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.

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