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Advances in the Assessment of Disease Activity in Inflammatory Bowel Disease

      Knowledge of the severity and extent of the inflammation in inflammatory bowel diseases provides a means of determining rational therapeutic strategies in affected patients. During the past 3 decades, several clinical, laboratory, and combined indices have been proposed for the assessment of inflammatory bowel disease; refinements in radiologic methods and the availability of endoscopy and biopsy have facilitated the accurate assessment of the extent and severity of the disease. In relapsing conditions such as inflammatory bowel disease, however, the use of such procedures is limited by the radiation exposure or the relatively invasive nature of the technique. In this article, we review the proposed methods and recent advances in assessment of patients with inflammatory bowel disease; we also discuss possible strategies at the time of diagnosis, during recurrence, and in evaluation of the efficacy of drug or dietetic therapy.
      The assessment of disease activity and extent in ulcerative colitis and Crohn's disease is a prerequisite for the rational choice of therapy for these disorders.
      • Truelove SC
      • Witts LJ
      Cortisone in ulcerative colitis: final report on a therapeutic trial.
      • Summers RW
      • Switz DM
      • Sessions Jr, JT
      • Becktel JM
      • Best WR
      • Kern Jr, F
      • Singleton JW
      National Cooperative Crohn's Disease Study: results of drug treatment.
      Such determinations are also necessary in the assessment of the effects of drug therapy,
      • Hodgson HJF
      Assessment of drug therapy in inflammatory bowel disease.
      and they facilitate the comparison of data collected in cooperative trials and in the study of the natural history of inflammatory bowel disorders. In general, four categories for assessment of disease activity have been proposed: (1) clinical criteria; (2) single laboratory indices; (3) radiology or endoscopy, with or without biopsies; and (4) noninvasive imaging with radiolabeled autologous leukocytes and collection of stool specimens for quantitation of excreted radiolabel. The purposes of this article are to review the advantages and disadvantages of these methods and to propose rational strategies to be followed in clinical practice and research.

      CLINICAL CRITERIA

      Clinical features suggestive of ulcerative colitis include frequent loose stools in association with blood and mucus; those suggestive of Crohn's disease are severe abdominal pain, tenderness, mass, distention, and fistulization.
      • Myren J
      • Bouchier IAD
      • Watkinson G
      • Softley A
      • Clamp SE
      • de Dombal FT
      The O.M.G.E. multinational inflammatory bowel disease survey 1976–1982: a further report on 2,657 cases.
      Various combinations of these symptoms have been developed as clinical criteria in an attempt to assess inflammatory activity adequately in inflammatory bowel disease. One of the earliest attempts at using clinical criteria for assessing disease activity was made by Truelove and Witts
      • Truelove SC
      • Witts LJ
      Cortisone in ulcerative colitis: final report on a therapeutic trial.
      during studies on the effects of corticosteroid therapy in patients with ulcerative colitis. Their assessment of disease activity in ulcerative colitis included laboratory measurements, such as hemoglobin concentration and erythrocyte sedimentation rate (Table 1). Such criteria are extremely useful as they depend primarily on clinical findings and widely available laboratory measurements.
      Table 1Proposed Criteria for Assessment of Disease Activity in Ulcerative Colitis
      FactorSevere
      Moderate disease is intermediate between severe and mild classifications.
      Mild
      Bowel frequency≥6 daily≤4 daily
      Blood in stool++±
      Temperature>37.5°C on 2 of 4 daysNormal
      Pulse rate (beats/min)>90Normal
      Hemoglobin (allow for transfusion)≤75%Normal or near normal
      Erythrocyte sedimentation rate (mm in 1 h)>30≤30
      Data from Truelove and Witts.
      • Truelove SC
      • Witts LJ
      Cortisone in ulcerative colitis: final report on a therapeutic trial.
      * Moderate disease is intermediate between severe and mild classifications.
      De Dombal and associates
      • De Dombal FT
      • Burton IL
      • Clamp SE
      • Goligher JC
      Short-term course and prognosis of Crohn's disease.
      modified these criteria by adding weight loss and abdominal pain, both prominent features of Crohn's disease, and applied these criteria to patients with active Crohn's disease. In the 1970s, the Crohn's disease activity index (CDAI) was developed for use in the National Cooperative Crohn's Disease Study. It was hoped that such a disease activity index would allow uniformity in clinical evaluation and in monitoring disease response to various medical treatments in clinical trials.
      • Best WR
      • Becktel JM
      • Singleton JW
      • Kern Jr, F
      Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study.
      Eight clinical variables were assigned various weighting scores, which are summed to yield a total symptom score indicative of inflammatory activity. A score of less than 150 indicates quiescence, whereas a score between 150 and 450 denotes increasing severity of disease. The CDAI, however, includes several subjective factors, such as general well-being, and is cumbersome, inasmuch as patients must maintain a diary of symptoms for 7 consecutive days. Because of these shortcomings, the CDAI has been modified not only by its original developers but also by others.
      Harvey and Bradshaw
      • Harvey RF
      • Bradshaw JM
      A simple index of Crohn'sdisease activity.
      reduced the number of clinical variables to five, simplified the numerical calculation, and shortened the period of clinical observation from 7 days to 1 day. This simplified index of Crohn's disease activity (Table 2) was further modified by the Organisation Mondiale de Gastroenterologie (OMGE) by limiting the maximal score for increased number of bowel movements to five.
      • Myren J
      • Bouchier IAD
      • Watkinson G
      • Softley A
      • Clamp SE
      • de Dombal FT
      The O.M.G.E. multinational inflammatory bowel disease survey 1976–1982: a further report on 2,657 cases.
      Table 2Variables Used for Assessment of Crohn's Disease Activity, as Proposed by the Organisation Mondiale de Gastroenterologie
      1.General well-being (0 = very well; 1 = slightly below par; 2 = poor; 3 = very poor; 4 = terrible)
      2.Abdominal pain (0 = none; 1 = mild; 2 = moderate; 3 = severe)
      3.Number of bowel movements (0 = normal; 5 = ≥10/day)
      4.Abdominal mass (0 = none; 1 = dubious; 2 = definite; 3 = definite and tender)
      5.Complications (score of 1 for each): arthralgia, uveitis, erythema nodosum, aphthous ulcers, pyoderma gangrenosum, anal fissure, new fistula, abscess
      Data from Myren and associates.
      • Myren J
      • Bouchier IAD
      • Watkinson G
      • Softley A
      • Clamp SE
      • de Dombal FT
      The O.M.G.E. multinational inflammatory bowel disease survey 1976–1982: a further report on 2,657 cases.
      A less quantitative assessment of disease activity was proposed by the International Organisation of Inflammatory Bowel Disease (IOIBD) at a meeting in Oxford, England, in 1980. The weighting of symptoms with different scores was eliminated. Instead, a simple severity score ranging from 1 to 10 was calculated by attributing one point to each of 10 symptoms or signs.
      • Myren J
      • Bouchier IAD
      • Watkinson G
      • Softley A
      • Clamp SE
      • de Dombal FT
      The O.M.G.E. multinational inflammatory bowel disease survey 1976–1982: a further report on 2,657 cases.
      Other clinical indices, including the Cape Town index
      • Wright JP
      • Marks IN
      • Parfitt A
      A simple clinical index of Crohn's disease activity—the Cape Town index.
      and the Dutch activity index,
      • Van Hees PAM
      • van Elteren PH
      • van Lier HJJ
      • van Tongeren JHM
      An index of inflammatory activity in patients with Crohn's disease.
      have been developed and have been used in epidemiologic research.
      • Sandler RS
      • Jordan MC
      • Kupper LL
      Development of a Crohn's index for survey research.
      The correlation between these indices and the final clinical diagnosis was evaluated conjointly by the OMGE Research Committee and the IOIBD.
      • Myren J
      • Bouchier IAD
      • Watkinson G
      • Softley A
      • Clamp SE
      • de Dombal FT
      The O.M.G.E. multinational inflammatory bowel disease survey 1976–1982: a further report on 2,657 cases.
      Assessment of 200 patients with Crohn's disease of the large bowel was based on the OMGE version of Harvey and Bradshaw's simplified CDAI
      • Harvey RF
      • Bradshaw JM
      A simple index of Crohn'sdisease activity.
      (Table 2), the Oxford IOIBD index,
      • Myren J
      • Bouchier IAD
      • Watkinson G
      • Softley A
      • Clamp SE
      • de Dombal FT
      The O.M.G.E. multinational inflammatory bowel disease survey 1976–1982: a further report on 2,657 cases.
      and the Dutch index.
      • Van Hees PAM
      • van Elteren PH
      • van Lier HJJ
      • van Tongeren JHM
      An index of inflammatory activity in patients with Crohn's disease.
      The modified CDAI correlated well with the clinical diagnosis, unlike the Dutch activity index. The Oxford IOIBD index compared favorably with the modified CDAI. Thus, the modified CDAI and Oxford IOIBD index allowed the clinician to gauge the severity of the inflammatory activity promptly and with reasonable accuracy and were therefore recommended by the OMGE and IOIBD. These indices, however, are not readily reproducible, even among investigators with interest in inflammatory bowel disease,
      • De Dombal FT
      • Softley A
      IOIBD report no 1: observer variation in calculating indices of severity and activity in Crohn's disease.
      and interobserver variations detract from their utility in clinical trials.
      Although relatively accurate in assessing inflammatory activity in certain clinical settings, these disease activity indices may provide erroneous information. The classic example is that of fibrous stricturing in Crohn's disease; a high score for abdominal pain in this instance is due to a fibrotic lesion and not to any medically relievable inflammatory activity. Hence, several laboratory indices, either alone or in combination with clinical criteria, have been proposed for more objective assessment of inflammatory activity.
      In summary, Truelove and Witts' criteria for ulcerative colitis
      • Truelove SC
      • Witts LJ
      Cortisone in ulcerative colitis: final report on a therapeutic trial.
      and the OMGE version of Harvey and Bradshaw's modification of the CDAI for Crohn's disease
      • Harvey RF
      • Bradshaw JM
      A simple index of Crohn'sdisease activity.
      are the most widely accepted and clinically applicable indices.

      SINGLE LABORATORY INDICES

      During the past 3 decades, numerous single laboratory measurements (Table 3) on blood, urine, feces, and tissue have been proposed for the assessment of disease activity in inflammatory bowel disease.
      • Sachar DB
      • Smith H
      • Chan S
      • Cohen LB
      • Lichtiger S
      • Messer J
      Erythrocyte sedimentation rate as a measure of clinical activity in inflammatory bowel disease.
      • Chambers RE
      • Stross P
      • Barry RE
      • Whicher JT
      Serum amyloid A protein compared with C-reactive protein, alpha 1-antichymotrypsin and alpha 1-acid glycoprotein as a monitor of inflammatory bowel disease.
      • Fagan EA
      • Dyck RF
      • Maton PN
      • Hodgson HJF
      • Chadwick VS
      • Petrie A
      • Pepys MB
      Serum levels of C-reactive protein in Crohn's disease and ulcerative colitis.
      • André C
      • Descos L
      • Vignal J
      • Gillon J
      C-reactive protein as a predictor of relapse in asymptomatic patients with Crohn's disease.
      • Dearing WH
      • McGuckin WF
      • Elveback LR
      Serum α1acid glycoprotein in chronic ulcerative colitis.
      • Helman CA
      • Novis BH
      • Bank S
      • Wormold L
      • Jacobs P
      Serum lysozyme in Crohn's disease and ulcerative colitis.
      • Jensen KB
      • Jarnum S
      • Koudahl G
      • Kristensen M
      Serum orosomucoid in ulcerative colitis: its relation to clinical activity, protein loss, and turnover of albumin and IgG.
      • Cooke WT
      • Fowler DI
      • Cox EV
      • Gaddie R
      • Meynell MJ
      The clinical significance of seromucoids in regional ileitis and ulcerative colitis.
      • Adeyemi EO
      • Neumann S
      • Chadwick VS
      • Hodgson HJF
      • Pepys MB
      Circulating human leucocyte elastase in patients with inflammatory bowel disease.
      • Fiasse R
      • Lurhuma AZ
      • Cambiaso CL
      • Masson PL
      • Dive C
      Circulating immune complexes and disease activity in Crohn's disease.
      • Das KM
      • Kadono Y
      • Fleischner GM
      Antibody-dependent cell-mediated cytotoxicity in serum samples from patients with ulcerative colitis: relationship to disease activity and response to total colectomy.
      • Niederwieser D
      • Fuchs D
      • Hausen A
      • Judmaier G
      • Reibnegger G
      • Wachter H
      • Huber C
      Neopterin as a new biochemical marker in the clinical assessment of ulcerative colitis.
      • Reibnegger G
      • Bollbach R
      • Fuchs D
      • Hausen A
      • Judmaier G
      • Prior C
      • Rotthauwe HW
      • Werner ER
      • Wachter H
      A simple index relating clinical activity in Crohn's disease with T cell activation: hematocrit, frequency of liquid stools and urinary neopterin as parameters.
      • Rhodes JM
      • Gallimore R
      • Elias E
      • Allan RN
      • Kennedy JF
      Faecal mucus degrading glycosidases in ulcerative colitis and Crohn's disease.
      • Rhodes JM
      • Gallimore R
      • Elias E
      • Kennedy JF
      Faecal sulphatase in health and in inflammatory bowel disease.
      • Meyers S
      • Wolke A
      • Field SP
      • Feuer EJ
      • Johnson JW
      • Janowitz HD
      Fecal α1-antitrypsin measurement: an indicator of Crohn's disease activity.
      • Grill BB
      • Hillemeier AC
      • Gryboski JD
      Fecal α1-antitrypsin clearance in patients with inflammatory bowel disease.
      • Ehsanullah M
      • Filipe MI
      • Gazzard B
      Mucin secretion in inflammatory bowel disease: correlation with disease activity and dysplasia.
      • Thompson JS
      • Burnett DA
      • Markin RS
      • Vaughan WP
      Intestinal mucosa diamine oxidase activity reflects intestinal involvement in Crohn's disease.
      The fact that so many indices have been proposed suggests that none is optimal.
      Table 3Laboratory Measurements Proposed for Assessment of Disease Activity in Inflammatory Bowel Disease
      MeasurementReference
      Plasma
       Erythrocyte sedimentation rateSachar et al
      • Sachar DB
      • Smith H
      • Chan S
      • Cohen LB
      • Lichtiger S
      • Messer J
      Erythrocyte sedimentation rate as a measure of clinical activity in inflammatory bowel disease.
       Serum amyloid A proteinChambers et al
      • Chambers RE
      • Stross P
      • Barry RE
      • Whicher JT
      Serum amyloid A protein compared with C-reactive protein, alpha 1-antichymotrypsin and alpha 1-acid glycoprotein as a monitor of inflammatory bowel disease.
       C-reactive proteinFagan et al
      • Fagan EA
      • Dyck RF
      • Maton PN
      • Hodgson HJF
      • Chadwick VS
      • Petrie A
      • Pepys MB
      Serum levels of C-reactive protein in Crohn's disease and ulcerative colitis.
      André et al
      • André C
      • Descos L
      • Vignal J
      • Gillon J
      C-reactive protein as a predictor of relapse in asymptomatic patients with Crohn's disease.
       α1-Acid glycoproteinDearing et al
      • Dearing WH
      • McGuckin WF
      • Elveback LR
      Serum α1acid glycoprotein in chronic ulcerative colitis.
       LysozymeHelman et al
      • Helman CA
      • Novis BH
      • Bank S
      • Wormold L
      • Jacobs P
      Serum lysozyme in Crohn's disease and ulcerative colitis.
       OrosomucoidJensen et al
      • Jensen KB
      • Jarnum S
      • Koudahl G
      • Kristensen M
      Serum orosomucoid in ulcerative colitis: its relation to clinical activity, protein loss, and turnover of albumin and IgG.
       SeromucoidsCooke et al
      • Cooke WT
      • Fowler DI
      • Cox EV
      • Gaddie R
      • Meynell MJ
      The clinical significance of seromucoids in regional ileitis and ulcerative colitis.
       Leukocyte elastaseAdeyemi et al
      • Adeyemi EO
      • Neumann S
      • Chadwick VS
      • Hodgson HJF
      • Pepys MB
      Circulating human leucocyte elastase in patients with inflammatory bowel disease.
       Immune complexesFiasse et al
      • Fiasse R
      • Lurhuma AZ
      • Cambiaso CL
      • Masson PL
      • Dive C
      Circulating immune complexes and disease activity in Crohn's disease.
       Antibody-dependent cell-mediated cytotoxicityDas et al
      • Das KM
      • Kadono Y
      • Fleischner GM
      Antibody-dependent cell-mediated cytotoxicity in serum samples from patients with ulcerative colitis: relationship to disease activity and response to total colectomy.
      Urine
       NeopterinNiederwieser et al
      • Niederwieser D
      • Fuchs D
      • Hausen A
      • Judmaier G
      • Reibnegger G
      • Wachter H
      • Huber C
      Neopterin as a new biochemical marker in the clinical assessment of ulcerative colitis.
      Reibnegger et al
      • Reibnegger G
      • Bollbach R
      • Fuchs D
      • Hausen A
      • Judmaier G
      • Prior C
      • Rotthauwe HW
      • Werner ER
      • Wachter H
      A simple index relating clinical activity in Crohn's disease with T cell activation: hematocrit, frequency of liquid stools and urinary neopterin as parameters.
      Feces
       Mucus-degrading glycosidasesRhodes et al
      • Rhodes JM
      • Gallimore R
      • Elias E
      • Allan RN
      • Kennedy JF
      Faecal mucus degrading glycosidases in ulcerative colitis and Crohn's disease.
       SulfataseRhodes et al
      • Rhodes JM
      • Gallimore R
      • Elias E
      • Kennedy JF
      Faecal sulphatase in health and in inflammatory bowel disease.
       α1-AntitrypsinMeyers et al
      • Meyers S
      • Wolke A
      • Field SP
      • Feuer EJ
      • Johnson JW
      • Janowitz HD
      Fecal α1-antitrypsin measurement: an indicator of Crohn's disease activity.
      Grill et al
      • Grill BB
      • Hillemeier AC
      • Gryboski JD
      Fecal α1-antitrypsin clearance in patients with inflammatory bowel disease.
      Tissue
       MucinEhsanullah et al
      • Ehsanullah M
      • Filipe MI
      • Gazzard B
      Mucin secretion in inflammatory bowel disease: correlation with disease activity and dysplasia.
       Diamine oxidaseThompson et al
      • Thompson JS
      • Burnett DA
      • Markin RS
      • Vaughan WP
      Intestinal mucosa diamine oxidase activity reflects intestinal involvement in Crohn's disease.
      The best-known laboratory indices are (1) the nonspecific acute phase reactants, such as erythrocyte sedimentation rate, C-reactive protein, and orosomucoid, and (2) measures of increased intestinal permeability, such as fecal α1-antitrypsin. Several studies have reached different conclusions about the reliability of using the erythrocyte sedimentation rate to assess the severity of disease activity in inflammatory bowel disease. A strong correlation between the erythrocyte sedimentation rate and disease activity in both ulcerative colitis and Crohn's disease was reported by Talstad and Gjone.
      • Talstad I
      • Gjone E
      The disease activity of ulcerative colitis and Crohn's disease.
      Similarly, van Hees and colleagues
      • Van Hees PAM
      • van Elteren PH
      • van Lier HJJ
      • van Tongeren JHM
      An index of inflammatory activity in patients with Crohn's disease.
      found a good correlation between the erythrocyte sedimentation rate and disease activity in Crohn's disease and included it in their activity index. In contrast, several other investigators have found no correlation between erythrocyte sedimentation rate and disease activity assessed clinically
      • Fagan EA
      • Dyck RF
      • Maton PN
      • Hodgson HJF
      • Chadwick VS
      • Petrie A
      • Pepys MB
      Serum levels of C-reactive protein in Crohn's disease and ulcerative colitis.
      • Cooke WT
      • Prior P
      Determining disease activity in inflammatory bowel disease.
      or endoscopically.
      • Powell-Tuck J
      • Day DW
      • Buckell NA
      • Wadsworth J
      • Lennard-Jones JE
      Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis.
      Because some studies found no correlation between erythrocyte sedimentation rate and evidence of small bowel involvement in Crohn's disease or rectal inflammation in ulcerative colitis,
      • Sachar DB
      • Smith H
      • Chan S
      • Cohen LB
      • Lichtiger S
      • Messer J
      Erythrocyte sedimentation rate as a measure of clinical activity in inflammatory bowel disease.
      • Prantera C
      • Luzi C
      • Olivotto P
      • Levenstein S
      • Cerro P
      • Fanucci A
      Relationship between clinical and laboratory parameters and length of lesion in Crohn's disease of small bowel.
      the erythrocyte sedimentation rate seems to be a more useful factor in patients with colonic inflammation (ulcerative colitis or Crohn's disease) that extends beyond the rectum and sigmoid.
      As with other acute phase serum proteins, the concentration of C-reactive protein is increased in inflammatory bowel disease. Fagan and colleagues
      • Fagan EA
      • Dyck RF
      • Maton PN
      • Hodgson HJF
      • Chadwick VS
      • Petrie A
      • Pepys MB
      Serum levels of C-reactive protein in Crohn's disease and ulcerative colitis.
      demonstrated that serum C-reactive protein was significantly increased in patients with Crohn's disease and correlated well with the CDAI.
      • Best WR
      • Becktel JM
      • Singleton JW
      • Kern Jr, F
      Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study.
      Unlike other acute phase reactants, C-reactive protein responds more rapidly to an acute insult and with large incremental changes. Such properties would suggest that C-reactive protein is a more precise laboratory marker of disease activity than other indices. The actual level of C-reactive protein, however, seems to have little predictive value in terms of the severity of inflammatory activity assessed by CDAI.
      • Fagan EA
      • Dyck RF
      • Maton PN
      • Hodgson HJF
      • Chadwick VS
      • Petrie A
      • Pepys MB
      Serum levels of C-reactive protein in Crohn's disease and ulcerative colitis.
      In most cases, fluctuations in serial measurements of acute phase reactants in serum provide confirmatory information about the patient's clinical status. In certain instances, however, the clinical and laboratory assessments of intestinal inflammation do not parallel each other, and a low level of a single laboratory index may occur in a patient with a high clinical activity score as a result of abdominal pain caused by fibrotic obstruction. Conversely, changes in such reactants are not specific for bowel inflammation, and high levels of a single laboratory measurement in conjunction with a low clinical activity score may be seen in patients with inflammation unrelated to intestinal disease.
      In summary, although single laboratory measurements are useful in confirming the clinical assessment of disease activity and in monitoring the response to therapy, they cannot alone establish the severity of intestinal inflammation.

      ENDOSCOPY VERSUS RADIOLOGY

      Advances in radiologic techniques, such as the introduction of double-contrast colon roentgenography
      • Williams Jr, HJ
      • Stephens DH
      • Carlson HC
      Double-contrast radiography: colonic inflammatory disease.
      and small bowel enteroclysis,
      • Ekberg O
      Crohn's disease of the small bowel examined by double contrast technique: a comparison with oral technique.
      • Nolan DJ
      • Cadman PJ
      The small bowel enema made easy.
      • Maglinte DDT
      • Lappas JC
      • Kelvin FM
      • Rex D
      • Chernish SM
      Small bowel radiography: how, when, and why?.
      have dramatically improved the potential for detection of superficial lesions and assessment of disease activity and extent in inflammatory bowel disease.
      • Williams Jr, HJ
      • Stephens DH
      • Carlson HC
      Double-contrast radiography: colonic inflammatory disease.
      Fluoroscopy of the small intestine in conjunction with vigorous manual palpation is still a sensitive method of detecting Crohn's disease.
      • Carlson HC
      Perspective: the small bowel examination in the diagnosis of Crohn's disease.
      Hence, studies in which radiology has been compared with endoscopy in the assessment of inflammatory bowel disease
      • Hogan WJ
      • Schmitt MG
      • Wu WC
      • Geenen JE
      The role of colonoscopy in assessing the presence, extent and severity of chronic inflammatory bowel disease (CIBD) (abstract).
      • Gabrielsson N
      • Granqvist S
      • Sundelin P
      • Thorgeirsson T
      Extent of inflammatory lesions in ulcerative colitis assessed by radiology, colonoscopy, and endoscopic biopsies.
      • Williams C
      Evaluation of the colonoscopic examination: results of three studies.
      • Farmer RG
      • Whelan G
      • Sivak Jr, MV
      Colonoscopy in distal colon ulcerative colitis.
      are less relevant today than they were a decade ago, when comparisons were made chiefly with single-contrast studies. Nevertheless, the wide applicability and ease with which endoscopic assessment of the stomach, duodenum, distal ileum, and colon can be done, as well as the ability to obtain biopsy specimens for histologic confirmation, render the endoscopic route the generally preferred one among gastroenterologists for diagnosing inflammatory bowel disease.
      In several situations, however, radiology will be the preferred method, such as in the assessment of small bowel involvement in Crohn's disease or in the patient who has severe acute colitis with impending danger of perforation of the colon or at least a theoretic risk of precipitation of toxic megacolon. Furthermore, in the follow-up of a patient with a known histologic diagnosis, the cost of a double-contrast colon roentgenogram is generally less than that of colonoscopic and histologic assessment. The main disadvantages of radiologic assessment, however, are the radiation exposure and the lack of tissue diagnosis (Table 4).
      Table 4Radiation Exposure With Use of Various Radiologic Techniques for Assessment of Activity and Extent of Inflammatory Bowel Disease
      Factor111In-labeled leukocytes99mTc-HMPAO-labeled leukocytes
      HMPAO = hexamethylpropylene-amineoxime.
      Double-contrast roentgenogram of colon
      Usual dose (mCi)0.516.2
      Radiation exposure (rad)
       Total body0.30.29
       Bone marrow1.41.30.18
       Ovaries0.200.240.83
       Testes0.10.10.01
       Spleen12.07.2
       Skin entrance site8.1
      * HMPAO = hexamethylpropylene-amineoxime.
      The endoscopic grading of inflammation in the colon has traditionally been based on the macroscopic appearance at sigmoidoscopy.
      • Baron JH
      • Connell AM
      • Lennard-Jones JE
      Variation between observers in describing mucosal appearances in proctocolitis.
      The spectrum of findings includes the loss of vascular pattern or the presence of mucosal edema as the earliest sign of inflammation; the presence of contact hemorrhage as an index of moderate inflammatory activity; and frank ulceration, inflammatory pseudopolyps, or surface mucopus as indicators of severe inflammation. Colonoscopy and histologic assessment of mucosal biopsy specimens are regarded as the gold standard for the assessment of disease extent and activity in colitis.
      • Saverymuttu SH
      • Camilleri M
      • Rees H
      • Lavender JP
      • Hodgson HJF
      • Chadwick VS
      Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease: a comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion.
      • Gomes P
      • du Boulay C
      • Smith CL
      • Holdstock G
      Relationship between disease activity indices and colonoscopic findings in patients with colonic inflammatory bowel disease.
      Nevertheless, such studies cannot be performed in the assessment of every patient with an exacerbation of inflammatory bowel disease, particularly in view of the need for extensive bowel preparation, cost, and patient discomfort. Often clinicians will use a combination of the aforementioned clinical and laboratory criteria as well as the appearance of the mucosa in the left side of the colon on rigid proctosigmoidoscopy or flexible sigmoidoscopy in determining the severity of a recurrent attack of inflammatory bowel disease. This approach has been used in recent clinical trials.
      • Sutherland LR
      • Martin F
      • Greer S
      • Robinson M
      • Greenberger N
      • Saibil F
      • Martin T
      • Sparr J
      • Prokipchuk E
      • Borgen L
      5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.
      • Schroeder KW
      • Tremaine WJ
      • Ilstrup DM
      Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study.
      Such an approach, however, seems more appropriate in patients with ulcerative colitis than in those with Crohn's disease, in whom involvement of the right side of the colon or of the small bowel cannot be surmised if endoscopic examination is limited to the distal aspect of the colon. Furthermore, even in patients with ulcerative colitis, such an assessment would not identify extension of the disease process, a clinically important development because proximal extension of the disease generally necessitates treatment with systemic corticosteroids or other immunosuppressive agents.
      In summary, colonoscopy and histology remain the primary methods of assessment of colonic inflammation in ulcerative colitis or Crohn's disease during the time of initial manifestation and diagnosis. Knowledge of the extent of the disease at the time of diagnosis facilitates evaluations during subsequent exacerbations. Thus, in patients with ulcerative pancolitis, flexible sigmoidoscopy suffices to confirm the recurrence of inflammation and commence treatment of the pancolitis; in contrast, patients with previously substantiated left-sided colitis should undergo examination of the entire colon if inflammation is evident beyond the area reached with the flexible sigmoidoscope. At the time of initial examination, all patients with Crohn's disease should undergo roentgenography of the small bowel. During exacerbations of Crohn's disease, the clinical manifestations (abdominal pain, diarrhea, blood loss, or features of malabsorption) determine which strategy to pursue.

      RADIOLABELED INFLAMMATORY CELLS

      The ability to assess the gastrointestinal tract noninvasively for involvement of the small bowel and right side of the colon may have potential advantages in the management of individual patients. In recent years, noninvasive management has become possible with the advent of radiolabeled autologous leukocyte scanning. The most frequently used method involves 111In-radiolabeled leukocytes.
      • Saverymuttu SH
      • Camilleri M
      • Rees H
      • Lavender JP
      • Hodgson HJF
      • Chadwick VS
      Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease: a comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion.
      Such scans provide a means for localization of the diseased segment (Fig. 1), although this localization is much clearer for the anatomically fixed colon than for small bowel loops. Sequential scans dynamically show the accumulation of labeled leukocytes in diseased segments, and Saverymuttu and co-workers
      • Saverymuttu SH
      • Peters AM
      • Hodgson HJF
      • Chadwick VS
      Assessment of disease activity in ulcerative colitis using indium-111-labelled leukocyte faecal excretion.
      • Saverymuttu SH
      • Peters AM
      • Lavender JP
      • Pepys MB
      • Hodgson HJF
      • Chadwick VS
      Quantitative fecal indium 111-labeled leukocyte excretion in the assessment of disease in Crohn's disease.
      verified a correlation between ulcerative or Crohn's colonic disease activity as detected roentgenographically and the fecal excretion of radiolabeled leukocytes in 24 hours. Autoradiographic studies of biopsy specimens obtained from the colon after the intravenous injection of labeled autologous leukocytes also demonstrated the migration of the leukocytes in histologically proved areas of inflammation.
      • Keshavarzian A
      • Price YE
      • Peters AM
      • Lavender JP
      • Wright NA
      • Hodgson HJF
      Specificity of indium-111 granulocyte scanning and fecal excretion measurement in inflammatory bowel disease—an autoradiographic study.
      A comparison of 111In-labeled granulocyte scanning with colonoscopy and histology in the assessment of 52 patients with Crohn's disease or ulcerative colitis revealed excellent correlations for the extent and severity of disease. Severity graded by scanning also showed a close correlation with fecal 111In-labeled granulocyte excretion.
      • Saverymuttu SH
      • Camilleri M
      • Rees H
      • Lavender JP
      • Hodgson HJF
      • Chadwick VS
      Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease: a comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion.
      Therefore, this study suggested that colonic disease extent and activity were accurately determined in the 30-minute and 3-hour scans of the abdomen. Thus, radiolabeled leukocytes offer the advantage of being less invasive than colonoscopy. Segments of small bowel involvement in acute exacerbations of Crohn's disease could also be identified on 111In-labeled leukocyte scanning;
      • Saverymuttu SH
      • Peters AM
      • Lavender JP
      • Pepys MB
      • Hodgson HJF
      • Chadwick VS
      Quantitative fecal indium 111-labeled leukocyte excretion in the assessment of disease in Crohn's disease.
      however, the anatomic definition of the segment affected may be difficult. Recent studies suggest that such scanning techniques are inferior to radiology for assessment of small bowel disease.
      • Crama-Bohbouth GE
      • Arndt JW
      • PenTa AS
      • Verspaget HW
      • Tjon A Tham RTO
      • Weterman IT
      • Pauwels EKJ
      • Lamers CBHW
      Value of indium-111 granulocyte scintigraphy in the assessment of Crohn's disease of the small intestine: prospective investigation.
      Also of importance, radiolabeled leukocyte scans disclose abnormal findings in any inflammatory disease of the bowel including, for example, acute gastroenteritis
      • Kordossis T
      • Joseph AEA
      • Gane JN
      • Bridges CE
      • Griffin GE
      Fecal leukocytosis, indium-111-labelled autologous polymorphonuclear leukocyte abdominal scanning, and quantitative fecal indium-111 excretion in acute gastroenteritis and enteropathogen carriage.
      and vasculitis of the intestine;
      • Keshavarzian A
      • Saverymuttu SH
      • Chadwick VS
      • Lavender JP
      • Hodgson HJF
      Noninvasive investigation of the gastrointestinal tract in collagen-vascular disease.
      hence, the usual strict histologic criteria for definitive diagnosis remain a prerequisite for initiation of treatment.
      Figure thumbnail gr1
      Fig. 1111In-labeled autologous leukocyte scan, showing accumulation of radiolabeled leukocytes in active inflammatory bowel disease involving right and transverse colonic areas. Note background uptake in bone marrow, spleen, and liver.
      (Illustration courtesy of Dr. Lee A. Forstrom, Section of Diagnostic Nuclear Medicine, Mayo Clinic.)
      Recently, 99mTc-labeled hexamethylpropylene-amineoxime (HMPAO) has been used to label leukocytes for imaging of intestinal inflammation due to ulcerative or Crohn's colitis.
      • Peters AM
      • Danpure HJ
      • Osman S
      • Hawker RJ
      • Henderson BL
      • Hodgson HJ
      • Kelly JD
      • Neirinckx RD
      • Lavender JP
      Clinical experience with 99mTc-hexamethylpropylene-amineoxime for labelling leucocytes and imaging inflammation.
      • Schölmerich J
      • Schmidt E
      • Schümichen C
      • Billmann P
      • Schmidt H
      • Gerok W
      Scintigraphic assessment of bowel involvement and disease activity in Crohn's disease using technetium 99m-hexamethyl propylene amine oxine as leukocyte label.
      The images obtained with this chelate were comparable or superior to those obtained with 111In-labeled leukocyte scans,
      • Peters AM
      • Danpure HJ
      • Osman S
      • Hawker RJ
      • Henderson BL
      • Hodgson HJ
      • Kelly JD
      • Neirinckx RD
      • Lavender JP
      Clinical experience with 99mTc-hexamethylpropylene-amineoxime for labelling leucocytes and imaging inflammation.
      and this technique has several technical advantages, such as the labeling of cells in 10% plasma rather than saline and the greater selectivity for granulocytes shown by HMPAO than the previous chelators (such as tropolonate) that were used for 111In. 99mTc-labeled autologous phagocytes provide similar accuracy in defining ulcerative and Crohn's colitis.
      • Pullman WE
      • Sullivan PJ
      • Barratt PJ
      • Lising J
      • Booth JA
      • Doe WF
      Assessment of inflammatory bowel disease activity by technetium 99m phagocyte scanning.
      Radiolabeled autologous leukocyte scans can also demonstrate complications that may necessitate surgical treatment—for example, abscesses (by the persistence of radiolabel for more than 24 hours in one locus on sequential delayed scans) or fistulas (by the appearance of radiolabeled leukocytes along fistulous tracks or in adjoining viscera).
      In summary, although autologous leukocyte scans are accurate in assessment of colonic inflammation due to ulcerative and Crohn's colitis, they are suboptimal in the evaluation of Crohn's disease of the small bowel. Because such scans are also associated with radiation exposure, such as to the bone marrow and the spleen, frequent scanning is impractical (Table 4).

      ASSESSMENT OF EXTENT AND SEVERITY OF DISEASE

      Clearly, the choice of treatment is often determined on the basis of the extent and severity of inflammatory bowel disease. Similarly, the choice of candidates for surgical therapy and for long-term cancer surveillance will often be swayed by knowing the extent and severity of inflammatory bowel disease. Clinicians are faced with the question of which of several methods to use for assessment of the extent and severity of disease.

      At Diagnosis.

      At the time of diagnosis, Truelove and Witts' criteria,
      • Truelove SC
      • Witts LJ
      Cortisone in ulcerative colitis: final report on a therapeutic trial.
      as well as colonoscopy and multiple biopsies, provide all the necessary information in patients with ulcerative colitis. Colonoscopy should be avoided if the patient has a severe initial attack or features suggestive of toxic megacolon. At the time of diagnosis of Crohn's disease, no clear advantage exists for any specific clinical or laboratory group of indices. Nonetheless, many investigators tend to prefer use of the CDAI
      • Best WR
      • Becktel JM
      • Singleton JW
      • Kern Jr, F
      Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study.
      as modified by Harvey and Bradshaw,
      • Harvey RF
      • Bradshaw JM
      A simple index of Crohn'sdisease activity.
      despite the potential lack of specificity of such features as well-being and abdominal pain in the calculation of these indices. Colonic involvement is probably best assessed by colonoscopy and biopsies, whereas small bowel enteroclysis or follow-through with vigorous manual palpation is essential for the identification of the more subtle lesions in Crohn's disease of the small bowel.

      During Recurrence.

      During the assessment of patients with a recurrence of inflammatory bowel disease, Truelove and Witts' criteria
      • Truelove SC
      • Witts LJ
      Cortisone in ulcerative colitis: final report on a therapeutic trial.
      are again extremely useful in those with ulcerative colitis. The high degree of accuracy of radiolabeled leukocyte scanning in determining the severity and extent of ulcerative and Crohn's colitis suggests that this procedure may well have a role in clinical practice in the future if their effectiveness, as shown in clinical trials, is confirmed. The current alternative for assessment of recurrence in either ulcerative or Crohn's colitis is repeat colonoscopy (with or without biopsies) or flexible sigmoidoscopy and colon roentgenography. In patients with recurrent Crohn's disease, clinical and laboratory indices and small bowel roentgenography, when clinically indicated (for example, in patients with abdominal pain or malabsorption), provide a relatively noninvasive means of assessing the extent and severity of disease and thereby assist the clinician in recommending treatment. The clinical role of radiolabeled leukocyte scanning in small bowel inflammation is still to be delineated, but initial experience suggests that it is unlikely to prove superior to radiologic assessment.

      For Effects of Drug or Dietetic Therapy.

      In the assessment of the effects of drug or dietetic therapy (for example, elemental diets or total parenteral nutrition and antibiotics), patients with both types of inflammatory bowel disease are now most often monitored with clinical and laboratory indices and usually colonoscopy
      • Sutherland LR
      • Martin F
      • Greer S
      • Robinson M
      • Greenberger N
      • Saibil F
      • Martin T
      • Sparr J
      • Prokipchuk E
      • Borgen L
      5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.
      • Schroeder KW
      • Tremaine WJ
      • Ilstrup DM
      Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study.
      or, less often, radiolabeled leukocyte scanning.
      • Saverymuttu S
      • Hodgson HJF
      • Chadwick VS
      Controlled trial comparing prednisolone with an elemental diet plus non-absorbable antibiotics in active Crohn's disease.
      In clinical trials, quantitative data obtained from the 3-hour abdominal scans and from the 24-hour stool excretion of labeled leukocytes provide a less invasive method for determining disease activity and its response to treatment than with colonoscopy and multiple biopsies. In clinical practice, pursuing such a quantitative demonstration of reduced inflammatory activity is usually unnecessary.

      CONCLUSION

      Although several methods have been proposed for the evaluation of the extent and severity of inflammatory bowel disease during the past 3 decades, use of single determinations alone generally has not been accepted by most investigators in the field. Clinical and laboratory scores based on weighted indices provide a noninvasive method for this assessment, although the sensitivity and specificity of these criteria may be suboptimal. The OMGE has recommended a modified version of the CDAI because a comparative study of various indices with extensive evaluations by experienced clinicians showed a high correlation of the modified CDAI with clinical assessment.
      Double-contrast colon roentgenography, enteroclysis of the small bowel, and colonoscopy in conjunction with multiple biopsies have all ensured the possibility of a thorough analysis of each patient with inflammatory bowel disease, albeit with some discomfort imposed by the intubation processes and a slight risk of morbidity from the intubations and biopsies. Recently, radiolabeled autologous leukocyte scanning has been shown to be an objective, noninvasive procedure for the assessment of disease activity in clinical research on inflammatory bowel disease. The role of such scans in clinical practice is still to be determined; available data suggest that scanning would be a useful adjunct to the assessment of colonic but not small bowel inflammation.

      ACKNOWLEDGMENT

      We thank Cynthia L. Stanislav for secretarial assistance in the preparation of the submitted manuscript.

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