CCFA: Updates in Inflammatory Bowel Disease 2017 (part 3)

More from our recent CCFA Conference.  My notes may include some errors in transcription and errors of omission.

Subra Kugasthasan -RISK Updates

Dr. Kugasthasan’s lecture was excellent.  He reviewed the typical clinical course of Crohn’s disease; in most patients, it has a remitting and relapsing course.  The goal of the CCFA-sponsored RISK study was to determine how early approaches to treatment affect long-term outcomes.  There is likely a window of opportunity to more favorably affect natural history of the disease. In addition, the goal is to determine whether there are predictive markers of severe disease course.  This prospective study analyzed 913 patients.  In this cohort, 835 remained with B1 (inflammatory) phenotype and 90 developed either B2 (stricturing) phenotype or B3 (penetrating) phenotype.

RISK Study AbstractPrediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study (S Kugathasan et al. Lancet 2017; 389: 17108. DOI: http://dx.doi.org/10.1016/S0140-6736(17)30317-3)

Key findings:

  • Early TNF therapy reduced the likelihood of penetrating (B3) but not stricturing (B2) disease
  • Based on analysis of genetic expression at baseline, individuals who are likely to develop B2 or B3 disease can be identified. This assay may be available clinically in a few years

Jahnavi Srinivasan -Multi-Disciplinary Approach to IBD A Surgical Perspective

  • Teeuwen PH et al study spans a long period and there have been many changes since that time. The study’s 9% 30-day mortality rate is very high (current Whipple 30-day mortality ~2%)
  • 3-stage surgery most common now for ulcerative colitis due to sicker patients who now need operation
  • Harder to differentiate UC and CD
  • Try to get patients off steroids; this is a key factor in surgical complications. Nutritional support may be helpful though some effects may be mediated by helping with steroid tapering

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet 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.

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CCFA: Updates in Inflammatory Bowel Disease 2017 (part 2)

Douglas Wolf -New Treatments and New Strategies

  • More proactive approach is recommended; this leads to less surgery, less hospitalization, and less antibodies to infliximab
  • Risk assessment should guide treatment; higher risk indicates a need for more aggressive therapy
  • Higher doses of anti-TNFs appropriate in some cases (eg weekly Humira)
  • For distal colitis/proctitis, budesonide foam is an alternative to cortifoam
  • Azathioprine monotherapy has a low response rate
  • Combination therapy may not be needed if good IFX levels obtained.  Though, it is possible that development of antibodies precludes achieving good levels; thus, combination therapy may increase likelihood of good levels by reducing antibody formation, particularly earlier in course
  • Vedolizumab can be shortened to q4weeks if not improving.
  • CALM study: symptom based management compared to management based treat-to-target relying on CRP, and calprotectin. Improved outcomes with treatment based on CRP, calprotectin in addition to symptoms.
  • Tofacitinib –will be available in 2018 for ulcerative colitis

Chiristina Ha -Treatment Strategies in the Elderly

Dr. Ha referenced Dr. Sandborn who recently stated that combination therapy should be first-line therapy in moderate-to-severe disease –though this may be different in elderly patients.

  • Older age –increases mortality risk
  • Immunosenescence -relative immunodeficiency state associated with aging
  • Pharmokinetic changes with aging
  • Increased susceptibility to drug toxicity (eg. Renal, hepatic)
  • Older patients usually excluded from therapeutic trials
  • Polypharmacy is more common

Treatment:

  • Frequent strategy in elderly has been using 5-ASAs and steroids, even in moderate-to-severe disease. This has been due to increased fear of adverse events with IMM and anti-TNFs.  However, using data from rheumatoid arthritis, older patients’ biggest risk is steroids.
  • Thiopurines have unfavorable risk profile in the elderly.
  • Anti-TNFs are not as effective in the elderly
  • Preliminary data on vedolizumab -very limited data, may work better in older patients
  • Most common infections by be reduced considerably by immunizations. (eg.  ,bacterial pneumonia, herpes zoster)
  • Correct anemia, nutritional deficiencies

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet 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.

CCFA: Updates in Inflammatory Bowel Disease 2017 (part 1)

Our local CCFA chapter provided a useful physician CME meeting.  The following are my notes/picutres. My notes may include some errors in transcription and errors of omission.

Nancy McGreal  -Complementary Therapies in IBD

Key points:

  1. Curcumin and VSL#3 are likely helpful
  2. Most complementary and alternative medicine (CAM) therapies are not inherently dangerous, but most are unproven
  3. Biggest risks: Nonadherence rates are increased in patient taking CAM.
  4. Despite the low overall risk of most CAM treatments, Dr. McGreal cautioned against the following:
    1. Cannabis is NOT recommended due to neurocognitive effects. It may mask active disease.
    2. FMT investigational. There are unknown risks but FMT could cause metabolic problems. Donor selection is important and we still have a lot to learn.

This final slide is from CCFA about how to order more patient information brochures.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet 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.

Outcomes of Children Whose Mothers Have Inflammatory Bowel Disease

A recent study (LR Jolving et al. Inflamm Bowel Dis 2017; 23: 1440-46) used a nationwide (Denmark) register-based cohort to examine the health outcomes of children whose mothers have inflammatory bowel disease (IBD).  This cohort of 9238 children were compared with nearly 1.4 million children born to women without IBD. Median follow-up time was 9.7 years of the children whose mothers had IBD.

Key findings:

  • Hazard ratio for developing IBD in the offspring was 4.63 if maternal ulcerative colitis
  • Hazard ratio for developing IBD in the offspring was 7.70 if maternal Crohn’s disease
  • “Our data otherwise do not provide evidence for an increased risk of any of the other examined diseases in the offspring.” This included diabetes mellitus, thyroid diseases, rheumatoid arthritis, epilepsy, chronic lung disease, mood disorders, schizophrenia, epilepsy, and anxiety disorders.

Raw numbers for developing IBD:

My take: This study documents the expected finding of an increased risk of IBD among the offspring of women with IBD. No other chronic diseases were increased in this study.

Briefly noted: SM Yoon et al. Inflamm Bowel Dis 2017; 23: 1382-93.  This retrospective registry study included the following:

  • 314 subjects with Crohn’s disease (CD) who were primary nonresponders, and 179 with CD who were secondary nonresponders
  • 145 subjects with ulcerative colitis (UC) who were primary nonresponders and 74 with UC who were secondary nonresponders

Key findings: “Colonic involvement (OR 8.0) and anti-TNF monotherapy (OR 4.9) were associated with primary nonresponse to anti-TNF agents in CD.” Higher ANCA levels in UC (HR 1.6) were associated with time to loss of response to anti-TNF agents.

 

Combination Therapy with Adalimumab -Is it Helpful?

A recent study (JM Chalbhoub et al. Inflamm Bowel Dis 2017; 23: 1316-27) performed a systematic review and meta-analysis to examine the effectiveness of Adalimumab (ADA) combination therapy compared with monotherapy.  With infliximab (IFX), the SONIC study, showed that combination therapy with an immunomodulator (IMM) (azathioprine) improved response; combination therapy resulted in reduced immunogenicity, lower rates of infusion reactions, and higher IFX levels.

With the advent of widespread use of therapeutic drug monitoring, some have questioned the need for combination therapy with IFX.  The need for combination therapy for ADA is also a matter of debate.  ADA has less immunogenicity than IFX and it is unclear if combination therapy will improve outcomes. There have been conflicting studies regarding combination therapy with ADA, prompting the current meta-analysis.

The authors identified 24 articles for inclusion from an initial pool of 1194. Key findings:

  • No significant difference between combination therapy and monotherapy was noted for induction of remission (OR 0.86) or response (OR 1.01). The induction of remission is based on data from 3096 patients (1400 on combination treatment).
  • No difference was noted for maintenance of remission (OR 0.97) or response (OR 0.91). The maintenance of remission is based on data from 1885 patients (859 on combination treatment).
  • Patients receiving combination therapy had lower odds of developing antidrug antibodies (OR 0.24)
  • Subgroup analysis in anti-TNF experienced patients showed improved successful induction of remission (OR 1.26) but also more frequent opportunistic infections (OR 2.44)

Overall, the authors conclude that “combination of ADA and immunomodulators does not seem superior to ADA monotherapy for induction and maintenance of remission and response to Crohn’s disease.” They do comment on the recent DIAMOND study which was a randomized open-label top-down strategy trial in anti-TNF-naive and IMM-naïve patients.  While no overall advantage of combination therapy was evident, better endoscopic response (84% vs. 64% with monotherapy) was seen at 26 weeks (but not at 52 weeks).

This study has several limitations.  Overall, there were a small number of randomized trials and the trials had significant heterogeneity.

My take (borrowed from authors): “It is unclear whether the addition of IMM impacts the efficacy of a less immunogenic anti-TNF biologic such as ADA in CD.” Though, in the subgroup of anti-TNF exposed patients, “combination therapy was associated with higher odds of induction of remission.”

Related blog posts:

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

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)

Calprotectin in Triaging Potential Pediatric IBD Cases

Thanks to KT Park’s Twitter feed for this reference: GA Holtman et al. JAMA Pediatr. Published online August 14, 2017. doi:10.1001/jamapediatrics.2017.1736

An excerpt from abstract:

Results  Of the 16 eligible studies, authors of 8 studies (n = 1120 patients) provided their data sets. All blood markers and fecal calprotectin individually significantly improved the discrimination between pediatric patients with and those without IBD, when added to evaluation of symptoms. The best marker—fecal calprotectin—improved the area under the curve of symptoms by 0.26 (95% CI, 0.21-0.31). The second best marker—erythrocyte sedimentation rate—improved the area under the curve of symptoms by 0.16 (95% CI, 0.11-0.21). When fecal calprotectin was added to the model, the proportion of patients without IBD correctly classified as low risk of IBD increased from 33% to 91%. The proportion of patients with IBD incorrectly classified as low risk of IBD decreased from 16% to 9%. The proportion of the total number of patients assigned to the intermediate-risk category decreased from 55% to 6%.

Conclusions and Relevance  In a hospital setting, fecal calprotectin added the most diagnostic value to symptoms compared with blood markers. Adding fecal calprotectin to the diagnostic workup of pediatric patients with symptoms suggestive of IBD considerably decreased the number of patients in the group in whom challenges in clinical decision making are most prevalent.

From: Inflamm Bowel Dis. 2017 Aug 16. doi: 10.1097/MIB.0000000000001202. [Epub ahead of print]