Improving the Management of Ulcerative Colitis – Issue 1 – Page 2

NSCLC iNewsletter Series - Issue 1
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Assessment of Disease Prognosis

Risk factors for subsequent relapse include a short duration of time between diagnosis and the first flare (2 years or less), the presence of fever or weight loss at diagnosis, and active disease in the preceding year.5 The extent of anatomic involvement of the colon can change over time. At the time of diagnosis, 30% to 50% of patients have disease confined to the rectum or the sigmoid colon (ulcerative proctitis and proctosigmoiditis), 20% to 30% have left-sided colitis, and approximately 20% have pancolitis. Patients with young age at diagnosis (eg, 15-30 years), and those with concomitant primary sclerosing cholangitis, are more likely to have extensive disease at diagnosis. Among patients with ulcerative proctitis or proctosigmoiditis, 25% to 50% will progress to more extensive forms of the disease over time.6 Disease flares associated with progression of anatomic extent (eg, from proctitis to left-sided colitis or pancolitis) are often more severe and require more intensive medical treatment than do flares that are not associated with progression. The anatomic extent of inflammation is an important factor in determining the disease course, with patients who have a more severe disease course tending to have more extensive disease (pancolitis). The anatomic extent of disease is also an important predictor of colorectal cancer and colectomy (the risk for patients with extensive colitis is increased 3.5-4 times relative to proctitis).2 Patients with UC do not have an increased risk of mortality relative to the general population.



Laboratory Parameters/Biomarkers

Laboratory parameters that may be associated with active UC include anemia, reactive thrombocytosis, and hypoalbumenia. Other biomarkers include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin.7

ESR indirectly measures plasma acute phase protein concentration. It is influenced by erythrocyte morphology as well as immunoglobulins and other plasma components.8 Because the concentrations of the large variety of serum proteins in patients with UC are variable, and some have long half-lives, the ESR does not change rapidly in response to changes in clinical status (ie, the ESR may lag clinical improvement by several days). For this reason, the ESR is a somewhat imprecise measure of disease activity. In UC, the correlation between clinical, endoscopic and histological activity, and ESR is good.9 However, it may be normal in patients with ulcerative proctitis and proctosigmoiditis.

CRP is an acute phase reactant produced in the liver in response to stimulation by interleukin (IL)-6, TNFα and IL-1β, which are produced at sites of inflammation.10 Liver synthesis of CRP is the only factor determining plasma CRP concentration. Thus, therapies affecting acute phase stimulus or liver failure will result in a decrease in CRP. CRP has been used as a biomarker to both diagnose and measure the activity of inflammatory diseases. The normal value of CRP for systemic inflammation is 0.8 mg/dL (8 mg/L). With high sensitivity CRP (hsCRP) the normal value is 0.3 mg/dL (3 mg/dL), and the cutoff associated with active inflammatory bowel disease is 5 mg/L. In the presence of acute phase stimulation (active inflammation), CRP production is rapidly up-regulated. Once the acute phase stimulation disappears (ie, the inflammation resolves), CRP concentrations can quickly decrease back to normal due to its short 19-hour half-life. In patients with UC, CRP elevation was significantly associated with severe clinical activity and active disease at colonoscopy, but not with histological inflammation.11

Calprotectin was initially isolated from granulocytes and was called the L1 protein. Subsequently, the name was changed to calprotectin because it binds to calcium and it has antimicrobial properties.12 Calprotectin comprises 50% to 60% of cytosolic protein in neutrophils. Calprotectin is released from cells during death or cell activation. It is stable in feces for several days after excretion. Calprotectin is easily measured in feces using enzyme-linked immunosorbent assays (ELISA) that are commercially available. Fecal calprotectin has been shown to correlate well with endoscopic and histologic activity in UC.13,14 However, the clinical relevance of elevated calprotectin during clinical remission in UC is not known and, until further evidence accumulates, does not indicate therapy escalation.15



Endoscopic Evidence of Disease Activity

The current gold standard for assessing disease activity in UC is endoscopy. In the 1950s and 1960s, this was accomplished with rigid sigmoidoscopy. In the 1970s this transitioned to flexible sigmoidoscopy and colonoscopy. The most commonly used endoscopic scoring system is the 4-point endoscopy component of the Mayo Score, in which patients are classified as having remission (0), mild (1), moderate (2), or severe (3) endoscopic findings.16 More recently the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) was developed.17 The UCEIS is still undergoing validation, but it will likely ultimately replace the Mayo Score for assessment of endoscopic activity in clinical trials, and potentially, in clinical practice.



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