Toronto Consensus Guidelines for Luminal Crohn’s Disease

The recommendations from the Canadian Association of Gastroenterology for luminal Crohn’s Disease in adults were published in two journals.  R Panaccione et al. Clin Gastroenterol Hepatol 2019; 17: 1680-1713 and R Panaccione et al . 2019 Aug; 2(3): e1–e34.

Full text link : Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Luminal Crohn’s Disease

A few of the 41 statement recommendations:

  • 6. In patients with mild to moderate ileal and/or right colonic Crohn’s disease, we suggest oral budesonide beginning at 9 mg/day as first-line therapy to induce complete remission. GRADE: Conditional recommendation, low-quality evidence
  • 20. In patients with moderate to severe luminal Crohn’s disease with risk factors of poor prognosis, we recommend anti-TNF therapy (infliximab, adalimumab) as first-line therapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
  • 23. In patients with active Crohn’s disease, when starting anti-TNF therapy, we suggest it be combined with a thiopurine or methotrexate over monotherapy to improve pharmacokinetic parameters. GRADE: Conditional recommendation, very low-quality evidence for infliximab, very low-quality evidence for adalimumab
  • 29. We suggest against switching between anti-TNF therapies in patients who are doing well on anti-TNF therapy. GRADE: Conditional recommendation, low-quality evidence
  • 30. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend vedolizumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
  • 34. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend ustekinumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
  • 37-41: Authors against the use of probiotics, omega-3 fatty acids, marijuana, naltrexone and enteral nutrition/diet therapies.

Crater Lake and Wizard Island

Should All Pediatric Patients with Crohn’s Disease Continue Combination Therapy?

Among patients/families who are not in denial about their inflammatory bowel disease, especially Crohn’s disease, an important discussion is the use of combination therapy.  This has been discussed on this blog before (see some links below).  More data on this subject has been published and again favors the use of combination therapy (V Grossi, T Lerer, et al. Clin Gastroenterol Hepatol 2015; 13: 1748-56).

This study collected data from 2002-2014 on 502 children who participated in a prospective multicenter study. This data was derived from an observational registry rather than a randomized trial, but likely reflects real-world experience with regard to newly diagnosed patients. The authors excluded those with prior biologic therapy and prior resectional surgery.

KEY FINDINGS:

  • Children receiving combination immunomodulator (IM) treatment were more likely to have durable infliximab therapy at 1 year, 3 years, and 5 years.
  • Greater length of concomitant IMs was associated with better durability.
  • For patients who had IM > 6 months after starting infliximab (n=194), durability was 0.70 at 5 years compared with 0.55 for patients with IM <6 months (n=144), and 0.48 for those who did not receive IMs (n=135).
  • In boys, methotrexate appeared to be superior to thiopurines (P<.01): 0.98 at 5 yrs compared with 0.58.  However, there were 60 males receiving methotrexate.  In the study, only 21 females received methotrexate which limited any conclusions.

Among patients who stopped IFX, the reasons included loss of response (n=61, 43%), hypersensitivity reaction (n=41, 29%), elective (n=25, 18%), lost to f/u (n=5, 3%), and other causes (10, 7%).

The “right” dose of methotrexate as a combination agent remains unclear.  There was a wide range of dosing schedules in this study.  It is worth observing that the COMMIT study in adults found no significant difference in adults who received methotrexate in addition to infliximab compared with those receiving infliximab monotherapy.

Take-home message: In this large pediatric observational study, the use of immunomodulators increased the likely durability of infliximab.  Given prior conflicting data (particularly with regard to methotrexate), even more studies are needed to determine exactly how useful combination therapy is and when monotherapy will suffice.  From my viewpoint, I worry much more about loss of efficacy to infliximab than I worry about medication adverse effects.  As such, I will continue to inform families that combination therapy appears to improve infliximab durability.

Related blog posts:

Mount Washburn, Yellowstone

Mount Washburn, Yellowstone

Withdrawing Therapy Leads To Relapse, Even if in Deep Remission

A recent study, presented as an oral abstract (thanks to Jeff Lewis for forwarding this reference), indicates that even in patients in deep remission, withdrawal of anti-TNF therapy leads to relapse in about 50% even when thiopurines are continued; this is in agreement with previous posts (see below).

Full abstract: OP007 Relapse after Deep Remission in Crohn’s disease. Here are the results and conclusion from the abstract:

Results

Sixty one patients were included and followed-up for a median of 28 months (range 7-47). After withdrawal of anti- TNFa therapy (44 infliximab and 17 adalimumab) 47 (77%) patients continued thiopurines. 32 (52.5%) patients relapsed until the end of follow-up with a median time to relapse of 8 months (range 1-25). The cumulative probability of maintaining remission was 82% at 6 months, 59% at 1 year and 51% at 2 years. Analysis of 28 patients who were in deep remission (endoscopic healing; faecal calprotectin <150mg/kg; CRP <5mg/l) revealed no better survival (82%, 64% and 40% at 6 months, 1 and 2 years, respectively). Four (8%) of relapsing CD patients required surgery 5 to 19 months after anti-TNFa cessation (2 for new stricture development, 1 for medically refractory flare and 1 for high grade dysplasia). In multivariate model only disease localization was risk factor of disease relapse (colonic vs. ileal/ileocolonic: OR 0.16, 95%CI: 0.03-0.72; p=0.02). Type of anti- TNFa preparation, smoking, disease behaviour, corticosteroid or thiopurine therapy, biological markers and anti-TNFa trough levels did not impact disease relapse.

Conclusion

Approximately half of CD patients relapsed within 2 years after anti- TNFa discontinuation despite being in endoscopic remission when anti-TNFa was stopped. The highest relapse rate was observed during the 1st year. Ileal disease increased the risk of disease flare, while no other risk factor was identified.

Related blog posts:

Bryce Canyon

Bryce Canyon

Liver Disease Associated with Inflammatory Bowel Disease

A useful review on the hepatobiliary manifestations of inflammatory bowel disease (IBD): Inflamm Bowel Dis 2014; 1655-67.

A few topics/comments from review:

Primary sclerosing cholangitis (PSC):

  • “among those with PSC, about 70% to 80% have UC and 15% to 20% have CD.  Those IBD patients with PSC are more likely to develop malignant complications and to require liver transplantation. Conversely, only about 0.4% to 7.5% of patients with IBD will develop PSC.”
  • “Currently, no medical treatment has been proven to decrease the progression of PSC.”
  • “At the time of diagnosis of PSC, IBD must be ruled out and a complete colonoscopy with multiple segmental biopsies of the mucosa needs to be performed.”  Among PSC-IBD patients, “annual surveillance colonoscopy is recommended.”
  • Further surveillance recommendations (eg. annual imaging/CA 19-9 annually) discussed in Table 2.

Cholelithiasis: Gallstones are reported in 13% to 24% of all patients with CD.  In UC, the risk of cholelithiasis “does not seem to be increased.”

Drug-induced liver disease: (see liver tox website)

  • Thiopurines
  • Methotrexate
  • Sulfasalazine/mesalamine
  • Biologic agents

Viral hepatitis in immunosuppressed IBD patients:

Hepatitis B reactivation -algorithm for screening/management of latent hepatitis B provided in Figure 3

Other liver problems seen in IBD patients:

  • Portal Vein Thrombosis
  • Nonalcoholic Fatty Liver Disease
  • Secondary amyloidosis
  • Hepatic abscess

Related blog posts:

More NASPGHAN Meeting Notes: IBD Hot Topics

The best preparation for tomorrow is to do today’s work superbly well”  –William Osler (quote cited in NEJM 2014; 371: 1565-66).

This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

For me, these lectures were a useful review and represent an effort to achieve Osler’s objective of doing superb work.  If I had to choose a single issue that may affect my practice: when initiating infliximab, consider checking week 14 trough levels of infliximab and optimize dosing.

The role of the microbiome in IBD   –Subra Kugathasan (Emory)

This was a terrific lecture though with some overlap with a number of other presentations at the meeting. The lecture reviewed how to interpret microbiome studies and what we are learning from these studies with regard to inflammatory bowel disease.

Enteral Nutrition and Microbiota –conclusion:

  • EN may work by suppressing the entire microbiota in Crohn’s disease thus lowering antigenic effect to the gut
  • Some microbes may be pro-inflammatory and others pro-fibrotic
  • Chicken and egg: preliminary evidence suggests that dysbiosis is probably a preceding predisposing factor rather than due to the consequence of having inflammatory bowel disease.

The Role of Drug Monitoring in Inflammatory Bowel Disease –Jennifer Strople (Children’s Hospital of Chicago)

TPMT Testing/thiopurine metabolite monitoring

  • goal: minimize adverse effects and optimize thiopurine dosing.
  • those with lower (but not absent) activity may be best candidates for treatment with azathioprine/6-mercaptopurine (thiopurines).
  • normal TPMT testing does NOT exclude complications like bone marrow suppression or pancreatitis.
  • obtaining TPMT at baseline is cost-effective
  • goal of 6-thioguanine level of >235 (odds ratio favorable of responding to/remission with treatment)
  • drug levels: allows monitoring for noncompliance; limitation of costs and using levels inappropriately. Routine testing “has no role in patients who are doing well on acceptable doses of thiopurines”
  • younger patients often need higher doses

Monitoring for anti-TNF Therapy

  • Loss of response most common in first year of therapy.
  • For infliximab (IFX), IFX trough levels >3 mcg/mL predicted sustained response. Gut 2014; 63: 1721.
  • Week 14 IFX levels predict outcomes:
IFX Levels at 14 weeks

IFX Levels at 14 weeks

  • Preliminary data with ulcerative colitis shows that troughs >3.7 mcg/mL increases likelihood of mucosal healing and remission.
  • Undetectable trough levels of IFX associated with increased risk of colectomy with ulcerative colitis Gut 2010 59: 49
  • If a patient develops high levels of anti-drug antibodies (ADAs), this makes likelihood of response to medications unlikely. The specific ADA level is helpful; high levels of drug antibody are particularly problematic. If low levels of drug without ADAs, then increasing dose is typically effective.
IFX Algorithm

IFX Algorithm

  •  If losing response to therapy and if active disease is present, then check drug concentration. If subtherapeutic with no ADAs or low ADAs, dose escalation with or without immunomodulator is indicated.
  • If subtherapeutic with high ADA, then change drug
  • If therapeutic level, then may need to change to different anti-TNF or drug class.

Related posts on this topic:

Debate: Immunomodulators versus Biologic agents 

  • James Markowitz –consider starting with immunomodulators
  • Maria Oliva-Hemker –consider starting with biologics

In the face of the “Biologic Tsunami,” Dr. Markowitz suggested –“Don’t throw the baby out with the bathwater”

  • Reviewed infliximab data, and adalimumab data. 1-year remission rates 50-60%.
  • Durability of infliximab may be influence by immunomodulators (IMs): patients who had IM prior to IFX had better durability of response:  45% durability in those who had no IM prior to biologic, 53% durability in those who had IM for ❤ months, 66% durability in those who had IM for >6 months prior to IFX.
  • Adult data showing lack of efficacy with IMs influenced by different characteristics compared with children (eg. different disease location, ~40-50% of adults were smokers)
  • Reviewed toxicity of IMs and biologics
  • Children with severe disease do best with “early infliximab.”
  • IMs with 40-60% efficacy over 18 months and then relatively stable.
  • In Dr. Markowitz’ practice, IM use: girls receive thiopurines and boys receive methotrexate

Biologics –important to start before disease phenotype changed to stricturing/penetrating disease. (See images below)

Related posts:

Early anti-TNF -RISK Cohort

Early anti-TNF -RISK Cohort

 

Long Term Risk of Stricturing (Cosnes et al)

Long Term Risk of Stricturing (Cosnes et al)

IBD Update 2014 (part 2)

5. Inflamm Bowel Dis 2013; 19: 2927-36.  This reference is another article that tries to help discuss the risks and benefits of biologic therapy for pediatric inflammatory bowel disease.  After reviewing the potential risks, the authors provide their “Option Grid” (Page 2932).  The authors state, “in summary, the adult literature supports the concept of the early use of combination therapy…the risks associated with anti-TNF therapy are really not significantly different as compared with thiopurine therapy and perhaps in some cases safer.  Therefore, we should be moving closer to the idea of using anti-TNF therapy early, with or without an immunomodulator.  In the sickest patients, combination therapy probably adds benefit, and then once in remission, consideration can be given for stopping one of the medications, more likely the thiopurine.

6. Gut 2013; 62: 689-94.  Risk of ischemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study.  From 1997 to 2009, the authors compared 28,833 IBD persons to >4.5 million persons without IBD who were matched for age, gender, socioeconomic status, and calendar year.  With a mean follow-up of 13 years, they identified a 59% higher incidence rate of ischemic heart disease in patients with IBD.  Long-term use of immunosuppressive medications, such as azathioprine and anti-tumor necrosis factor-alpha agents, was not associated with an increased risk of ischemic heart disease.

7.   Gastroenterol 2013; 145: 1459-63.  AGA Guideline for Use of Thiopurines, Methotrexate, and Ant-TNF-alpha Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease. This reference was previously noted in blog (with a link) AGA Guidelines for the Use of Thiopurines and Anti  – gutsandgrowt.  The print version does have a nice algorithm (pg 1463).  The accompanying technical review: Gastroenterol 2013; 145: 1464-78.

8. BMJ 2013;347:f6633. Free full-text BMJ article PDF. (Thanks to Mike Hart for this reference) From the abstract:  During 3 421 972 person years of follow-up, we documented 284 cases of Crohn’s disease and 363 cases of ulcerative colitis. The risk of Crohn’s disease was inversely associated with physical activity (P for trend 0.02). Compared with women in the lowest fifth of physical activity, the multivariate adjusted hazard ratio of Crohn’s disease among women in the highest fifth of physical activity was 0.64 (95% confidence interval 0.44 to 0.94). Active women with at least 27 metabolic equivalent task (MET) hours per week of physical activity had a 44% reduction (hazard ratio 0.56, 95% confidence interval 0.37 to 0.84) in risk of developing Crohn’s disease compared with sedentary women with ❤ MET h/wk. Physical activity was not associated with risk of ulcerative colitis (P for trend 0.46). The absolute risk of ulcerative colitis and Crohn’s disease among women in the highest fifth of physical activity was 8 and 6 events per 100 000 person years compared with 11 and 16 events per 100 000 person years among women in the lowest fifth of physical activity, respectively. Age, smoking, body mass index, and cohort did not significantly modify the association between physical activity and risk of ulcerative colitis or Crohn’s disease (all P for interaction >0.35). Conclusion In two large prospective cohorts of US women, physical activity was inversely associated with risk of Crohn’s disease but not of ulcerative colitis.

Comment: While physical activity may directly reduce the risk of Crohn’s disease, it could also be an epiphenomenon of another unmeasured variable (eg. dietary habits) that modifies this risk.

Related blog post:

Understanding IBD Therapy Risks -A Good Link | gutsandgrowth  Provides link to useful 6-minute internet video for families.

Malignancy Risk with Thiopurines

Based on a large retrospective, nationwide cohort study, it has been estimated that patients with ulcerative colitis have a 4-fold increase in the risk of lymphoma compared with patients who have not been treated with thiopurines (Gastroenterol 2013; 145: 1007-15).  While this study enrolled data from 36,891 patients followed for a median of 6.7 years, this study should not be interpreted in isolation.  The editorial (pages 927-30) provides some important context.

Besides the risk of lymphoma in patients treated with the thiopurines, the editorial briefly states the potential for life-threatening infections, primarily varicella and hemophagocytic lymphohistiocytosis which may complicate primary EBV infection.  The latter is much more common in younger patients.

With regard to malignancy, besides lymphoma, thiopurines also increase the frequency of nonmelanoma skin cancer.  Since these are not life-threatening, in many patients the risk of lymphoma is “the major limiting factor for the prolonged use of thiopurines.”  Furthermore, the risk of lymphoma may increase relative to treatment duration according to the above-referenced study. The editorial notes that there are three types of lymphoma to be considered:

  1. Posttransplant-like lymphoma associated with EBV seropositivity. Absolute risk in all IBD patients ~ 1 per 1000 patient-years.  All EBV-seropositive patients are at risk.
  2. Early post-mononucleosis lymphomas. Absolute risk in all IBD patients ~0.1 per 1000 patient-years; however, the risk in young men who are seronegative for EBV (<35 years) is ~3 per 1000 patient-years.
  3. Hepatosplenic T-cell lymphomas.  Absolute risk in all IBD in all IBD patients ~0.05 per 1000 patient-years; again, in young patients (mostly men) the risk is ~0.1 per 1000 patient-years.

The second and third types of lymphomas can be reduced by limiting thiopurines in young men.

Despite the risks posed by thiopurines, the overall benefit-risk balance needs to consider the fact that the risk of colorectal cancer “is markedly reduced in patients with long-standing extensive colitis exposed to thiopurines.”  Thus, the lowered risk of colorectal cancer “may outweigh the excess risk of lymphoma.”

Also, in considering thiopurines:

Inflamm Bowel Dis 2013; 19: 2801-08.  “Thiopurines are Associated with a Reduction in Surgical Re-resections in Patient’s with Crohn’s Disease.”  This study was a retrospective review of 567 patients of whom 237 (41.8%) developed a surgical recurrence after a median of 70 months.  Taking thiopurine was associated with a hazard ratio of 0.51.  Due to small numbers, the results with anti-TNF therapy was not conclusive, but “seems promising as well.”

Related blog posts: