Tag Archives: adalimumab

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.

Related blog posts:

 

CCFA Conference Notes 2014 (part 1)

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Each year our local CCFA chapter holds a one day seminar with separate lectures for health care providers and families.  Overall, it is a good opportunity to hear ‘cutting edge’ material.  I did not pick up as much at this year’s seminar as in previous years, but will highlight what I thought was most important.

Key points:

  1. Symptoms are not accurate at determining effectiveness of IBD therapy.
  2. More frequent use of objective markers are needed to optimize treatment.  Mucosal healing is starting to be a target in clinical practice, but limited by number of medications available.
  3. Stricture classification and operative techniques were reviewed.
  4. IBD frequently results in psychological problems: anxiety, depression, pain, sleep. 15% of kids and 25% of adults are having thoughts of death on screening tool intake.
  5. Fecal microbiota transplantation (FMT) –not enough data to recommend for IBD.  Clinical trials ongoing.

Debate: What should be the End Points in Therapy? 

  • Tanvi Dhere (Emory): Goal: clinical symptoms
  • Cary Sauer (Emory Pediatrics): Goal: mucosal healing and normal bloodwork

In my opinion, this was the most thought-provoking and best presentation

Mucosal healing (MH) consensus definition –normal mucosa after previously abnormal with complete absence of ulceration, macroscopic and histologic signs of inflammation.  In practice MH = absence of ulcerations.

Reasons why mucosal healing as a target is problematic:

  • Problems with MH –not validated.  No long-term data utilizing endoscopic scoring indices of MH.
  • MH relies on a binomial endpoint –Yes or no, but there may be intermediate endpoints.
  • How likely is MH (different definitions in these studies)?  SONIC –MH in 43.9% of combination Rx (30.1% in those with infliximab monotherapy); EXTEND (Adalimumab) 27% and 24.2% 12/52 weeks; MUSIC (certolizumab at 10/54 weeks) 11.5% and 18.9%.

In practice, Mayo Score 0-1 both considered to have MH.

MayoScore Visual

Images above online at www.nature.com

In small study, MH at 1 year were not associated with improved outcomes at 5 years.  Risks of MH: more procedures, more costs of treatment, and potential for more complications.

Dr. Sauer’s reply.  Three simple questions –why should I try to target MH, is it possible, what is needed to get this done?

  1. If the goal were only an asymptomatic patient – why do screening colonoscopy in the general population, much less in IBD?
  2. In IBD, long-term evolution of IBD (Cosnes J et al. Inflamm Bowel Dis. 2002 Jul;8(4):244-50) is toward structuring and penetrating disease. CD Evolution This needs to be modified if possible.

Why MH? Improved symptoms, better quality of life, less likely to develop colon cancer, and it is an objective measure of treatment response.

  • In MH patients, less steroids and fewer flares over 2 year period.
  • MH healing patients have sustained clinical benefit over 96 months.
  • With MH, there is a decreased colectomy in UC.  In one study, there was a lower  colectomy rate at 8 years if colonic CD (62% vs 8%), decreased steroids in CD, decreased hospitalizations, & decreased fistulae.

Is MH possible in clinical practice?  The accuracy of CDAI to detect endoscopic healing is low in patients with CD. (Bouguen G et al Clin Gastrohep 2014).  More frequent adjustments in medical therapy –could lead to MH in up to 80% over 80 week study period.  Same story in UC (Bouguen G et al IBD 2014).

What do I need to do to obtain MH? Endoscopy (or MRE), maximize medications (checking levels), change medications, and most important –set a target. “Adjusting infliximab dose alone could lead to MH in up to 60%.”

When to assess for MH?  Consider endoscopy at 6 months into treatment if symptoms and at 12 months if in clinical remission.

Other viewpoints on MH from panel:

Dr. Loftus –“I think of this like oncology.” He agreed with using the best evaluating tool 6 months into treatment.  Cross-sectional imaging is often more helpful, but may need more than one tool.

Dr. Long—“Are we going to check every 6 months?” No.  She stated that she does not do this and tries to avoid repeated endoscopic procedures if this will not change treatment.  Goal is to make sure patient is headed in right direction, often after starting therapy.  Dr. Long stated that stool biomarkers most useful for colonic disease.

Dr. Dhere—documenting MH is important for deescalating treatment.

Millie Long  “Quality of Care in IBD”

  • 75% of Crohn disease patients will need surgery, 10% in 1st year
  • “One way to gauge quality of care is to examine the degree of consistency in care”
  • High variability in care in IBD (Aliment Pham Ther 2007; 26: 1005-18)
  • “Over half of institutions with worst quality have mortality in normal range.” Outcomes may not occur until several years after treatment, thus more useful to measure process measures

PQRS IBD Quality Measures in Adults: 10 Measures

  • #1 Establishing/documenting IBD type, anatomic location, and activity
  • #2 Preventive care: corticosteroid sparing.  Steroids associated with mortality (OR 2.1 in TREAT registry)
  • #3 Preventive care:  Preventing bone loss.  Limiting steroid use.  Recommend weight-bearing exercise, Quit Smoking, Measure DEXA, added Calicum/Vit D/Bisphosphonates
  • #4: Vaccination –pneumococcal vaccine.  Avoid live virus vaccines
  • #5 Vaccination –influenza vaccine, zoster vaccine
  • #6 Testing for latent TB prior to anti-TNF
  • #7 Testing for hepatitis B virus
  • #8 Testing for C diff with patients hospitalized with IBD
  • #9 VTE prophylaxis in adult IBD patients.  Risk assessment on admission to hospital is recommended.  IBD patients have 1.5-3.5-fold higher risk of VTE àwhich can increase mortality risk
  • #10 Screening for tobacco.  Tobacco use after surgery increases recurrence by 2.5-fold.  It also increases risk for reoperation.

Last year’s notes:

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.

In PURSUIT of Better Treatment for Ulcerative Colitis

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Patient education materials:

#1  Ulcerative Colitis For Dummies | UC Patient Resource This link connects to a free educational book promoted by Salix pharmaceuticals.  In order to receive a free download, you have to register and include your email.  I have not read this book but other similar books (eg. Colonoscopy for Dummies) by Salix have been well-written.

#2 This link, ow.ly/sPX95, is to the ImproveCareNow visit planner website.  It poses of ~ 8 questions and a text box  for “my list of things I’m concerned about and questions that I have.”  Families that use this planner may help themselves achieve more comprehensive care.

Anyone who follows this blog knows that I really enjoy a good study acronym.  The Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) is responsible for two papers in the most recent Gastroenterology issue:

  • Gastroenterol 2014; 146: 85-95
  • Gastroenterol 2014; 146: 96-109

PURSUIT is composed of >200 sites from around the world.  The first study was a combined phase 2 and phase 3 study. It enrolled 1064 adults with moderate to severe ulcerative colitis (UC) who were randomly assigned to either placebo, 200/100 mg or 400/200 mg of SC golimumab at 0 and 2 weeks.  All patients were naive to previous anti-TNF therapies. The average duration of disease was 6 years among the participants. The primary endpoint of the phase 3 part of this study was the clinical response at 6 weeks.  Clinical response was at least a 30% improvement and a ≥3-point improvement in the Mayo score. At baseline, the average Mayo score was 8.

  • The golimumab groups had response rates of 51.8% and 55.0% respectively compared to 29.7% for placebo.
  • Approximately 18% of patients achieved a clinical remission with treatment compared with 6% of placebo patients.
  • Approximately 10% had healed mucosa compared with ~4% in the placebo group.
  • Adverse events: Rates of serious infection were 1.8% for the active treatment group compared with 0.5% for placebo-treated patients.  In the 400/200 mg dosing group, there was 1 death attributed to peritonitis and sepsis after multiple procedures for ischiorectal abscess repair.  In addition, a single case of demyelination was noted in this group.

The second study, a phase 3 double-blind trial, evaluated the efficacy of maintenance treatment of 50 mg or 100 mg SC every 4 weeks in those with a successful induction (n=464).  This study took place at 251 centers between 2007-2011. At 54 weeks, the actively-treated gourds had maintained a clinical response, using the Mayo score, in 47.1% and 50.6% respectively compared to 31.4% for placebo.  Antibodies to golimumab developed in 2.9%, two-thirds of these antibodies were neutralizing.  Antibody formation was lower in those receiving concomitant immunomodulators. 4 cases of tuberculosis were noted from endemic regions despite previous screening.  Overall, infections occurred in 28% of those treated with placebo compared with 39% of those treated with golimumab.

During the course of the study, three deaths were reported, all in the 100 mg golimumab maintenance group.  The causes were malnutrition/sepsis, cardiac failure/thrombosis, and disseminated tuberculosis (patient was receiving isoniazid). After the study, another 6 deaths were reported, including two in the placebo group.  Three malignancies were reported through week 54 in patients receiving golimumab maintenance, two of these presented in the induction period while receiving placebo rectal cancer and thyroid cancer) and one (lung adenocarcinoma) occurred in a patient with a 40-year smoking history who received golimumab for induction and maintenance.

Taken together, about 25% of patients randomized to and maintained on golimumab achieved a clinical response lasting >1 year; similarly, about 17% had clinical remission at 1 year.

In the commentary (page 13-15), Stephen Hanauer notes that better response was noted with higher serum levels and there remains “a strong possibility that optimal dosing was not achieved.”  He and the authors comment on the observation that less-severe patients had a better response, indicating that  “greater disease severity may be correlated with more rapid clearance.”

Bottomline: These studies demonstrate that golimumab is an effective treatment for UC with a similar risk of adverse reactions as other anti-TNF agents.  The published studies are complicated and take some time to analyze.

Plus more references:

Gastroenterol 2014; 146: 110-18. “Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis.” Data for this studies was derived from ULTRA1 and ULTRA2 trials with 963 patients.  Risk for hospitalization, whether due to UC or all-causes, was reduced between 40-50% compared to placebo within the first 8 weeks of adalimumab administration.

Clin Gastroenterol Hepatol 2013; 11: 1538-49.  Excellent review on pouchitis. Figure 5 (pg 1545) provides a nice treatment algorithm.  Initial approach is antibiotics (metronidazole or ciprofloxacin); in those responsive, either prn therapy or chronic treatment.  In those not responsive, look for pathogens (eg. CMV and C difficile) or determine it is immune-mediated (PSC-associated, IgG4-associated, or autoimmune).  The immune-mediated may respond to 5-ASA/budesonide or immunomodulators.

Clin Gastroenterol Hepatol 2013; 11: 1601-08. This case-control study with 141 UC controls and 59 patients who developed colorectal neoplasia found that increased inflammation was associated with colorectal neoplasia.  Use of immune modulators reduced the risk of colorectal neoplasia.

Related blog post:

Simponi (Golimumab) Approved for Ulcerative Colitis | gutsandgrowth

What you might not know about anti-TNF monitoring…

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At a recent group dinner meeting, we had the opportunity to review therapeutic anti-TNF monitoring. In addition, we discussed emerging treatments for inflammatory bowel disease, like golimumab, tofacintinib and vedolizumab.

As noted in previous blog entries (see below), therapeutic anti-TNF monitoring can help adjust treatment.  Namely, if a patient loses response to therapy and has low trough levels of anti-TNF (Infliximab ❤ μg/mL, Adalimumab <8 μg/mL, or certolizumab <27.5 μg/mL) without antidrug antibodies (ADAs), then increasing the dose is likely to be effective.  However, if a patient has a therapeutic level and is not responding, changing to another agent and/or further investigation is worthwhile.

So, what information is new?

  • Only about 20% of patients who lose clinical response develop ADAs.  So, drug level, rather than ADAs, is most helpful.
  • For infliximab, adjusting dose 14 weeks into therapy to achieve a target trough level between 3-7 mcg/mL may be helpful.
  • Severe colitis patients may need higher initial doses (?as high as 20 mg/kg) due to potential for ‘antigen sink.’  This is due to notably higher clearance in the presence of low albumin, and high CRP.  Other factors that increase clearance include higher BMI and male gender.
  • About 1/2 of patients who receive higher doses due to severe disease may be able to deescalate dosage when improved. (?which half)
  • Currently, a reactive approach to checking levels is common in U.S. in part due to costs associated with checking trough levels and ADAs (as much as $2500).  That is, most commonly checking levels is undertaken in patients with suboptimal clinical response.  A proactive approach to achieve target levels may be shown to be helpful.
  • While studies have not shown higher adverse reactions with higher trough levels, there are a few clinical situations in which lower trough levels can be important.  In patients with psoriatic skin lesions and arthralgias, if trough levels are elevated, lowering the dose may be helpful.

Outstanding questions?

  • Should patients have drug levels checked when they are asymptomatic?
  • How does a practitioner account for variability among different laboratory assays?
  • What is the optimal target level for each anti-TNF agent? Is this different in Crohn disease compared with ulcerative colitis? Is the trough target level different in adults than children?
  • Is there a toxic level?
  • If a rapid test response were available, would checking drug levels be needed for hospitalized patients to assess anti-TNF rescue therapy?

Related blog links:

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

Reporting Bias: Infections with TNF Inhibitors

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A recent article (Clin Infect Dis 2013; 57: 1318-30 -thanks to Jeff Lewis for this reference) summarized the pediatric literature on infectious complications associated with tumor necrosis factor-α (TNF) inhibitors for both Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD).

In total 33 studies for JIA were included and 39 studies for IBD.  Many others were excluded due to overlapping cohorts or lack of sufficient data.

For JIA, the authors identified 296 infliximab (IFX) patients, 2465 etanercept patients, and 242 adalimumab patients.  Most infectious were mild and mainly viral etiology.  For example, 1016 upper respiratory illnesses with etanercept were reported.  However there were a significant number of more serious infections which included lower respiratory infections (n=37), cellulitis/abscess (n=15), histoplasmosis (n=2), and meningitis (n=4). Four patients had infectious fatalities.

Similarly, for IBD, most patients had mild infections.  Among 1407 IFX patients and 241 adalimumab (ADA) patients, there were 105 URIs noted.  Again, more serious infectious were noted in many.  Four fatalities were reported; 1 was due to disseminated CMV, 1 due to bacterial sepsis, and 2 were due to central line infections.

When examining this report, the question of reporting bias cannot be avoided. The various reports that were summarized included 30 prospective studies, 23 retrospective studies, and 19 various reports (case reports, case series, and FDA reports).  The composite, in my view, likely overestimates the risk of serious infections.  In addition, many of the infections may have been due to concurrent immunosuppressive therapy, but the details for this are lacking.

With regard to microbiology:

  • 5 JIA patients had tuberculosis; there were no tuberculosis cases reported in the IBD cohort
  • Varicella/zoster was the most frequent viral infection and was frequently severe.  In JIA cohort, there were 39 VZV cases (11 severe); among IBD cohort, there were 16 VZV cases (3 severe).

Bottomline: Given the frequent use of anti-TNF agents, better prospective pediatric data are needed.  In addition, careful analysis of the data is needed for better attribution; the risk for many of these infections is likely due to concurrent medications like corticosteroids.

Also Noted:

Clin Gastroenterol Hepatol 2013; 11: 826-31.  In a prospective cohort of 200 anti-TNF-naive adult patients (100 treated with IFX and 100 with ADA), the effectiveness was similar for IFX and ADA at both 1 and 2 year followup.  Improved efficacy was noted when these agents were combined with immunomodulators, though this was statistically significant for IFX. The total patient response was 63.5% at 1 year and 45% at 2 years.

Related posts:

Anti-TNF therapy for IBD

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In the same issue as the vedolizumab phase 3 studies, there is a succinct review of tumor necrosis antagonist therapy (anti-TNF) therapy for IBD (NEJM 2103; 369: 754-62).

Useful points about IBD:

  • Prevalence of ulcerative colitis (UC) and Crohn’s disease (CD) in North America: 780,000 and 630,00 respectively
  • In first 10 years of CD, cumulative rate of surgery is 40-55%.
  • In first 20 years of UC, rate of colectomy is ~15%.
  • “Recent meta-analysis do not indicate that this drug (mesalamine) has any clinically relevant efficacy in patients with” Crohn’s disease.

Anti-TNF agents:

  • Agents for IBD include infliximab, adalimumab, certolizumab pegol, and golimumab.
  • No head-to-head comparisons have been studied, though the “clinical trials suggest similar efficacy among the available drugs.”
  • Newest approved anti-TNF is golimumab which is administered subcutaneously at a dose of 200 mg at week 0, followed by 100 mg at week 2 and then 100 mg every 4 weeks.
  • A “considerable number of patients with Crohn’s disease (10-40%, depending on selection criteria) do not have a clinically relevant response to currently available TNF inhibitors (primary treatment failure) and among patients with ulcerative colitis, this proportion may be as high as 50%.”
  • “In addition, only about one third to one half of patients with Crohn’s disease have a complete remission, and about two thirds of patients do not have a response that is sustained during 12 months of continuous treatment (secondary treatment failure).”  Many of these patients will respond to dose escalation.
  • The “annual projected cost of each biologic agent for a 70-kg patient with inflammatory bowel disease is approximately $19,000 in the first year and $15,000 in subsequent years.”  These figures exclude the costs associated with administration and dose escalation.

Areas of uncertainty according to the authors:

  • “The value of concomitant treatment with immunosuppressive agents and TNF inhibitors has been debated intensely.”  Combination therapy results in superior efficacy and lower rates of antibodies to anti-TNF agents.  However, “the benefit of combined treatment for more than 12 months is uncertain.”
  • “There are no data to confirm that it (top-down treatment) is actually superior to conventional step-up therapy in terms of disease progression”

Related blog links:

TNF Antagonists and Psoriasis

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Using data from the adverse event reporting system (AERS) from the FDA, the authors of a recent report identified a large number of psoriasis rashes which developed among patients receiving tumor necrosis factor α (TNF) antagonists (Inflamm Bowel Dis 2013; 19: 1164-72).

From more than 13 million AERS reports (2004-2011), a total of 5432 reports of psoriasis were noted: 1789 for infliximab, 3475 for adalimumab, and 168 for certolizumab compared with 88 for a control group which consisted of the following medications: propranolol, melamine, and lithium. While the absolute number for certolizumab is lower, the relative risk is similar to infliximab when adjusted for frequency of usage.

The AERS database relies on voluntary reporting and there are numerous reporting biases.  Given that AERS captures only a fraction of all true adverse events, the authors extrapolate that more 15,000 psoriasisiform adverse events occur each.  They note that these reactions typically occur in individuals without a personal or family history of psoriasis.  The onset is variable, but typically occurs 9-11 months after initiating therapy.

Additional references:

  • -IBD 2011; 17: 2512.  n=50.  Skin reactions with adalimumab.  62% of pts develop skin reactions: eczema, acne-like dermatitis, psoriasis-like (6 of 50).  Adalimumab d/c’d in 22%.
  • -JPGN 2010; 52: 230. 6 of 73 pts (8%) developed IFX-induced psoriasis -managed with topical Rx.
  • -Clin Gastro & Hep 2010; 8: xxiv. Image of psoriaform rash assoc with infliximab
  • -Aliment pharmacol Ther 2009; 29: 921-27. Review of psoriaform rash assoc with infliximab. Majority improved when TNF stopped.  Options: Rx w steroids for 3 days around Rx or add MTX.
  • -NEJM 2009; 361: 496. Review of psoriasis.

Unrelated link:

For those of you who do not have teenage sons, perhaps you are not familiar with Jimmy Kimmel’s:  This Week in Unnecessary Censorship – YouTube

Remission in Crohn’s Disease

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A recent article highlights the issue of remission in Crohn’s disease (CD) (Inflamm Bowel Dis 2013; 19: 1645-53).

As noted in previous blog entries (see links below), improvements in remission with ImproveCareNow and with previous drug trials have several limitations due to the current definition of remission.  Currently, even during periods of clinical remission (defined currently mainly by symptoms), laboratory or endoscopic evidence of persistent inflammation can be seen.  Persistent inflammation is likely to lead to progressive bowel damage. With the advent of more effective treatments as well as better biomarkers, a more objective measure of remission is needed.

“Remission is an evolving concept in CD. At its most fundamental level, remission should be a state with little or no risk of disease progression, likely implying the absence of biological evidence of inflammation.”

The authors proposed definitions of remission based on whether the patient has “early” disease or “late” disease.  Early disease “may be defined as disease duration ≤18 months without previous exposure to immunosuppressants or biologics.”

Early disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission in practice (symptom control): complete absence of symptoms; 1-2 formed stools per day without abdominal pain.  In a clinical trial, CDAI <150 points.
  • Outcomes: no disease progression or complications, normal quality of life

Late disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission (symptom control): a: inflammatory symptom improvement (may have residual symptoms due to previous damage or surgery). In clinical trial, CDAI 150-220 points.
  • Outcome: stabilization of noninflammatory symptoms and no progression of structural damage, improved quality of life

The authors goal is to rework remission to include symptom control and histologic/mucosal healing.  This concept is not novel.  Investigators in the adalimumab EXTEND study coined the term “deep remission.” This term referred to patients with both CDAI remission and complete mucosal healing.  Patients who achieved deep remission had improved outcomes, including fewer hospitalizations and fewer surgical resections (Gut 2010; 59: A80).

Bottomline: Improvements in both objective measures of biologic inflammation along with resolution of clinical symptoms are needed to change the long-term outcome for patients with Crohn’s disease.  The definition of remission should reflect this reality.

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

Related blog entries:

Rethinking top-down treatment?

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Given the effectiveness of biologic therapy and the potential for disease modification, the threshold for “top-down” treatment has been lower at this time as compared with “step-up” treatment.  What about long-term outcomes, does starting soon increase or decrease the likelihood of doing well?  A recent study suggests that “early biologic therapy did not improve disease activity or quality of life” (Inflamm Bowel Dis 2013; 19: 1397-1403).

In this retrospective chart review involving 93 patient’s with Crohn’s disease (between 2004 and 2010), patients whose data was prospectively maintained were categorized into either early biologic therapy or a step-up group. For these patients, the mean age at diagnosis was 28 years.  There were no apparent differences in demographic variables between the groups; however, the early biologic therapy group had higher disease activity and lower quality of life scores at baseline. 20% were current smokers and 61% never smoked.  Disease location was similar in both groups; overall, 35% had ileal disease, 13% colonic disease, 34% ileocolonic, and 7% isolated upper tract disease.

Results:

  • Mean Harvey-Bradshaw index and Short Inflammatory Bowel Disease Questionnaire scores at 3, 6, and 12 months were not different between the groups.
  • Early biologic therapy group had more hospitalizations.
  • No difference in steroid use or surgeries was noted at one year.

Take-home message: This study suggests that differences in outcomes between “top-down” therapy and step-up therapy are more pronounced early in the treatment course but may wane after 1 to 2 years.  However, early biologic therapy “may be a more effective strategy in patients with Crohn’s disease with higher disease activity.”

Relating blog posts:

Anti-TNF Therapy for Eosinophilic Gastroenteritis

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A recent report highlights the use of anti-TNF therapy (eg. infliximab (IFX) and adalimumab [ADA])  for eosinophilic enterocolitis/eosinophilic gastroenteritis in eight patients who had not responded to other treatments (JPGN 2013; 56: 492-97).

The mean age of these patients was 8 years with a range of 1 to 14 years.  Prior to use of IFX therapy, multiple therapies had been used.  Four patients had been treated with complete elemental diet; medications that were used included montelukast, hydroxyzine, sodium cromogylcate, budesonide, amitriptyline, prednisone, ketotifen, cyproheptadine, thiopurines, and methotrexate (Table 1 in study).

Complete clinical remission was noted to occur in 6 (75%) with IFX induction treatment; this was associated with mucosal healing in 3, mucosal improvement in 2, and unknown in 1 patient.

The six responders were followed for a median of 7 years.  During that timeframe, four of six had secondary loss of response and were switched to ADA.  Three of these four maintained a clinical response with ADA using high doses (80 mg EOW).

Additional References:

  • -Clin Gastroenterol Hepatol 2011; 9: 950.  40% of Eosinophili gastroenteritis resolved.
  • -JPGN 2010; 51: 723. n=91.  Incidental gastric eosinophils does not predict a worse response to fluticasone then isolated EoE.
  • -NEJM 2009; 361: 1387.  Description of a case of eosinophilic gastroenteritis.
  • -Gut 2009; 58: 721-32. Review of primary Eos d/o of GI tract.
  • -JPGN 2008; 47: 234-8.  EGIDs.