Assessing Disease Activity

The selection of endpoints is of fundamental importance in the design of a clinical trial in IBD. A daunting array of options face the clinical investigator at the point of designing the clinical trial, ranging from QoL indices, measures of clinical disease activity, and endoscopic scores, to more detailed measures of systemic or mucosal inflammation. In addition, there are increasing opportunities to employ biomarkers, which can give valuable information concerning the pharmacological activity of the molecule under investigation.

The most frequently used primary outcomes are either disease remission or clinical improvement, both of these parameters being defined prospectively as either a fall beneath a threshold, or a reduction of a preset magnitude, on a clinical disease measure. Many such clinical disease indices exist, both for CD and UC, but none are without issues or can be considered unequivocally superior to the others. The limitations in some of these indices may limit their usefulness to the selection of patients for inclusion in clinical trials, rather than in demonstrating clinical utility for investigational drugs. In addition, the definition of remission or of the magnitude of reduction that constitutes a clinically significant improvement may be somewhat arbitrary.

In UC, the most commonly applied index is that of Truelove and Witts,26 used initially to assess the efficacy of the corticosteroids. Although widely used, this index has a number of weaknesses, particularly the difficulty in defining improvement within its categorical framework. A number of indices based on modifications to this original index have also been suggested, the most widely known being the Powell-Tuck index,27 which includes an endoscopic score as well as assessment of a greater range of symptoms and generating a quantitative index.

Scoring systems derived more recently vary mainly in their complexity. The desire for simplified indices led to the development of the Mayo scoring system,28 which produces a quantitative index from four domains: bowel movements, fecal blood, and endoscopic score, together with a physician assessment, the latter of which is subjective by definition. In addition, the domains may be more closely associated with distal disease and may underestimate more proximal disease. Conversely, the complex index of Seo et alP produces a quantitative index from a complex mathematical algorithm that combines symptom measures (fecal blood and bowel movement) with biochemical ones (hemoglobin, albumin, and erythrocyte sedimentation rate (ESR)). The simple clinical colitis index30 has been constructed from the five clinical domains that correlate most closely with the Powell-Tuck index, although it also correlates closely with Seo index. It appears to have utility as a screening tool, but its usefulness as an outcome index in clinical trials is still unclear.

In CD, the use of the Crohn's disease activity index (CDAI) predominates. This index is constructed from eight domains that are given a relative weighting, and involves the collection of patient data through the use of a diary. Disease severity bands have been constructed within a scale of 0-750. Disease remission has been attributed to a score of less than 150 and clinical improvement defined as a reduction of greater than 70 points (or more recently 100 points), although the clinical significance of such a reduction in patients with severe disease is questionable. Used widely in clinical trials, criticisms still abound on the use of CDAI. These include the near reliance on subjective symptoms, the complexity of the index, and the need for a 1-week patient diary. Studies have also demonstrated substantial interobserver variation in scoring. The poor representation of parameters relating to perianal disease makes improvements in this troublesome presentation difficult to assess using CDAI and so a specific perianal disease activity index has been devised.

Several additional indices have been proposed, aimed at either simplifying the CDAI or reducing its subjectivity. The best known of these are the Harvey-Bradshaw and Oxford indices,31'32 both of which remove the relative weightings of the parameters, while the Harvey-Bradshaw removes the need for the diary. Both correlate well with the CDAI.

The limitations of clinical scoring systems of disease activity strongly suggest that the demonstration of clinical efficacy should not rely entirely on such indices. The use of endoscopy can provide valuable support and to that end endoscopic indices of severity have been developed. In UC, the Baron score was first described in the mid-1960s, but is used with few modifications to the present day. For CD, the Crohn's disease endoscopic index of severity (CDEIS) has been developed but, although used in therapeutic trials, has to date not been used widely outside of Europe. CDEIS is complicated and time-consuming and so attempts have been made to simplify its use, most recently in producing the simple endoscopic score for Crohn's disease (SES-CD).33 The SES-CD is simple to use and is highly correlated with the CDEIS, C-reactive protein, and clinical parameters.

Visualizing the mucosa of the small intestine in CD remains an obstacle to routine endoscopic evaluation in clinical trials in this patient population. The potential of wireless capsule endoscopy to overcome this hurdle remains to be fully assessed.

Further supportive data of efficacy can be provided from mucosal biopsies. The degree of inflammatory cell infiltration can be assessed microscopically and these data have been used to support the beneficial effect of a number of agents in development for the treatment of IBD. While relatively straightforward in UC patients, obtaining mucosal biopsy samples from CD patients with small bowel involvement is challenging.

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