Objective Assessment of Clinical Disease Activity

Stool frequency ^a

0: Normal

1: Number of stools for this patient 1–2 stools more than normal

2: 3–4 stools more than normal

3: 5 or more stools more than normal

Rectal bleeding ^b

0: No blood seen

1: Streaks of blood with stool less than half the time

2: Obvious blood with stool most of the time

3: Blood alone passed

Findings of flexible proctosigmoidoscopy

0: Normal or inactive disease

1: Mild disease (erythema, decreased vascular pattern, mild friability)

2: Moderate disease (marked erythema, absent vascular pattern, friability, erosions)

3: Severe disease (spontaneous bleeding, ulceration)

Physician’s global assessment ^c

0: Normal

1: Mild disease

2: Moderate disease

3: Severe disease

^aEach patient served as his or her own control to establish the degree of abnormality of the stool frequency

^bThe daily bleeding score represented the most severe bleeding of the day

^cThe physician’s global assessment acknowledged the three other criteria, the patient’s daily record of abdominal discomfort and general sense of well-being (patient’s functional assessment [Patient’s functional assessment was not included in the 12-point index calculation but represented a general sense of well-being; it was also measured (score 0 = generally well, score 1 = fair, score 2 = poor, score 3 = terrible) and participated to evaluation of physician’s general assessment]) and other observations such as physical findings and the patient’s performance status. Score of 0 meant there were no symptom of colitis, the patient felt well and the flexible proctosigmoidoscopy score was 0. A score of 1 indicated mild symptoms and proctoscopic findings that were mildly abnormal. A score of 2 reflected more serious abnormalities and proctosigmoidoscopic and symptom scores of 1 to 2. A score of 3 indicated that proctosigmoidoscopic and symptom scores were 2–3 and the patient probably required corticosteroid therapy and possibly hospitalization

Sutherland et al. described another simple disease assessment tool named the Sutherland Index (also called Disease Activity Index—DAI and the UC Disease Activity Index—UCDAI) in a placebo-controlled trial of mesalamine enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis [14]. This index is very close to the Mayo score. It consists of four items: stool frequency (range 0–3), rectal bleeding (range 0–3), mucosal appearance (range 0–3), and physician’s rating of disease activity (range 0–3). Total score ranges from 0 to 12 points. Efficacy was defined as a statistically significant reduction in the Sutherland Index Score and a significant reduction in the individual subscores (both calculated individually for each patient). Neither the Sutherland Score nor the definitions of complete or partial responses have been validated. Subsequent studies have modified the definitions of remission and clinical improvement. Remission was defined as Sutherland score of ≤1 point with a score of 0 for rectal bleeding and stool frequency, while clinical improvement was defined as a reduction in the Sutherland score ≥3 points from baseline [39, 40]. Despite the lack of formal validation, the Sutherland Index has been shown to correlate with an index based on patient’s opinion developed by Higgins et al. [29].

Feagan et al. described the Ulcerative Colitis Clinical Score in a double-blind placebo-controlled trial on a humanized α4β7 integrin-antibody for the treatment of ulcerative colitis [19]. This instrument was a modification of the Mayo Score and consisted on four items which were scored from 0 (normal) to 3 (severe): stool frequency (referring to the usual normal number of stools per day when the patient was in remission), rectal bleeding, functional assessment by the patient , and global assessment by the physician. To define clinical remission and response it was used with a modified version of a previously described endoscopic index: the Baron score [41]. This score consisted of a four-point scale mainly based on the severity of bleeding and not including ulceration. The modified Baron score was based on a five-point scale (0–4). Clinical remission was defined as a UCCS score of 0 or 1 without rectal bleeding and with a normal mucosa or only granular mucosa with an abnormal vascular pattern on sigmoidoscopy. Clinical response was defined as an improvement of three points or more on the UCCS and endoscopic response (defined by a Baron score of zero or a decrease of at least two points). Neither the UCSS nor the definitions of clinical remission and clinical response have been validated.

Rachmilewitz et al. reported an instrument subsequently named the Clinical Activity Index (CAI) in a randomized trial comparing coated mesalamine versus sulfasalazine in the treatment of active ulcerative colitis [17]. This index was composed of seven variables: number of stools (range 0–3), blood in stools (range 0, 2, or 4), investigator’s global assessment of symptomatic state (range 0–3), abdominal pain or cramps (range 0–3), temperature due to colitis (range 0 or 3), extraintestinal manifestations (range 0, 3, 6, or 9), and laboratory findings (range 0, 1, 2, or 4). Total score ranges from 0 to 29 points. It has been validated in one study in which remission was defined as a CAI score ≤4 points [42].

Towards More Emphasis on Patients Reported Symptoms to Complement Endoscopic Assessment

In 2002, Levine et al. reported an instrument to measure disease activity in a randomized, double-blind controlled trial on balsalazide versus mesalamine treatment in active mild to moderate ulcerative colitis [18]. This instrument was based on individual symptom scores including rectal bleeding, patient functional assessment, stool frequency, abdominal pain, but also on sigmoidoscopic grade, and physician global assessment. The scores of each item were graded from 0 to 3 points (0 = normal, 1 = mild, 2 = moderate, 3 = severe). Improvement was defined as a reduction from baseline of ≥1 point in rectal bleeding and at least one of the other individual symptoms. This instrument has not been validated. More recently, it was showed that a score based on the six-point MayoEndoscopic assessment (stool frequency and rectal bleeding) and a general well-being question (from the SCCAI) correlated well with more complete activity indexes and was able to determine remission status [43].

Clinical Scores in Crohn’s Disease

Assessment of Crohn’s disease (CD) activity and monitoring for treatment response require the establishment of reliable and reproducible tools. The development of instruments that would accurately reflect the activity of CD has been more complex than in ulcerative colitis (UC) due to the heterogeneity of the disease and the unreliable translation of intestinal lesions into clinical symptoms. Hence, these complicated scores tend to be abandoned for a dual assessment of the disease based on objective markers (mainly endoscopy and cross sectional imaging associated with blood and stool biomarkers) and patients reported symptoms.

Crohn’s Disease Activity Index

In 1970, the National Cooperative Crohn’s Disease Study (NCCDC) was initiated to test the efficacy of prednisone, sulfasalazine, and azathioprine in clinical controlled trials. The Crohn’s Disease Activity Index (CDAI) was developed to investigate the efficacy of these drugs [44]. It was published in 1976 and, has remained the most suitable instrument to evaluate CD activity in clinical trials for more than 30 years [45–50]. CDAI was initially developed from 112 patients and then later reanalyzed on a larger group with the same conclusions. Eighteen variables were first tested and eight were finally retained for the regression equation, out of which seven variables are purely clinical and one is biological (hematocrit). Moreover, four of them (liquid stools, well-being, use of loperamide, and abdominal pain) should be determined prospectively by keeping a 7-day patient diary; CDAI is therefore considered as a prospective index. In order to establish threshold cutoff value that indicates the disease activity, the global assessment of physicians was confronted to CDAI score. A value less than 150 was defined as remission and over 450 as a severe active disease. The clinical response to a treatment has generally been defined as a reduction of 70 or 100 points of the CDAI. The use of 100 points in CDAI decrease instead of 70 has been promoted to have more stringent criteria to differentiate between active drugs and placebo in clinical trials. However, the superiority of these judgment criteria has not been fully demonstrated [51]. CDAI has a good interobserver reproducibility. This index has been used to assess the efficacy of mesalamine, azathioprine, corticosteroid, methotrexate, cyclosporine, and more recently the biological therapies [47–50]. It has also been demonstrated recently that a retrospectively assisted evaluation of the CDAI was as accurate as the traditional prospective evaluation [52]. Although CDAI has been considered for a long time as the gold standard for the evaluation of CD activity, it may not reflect all the aspects of the disease and has some limitations. For instance, CDAI is not suitable for pediatric patients whose disease presentation differs from that of adults. Therefore, a Pediatric Crohn’s Disease Activity Index (PCDAI) has been developed [53]. Moreover, CDAI does not take into account symptoms linked to predominant perianal CD and refers to unsuitable parameters in case of previous surgery or stoma, like the use of loperamide or stool frequency, which can be affected by biliary salt malabsorption or short bowel syndrome. Therefore, CDAI is not applicable for the assessment of perianal or operated CD. A prospective cohort study has also showed the inability of CDAI to differentiate between active CD and irritable bowel syndrome, both diseases giving rise to similar levels of CDAI increase [54]. Studies comparing CDAI and serum or stool biomarkers, mainly CRP and fecal calprotectin, have demonstrated only weak correlations [3, 55]. Poor correlation between CDAI and endoscopic examination has also been demonstrated [3, 56, 57]. For these different reasons, FDA decided in 2014, no longer to recommend CDAI as a primary judgement criteria for the assessment of the efficacy of new drugs in CD and to prefer a composite evaluation including endoscopic assessment and patients reported symptoms [8].

Harvey–Bradshaw Index

Because the CDAI has been reported to be difficult to use in daily clinical practice, other scores have been developed. The more practical one is the Harvey–Bradshaw Index (HBI), also known as the Simple Index or the Modified CDAI (Table 23.2) [28]. The HBI is based on subjective and clinical factors. It reduced the original eight items of the CDAI to five, removing the use of antidiarrheal drugs, the hematocrit and the body weight. It looks only at symptoms over the preceding 24 h which makes the measurement of severity easy and quick at an outpatient visit. However, it could be less reliable and its value could significantly change from one day to another. The original prospective study of 112 patients demonstrated a good correlation (r = 0.93) between HBI and CDAI. More recently, one study compared the CDAI and HBI in the assessment of CD activity in two large clinical trials, PRECISE 1 and PRECISE 2 and confirmed a good correlation between the two scores [58]. This suggests that HBI might permit simpler CD activity assessment, particularly for routine practice. To this end, a study showed that a patient-based HBI index correlated well with the physician-based HBI and that the discordances rarely translated into a change in the remission vs active disease status of the patient [59]. This would allow the patient to monitor disease activity more regularly and communicate more proactively with the physician.

Table 23.2

Harvey–Bradshaw index

Patient’s general well-being (for the previous day)

0 = well

1 = slightly below par

2 = poor

3 = very poor

4 = terrible

Abdominal pain (for the previous day)

0 = none

1 = mild

2 = moderate

3 = severe

Number of liquid stools per day (for the previous day; score 1 per movement)

Abdominal mass

0 = none

1 = dubious

2 = definite

3 = definite and tender

Complications (score 1 per item)

Arthralgia, uveitis, erythema nodosum, aphthous ulcers, pyoderma gangrenosum, anal fissure, new fistula, abscess

Harvey–Bradshaw index score: remission <5; mild disease 5–7; moderate disease 8–16, severe disease > 16

Van Hees Index

In order to overcome the disadvantages and the potential subjectivity of the CDAI, Van Hees et al. elaborated in 1980 an activity index, the Van Hees Index (VHI), based on entirely objective variables of which albumin serum level contributed the most [60]. A score of less than 100 is considered as clinical remission and over 210 as a severe disease. Its correlation with the CDAI is poor, which is due to an absence of consideration of clinical symptoms. This score calculation is more complex and has not supplanted the CDAI in clinical practice.

Focus on Patients Reported Outcomes

While the insufficient correlation between CDAI and tissue healing has been confirmed [61, 62], standardized symptoms-based assessment is still meaningful to describe the disease state and is particularly relevant and important for the patients. As a matter of fact, simple clinical disease activity still very significantly correlates with self-reported disability index [63]. However, as highlighted here above, there was a perceived necessity for simpler scores or indexes, mainly reflecting patients’ perceptions. Khanna et al. showed that a simple symptoms assessment by the patient correlated well with CDAI [64]. The investigators could build two patient-reported outcome scales based on two or three symptoms (abdominal pain, liquid stools frequency, well-being) and, using database from previous clinical trials, determined cutoff values for remission and response to therapy. This kind of simple symptoms assessment could even be transferred to a web-platform to facilitate patient–physician communication. This was tested in a Korean study where the five items of the HBI were recorded online by the patients before the consultation [65]. A very good correlation was found with CDAI. Another study tried to further simplify the patient-based assessment using a simple numeric rating scale [66]. This showed an encouraging correlation with both CDAI and the health related quality of life score IBDQ.

Conclusions

In IBD, disease activity can be measured in different ways. For a long time it has been mainly based on the assessment of the clinical activity of the disease, mainly based on symptoms collected by the physician at the consultation or by the patient and the physician through diaries. This clinical assessment of the disease is considered as too subjective and correlating poorly with objective markers of disease activity, including biomarkers and endoscopic or medical imaging assessment. This is particularly the case in CD, while in UC the symptoms still reflect reasonably well the endoscopic activity of the disease. That is why complex clinical activity scores like the CDAI are progressively abandoned in clinical trials and are replaced by a combination of endoscopic or cross-sectional imaging assessment with symptoms-based patient reported outcomes.

Nevertheless, for routine practice, the increase in the number of drugs available to treat these illnesses and the increasing complexity of therapeutic strategies and algorithms require some quantitative clinical activity assessment to allow optimal patients management. To this end, simple and reproducible scoring systems, even potentially recorded by the patient him/herself like the HBI for CD or the clinical part of the Mayo for UC, seem well adapted.

References

Wright R, Truelove SR. Serial rectal biopsy in ulcerative colitis during the course of a controlled therapeutic trial of various diets. Am J Dig Dis. 1966;11:847–57.CrossRefPubMed

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