Combination Therapy Associated with Treatment Persistence

Another large retrospective ‘real-world’ study (C Chen et al. Inflamm Bowel Dis 2019; 1417-27) examined persistence profiles of biologic therapies in newly diagnosed IBD patients.  This study, based on Truven Health MarketScan data (2008-2015) included 5612 patients with Crohn’s disease (CD) and 3533 with ulcerative colitis (UC). There were 1156 persons (20.6%) in the pediatric age range (0-18)

Key findings:

  • Less than half of the patients continued using their initial biologic treatment after 1 year (48.5% of CD cohort and 44.8% of UC cohort).
  • For infliximab (IFX) in the CD cohort, the 1 year continued rate was 47.6% and the 5 year rate was 20.0%. In the UC cohort, the rates were 44.9% and 15.7% respectively.
  • For adalimumab (ADA) in the CD cohort, the 1 year continued rate was 50.9% and the 5 year rate was 9.1%. In the UC cohort, the rates were 45.4% and 7.7% respectively.
  • Combination therapy with immunomodulators (IMM) significantly decreased the risk of discontinuation, especially if IMM was started more than 30 days before the biologic agent (HR 0.22).  Simultaneous starting had HR of 0.32.
  • The major predictors for noncompliance included infection and hospitalization.

Why did combination therapy result in higher medication persistence rates?

  • Potential reasons included improved efficacy by direct inflammatory effects and reduced drug antibodies to TNF antagonists.  It is possible that patients receiving combination therapy had more severe disease and thus less likely to discontinue therapy.

Limitation: This study may overestimate drug discontinuation as some patients may simply have had a dosing delay.

My take: This study shows a higher-than-expected rate of drug discontinuation indicating dissatisfaction related to efficacy, cost or complications. Those receiving immunomodulators (combination therapy) were much less likely to discontinue treatment.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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

Do Anti-TNF Agents Reduce Surgeries and Hospitalizations?

Briefly noted:

A recent study (; SK Murthy et al. BMJ indicates that anti-TNF therapy has not been effective in significantly lowering CD-related hospitalizations or surgeries.

Full Text Link (from Eric Benchimol twitter feed): Introduction of anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study)

My take: While big changes in the frequency of these outcomes were not demonstrated in this large study, prior studies, including the RISK study, have shown that anti-TNF therapy can be disease-modifying and reduce the risk of penetrating disease in Crohn’s disease.

Related blog post: CCFA Updates in IBD


Practice Tips for New IBD Therapies

A recent review provides some helpful advice: “A Practical Guide to the Safety and Monitoring of New IBD Therapies” (B Click, M Regueiro. Inflamm Bowel Dis 209; 25: 831-42).

This review discusses infection risk, malignancy risk, immunologic issues and other complications.

In terms of infection risk assessment, the authors describe a pyramid in which they stratify the risks of medications.  The safest to least safe in their assessment: vedolizumab –>ustekinumab–>anti-TNF monotherapy–>thiopurine or tofacintinib–>thiopurine/anti-TNF combination–>steroids.

Their Tables:

  • Table 1 lists potential infections and vaccination recommendations
  • Table 2 suggests management of active infections by IBD Medication Class
    • For anti-TNF agents and for IL12/23 agents: the authors recommend continuation of agent if viral (eg EBV, VZV, HSV) or bacterial (eg. Strep/Staph)/C difficile infections (unless severe) but holding for opportunistic infections.
    • For integrin agents, the authors recommend continuation of medications in the face of infections except “consider holding dose” during active C difficile infection
    • For JAK agents, the authors recommend stopping during viral infections and with opportunistic infections.  They recommend continuing with bacterial infections (hold if severe) and continuing with C difficile infection
  • Table 3 suggests management in the setting of active malignancy
    • Table 4 lists recommendations in the setting of immunologic complications.  Theses categories include antidrug antibodies,lupus-like reactions, demyelinating conditions, and psoriasis.
    • One of the points alluding to in this chart is that addition of methotrexate may help in patients receiving anti-TNF therapy with psoriasis.
    • No psoriatic reactions have been reported with vedolizumab, ustekinumab or tofacitinib; ustekinumab is FDA-approved for use in psoriasis and tofacitinib is FDA-approved for psoriatic arthritis.
  • Table 5 suggests recommendations in the setting of altered liver enzymes and altered lipids/creatine kinase

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Toronto Consensus for Perianal Fistulizing Crohn’s Disease

A recent consensus report (AH Steinhart, R Panaccione et al. Inflamm Bowel Dis 2019; 1-13) provides updated guidelines for the management of perianal fistulizing Crohn’s disease (CD).

As an aside, the article starts off with an extremely lengthy disclosure (of financial interests) –more than 30 lines of extremely small font!

The scope of the problem:

  • About 21% of CD patients have developed perianal fistulizing disease by 10 yrs and 26% after 20 years.
  • This complication leads to significant morbidity/reduced quality of life and about 70% require surgical treatment during long-term followup.

The substance of the article are summarized in Table 4 and Figure 1. The recommendations all are considered to be based on either low quality of evidence or very low quality of evidence:

  • In those with active fistulizing disease, the authors recommend imaging (EUS or MRI)
  • In those with evidence of complicated fistulizing disease, “we suggest surgical consultation.”
  • In those with active fistulizing CD, “we suggest the use of antibiotic therapy for initial management.”
  • In those with active fistulizing CD, “we recommend the use of anti-TNF therapy” for induction and maintenance.
  • In those with active fistulizing CD, “when starting anti-TNF therapy, we suggest it be combined with thiopurine or methotrexate over monotherapy to optimize pharmacokinetic parameters.”
  • In those with active fistulizing CD, surgical management is recommended in those when there is an inadequate response to medical management.

Some additional pointers:

  • Early surgical consultation is recommended in setting of suspected clinical abscess (eg. pain, fever, leukocytosis).
  • The authors’ algorithm suggests that if early surgical intervention is not required, then patients should first receive antibiotics for initial symptom control, followed by imaging, and, if uncomplicated fistulizing disease on imaging, followed by anti-TNF therapy (with either MTX or thiopurine).  If complicated fistulizing disease, then surgical intervention may be needed prior to institution of anti-TNF therapy.
  • “The rate of fistula healing was 43% with medical therapy alone and 53% with combination surgical and medical therapy” based on a systematic review of 8 cohort studies.

My take: This article helps simplify/streamline the approach to this troubling complication.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.


Shoshone, California

Iron Metabolism Improves after Anti-TNF Therapy for Crohn’s Disease

A previous study has shown that low vitamin D levels improved with anti-TNF therapy for Crohn’s disease in the absence of supplemental vitamin D.  Similarly, a recent study (MA Atkinson, MB Leonare, R Herskovitz, RN Baldassano, MR Denburg. JPGN 2018; 66: 90-4) showed improvement in iron metabolism with anti-TNF therapy.

In 40 children and adolescents with Crohn’s disease, the authors measured serum hepcidin-25 and hemoglobin at baseline and then 10 weeks after anti-TNF therapy.

Key findings:

  • Median hepcidin concentrations decreased (27.9–>23.2 ng/mL) and mean hemoglobin increased (10.6–>10.9).
  • Disease activity and markers of inflammation also decreased.

My take: This study shows that improvement in inflammation is associated with meaningful improvement in anemia.  However, most patients will need additional treatment for anemia, particularly as anemia may be related to blood loss in addition to anemia of chronic disease/inflammation.

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Expert Guidance on Pediatric Postoperative Crohn’s Disease

A recent NASPGHAN clinical report (JB Splawski et al JPGN 2017; 65: 475-86) updates recommendations to lower the rate of postoperative recurrence in pediatric Crohn Disease (CD).  In this report, after review of a number of studies, the authors provide a management algorithm (Figure 1).  In addition, they review risk factors for surgery/postoperative recurrence in CD.

Key points:

  • “Endoscopic recurrence precedes clinical recurrence, and is a better predictor of the risk for future surgery.”
  • “Anti-TNF agents appear to be the most effective treatment in preventing postoperative recurrence.”  These agents “can be started as early as 4 weeks after surgery.”
  • “Prophylactic treatment to prevent recurrence rather than treating after the disease recurs, appears to be more effective in preventing further surgery.”
  • “Early postoperative surveillance for disease recurrence allows for a change in management to prevent complications that may lead to further surgery.” The authors note that fecal calprotectin (and lactoferrin) return to baseline around 2 months after surgery, and “monitoring disease activity postsurgery with these tests may help determine appropriate selection for more invasive testing such as endoscopy.”

My take: The authors emphasize that “whatever treatment is chosen, early surveillance for disease recurrence is clearly needed.”  In addition, anti-TNF agents are most likely to lower risk of further surgery.

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Two Viewpoints: Anti-TNF Therapy Shortly After Crohn’s Disease Surgery

A recent AGA perspectives issue provides two viewpoints on when to start/resume anti-TNF therapy after Crohn’s disease surgery:

Dr. Bressler states that he considers anti-TNF therapy for patients with ongoing immune dysfunction after surgery who are at high risk for recurrence.  Attributes of high risk disease include the following:

  • younger age (<30 years)
  • smoker
  • two or more surgeries for penetrating disease.

His commentary indicates that a “‘wait and see’ approach is appropriate for most patients. He frequently will measure a calprotectin three months postoperatively and every three months and perform a colonoscopy typically 6-9 months postoperatively. Those with endoscopic recurrence will be placed on anti-TNF therapy.

Dr. Requiero states:

  • The most effective way to prevent recurrence is to initiate an anti-TNF within four weeks of surgery. It has been my practice that patients at high risk for postoperative Crohn’s disease recurrence initiate anti-TNF shortly after they are discharged from the hospital.
  • If a patient had been on an anti-TNF prior to the surgery, I will usually resume the same anti-TNF after the surgery. In these patients, I do not give a re-induction course unless they had not received the anti-TNF for more than three months prior to surgery.
  • Concomitant therapy: “In the majority of patients, I treat with an anti-TNF, I will use a concomitant immunomodulator…One year after surgery, if there is no disease recurrence, I will decrease and often stop the immunomodulator. With the advent of therapeutic drug monitoring, I have a number of postoperative anti-TNF patients on monotherapy without an immunomodulator.
  • [In] patients at moderate risk for postoperative recurrence… I perform an ileocolonoscopy six months postoperatively and, if there is evidence of endoscopic recurrence, I add an anti-TNF agent. After finding a high rate of recurrence in these patients, I am beginning to shift my practice to initiating anti-TNFs in this moderate-risk group as well.

My take: I tend to favor Dr. Reguieiro’s approach in my patient population.

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