Three Studies Show Benefit of Concomitant Therapy for Inflammatory Bowel Disease (Part 1)

In the first study (J Cheng et al. Inflamm Bowel Dis 2017; 23: 1762-73), the authors retrospectively reviewed 148 children (113 with Crohn’s disease, 35 with ulcerative colitis). 90 patients received concomitant therapy (infliximab with either a thiopurine [n=67], methotrexate [n=23]) and 58 received infliximab monotherapy. Key findings:

  • Concomitant therapy >6 months  significantly lowered the risk of secondary loss of response in Crohn’s disease (CD) (HR =0.39) compared to monotherapy.   A similar trend was noted with ulcerative colitis (UC) but did not reach statistical significance.
  • Steroid-free remission rates at 1 year were 78% for CD patients with concomitant therapy compared with 54% on monotherapy
  • Among primary nonresponders, 67% of CD patients and 75% of UC patients were receiving IFX monotherapy.
  • No differences in adverse events were evident between patients receiving monotherapy compared with concomitant therapy. One patient (receiving azathioprine) developed a follicular lymphoma; this patient was well 10 years later.

The second study (Y Qui et al. Clin Gastroenterol Hepatol 2017; 15: 1359-72) was a systemic review of 35 studies that met the authors’ inclusion criteria. In total, 6790 patients with inflammatory bowel disease were enrolled in these studies. This study looked at multiple anit-TNF agents including infliximab, adalimumab, certolizumab, and golimumab. Key finding:

  • Antidrug antibodies were reduced by 51% in patients receiving concomitant therapy
  • Conclusion from authors: “concomitant use of immunomodulators should be considered in patients treated with anti-TNF treatment.”

My take: Overall, for most pediatric patients with CD, to date, concomitant therapy has been the most effective treatment.  More prospective studies are needed to determine more conclusively the benefit and optimal duration/timing of combined therapy, particularly with the more frequent use of therapeutic drug monitoring.  Also, as will be noted in future posts from annual meeting, thiopurine use is declining.

More on this topic tomorrow.

Related blog posts:

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.

Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy

While there have been a number of studies which have highlighted the potential risks of biologic agents, many studies have NOT identified any risk of infection or malignancy.

Another recent systematic review/meta-analysis (S Bonovas et al. Clin Gastroenterol Hepatol 2016; 14: 1385-97) provides reassuring data regarding the following biologics: infliximab, adalimumab, certolizumab, golimumab, natalizumab, and vedolizumab.

The authors identified 49 randomized placebo-controlled studies with 14,590 participants.

Key findings:

  • There was a moderate infection risk with odds ratio of 1.19 (19% increase in odds of developing an infection) and significant increase in opportunistic infections (eg. tuberculosis) OR 1.90
  • Risk of serious infections was NOT increased in patients treated with biologics with OR 0.89.  In studies with low risk of bias, the risk of serious infections had OR of 0.56.
  • No increase in malignancy risk was identified with OR 0.90 but the authors note that data was insufficient in terms of exposure and follow-up to be conclusive.

The authors note that the studies including in this review challenge some of the findings of observational studies. “However, observational studies lack the experimental random allocation of participants…the discrepancies between observational studies and randomized trial evidence might be explained by the inability of observational designs to fully address the complex and important differences between the IBD patients receiving and those not receiving biologics.”

Study limitations include “sponsorship bias -because the trials were supported by pharmaceutical companies and limited followup of 24 months. In addition, most of the trials in the meta-analysis were judged to be at high or unclear risk of bias because of their methodological characteristics.

My take: This study indicates that biologic therapies do not appear to increase the risk of serious infections and may not increase the overall risk of malignancy.

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‘Don’t Believe Our Study’

The message I inferred from a recent study (CA Siegel et al. Clin Gastroenterol Hepatol 2015; 13: 2233-40) was to disregard their results which generally showed a lack of benefit of combination therapy (aka “concomitant immunomodulator” or dual therapy) compared with anti-tumor necrosis factor (anti-TNF) monotherapy for Crohn’s disease.

Specifically, the authors state the following in their discussion:

Although our results challenge the clinical importance of combination therapy in this specific scenario, it is hard to ignore the preponderance of data to date relating to the pharmacokinetics of anti-TNF medications that support the approach of combination therapy over monotherapy.

Here’s the background for this study.  The authors performed a meta-analysis of placebo-controlled trials (n=1601 subjects) to examine the question of whether continued use of immunomodulators (IMs) would be of benefit in patients who had failed monotherapy with IMs (“IM-experienced”).  The authors note that the SONIC study showed that combination therapy (infliximab and azathioprine) was more beneficial in patients who were IM-naive than monotherapy.  This meta-analysis included data from 3 anti-TNF agents: infliximab, adalimumab, and certolizumab.

Key findings:

  • Combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio 1.02) or in maintaining a response (OR 1.53).
  • In subgroup analysis, there was a statistically-significant protective effect of baseline IM exposure versus no baseline IM exposure among those treated with infliximab.
  • Generally, combination therapy was not associated with any change in adverse reactions; however, combination therapy with infliximab had lower adverse events, which was driven by infusion reactions.

My take: This study indicates that combination therapy is likely helpful in IM-experienced patients who are starting infliximab and possibly not effective with the other anti-TNF agents.  The authors emphasize the need for well-designed, prospective, randomized, placebo-controlled trial for a definitive answer.  Until then, don’t believe their study.

Of interest: Recently I became aware of a college scholarship opportunity for young adults with IBD: Abbvie Scholarship Program.

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Sticky Decisions with IBD Therapy – When an Infection or Malignancy Develops

A recent review article provides advice for management of biologics and immunomodulators when an infection or malignancy develops (Inflamm Bowel Dis 2014; 20: 926-35).  Serious infections are noted in 3-5% of adults receiving either thiopurines or anti-tumor necrosis factor agents (anti-TNFs); less than 0.1% of adults develop treatment-related lymphoma.  The recommendations are provided in 5 separate tables.

Table 1 addresses the issue of bacterial infectionsFor mild infections, the authors recommend that thiopurines (azathiopurine, 6-mercaptopurine) as well as anti-tumor necrosis factor agents (infliximab, adalimumab, certolizumab, golimumab) be continued.  Examples of these ‘mild’ infectious included E. coli UTI and strep pharyngitis.  For severe bacterial infections (eg. pneumococcal pneumonia), for both these therapies, the authors recommend: “stop, but may restart once treated.”  For bacterial opportunistic infections (eg. mycobacterium), for latent infections, “do not start until 2 to 4 wk INH” whereas for active infections, the authors recommend (for anti-TNFs) “stop, only restart after full treatment, and if IBD is severe.”

  • Table 2 addresses fungal infections.
  • Table 3 addresses viral infections (eg. CMV, EBV).  For EBV, the authors recommend stopping thiopurines and not restarting in male patients.
  • Table 4 addresses malignancy: solid tumors, hepatosplenic T-cell, EBV-associated lymphoma, and lymphoproliferative lymphoma.
  • Table 5 addresses skin cancers.

Towards the end of the review, the authors provide some context for the risks with thiopurines and anti-TNFs.  “The majority of side effects associated with thiopurines and anti-TNFs are mild, self-limited and reversible…the risk of a lymphoma developing on AZA/6-MP (4/10,000 patient-years) is comparable with the lifetime risk of dying from drowning (1/1112) or dying in a bicycle accident (1/5000).  The risk is much less than the risk of dying in an automobile accident (1/108).  Patients are willing to accept risks..if their disease is severe and the chance of a clinical response outweighs the risk.”

With regard to dual therapy, the authors note, “it has been our practice to lower the concomitant AZA/6-MP in patients on combination therapy with anti-TNF and then to stop the thiopurine in patients in deep remission for 3 years. However, this decision must be individualized, and for patients with severe, disabling disease, we generally do not alter treatment.”

Bottomline: This is a useful advice/handy reference for the sticky situation of managing IBD in the face of infections and malignancy.

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.

 

CCFA Conference Notes 2014 (part 1)

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.

What you might not know about anti-TNF monitoring…

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

Anti-TNFs and Pregnancy

While pregnancy does not occur commonly while patients are in a pediatric gastroenterology practice, the possibility of becoming pregnant certainly influences our choice of medications.  With inflammatory bowel disease (IBD), I rarely recommend methotrexate in young women due to its teratogenicity.  With regard to the anti-TNF agents, there is less data available.   Two recent studies add some insight into this issue.

The first study ((Clin Gastroenterol Hepatol 2013; 11: 318-21) followed 31 pregnancies in 28 women with IBD (2006-2011).  18 patients received infliximab (IFX) and 13 adalimumab (ADA).  Most were receiving lower doses; only one IFX patient was receiving 10 mg/kg/dose and only two ADA patients were receiving weekly dosing.  Levels of anti-TNF agents were measured from cord blood from 18 newborns (12  IFX, 6 ADA).

Results:

  • 28 live births.  3 miscarriages (1 IFX, 2 ADA).  No congenital malformations were noted.
  • Mean cord IFX level was 6.4 mcg/mL.  A level of 2.8 mcg/mL was noted in the early discontinuation group –stopping 10 weeks prior to delivery .
  • Mean ADA level was 1.7 mcg/mL in five infants.  One infant had an undetectable level. All mothers had stopped ADA at gestational week 22.

In the second study (Clin Gastroenterol Hepat 2013; 11: 286-92) there were 31 pregnant patients. Anti-TNF treatment: Certolizumab (CZP) (n=10), IFX (n=11), ADA (n=10).  Serum levels were measured at birth in the mother, infant, and in cord blood. Then, levels were followed monthly until undetectable.  Among women receiving IFX, two were receiving 10 mg/kg/dose.  Women were identified through the Crohn’s Colitis Foundation of America Pregnancy IBD and Neonatal Outcomes (PIANO) Registry.

Results:

  • IFX was detectable for 2-7 months postpartum (median interval prior to delivery and last dose was 35 days).  Median IFX level in the cord was 160% that of the mother.
  • ADA was detectable for at least 11 weeks in infant’s circulation (median interval prior to delivery and last dose was 5.5 weeks). Median ADA in the cord was 153% of the mother.
  • Median CZP in the cord was 3.9% that of the mother.
  • No congenital anomalies or complications were reported in any of the infants.

Bottomline from these studies:

Stopping these drugs after the second trimester lowers the level of these medications in the infant.  This likely results in a lower likelihood of the infant developing an opportunistic infection but also results in a low risk for the mother of an IBD flareup.  Certolizumab pegol has very low levels of placenta transfer.

Related references:

  • -J Am Acad Dermatol 2011; 65: 870.  Death noted in infant whose mother took IFX after BCG vaccination.
  • -J Crohns Colitis 2011; 5: 555-8.  Low levels of IFX detected in infants from nursing mothers with IBD  (1/200th of the maternal level in serum 2 to 3 days after infusion).
  • -Clin Gastroenterol & Hep 2010; 8: 509. n=2377. Crohn dz assoc w prematurity but not birth defects.
  • -Gastroenterol 2003;124: 9-17. Safety of 6-MP in pregnancy. n=155, at least 1 pregnancy. No adverse effect noted.
  • -Clin Gastroenterol & Hepatology; 2006: 4: 1255.  Infliximab crosses placenta but was not detected breastmilk.

Monitoring TNF antagonists in inflammatory bowel disease

Previously, this blog has discussed the use of drug monitoring in inflammatory bowel disease (Drug levels for inflammatory bowel disease | gutsandgrowth).  A good review of this topic has been published recently (Clin Gastroenterol Hepatol 2012; 10: 1079-87).

Some of the useful pointers:

  • Factors that influence clearance of TNF antagonists are reviewed:
  1. Antidrug antibodies (ADA) increase clearance and worsen outcomes
  2. Use of concomitant immunosuppressives reduces the likelihood of ADA formation and increase drug concentration.   In the SONIC trial, use of azathioprine was associated with trough infliximab (IFX) levels of 3.5 μg/mL compared with 1.6 μg/mL with monotherapy.  Also, ADA was reduce: 0.9% compared with 14.6% in the monotherapy group. [Other studies though have found variable effects of cotherapy.]
  3. Low serum albumin and high CRP are associated with increased drug clearance
  4. Individuals with high body size and males are more likely to have increased drug clearance.
  • Better assays for measurement of IFX and adalimumab (ADL) are now available.
  • Currently a trial evaluating trough levels is underway: Trough Level Adapted Infliximab Treatment (TAXIT).  With this study, the accepted target range for trough levels is 3-7 μg/mL.  Levels >7 μg/mL are considered supratherapeutic and allows for a prolongation of dosing interval.  Preliminary data confirm that trough levels inversely correlate with CRP.
  • Proposed algorithm in individuals with loss of response & positive ADA.  If ADAs present at high titer, then switch to different TNF antagonist.  If low  titer, could either switch or attempt drug escalation.
  • With IFX, when antibodies to infliximab (ATIs) are present, the likelihood of responding to increased dose is less than 20% whereas changing to different TNF antagonist has about an 90% response (in patients who were previous responders).
  • Proposed algorithm in individuals with loss of response & negative ADA.  If subtherapeutic trough levels (IFX ❤ μg/mL, ADL <8 μg/mL, or certolizumab <27.5 μg/mL), then dose escalation is worthwhile.  If drug levels are therapeutic, then dose escalation will not be effective.
  • With IFX, more than 85% of patients will respond to drug escalation when the trough level is subtherapeutic. This is much more favorable than switching agents.
  • One other issue with ADAs is that they may be transient is some patients.  Perhaps one-fourth of ATIs may be transient which may explain why some individuals with ATIs may still respond to dose escalation.

These points give several reasons why drug monitoring is useful in individuals with loss of response and may help determine whether patients responding to therapy may be able to prolong dose intervals.  At the same time, when an individual is not responding to therapy, it is also important to determine if in fact active inflammation is present with objective markers and to consider alternative explanations for GI symptoms (eg. Clostridium difficile infection, irritable bowel, bacterial overgrowth, etc.).

Related blog entries:

Only one chance to make first impression | gutsandgrowth

When nothing else is working | gutsandgrowth

Infliximab for children with Ulcerative Colitis | gutsandgrowth

Adalimumab for children with Crohn’s disease | gutsandgrowth

CHOOSE TNF TRIAL | gutsandgrowth

CHOOSE TNF TRIAL

While most physicians consider drug efficacy as the most important factor in choosing therapy, this is not always the determinant factor in patient choice.

The “CHOOSE TNF TRIAL” (Inflamm Bowel Dis 2012; 18: 1523-30) was a prospective survey of 100 adult patients with Crohn’s disease who were naive to anti-TNF therapy (infliximab, adalimumab, certolizumab).

Most important to patients:

  • Ease of use 69%
  • Time for therapy 34%
  • Time between applications 31%
  • Evidence for efficacy 19%
  • Fear of syringes 10%

Patient choice: Adalimumab preferred in 36%, certolizumab in 28%, and infliximab in 25%

While patient concerns need to be considered, others have shown that physician opinion is an important factor for patient decisions (J Rhemumatol 2008; 35: 618-24).  The discussion notes that “three anti-TNF drugs used in inflammatory bowel disease treatment have not been compared side-by-side in clinical trials.”  Thus far in pediatrics, infliximab is the only TNF approved for clinical use; as such, the other anti-TNF agents have been used primarily when infliximab loses effectiveness.

One drawback with injectable medications has been reduced adherence; up to 50% of patients fail to maintain regular injection interval; in addition, in patients who have had intravenous infusions (rather than patients who are naive) it is preferred over injections (Jay Popp, medical director of Janssen pharmaceuticals–personal communication).

As such, when patients receive infusions (eg. infliximab), closer followup and better adherence are more likely in comparison to injections.  This certainly improves efficacy.

Related blog entries:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression

Biomarkers identify patients who benefit and how

Fecal calprotectin and serum CRP levels are helping to identify which patients benefit most from biologic therapies, how frequently to dose individuals and how well inflammation correlates with changes in CDAI.  Several abstracts from ACG highlight these issues:

Abstract #1175: Fecal calprotectin concentration and clinical remission in patients with active Crohn’s disease treated with certolizumab pegol: results from PRECiSE 1 (Sandborn W et al).

Abstract #1164: Baseline C-reactive protein is associated with disease progression in  patients with Crohn’s disease (Colmbel J-F et al).

Abstract #1165: Association of baseline C-reactive protein with maintenance of remission in patients with moderate to severe Crohn’s disease treated with adalimumab (Sandborn W et al)

Abstract 1175 uses a post hoc analysis of patients with active Crohn’s disease (CD) who were treated with certolizumab or placebo for 26 weeks.  Baseline calprotectin concentrations were higher in patients who achieved remission.  Another interesting finding of this study was that placebo patients did not have improvement in calprotectin levels.  So, even though some patients  had improvement in CDAI scores, indicating subjective improvement, inflammatory activity did not decline.  This is another indicator of how flawed a CDAI is for indicating the effectiveness of an IBD therapy.

Abstract 1164 looked at 238 patients with moderate to severe CD who were randomized to placebo arm in the CHARM study.  These patients were given open-label adalimumab for induction (80 mg week 0, 40 mg week 2) followed by blinded weekly placebo treatment from weeks 4-56 with a switch to open-label adalimumab after week 12 for a disease flare.  Higher baseline CRP levels in patients with moderate or severe CD were associated with higher disease scores after four weeks and after one year.  This suggests that a patient with higher CRP is more likely to have disease progression without adequate treatment.

Abstract 1165 examined the relationship between CRP and remission in CHARM patients. In the high baseline CRP group, 39 patients received adalimumab every other week, 28 weekly, and 34 received placebo.  In the low baseline CRP group, there were 42 every other week patients, 33 weekly, and 39 placebo patients.  In the high baseline CRP group, remission rates were 50% higher in the weekly treatment group compared to the every other week group.  Patients with low baseline CRP had similar results when treated weekly versus every other week.  Thus, patients with high baseline CRP are more likely to benefit from dose escalation and low CRP patients are more likely to have coexistent issues contributing to their symptoms (eg. IBS).

One other caveat: CRP production is geneticallly-determined and some patients do not make CRP in spite of active inflammation.

Related blog entries:

Food as medicine

Speed matters

Additional calprotectin references:

  • -IBD 2010; 16: 482. Calprotectin correlated with inflammation of ileum after pouch creation in children.
  • -IBD 2009; 12: 1851. Calprotectin was the only marker to correlate with endoscopic activity; n=134.
  • -JPGN 2009; 48: 48. Good sensitivity/specificity of calprotectin & lactoferrin. Up to 96% sensitivity & specificity.
  • -Clin Gastro & Hep 2008; 6: 1218. Lack of correlation between clinical symptoms and fecal biomarkers. However, biomarkers do correlate with mucosal/endoscopic disease. n=164.
  • -IBD 2008; 14: 1392. Monitoring IBD activity level c calprotectin & lactoferrin; n=15.
  • -IBD 2008; 14: 1229. Clinical utility in assessing histological relapse in kids. n=73 over 8yrs…may allow avoidance of invasive tests; cut off of 275mcg/gm had 97% sensitivity/neg pred value 85% pos pred value/specificity at predicting relapse.
  • -IBD 2008; 14: 669. Fecal calprotectin good at predicting relapse in pediatric IBD w cutoff of 400.

C-reactive protein references:

  • -J Pediatr 2011; 159: 340. CRP helps identify IBD.
  • -Clin Gastro & Hepatology 2011; 9: 421. CRP predicts response to IFX. n=718. those with high CRP had 91% response vs 83% in pts with NL CRP.
  • -Gastro 2004; 126: 1574-81. Crohn’s review. High CRP suggests likely response to anti-TNFα treatment.
  • -JPGN 2004; 38: 509-12. CRP more reliable than ESR for IBD.
  • -NEJM 1999; 340: 448. Review on acute phase reactants. CRP better than ESR as ESR is an indirect measure (resistance of plasma, due to fibrinogen, to the falling of RBCs) & broader range for CRP.