Tag Archives: deep remission

IBD Update -September 2020

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Briefly noted:

Safety of Thiopurine Use in Paediatric Gastrointestinal Disease. E Miele et al. JPGN 2020; 71: 156-62. Useful review of thiopurines for IBD and for autoimmune hepatitis

The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial. M Matar et al. JPGN 2020; 71: 237-42. This study showed that 66 (of 78) who completed 72 weeks of treatment had improved (but not normalized) linear growth (height z-score at baseline improved from -0.62 to -0.33 (P=0.005) and normalization of weight and BMI. The presence of perianal disease was associated with diminished growth velocity.  Overall, this study adds to the literature that anti-TNF agents can reverse growth failure associated with Crohn’s disease.

Full text: Deep Remission at 1 Year Prevents Progression of Early Crohn’s Disease  RC Ungaro et al. Gastroenterol 2020; DOI: https://doi.org/10.1053/j.gastro.2020.03.039 Key finding: When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07–0.31) was significantly associated with a lower risk of major adverse outcome.  This study is reinforced by recent data published at DDW 2020 -Abstract 401: N Plevris et al. “Early Mucosal Healing Key to Long-Term Success.”  This was highlighted by Miguel Regueiro in Gastroendonews.com.  Among 375 patients, those who achieved a fecal calprotectin (FC) <250 mcg/g within one year of diagnosis, the disease progression was 65% slower than those with FC values that did not normalize within a year.  Initiation of a biologic within 3 months of diagnosis, more than quadrupled the likelihood of FC normalization within one year.

 

Withdrawing Therapy Leads To Relapse, Even if in Deep Remission

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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.

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Bryce Canyon

Bryce Canyon

Marriage, Divorce and Separation with Anti-TNF Therapy

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This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.

EXTEND & MUSIC: Optimizing Crohn Disease Care

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As noted in recent posts (see links below), there is increased interest in showing direct mucosal healing and achieving optimal drug levels in controlling Crohn disease (CD).

  1. Clin Gastroenterol Hepatol 2014: 12: 414-422.
  2. Clin Gastroenterol Hepatol 2014: 12: 423-431.

The first study examines the rates of deep remission induced by adalimumab.  Deep remission is “defined as the absence of mucosal ulceration and CD Activity Index scores less than 150.”

Design: The data is derived from the EXTEND (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing) trial.  EXTEND was a 52-week randomized, double-blind, placebo-controlled trial of adalimumab (ADA) for adults (n=135) with moderate to severe ileocolonic CD.  All patients received open-label induction with ADA (160/80 mg at weeks 0/2), then were randomized to ongoing ADA 40 mg every other week or placebo.

Results: Rates of DR were 16% in ADA patients compared with 10% of placebo-treated patients at week 12.  By week 52, 19% of ADA patients were in DR compared with 0% of placebo-treated patients.

Key findings:

  • Analysis showed that shorter disease duration was associated with DR.  One-third of patients with CD for <2 years achieved DR.
  • Patients with DR had better outcomes than those with only mucosal healing (n=8); those with isolated clinical remission (n=19, no mucosal healing), but not DR, had similar outcomes to those with DR.  The associated editorial (pg 432) notes “symptoms will still make patients go to the emergency department, or miss work, or feel miserable, regardless of how good their mucosa looks.”
  • The authors state that during the 40 weeks after early CR, “estimated savings were $6117 for direct medical costs and $4243 for indirect costs” (total $10,360).  This monetary savings may not be offset in clinical practice by ileocolonoscopy which is not only invasive but also expensive.

Conclusion (from the authors): “Before any recommendation to adopt DR as a treatment target, establishing a clear association between achievement of DR and better long-term prognosis is necessary.”  The editorial advises against adopting DR as a treatment goal: “combining symptoms and mucosal healing into 1 end-point should be reconsidered as a measure of response to anti-inflammatory therapies.”

The second study, referenced above, examined plasma concentrations of certolizumab pegol (CZP) and endoscopic outcomes of patients with Crohn disease.

Design: The authors analyzed data (post hoc analysis) from the MUSIC (The Endoscopic MUcoSal Improvement in Patients with Active CD Treated with CZP) study. Adult patients received subcutaneous CZP (400 mg) at weeks 0, 2, and 4 followed by every 4 week treatment for 52 weeks.  Endoscopic evaluation took place at weeks 0, 10, and 54 and CZP concentrations were measured at weeks 8 and 54. At week 10, there were 45 patients analyzed and at week 54, 18 patients.

Key findings:

  • Mean CZP concentrations: 11.1 mcg/mL at week 8 (4 weeks after previous dosing) and 14.9 mcg/mL at week 54 (2 weeks after previous dosing).
  • Higher CZP concentration (by quartile values) correlated with endoscopic response (P=.0016) and remission (P=.0302) at week 10.
  • Among those with the highest CZP values, their 8-week CDEIS (CD Endoscopic Index of Severity) remission rate was 75% (12/16).  Overall, CDEIS remission was noted in 56% (25/45) at week 8.
  • At week 54, endoscopic remission correlated with plasma CZP values (P=.0206).
  • Both high CRP and high body weight inversely correlated with CZP concentrations.

Conclusion from this study: As with other anti-TNF agents, higher serum levels were associated with mucosal healing.  However, the data do not prove causality.  “It is possible that higher trough concentrations at week 8 may be a consequence of mucosal healing” rather than the reverse.

Bottomline: These two studies together show that achieving optimal long-term response correlates with therapeutic drug levels and mucosal healing.  At the same time, these studies along with many other indicate that we have along way to go in order for us to achieve these objectives consistently.

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