C-Reactive Protein: Informative or Misleading Marker of Crohnʼs Disease?

In a recent study, the Radford-Smith group addressed the important question of whether it was possible to identify and characterize patients with normal or low serum C-reactive protein (CRP) levels in a prospective cohort of patients with active Crohn's disease (as per the criteria of the Crohn's Disease Activity Index [CDAI]).1 Florin et al compared patients with active CD who had low CRP levels with those who had high CRP levels and found significantly more ileal localization, less pure colonic localization, and lower body mass index (BMI) in the low-CRP group. The 2 groups showed no significant differences in age at diagnosis, smoking status, rate of appendectomy, duration of disease, number of relapses, disease behaviors, or extra-intestinal manifestations. Prior to inclusion in the study, the patients in the low-CRP group had undergone CD abdominal surgical procedures significantly more often than had those in the high-CRP group because of the high frequency of ileal involvement in the low-CRP group. Because NOD2 mutations are more often associated with CD patients with ileal disease, this study examined NOD2 variants but found no significant differences in their allelic frequency between the 2 groups. Thus, patients with active disease (as per CDAI criteria) and low serum CRP would be patients with pure ileal disease. Onset or relapse of Crohn's disease is often associated with diarrhea and abdominal pain and sometimes with fatigue, fever, and weight loss. However, these symptoms may be misleading as they can also reflect a concomitant disease. Thus, efforts must be made to exclude other causes of these symptoms such as gastroenteritis, irritable bowel syndrome (IBS), bacterial overgrowth, bile salt wastage, secondary lactase deficiency, short bowel syndrome, and medication-induced diarrhea.2 Although only a small number of patients with active disease go into remission without specific treatment, recent double-blind controlled trials of patients with moderately active Crohn's disease clearly demonstrated that a third of patients will go into remission on placebo.3 Indeed, the CDAI, widely used in most clinical trials, is mostly based on a grading score of various symptoms and thus has a large subjective component. Therefore, measuring the severity of disease and the subsequent treatment response/remission solely on the basis of symptoms is misleading as it does not always reflect the magnitude of inflammation because of interfering concomitant factors or disease. The resurgence of interest in C-reactive protein, a major liver-derived acute-phase protein, has provided a better definition of disease flare-up.4 When abscess formation or infections are ruled out, the level of serum CRP acts as a robust marker of intestinal inflammation and as an excellent biological marker of response for patients with elevated CRP and active luminal disease. The therapeutic action of some of the newer biologics is indeed more striking on stratification of treatment response according to serum CRP level.5,6 Importantly, this more objective and scientific parameter of disease activity decreases the placebo response in clinical trials. The high placebo response and modest therapeutic effect of new biologics in CD patients with a low CRP level led many investigators to consider these patients as having overlapping IBS, thereby falsely increasing their CDAI scores. Thus, an important task is to be able to differentiate among low-CRP CD patients, those patients with a true CD flare-up from those having overlapping IBS symptoms. In truth, there must be a subset of patients with low serum CRP who have active disease and intestinal inflammation that does not translate into increased serum CRP levels. Interestingly, this study suggests that patients with ileal disease tend to develop a more loco-regional inflammatory disease (as evidenced by the high rate of fat wrapping in the low-CRP group of patients who had ileal resection) than a systemic disease. It is unlikely that ileal disease would be associated with specific CRP promoter or gene polymorphisms affecting serum CRP level.7 Therefore, ileal disease may not trigger a liver-mediated acute-phase response and subsequent cytokine-induced release of CRP. It has long been recognized that colonic disease is more frequently associated with an inflammatory phenotype, a chronic active disease profile, and steroid dependence. These patients also have an improved response rate to immunosuppressants and new biologics. Indeed, the best predictive factors for response to infliximab are high CRP level, colonic disease, and treatment with immunosuppressants.8,9 An important message of this study is to consider that CD patients may have active disease with normal or low CRP levels if they suffer from a pure ileal disease. Thus, a new stratification of disease phenotype based on serum CRP level during active disease may affect therapeutic decision plans when considering current and novel therapies.

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