Immunological predictors of recurrence in patients with inflammatory bowel disease

JP WRIGHT. Immunological predictors of recurrence in patients with inflammatory bowel disease. Can} Gastroenterol 1993;7(2):223-225. The management of patients with inflammatory bowel disease is complicated by the poor correlation between symptoms and prognosis. This is due to the inconsistent and subJective nature of the symptoms of these diseases. Laboratory parameters which reflect the acute phase response offer an objective measure of disease activity and have been used in isolation as well as within clinical indices. The problem is that these parameters do not correlate very well with the indices of climcal activity. To predict disease recurrence it is presumed that an increase m disease activity, at the cellular level, precedes a clinical deterioration. An increase m acute phase proteins in the months before clinical recurrence confirms this supposition. TI1e poor correlation between the acute phase proteins suggests that they may be reacting to different stimuli. Where single parameters arc used the orosomucoid, C-n!active protein and cx.-1-antitrypsm levels are the best predictors of clinical relapse of Crohn's disease within the following three months, giving true positive rates of approximately 20% overall with a sensitivity of approximately 60%. The efficiency of these parameters improves in patients with Crohn's ileocolitis where rates of 27% and 63% are found. The less expensive erythrocyte sedimentation rate is almo::.t as useful but is less specific. To improve the predictive ability of the acute phase proteins various indices have heen proposed. These indices offer true positive mtes of 29% to 77%. The wiJe range ts prohably due to patient selection, differing predictive periods anJ attack definitions in the orginal reports. In conclusion, the acute phase protein response can be used to predict disease recurrence but further refinement and verif1catton is needed.

Facteurs immunologiques de previsibilite de la recurrence chez les patients atteints de maladie intestinale inflammatoire RESUME: Le traitement des patients qui souffrent de maladie intestinale mflammatoire est compliquc par la faible correlation entre symptomes et pronostic.Cela est du a la nature irreguliere et subjective des symptomes de ces maladies.
Les paramcrres de laborato1rc qui reflerent la phase aiguc de la reponse offrent une mesure objective de l'acrivitc de la malaJie ct om cte utilises soit isolement, so1t avec d<.::s indices dmiques.Malheureusement, ces parametres ne concordenr with mflammatory bowel disease 1s complicated by the poor correlation between symptoms and prognosis.This 1s Jue to the inconsistent and subjective nature of the symptoms of these diseases.In order to quantify more objecnvely disease severity, vario us laboratory parameters have been proposed as indicators of currem and future clinical activity erythrocyte sed11nencat1on rate {l-3), platelet count (4,5), alhumin (6), iron (7,8), C-reactive protein ( 1,2,9-11 ), orosomucmds {l ,2, 12, l 3) and a-1-antitrypsin (l, 13,14).These parameters generally reflect the acute phase response but t hey are poorly correlated with each other (9), suggesting that they may be reacting to different stimuli ( 15).In order to predict disease course it b presumed that an increase in disease activity, at the cellular level, precedes a clinical detenoration.An increase 111 acute phase reactants in the months before clinical recurrence confirms this supposition (9).Th e specificity of this phenomenon needs to be determined in prospective studies of the ability of the acute phase reactants to predict acute recurrences 111 a defined population of patients.There 1s as yet limited published work (9,10,16).
When usmg the single parameters to predict recu rrence a test result will need to be classified as predictive off an attack or not based on a predetermined cut-off value.The normal ranges of the pas toujours tres bien avec les indices de l'activite clinique.Pour predire les recidives de la maladie, on presume qu'une augmentation de l'activite de la maladie au niveau cellulaire precede une deterioration climque.Une augmentation des proteines de la phase aigue, clans les mois qui precedent la recidive clinique confinne ceccc hypo these.La correlation faible entre les proteines de phase aigue suggere qu'elles pourraient reagir a des stimuli differents.La ou les parametres isoles soot utilises, les caux de proteines C -reactives orosomuco'ides et d'antitrypsine A-1 sont les meilleurs predicteurs de la rechute clinique de la maladie de Crohn <lans les trois mois qui suivent, cc qui donne des taux positifs vrais d'environ 20 % globalemcnt, avec un degre de sensibilite d'environ 60 %.L'efficacite de ces para metres est encore meilleure chez les patients qui prcsentem une ileocolite de Crohn ou les taux soot de 27 % et de 63 % respectivement.Le taux de sedimentation des erythrocytes, mains cher, est presque aussi utile, mais moins specifique.Pour ameliorer la capacite predictive des proteines de phase aigue, divers indices ont ete proposes.Ces indices offrent des taux positifs vrais de 29 % a 77 %.Lcur grande variabilite est probablement due a la selection des patients, aux differences periodes visees et a la definition des crises dans lcs rapports originaux.En conclusion, la reaction des proteincs a la phase aigue peut etre utilisee pour predire les recidives de la maladie, mais ii faut proceder a d'autres ajustements et verificatiom.analysis is better sui ted to the creation of an index.
In a study from Cape Town the prospectively collected data from 3522 visits of 193 patients were analyzed to determine the predictive value of the acute phase reactan ts.A ll patien ts had been clinically inactive (Crohn's disease activity index [20) [CDAI) less than 150) for three consecutive months.If the patient had an acute relapse within t he pred ictive period of three mon ths the patient was with-drawn and only re-entercJ when there had been no cl inical activity (COAi less than 150) fo r a further three months (21 ).
Attacks of Crohn's disease were divided on clinical grounds into three categories.Inflammatory: Increases diarrhea anJ abdominal pain with systemic feature, of inflammation (pyrexia and malaise) with o r without a tender abdominal mass.O bstructive: Severe cramping abdominal pain with or without concomitant vomiting or fluid levels on plain ahdominal x-ray.The patient characteristically reports that if the cramps were to be relieved he or she would feel well.Other: A variety of attack types including Crohn's esophagitis, sudden severe hypoprote inem ia w ith peripheral edema, perforation, hemorrhage anJ acute perianal d isease.
The best predictive cut-off values were calculated with the receiver operator characteristic cu rve technique (Table 1).Using these cut-off values the orosomucoid, C-reactive protein and a-1-antitrypsin levels are the best predictors of clinical relapse of Crohn's disease within the fo llowing three months, giving true positive rates of approximately 20% overall with a sensitivity of approximately 60% (Tahle 2).The efficiency of these parameter, improves in patients w ith Crohn's ileocolitis where rates of approximately 27% and 63% arc found (Table 3).The less expensive erythrocyte sedimentation rate is almost as useful but is lesi sensitive .
These apparently low predictive values must be compared to the underlying prevalence of recu rrence of 10% in the same patient population.
To improve the predictive abilttyof the acute phase proteins a combination index is proposed (22).A combination of a-1-antitrypsin and orosomucoid offe rs a true positive rate of 29% and a sensitivity of 62%.In patients with ileocolitis this increases to 38% and 64%, respectively.
A combination predictive index was reported by Brignola et al (16).They followed 41 patients with Crohn's d15-case for up to 18 months.The recurrence rate was calculated after nine and 18 mo nths and the predictive value of the acute phase reactants, which had been estimated at the start of the study, assessed.A discriminant analysis suggested an index consisung of a.-1glycoprotein, a-2-globulin and erythrocyte sedimentation rate.With this index an excellent lrue positive rate of 77% at nine months and 100% at 18 months was reported.The sensitivity was 62% and 71 Oto, respectively.The patients in this study were entered only if they had had no treatment for at least six months.As only 17 patients relapsed during the 18 month study the relapse rate appears to be of the order of 12 per year (ie, 29%).If the six months before emry ( when the patients were clinically well) arc included, the relapse rate for the tria l group foils to In condus11lll, thl ac ure ('hase response mirrors d1st'.ls(•activity .ismeasured h) the ac.utc phase ('Wteans and although eac h appears rn measun: a different aspect of rhe re~pnnscs tht'Y may be danacally useful in pred1ct111g cl1111cal recum:ncc.Further rcftnetnl'nt and venfi<.atttlllts needed, however.

TABLE 1
Predictive thresholds of acute phase reactants in patients with Crohn's disease

TABLE 3
Effect of disease extent on predictive statistics of acute phase reactants ----20%.This is lower than that re~meJ from De nmark and Cape Town where a relapse rate of approximately 50 1 \, per year is seen(23.24).The wide range of results found by the pred1ct1ve indices is probably due to patient selectio n, diffe rent attack definitions and prcdicttve penods in the original reports.