use for Simponi (golimumab) injection to treat adults with moderate to severe ulcerative colitis.

Here’s the link:

FDA approves Simponi to treat ulcerative colitis

From the link:

The U.S. Food and Drug Administration today approved a new use for Simponi (golimumab) injection to treat adults with moderate to severe ulcerative colitis.

Simponi works by blocking tumor necrosis factor (TNF), which plays an important role in causing abnormal inflammatory and immune responses. Previously approved to treat rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis (arthritis affecting the joints in the spine and the pelvis), Simponi is now approved to treat adults with moderate to severe ulcerative colitis that is resistant (refractory) to prior treatment or requires continuous steroid therapy.

Ulcerative colitis is a chronic disease that affects about 620,000 Americans. It causes inflammation and ulcers in the inner lining of the large intestine and is one of two main forms of chronic inflammatory bowel disease. The inflammation can lead to abdominal discomfort, gastrointestinal bleeding, production of pus and diarrhea.

“Simponi is an important new treatment option for patients with moderate to severe ulcerative colitis,” said Andrew E. Mulberg, M.D., deputy director of the Division of Gastroenterology and Inborn Errors Products in the FDA’s Center for Drug Evaluation and Research. “It is critical that patients suffering from the serious and painful symptoms of ulcerative colitis have additional treatment options since patients experience the effects of the disease and respond to treatments differently.”

The safety and effectiveness of Simponi for ulcerative colitis were established in two clinical studies. Evaluations of patients included measures of stool frequency, rectal bleeding, endoscopic findings and a physician’s overall assessment.

In the first study, 513 patients with moderate to severe ulcerative colitis who could not tolerate or failed to respond to other therapies were randomly assigned to receive Simponi or a placebo. Results showed that a greater proportion of Simponi-treated patients achieved clinical response, clinical remission and, as seen during endoscopy, had improved appearance of the colon after six weeks compared with the placebo group.

In the second study, 310 patients with moderate to severe ulcerative colitis who were responders to Simponi were randomly assigned to receive Simponi or placebo. A greater proportion of Simponi-treated patients maintained clinical response through week 54 and had clinical remission at both weeks 30 and 54.  

The most common side effects in patients treated with Simponi are upper respiratory infection and redness at the site of injection. Patients treated with Simponi are at increased risk of developing serious infections, invasive fungal infections, reactivation of Hepatitis B infection, lymphoma, heart failure, nervous system disorders and allergic reactions.

Liver Injury from Anti-TNF Agents

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While anti-TNF agents have been associated with drug-induced liver injury (DILI), it has been difficult to get a handle on how much importance to place on this.  A recent study provides more data and some reassurance (Clin Gastroenterol Hepatol 2013; 11: 558-64).

The authors searched the U.S. DILI Network database from 2003 to 2011 and describe 6 cases of anti-TNF DILI; in addition, they searched PubMed for articles related to anti-TNF agent associated hepatotoxicity and identified an additional 28 cases. Other causes of liver disease were excluded in these patients, including reactivation of hepatitis B, and acute viral hepatitis (eg. hepatitis C, hepatitis E).

Results of anti-TNF hepatotoxicity:

  • 26 cases due to infliximab, 4 cases due to etanercept, and 4 due to adalimumab.
  • Based on scoring system, the anti-TNF agent was considered a definite cause of DILI in 1 (3%), very likely in 21 (62%) and probable in 12 (35%).
  • Median latency (duration of therapy before onset of DILI) was 13 weeks with a range of 2-104 weeks.
  • 22 (67%) had positive anti-nuclear and/or smooth muscle antibodies.  15 of 17 of these patients had liver biopsy features consistent with autoimmunity.
  • Among those 22 with autoimmune features, there was a higher peak alanine aminotransferase compared with the 12 without these features (784 vs 528 U/L)
  • Favorable outcome: all but one patient improved after discontinuation of the implicated drug; 12 received corticosteroids. One patient with underlying cirrhosis underwent liver transplantation after infliximab-induced liver injury.

While the authors note the potential for a class effect of anti-TNF agents, in studies from patients with psoriasis, there was a lack of cross-toxicity between etanercept and infliximab.

Take-home messages:

The risk of hepatocellular injury from anti-TNF agents is very low.  DILI due to anti-TNFs often have autoimmune features. The prognosis is favorable, and alternative anti-TNFs can be given after resolution.

Related blog links:

“Family Feud” for Pediatric Crohn’s Abscess Management

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Initially, this blog entry was titled “What is the best way to manage an intra-abdominal abscess in pediatric Crohn’s disease?”  My answer was simple: it depends on who you ask (Inflamm Bowel Dis 2013; 818-25).  As I thought about this study, the responses reminded me of “Family Feud” minus Richard Dawson.

This survey examined the responses of NASPGHAN members.  Of the initial 1608 emails which were delivered, 248 fully completed surveys.  25% of respondents were in practice for >20 years and 26% treated >50 patients with Crohn’s disease (CD). 87% of respondents were from U.S.

  • What is the best way to image initially?  52% recommended CT scan, 26% MRI, and 21% ultrasound.
  • What is the best modality for followup imaging? 47% ultrasound, 33% MRI, and 13% CT
  • Antibiotics or drainage for abscess <2 cm? 61% recommended antibiotics; 51% would treat for 3-4 weeks, whereas 19% for 1-2 weeks.
  • Antibiotics or drainage for abscess >2 cm? 28% would attempt antibiotics alone
  • When is surgery indicated? 75% said only in select cases after completing antibiotics and interventional radiology drainage.
  • Anti-TNFα therapy?  The survey also questioned the shortest preoperative interval one would prescribe anti-TNFα therapy.  The results ranged from 12% for <1 week to 45% who would not give anti-TNFα therapy at all.

The authors note that there is “a paucity of research and practice guidelines for the optimal management of children with intra-abdominal abscess.”  There were no trends in management identified based on practitioner level of experience.  Some answers to the questions are alluded to by the authors but not expressed definitively. For example, “several studies have reported a lack of association between infliximab and an increased rate of postoperative complications.” “Most infections that occur while on anti-TNFα therapy tend to be opportunistic, not bacterial.”

The study’s conclusions are limited by the low participation rate.  In addition, when physicians are confronted with a specific situation, their response in practice may be different than in a theoretical scenario.  However, it appears that the answers to these important questions are closer to guesses on a game show rather than best care.  More research and collaboration is needed to reduce this highly variable care and determine the most effective approach.

Related blog entries:

Global increases in IBD incidence

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Two more studies have shown increasing incidence of pediatric inflammatory bowel disease.

First in Victoria, Australia (mostly Melbourne) (Inflamm Bowel Dis 2013; 19: 1-6).

Over a 60-year span (1950-2009), a retrospective review was undertaken of ulcerative colitis (UC) pediatric patients. In total, 342 children were diagnosed with UC. Key finding: The number of reported cases increased by 11-fold during the study period with a marked increase since 1990 (0.15 –>1.61/100,000).  In addition, recently diagnosed children have had more extensive disease.

Next in Spain (Inflamm Bowel Dis 2013; 19: 73-80).

This retrospective study from hospitals’ databases looked at the incidence between 1996-2009 in the pediatric population (<18 years).  A total of 2107 patients were identified: 1165 with Crohn’s disease, 788 ulcerative colitis, and 154 IBD unclassified. Median age at diagnosis was 12.3 years.  Key finding: in the last 14 years, pediatric IBD incidence has almost tripled (0.9 –>2.8/100,000).

Both of these studies have limitations related to large retrospective reviews in terms of potential problems with capturing all of the patients and the potential for misdiagnosis.  However, the trend is clear.  In addition, these studies show incidence rates comparable to several other Western studies.  The increasing incidence of IBD ‘argue for a common environmental factor in their pathogenesis.’  While interest has focused on microbial factors, the basis for this increased incidence currently remains elusive.

Related blog posts:

True red flags in recurrent abdominal pain

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For pediatricians and pediatric gastroenterologists alike, identifying which children need additional workup for recurrent abdominal pain (RAP) is facilitated by recognizing “red flags.”  “Red flags” are clinical features that indicate a higher likelihood of a nonfunctional disorder.  A recent study notes that reports of waking from sleep and joint pains do not distinguish functional from nonfunctional causes of RAP (J Pediatr 2013; 162: 783-7).

This study, performed between 2005 to 2008, had patients presenting to an outpatient pediatric gastroenterology clinic for RAP prospectively complete a detailed questionnaire. Data, though, was extracted retrospectively. In this population (n=606), 85% were Caucasian.  After their evaluation, patients with functional GI diseases (FGID, n=478) were compared with patients confirmed with Crohn’s disease (CD, n=128).  All FGIDs underwent biochemical testing, 41% had upper endoscopy, and 32% underwent colonoscopy.

Additional key findings:

  • Using a tree analysis, the cumulative sensitivity for Crohn’s disease was 54% with the presence of anemia, 78% when blood in stool was added to anemia, and 94% when weight loss was added as well.
  • FGID patients were more likely to report stress and headaches, more likely to have family history of FGID, and less likely to have anemia, hematochezia, or growth issues.
  • FGID patients were more likely to experience vomiting.

The sensitivity and specificity of these symptoms/signs will vary based on the population.  For a general pediatric clinic, it is likely that the sensitivity of these red flags would remain high; the specificity would likely be lower than in a pediatric gastroenterology office due to the increased prevalence of functional diseases in the general pediatric setting.

Related blog posts:

Paris Classification of Pediatric Crohn’s Disease

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A recent study described the phenotypic results of a prospective, web-based registry of new-onset pediatric inflammatory bowel disease (IBD) in 17 European countries and Israel (Inflamm Bowel Dis 2013; 19: 378-85).

The EUROKIDS Registry included 582 pediatric Crohn’s Disease (CD) patients classified according to Paris classification:

  • 16% with L1 involvement of the terminal ileum only
  • 27% with L2 colonic involvement only (more common in younger children)
  • 53% with L3 involvement of the ileum and colon
  • 4% with L4 isolated upper GI disease.  Upper tract disease can be further subdivided into L4A esophagogastric disease and L4B jejunal/proximal ileal disease.
  • *Upper GI disease can coexist with L1, L2 or L3.  In this study, 34 (6%) had esophageal involvement, 102 (18%) had gastric involvement, and 100 (17%) had duodenal involvement.
  • In this study, 165 of the 507 patients did not undergo small bowel imaging. Of those who did, 64% had small bowel follow-through, 38% had MRI, 6% CT, and 5% video capsule.

Other findings:

  • Perianal disease (e.g.. fistula or abscess) noted in 9% at diagnosis.
  • Granulomas were found in 43% of patients who had biopsies from at least 10 segments of the GI tract
  • 82% of CD patients had nonstricturing, nonpenetrating disease (B1), 12% had stricturing disease (B2) and 5% had penetrating disease (B3).  2% had both stricturing and penetrating disease.
  • Extraintestinal manifestations were seen in 20% of the study population.
  • The authors estimated that the diagnostic yield of upper endoscopy  in the workup for pediatric IBD was  7.5% and for intubation of the ileum/ileoscopy 13%.

Study limitations included a selection bias of centers and pediatric gastroenterologists with a special interest in IBD.  Also, in this registry, older adolescents are underrepresented. In about one-third of the centers, patients older than 15 years are seen primarily by adult gastroenterologists.

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:

Budesonide for Ulcerative Colitis

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Budesonide (Uceris) has been formulated with the MMX delivery technology and now has been FDA approved for mild to moderate ulcerative colitis in adults.  The potential advantage of budesonide compared with conventional corticosteroids is for targeting anti-inflammatory activity to the colon with less systemic side effects.  The potential downside includes the high cost.  According to one website (see below), the average wholesale cost is just below $1500 per month.  In addition, only a minority of individuals responded to budesonide in published studies:

Induction of Remission in Studies 1 and 2 (reference below)

Treatment Group

Study 1 n/N (%)

Study 2 n/N (%)

UCERIS 9 mg

22/123 (17.9)

19/109 (17.4)

UCERIS 6 mg

16/121 (13.2)

9/109 (8.3)

Reference Arm*

15/124 (12.1)

13/103 (12.6)

Placebo

9/121 (7.4)

4/89 (4.5)

Treatment Difference between UCERIS 9 mg and Placebo (95% CI)†

10.4% (2.2%, 18.7%)

12.9% (4.6%, 21.3%)

Data for budesonide for pediatric patients with ulcerative colitis is not available.

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.