IPAA (Pouch) for Crohn’s Disease and Indeterminate Colitis

Posted on September 1, 2017 by gutsandgrowth

A recent review (S Chang, B Shen, F Remzi. Gastroenterology & Hepatology 2017; 13: 466-75 Full text link: When Not to Pouch: Important Considerations for Patient Selection for Ileal Pouch-Anal Anastomosis) makes recommendations regarding Ileal pouch-anal anastomosis (IPAA) for Crohn’s disease and indeterminate colitis. Key points:

In CD patients with isolated colitis and without perianal disease, “there were no differences in the rates of postoperative complications, pelvic sepsis, or pouch failure compared with UC patients” (GE Reese et al. Dis Colon Rectum 2007; 50: 239-50).
Rates of pouch retention for CD (Table 2) ranged from 43% to 94% in 19 studies. Most of these studies had small numbers (less than 40 patients). In the two largest studies with 97 patients and 150 patients, both with ~10 year followup, pouch retention rates were 74% and 87% respectively.
“Patients carrying the diagnosis of IC have pouch function on par with patients with UC, with no significant difference in the number of bowel movements…However, ..are more likely to develop CD of the pouch. Nevertheless, pouch failure rates among IC, IBD-unclassified, and UC are similar in multiple cohorts.”
Rates of pouch retention for IC ranged from 73%-100% among the 13 cited studies, though only 2 studies reported rates less than ~90%. The two largest studies with ~340 patients had retention rates of ~95% and followup of 3.4 yrs and 10.2 years.

This review also discusses IPAA and other issues including obesity (which increases the likelihood of complications), sphincter dysfunction, elderly patients, and radiation therapy.

Of note, recent ESPGHAN IBD Porto Group guideline for surgical Crohn’s disease management in children (J Amil-Dias et al JPGN 2017; 64: 818-35) at first glance seems to be at odds with Chang et al recommendations:

“Statement 8. Ileal pouch-anal anastomosis is not recommended when a patient has CD. (Agreement 100%)”
The body of the report is more nuanced: “There is, however, recent growing evidence that supports highly selective use of restorative proctocolectomy with ileal pouch-anal anastomosis for CD. These patients have isolated colonic CD and no evidence of ileal or perianal involvement.”

To me, statement 8 should have been worded to include “except in limited circumstances.” As it stands now, it misleads those who do not carefully review the entire report.

My take: The report by Chang et al makes a strong case for its conclusion: “Although it is true that the diagnosis of CD is a potential contraindication to IPAA, patients with isolated Crohn’s colitis may thrive after pouch surgery. At this time, patients with isolated Crohn’s colitis (without perianal disease or small bowel involvement) have good pouch retention rates.” Their review prompted me to look more closely at the ESPGHAN IBD Porto Group guideline; their Statement 8 recommendation is, in fact, quite misleading.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Keyhole view , looking into the Rotunda UVa, of Thomas Jefferson (or TJ for those in the know)

Good Safety Data on Infliximab vis a vis Malignancy and Hemophagocytic Lymphohistiocytosis

Posted on August 2, 2017 by gutsandgrowth

Using data from 5766 pediatric participants with inflammatory bowel disease in a prospective DEVELOP study (JS Hyams, MC Dubinsky et al. Gastroenterol 2017; 152: 1901-14) provide more reassurance regarding the safety of infliximab. This study took place between 2007 to 2016 and accounted for 24,543 patient-years of followup. While the study examined rates of malignancy, the SEER database does not include non-melanoma skin cancer; thus, the authors did not have a suitable comparator for this outcome; there were two cases of basal cell carcinoma in the study population. This article’s abstract was published on this blog previously: Infliximab Not Associated with Malignancy

Key findings:

There was NO increased risk of malignancy or hemophagocytic lymphohistiocytosis (HLH) in patients exposed to infliximab as monotherapy.
Malignancy risk was 0.46 per 1000 patient-years in patients with infliximab exposure compared with 1.12/1000 patient-years in patients who had no exposure to biologics.
HLH risk was 0 in those with infliximab monotherapy compared with 0.56 per 1000 patient-years in those who had no exposure to biologics.
Patients exposed to thiopurines with or without biologics did have increased risks of malignancy compared with comparative populations. 13 of 15 patients who developed a malignancy and all 5 patients who developed HLH had thiopurine exposure.
Thiopurine exposed patients had 0.75 malignancy events per 1000 patient-years compared to 0.27 malignancy events per 1000 patient-years for patients who had no thiopurine exposure
Thiopurine exposed patients had 0.29 HLH events per 1000 patient-years compared to 0 HLH events per 1000 patient-years for patients who had no thiopurine exposure
In their discussion, the authors note that after discontinuation of thiopurine therapy for 1 or more years, the standardized incidence ratio (SIR) for malignancy approached the non-exposed group (1.48 compared to 1.30); whereas ongoing or recent thiopurine exposure had SIR of 4.45.

Limitations: Study duration (<10 years). Hard to detect changes in rare malignancies

My take: In this largest prospective pediatric cohort to date, there is NO increased risk of malignancy (excluding non-melanoma skin cancer) or HLH with infliximab therapy; however, there is a trend towards increased risk among those with thiopurine exposure. Nevertheless, as malignancy is a rare event, very low increased risk of malignancy with infliximab cannot be entirely excluded.

Related blog posts:

For HLH:

Long Distance (Medical) Relationships Don’t Always Work

Posted on July 18, 2017 by gutsandgrowth

Another study (NZ Borren et al Inflamm Bowel Dis 2017; 23: 1234-9) has shown detrimental outcomes due to distance from the health care team.

In this study with 2136 patients with IBD (1197 Crohn’s disease, 9393 ulcerative colitis) with mean age of 41 years, the distance from the hospital (Massachusetts General) was compared with need for IBD-related surgery and secondary outcomes of needing biological and immunomodulator therapy.

Key findings:

In the four quartiles, mean distance was 2.5, 8.8, 22.0, and 50.8 miles.
Need for surgery was increased with distance from hospital: closest with odds ratio of 1.0, quartile 2 had OR of 1.68, quartile 3 had OR of 1.94, and quartile 4 had OR of 2.44

According to the authors, with other indications besides IBD, “over three-quarters of the examined studies demonstrated a distance-decay association with worse outcomes in individuals living further away from health care facilities. Limitation: it is possible that patients who travel a greater distance have more disease severity and that those who have milder diseases are more likely to receive care closer to home.

My take: When highly qualified subspecialists are far away, the associated reduced access likely counters this potential benefit. Early effective therapy is important in reducing complications.

Related blog posts:

Shem Creek, SC

Low Rate of Ocular Disease in Pediatric Crohn’s Disease

Posted on June 18, 2017 by gutsandgrowth

A recent study (S Naviglio et al. Inflamm Bowel Dis 2017; 23: 986-90) confirms that there is a low rate of ocular disease in pediatric inflammatory bowel disease (IBD); in this cohort, half had Crohn’s disease (CD) and half had ulcerative colitis.

In this single center study, 94 children with a median age of 13.4 yrs were offered ophthalmologic examination (2014-2016). None of these patients reported ocular symptoms. The authors assert that 70% had intestinal remission, though 64% had elevated fecal calprotectin levels (>100 mg/kg). Key finding: One patient (1.06%) had ocular finding of uveitis (previously diagnosed prior to study)

The authors indicate that hepatobiliary manifestations, present in 9, were the most common extraintestinal IBD manifestation (EIM). Arthropathy occurred in 8, cutaneous manifestations occurred in 6 and ‘metastatic’ CD occurred in 4.

My take: Ocular disease is an infrequent EIM in pediatric patients with IBD.

Related article: K Hata et al. Inflamm Bowel Dis 2017; 23: 1019-24. This article found that patients with EIMs were more likely to have chronic pouchitis after colectomy for ulcerative colitis. Overall, chronic pouchitis developed in 3.3%, 7.6% and 16.6% at 2, 5, and 10 years respectively. Key finding: preoperative EIM yielded a HR of 4.52.

Surgical Reset for Anti-TNF Therapy with Crohn’s Disease

Posted on June 2, 2017 by gutsandgrowth

A recent study (A Assa et al. Inflamm Bowel Dis 2017; 23: 791-97) indicates that after surgery, anti-TNFα treatment is worth another try.

In this retrospective study with 53 children, 18 had “pharmacodynamic failure” with anti-TNFα medications (PK group) and 35 were controls. “Phamacocynamic failure is characterized by either a lack of improvement of CD symptoms or loss of response after initial improvement in the setting of adequate serum drug levels without ADAs” [antidrug antibodies].

Key findings:

Mean age at time of intestinal resection was 14.8 years
Median time from resection to anti-TNF initiation was 8 months
Compared to the control group, the PK group had similar response to anti-TNF therapy. “Similar proportions of patients from both groups were in clinical remission on anti-TNF treatment after 12 months and at the end of follow-up (1.8 years)”
At 12 months, remission rates were 89% (PK) versus 88.5% (control)

The authors propose an explanation: “A plausible explanation for this finding is that in severely inflamed tissue with high inflammatory burden, local high levels of TNFα serves as a sink for anti-TNFα antibodies and that tissue injury and local hypoxia might further limit drug penetrance to its target.”

My take: This information is useful. Many patients who have surgery may respond to anti-TNFα therapy subsequently. The unanswered question: Could more frequent dosing of anti-TNFα therapy have averted surgery in some patients by overcoming areas of intense disease?

Ileocecal Resection in Pediatric Crohn’s Disease

Posted on March 10, 2017 by gutsandgrowth

A recent retrospective study (K Diederen et al. Inflamm Bowel Dis 2017; 23: 272-82) provides data on the likelihood of complications and recurrence following ileocecal resection in pediatric Crohn’s disease (n=122).

Key findings:

Severe postoperative complications were noted in 9.8%. Risk factors included colonic disease (Odds ratio 5.6), microscopically positive resection margins (OR 10.4), and emergency surgery (OR 6.8)
Overall complication rate was reported as 29.5% which is similar to rates reported in adults
Clinical recurrence rates after 1, 5, and 10 years: 19%, 49%, and 71%
Surgical recurrence rates after 1, 5, and 10 years: 2%, 12%, and 22%
Immediate postoperative therapy reduced the risk of clinical recurrence (HR 0.3) and surgical recurrence (HR 0.5)
“In this study, postoperative catch-up growth was found in patients younger than 16 years in the year after surgery.” Thus, surgery could be an important to reverse growth retardation.

Complications within 30 days of surgery were categorized with the Clavien-Dindo classification. Those with grade ≥III which required either surgical, endoscopic or radiologic intervention were considered severe. In this population, the complications included intraabdominal septic complications and/or anastomotic leakage.

My take: In some patients, ileocecal resection should NOT be a last resort. Waiting too late, increases the risk of complications. The task at hand is prospectively identifying those who merit surgery sooner and then convincing the family to proceed.

Related blog posts:

Closer Look at Ustekinumab Data

Posted on February 9, 2017 by gutsandgrowth

At a recent dinner, we had the opportunity to hear a review of some of the recent data on ustekinumab. These notes may include some errors in transcription and errors of omission. Most of this data is derived from a recent publication that has been summarized in this blog: Landmark Publication for Ustekinumab (Stelara) | gutsandgrowth

Some key points:

In numerous studies of biologic agents, longer duration of disease is associated with a much lower response to therapy. For the UNITI-1/UNTI-2 studies, the patients enrolled had long duration of disease (~10 years in UNIT1-1, ~8 years in UNITI-2)
Recent data indicate that vedolizumab is effective for Crohn’s disease, but works slowly. It likely takes ~6 months to determine if it is working.
With ustekinumab, most patients respond within 3 weeks of the induction dose; however, among nonresponders, many responded after the first maintenance dose. Thus, probably need to give at least the induction dose and the first maintenance dose for determining whether ustekinumab is effective.
Overall safety profile looks very good for ustekinumab. More than 4000 patients in a psoriasis registry showed no serious safety signals (though psoriasis patients receive a lower dose).
Overall, the 6 mg/kg induction dose outperformed the 130 mg dose with regard to objective measures.
High placebo rate in the IM-UNITI study likely is due to some residual response to the initial induction dose.
Every 8 week dosing for ustekinumab was more effective than every 12 week dosing in these studies, though, there are likely patients who need more frequent and some who could benefit from less frequent dosing.
2.3% of patients in IBD studies had detectable antibody to ustekinumab but this did not preclude efficacy.
~20% of IBD patients do not develop increased CRP
Pediatric studies of ustekinumab are ongoing testing different dosing regimens.
One other anecdote in regards to magical thinking about which premedications are most effective: A man with a ridiculous hat was approached as he walked in an Atlanta.suburb. A lady asked him why he wore such an unusual hat. He replied that “the hat keeps elephants far away.” The lady said, “there are no elephants around here.” He said, “See it is working.”

Good News from the Bad News Department: Outcomes of Intestinal Transplantation in Patients with Crohn’s Disease

Posted on November 20, 2016 by gutsandgrowth

Briefly noted: A recent retrospective study (BN Limketkai et al. Clin Gastroenterol Hepatol 2016; 14: 1574-81) examined outcomes of 142 patients with Crohn’s disease (CD) out of a total of 1115 cases of intestinal transplantation. The authors examined the Scientific Registry of Transplant Recipients. Since intestinal transplantation would be a very undesirable outcome in patients with CD, I titled this post as coming from the “Bad News Department.” The good news is that in the last 15 years, patients with CD disease do not appear to have worsened outcomes compared to patients without CD. Overall, during the period 1990-2014, the risk of graft failure was higher, mainly due to the initial 10 years. Graft failure was 18.6% at 1 year, 38.7% at 5 years, and 49.2% at 10 years in patients with CD compared with 14.1%, 32.1% and 41.0% in non-CD patients. The cumulative risk of death at 10 years for CD patients was 59.7%.

My take: It is good that intestinal transplantation outcomes for CD patients are now similar to all patients. In addition, intestinal transplantation outcomes are improving. Nevertheless, there is still a high death rate over 10 years.

Briefly Noted: Inflammatory Bowel Disease Updates

Posted on October 13, 2016 by gutsandgrowth

Gut Microbial Diversity is Reduced in Smokers with Crohn’s Disease. JL Opstelten et al. Inflamm Bowel Dis 2016; 22: 2070-77. This study compared stools from 21 nonsmoking patients with Crohn’s disease (CD) with 21 smokers with CD. Smoking was accompanied by a reduced relative abundance of multiple genera. My take: It is unclear whether smoking’s effect on the microbiome directly contributes to worsened outcomes or whether the changes in the microbiome are only an epiphenomenon. Regardless, smoking increases the likelihood of worse outcomes in CD.

A Systematic Review on Infliximab and Adalimumab Drug Monitoring Levels, Clinical Outcomes and Assay. F Silva-Ferreira et al. Inflamm Bowel Dis 2016; 22: 2289-2301. This review selected 20 studies from an initial query of 1654 articles. Key points:

Different studies are difficult to compare due to distinct assays with different limitations. Thus, specific cutoffs are based on the specific assay used.
The authors state that proactive monitoring may be helpful at week 6, 14, 30 and 54 for infliximab. They recommend checking infliximab level and antidrug antibodies in those with loss of response, mucosal ulceration or elevated biomarkers (eg. CRP, Fecal calprotectin).

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Pediatric Gastroenterology

Tag Archives: Crohn’s disease