Mean platelet volume: a useful marker of inflammatory bowel disease activity

OBJECTIVES: We investigated whether the mean platelet volume would be a useful marker in the evaluation of inflammatory bowel disease activity. METHODS: Complete blood count, C-reactive protein, erythrocyte sedimentation rate, serum thrombopoietin and erythropoietin, plasma beta-thromboglobulin, and platelet factor 4 were measured in 93 patients with ulcerative colitis, 66 patients with Crohn's disease, and 38 healthy blood donors. Disease activity was assessed by the Clinical Colitis Activity Index in patients with ulcerative colitis and by the Crohn's Disease Activity Index in patients with Crohn's disease. RESULTS: Mean platelet count was increased in patients with active compared to inactive ulcerative colitis (p < 0.05), and in patients with active compared to inactive Crohn's disease (p = 0.0002) or healthy controls (p < 0.0001). On the other hand, mean platelet volume was significantly decreased in patients with active compared to inactive ulcerative colitis (p = 0.02) or healthy controls (p < 0.0001), and in patients with active compared to inactive Crohn's disease (p = 0.0005) or healthy controls (p < 0.0001). Mean platelet volume was inversely correlated with the white blood cell count (r = -0.17, p = 0.02), C-reactive protein (r = -0.46, p = 0.009) and erythrocyte sedimentation rate (r = -0.28, p = 0.008). No significant correlations were found between mean platelet volume and serum thrombopoietin or erythropoietin levels; however, a strong negative correlation between mean platelet volume and beta-thromboglobulin (r = -0.34, p < 0.0001) and platelet factor 4 (r = -0.30, p = 0.0002) was observed. CONCLUSIONS: Mean platelet volume is significantly reduced in active inflammatory bowel disease and is negatively correlated with the known inflammatory bowel disease activity markers and the platelet activation products. We propose that mean platelet volume provides a useful marker of activity in inflammatory bowel disease.     

Duration of recurrent ileitis after ileocolonic resection correlates with presurgical extent of Crohn's disease.

Crohn's disease of the terminal ileum recurs in a predictable sequence proximal to the ileocolonic anastomosis after surgical resection. To confirm the suspicion that the duration of recurrent ileitis correlates with the extent of presurgical disease, this study investigated 23 consecutive patients with recurrent Crohn's disease symptoms who had undergone ileocaecal resections between 1982 and 1992 at our institution and had both preoperative and postoperative small bowel follow through studies available for comparison. All films were reviewed by a blinded gastrointestinal radiologist using uniform criteria. Symptomatic recurrence was reported at a mean (SEM) of 29 (25) months after resection. Presurgical length of inflammation averaged 26 (15) (8-57) cm and at recurrence 24 (14) (7-55) cm. The correlation coefficient (r) between pre and postsurgical extent of ileal disease was 0.70 (p < 0.0001). Seven patients had sequential small bowel series after 20 (10) (7-36) months without intervening surgery. The extent of measured inflammation between examinations correlated with r = 0.995 (p < 0.0001), showing the consistency of the measurement process. The close correlation between the duration of postoperative recurrence with the extent of presurgical disease is another example of individual patterns of recurrent Crohn's disease and is an additional factor to be considered when contemplating surgical resections.     

Increased pulmonary and intestinal permeability in Crohn''s disease.

We tested the hypothesis that an increased epithelial permeability may affect sites other than the intestine in patients with Crohn's disease by simultaneously evaluating their pulmonary and intestinal permeability. Pulmonary and intestinal permeability were measured by clearance of inhaled technetium-99m diethylene triamine pentacetate (99mTc-DTPA) and by urinary recovery of chromium-51 ethylene diamine tetracetate respectively in 22 patients with Crohn's disease. The half time clearance of 99mTc-DTPA from lung to blood (t1/2LB) was decreased--that is pulmonary permeability increased--in the whole group of patients with Crohn's disease as compared with 13 controls (median 45.5 minutes (8-160) v 85 minutes (34-130) (p less than 0.003)). When analysed separately only patients with active Crohn's disease (n = 15) had a decreased t1/2 lung to blood v controls (42 minutes (8-160) v 85 minutes (34-130) (p less than 0.0025)). Among patients with active Crohn's disease, six were studied again when their disease was quiescent and their t1/2 lung to blood did not differ significantly. The intestinal permeability was increased in the whole group of Crohn's disease patients as compared with 15 controls (5.25% (1.2-24) v 1.7% (0.65-5.75) (p less than 0.0002)). When analysed separately both patients with active and inactive Crohn's disease had increased intestinal permeability v controls (8.1% (1.6-24) and 3.5% (1.2.9.2) v 1.7% (0.65-5.75)) (p less than 0.0001, p = 0.05 respectively). Six patients with active Crohn's disease were studied again when their disease was quiescent and their intestinal permeability decreased significantly p less than 0.04). Pulmonary permeability was increased in patients with Crohn's disease but was not greatly influenced by Crohn's disease activity as opposed to intestinal permeability. The mechanism of this increase is unknown, but may be related in some patients to the presence of an alveolitis.     

Surgical resections in parous patients with distal ileal and colonic Crohn's disease.

The surgical resection rates among parous women with distal ileal and colonic Crohn's disease have been compared with resection rates among distal ileal (n = 197) and colonic (n = 332) Crohn's disease patients. Thirty of 44 parous women with distal ileal Crohn's disease and 28 of 44 with colonic Crohn's disease had achieved their first pregnancy on average 8 years and 6.2 years respectively before the diagnosis of Crohn's disease was established. Resections for each patient were negatively correlated with parity in both groups. (Distal ileal disease (p = 0.034, rs = 0.3207), colonic disease (p = 0.051, rs = -0.2960)). Patients with distal ileal Crohn's disease and a history of pregnancy at diagnosis (n = 30, mean follow up = 15 years) had fewer resections/patient when compared with the published resection group: mean (SD); 1.17 (0.65) v 1.57 (1.05), p = 0.006. Patients with colonic Crohn's disease and a history of pregnancy at diagnosis (n = 28, mean follow up = 16.5 years) had fewer resections/patient when compared with the published resection group: mean (SD); 0.68 (0.77) v 1.05 (0.77), p = 0.019. In summary, patients with distal ileal and colonic Crohn's disease, who had been pregnant in the past subsequently need fewer surgical resections. Pregnancy could influence the natural history of Crohn's disease either by decreasing immune responsiveness or by retarding fibrous stricture formation, which is the commonest indication for surgical intervention.     

Adhesion molecules in inflammatory bowel disease.

The ability of leucocytes to adhere to endothelium is essential for leucocyte migration into inflammatory sites. Some of these adhesion molecules are released from the cell surface and can be detected in serum. The soluble adhesion molecules intercellular adhesion molecule 1 (ICAM-1), E selectin, and vascular cell adhesion molecule 1 (VCAM-1) were studied in the serum of patients with Crohn's disease, ulcerative colitis, and healthy controls. A second blood sample was taken from patients with active disease after one month of treatment and a third two months after remission was achieved. Tissue expression of the same adhesion molecules was studied by immunohistology. Circulating VCAM-1 concentrations were significantly higher in patients with active ulcerative colitis (n = 11, median = 165 U/ml) compared with patients with inactive ulcerative colitis (n = 10, median = 117 U/ml, p < 0.005), active Crohn's disease (n = 12, median = 124 U/ml, p < 0.02), and controls (n = 90, median = 50 U/ml, p < 0.0001). Within each disease group there were no significant differences in E selectin or ICAM-1 concentrations between the active and inactive states, however, patients with active Crohn's disease had significantly higher ICAM-1 concentrations (n = 12, median = 273 ng/ml) than controls (n = 28, median = 168, p < 0.003). VCAM-1 concentrations fell significantly from pretreatment values to remission in active ulcerative colitis (p < 0.01). In Crohn's disease there was a significant fall in ICAM-1 both during treatment (p < 0.01) and two months after remission (p < 0.02). Vascular expression of ICAM-1 occurred more often and was more intense in inflamed tissue sections from patients with ulcerative colitis and Crohn's disease than from controls. Vascular labelling with antibody to E selectin also occurred more often in patients with active inflammatory bowel disease. In conclusion, increased circulating concentrations of selected adhesion molecules are associated with inflammatory bowel disease. There is also evidence of local upregulation, particularly of ICAM-1. Differential expression of adhesion molecules in tissue may play a part in the initiation of leucocyte migration and local inflammation; the function of circulating adhesion molecules is unknown, but may play a physiological part in blocking adhesion.     

Ileal dysfunction in Crohn's disease assessed by the postprandial serum bile acid response.

We assessed ileal functional integrity in 20 consecutive patients with Crohn's disease by sequential measurement of the postprandial serum bile acid concentration. In all 14 patients with active Crohn's disease involving the terminal ileum, the mean (+/- SEM) peak response in the cholylglycine (0.4 +/- 0.04 mumol/l, n = 14) as well as in the total serum bile acid concentration (2.0 +/- 0.4 mumol/l, n = 10) was similar to that seen in a group of children who had undergone ileal resection. A significantly greater increase in the cholylglycine (1.8 +/- 0.18 mumol/l, n = 16, P less than 0.01) and in the total serum bile acid concentration (9.8 +/- 2.4 mumol/l, n = 11, P less than 0.025) was noted in normal children. In five of the six remaining patients (three with Crohn's disease shown not to involve the ileum and two of three with asymptomatic, treated Crohn's ileitis) and in seven patients with ulcerative colitis, the meal stimulated responses were normal. These preliminary results suggest that measurement of the serum bile concentration after a meal stimulus may provide a valuable index of ileal inflammation in patients with Crohn's disease.     

Soluble interleukin-2 receptor in Crohn's disease: relation of serum concentrations to disease activity.

Serum concentrations of soluble interleukin-2 receptor (sIL-2R) were measured as a marker of immune activation in a group of 30 patients with Crohn's disease. sIL-2R concentrations were determined by enzyme linked immunosorbent assay during periods of active and inactive disease and correlated with standard parameters of disease activity. Serum concentrations of sIL-2R were significantly raised in patients with active Crohn's disease compared with patients with inactive disease (p less than 0.001) and control subjects. There was a significant correlation between serum sIL-2R concentrations and disease activity as assessed by the Harvey-Bradshaw index (r = 0.42, p less than 0.01), platelet numbers (r = 0.49, p less than 0.01), and orosomucoid (r = 0.47, p less than 0.01), alpha 1 antitrypsin (r = 0.44, p less than 0.01), and C reactive protein concentrations (r = 0.48, p less than 0.001) but not with the erythrocyte sedimentation rate. Measurement of serum sIL-2R concentration is a simple and useful laboratory means of assessing disease activity. Raised concentrations in patients with active Crohn's disease is further evidence for in vivo immune activation occurring in this disease.     

Low ileal interleukin 10 concentrations are predictive of endoscopic recurrence in patients with Crohn's disease.

BACKGROUND: Endoscopic recurrence after surgery in Crohn's disease is frequent and unpredictable. Abnormal intestinal production of pro- (interleukin (IL)-1 beta, tumour necrosis factor alpha (TNF-alpha)) and anti- (IL-10) inflammatory cytokines has been associated with severe outcome in experimental models of colitis. PATIENTS AND METHODS: We evaluated if ileal TNF-alpha, IL-1 beta, or IL-10 mRNA levels measured at the time of surgery predict endoscopic recurrence, and if ileal IL-10 levels are associated with particular IL-10 promoter alleles. Ileal biopsies were obtained peroperatively from the healthy neoileum of patients undergoing a right ileocolectomy for Crohn's disease. Mucosal TNF-alpha, IL-1 beta, and IL-10 mRNA levels were quantified by competitive polymerase chain reaction. A cut off value was determined using a receiver operating curve. IL-10.G promoter haplotypes were analysed using a polymorphic dinucleotide repeat in the IL-10 promoter region. RESULTS: Three months after surgery, 53% of patients had endoscopic recurrence while 47% remained free of disease. The risk of endoscopic recurrence correlated with ileal IL-10 mRNA concentrations (r(2)=0.81). Endoscopic recurrence occurred more frequently in patients classified as low IL-10 producers than in those that were high producers (80% v 40%) (p=0.02). Patients with at least one of the two alleles G7-8 or G10-13 produced, respectively, higher (p=0.006) and lower (p=0.029) ileal IL-10 mRNA. The distribution of IL-10.G microsatellite genotypes was similar in patients with or without endoscopic recurrence. CONCLUSION: Low ileal IL-10 mRNA concentration is a good marker of endoscopic recurrence in Crohn's disease but the distribution of IL-10.G haplotypes cannot predict the postoperative evolution of the disease.     

Crohn's disease, pregnancy, and birth weight

OBJECTIVE: Although there is general agreement that conception should be avoided when Crohn's disease is active, many questions remain unanswered for the woman with Crohn's disease in remission who becomes pregnant. METHODS: Sixty-five charts of women with Crohn's disease quiescent at the start of pregnancy were identified between January 1993 and December 1997. Each pregnancy was matched to a healthy control pregnancy by date, age, parity, smoking status, and gestational age +/- 1 wk, and comparisons were carried out using matched analyses. RESULTS: The two groups were similar in terms of maternal height, weight, and body mass index (BMI), in addition to the matched variables. The incidence of pregnancy complications was similar for most of the complications examined, whereas the incidence of poor maternal weight gain differed significantly between the groups (17/65 vs 2/65, p < 0.001). Flare-up of the Crohn's disease was seen in 13/65 (20%) of pregnancies. The greatest differences in neonatal outcomes were in terms of birth weight (3150+/-80 g vs 3500+/-60 g) and birth weight percentile (36.7%+/-.6% vs 57.5%+/-3.4%). Overall, there were 16 (24.6%) small for gestational age (SGA) births in the Crohn's group, compared with only one (1.5%) in the control group (p = 0.0007). Multivariate analysis was performed to identify factors predictive of SGA births in the Crohn's group. Ileal Crohn's disease was a statistically significant predictor (p = 0.035), whereas previous bowel resection trended toward statistical significance (p = 0.065). CONCLUSIONS: In view of the risk of low birth weight, all women with Crohn's disease who become pregnant should be followed carefully during the pregnancy, particularly those who have ileal disease or who have previously undergone bowel resection. Furthermore, smoking cessation needs to be aggressively pursued in these patients.     

Multiple blood transfusions reduce the recurrence rate of Crohn's disease

In order to determine whether perioperative blood transfusion affects the recurrence of Crohn's disease, the authors reviewed the records of 79 patients with Crohn's disease who underwent their initial intestinal resection at their institution. Recurrence of Crohn's disease was documented by radiographic studies, endoscopy, or laparotomy. During the hospital admission for resection, 45 patients received multiple red blood cell transfusions. Recurrence developed in 22 percent of these patients by 36 months, and the median time to recurrence was 35 months. In the 34 patients who did not receive multiple transfusions, recurrence was found in 44 percent by 36 months, and the median time to recurrence was 20 months. These differences are significant, using the Kaplan-Meier analysis (P<0.04). Recurrence in patients with disease limited to the small bowel or to the colon was not significantly affected by the transfusion status. However, recurrence developed in only 10 percent of multiply transfused patients with ileocolic disease by 36 months, whereas recurrence developed in 45 percent of the patients who were not multiply transfused. (Significance,P=0.057). The authors believe that the observed decreased rate of recurrence of Crohn's disease in patients receiving multiple perioperative transfusions may represent another example of clinically significant immunosuppression from blood transfusion. Read at the Meeting of the American Society of Colon and Rectal Surgeons, Anaheim, California, June 12 to 17, 1988.     

Serum zinc, copper, and selenium levels in inflammatory bowel disease: effect of total enteral nutrition on trace element status

Serum levels of zinc, copper, and selenium, and alkaline phosphatase activity were prospectively studied in 29 patients with inflammatory bowel disease. Fifteen patients had extensive active colitis (active colitis group). Seven patients had active, and seven cases inactive small bowel or ileocecal Crohn's disease (small bowel disease group). Ninety-three healthy subjects acted as controls. Serum trace element levels were considered in relation to vitamin A and E levels, nutritional parameters, the activity of the disease, and the recent intake of steroids. The effect of total enteral nutrition on serum trace elements was studied in seven cases. Serum zinc levels were lower and serum copper levels higher in the active colitis group than in controls (p = 0.0007, and p = 0.02, respectively). More than 50% of patients with active colonic or small bowel disease showed zinc levels below the 15th percentile of the control group. Serum zinc levels correlated with plasma vitamin A in acute colitis (r = 0.67; p = 0.006), and with both serum albumin concentration (r = 0.76; p = 0.002) and disease activity score (r = -0.67, p = 0.009) in patients with small bowel disease. The copper:zinc ratio was higher in the active colitis group than in controls (p = 0.002). In spite of the increase in serum albumin levels and the decrease in disease activity, serum zinc levels remained low after total enteral nutrition. The implications of the abnormal trace element status in patients with inflammatory bowel disease are discussed.     

Microalbuminuria correlates with intestinal histopathological grading in patients with inflammatory bowel disease.

It has previously been shown that microalbuminuria is a useful disease activity marker for inflammatory bowel disease (IBD). Microalbuminuria correlates strongly with the markers of clinical and laboratory disease activity such as erythrocyte sedimentation rate (ESR), and C reactive protein (CRP). The aim of this study was to discover if microalbuminuria accurately reflects the intestinal inflammation by correlating it with intestinal inflammation using a standard histopathological grading system in patients with ulcerative colitis and Crohn's colitis. Forty two patients with IBD who had undergone endoscopic examination of the entire colon for the assessment of severity and extent of the disease (Crohn's colitis (n = 21), ulcerative colitis (n = 21)) were recruited to the study. Patients with small bowel Crohn's disease were not studied. Twenty four patients had left sided colonic disease and 18 patients had extensive colonic disease. Each patient's colonic biopsy specimens were scored blindly by a histopathologist and a composite score was compiled on the basis of the severity of changes in the enterocytes and crypts and the cellularity of the lamina propria. A clinical disease activity was obtained using the simple index of Harvey and Bradshaw. Microalbuminuria was measured in all patients by an immunoturbiditimetric method. ESR and CRP were also measured, as indicators of acute phase response in the same patients. It was found that patients with active IBD had higher concentrations of microalbuminuria compared with those patients in remission (median 222 micrograms/min (range 40-686 micrograms/min) v median 96 micrograms/min (range 30-376 micrograms/min); p < 0.001)). Significantly higher concentrations of microalbuminuria were also detected in patients with extensive colonic IBD compared with those patients with left sided disease (median 297 micrograms/min (range 132-686 micrograms/min) v median 101 micrograms/min (range 30-433 micrograms/min); p < 0.001)). A strong positive correlation was seen between microalbuminuria and intestinal histopathological score in IBD patient groups with left sided colitis (r = 0.77; p < 0.001) and extensive disease (r = 0.71; p < 0.01). The standard histopathological grading system correlated with the clinical disease activity (r = 0.64; p < 0.005) and CRP (r = 0.62; p < 0.02), however, it did not correlate with ESR. In conclusion, the strong correlation of microalbuminuria with a standard intestinal histopathological grading system suggests that microalbuminuria accurately reflects the severity of colonic inflammation in patients with Crohn's colitis and ulcerative colitis.     

The importance of ileocaecal integrity in the arthritic complications of Crohn's disease.

Experiments in animal models have suggested a role for bacterial overgrowth in the caecum in the pathogenesis of extracolonic inflammation in IBD. The aim of this study was to identify patients with Crohn's disease who have undergone ileocaecal resection and to compare the incidence of new arthritic complications in these patients with those who have never undergone surgery. Patients who had undergone surgery were identified by case note review. The date and nature of surgery were noted. The occurrence of new joint complications (Type 1 and 2 peripheral arthropathy and AS) was noted in patients who had undergone ileocaecal resection and in patients who had never undergone surgery. In the surgery group the timing in relation to surgery was determined. The groups were compared using Kaplan-Meier survival curves and the Logrank test. One hundred sixty-four patients who had undergone ileocaecal resection and 221 patients who had never undergone surgery for Crohn's disease were studied. The rate of development of arthritic complications in patients presurgery and in the nonsurgical group was identical. However few arthritic complications occurred postoperatively. There were highly significant differences between the nonsurgical group and the postsurgical group (p = 0.0001) and between patients presurgery and postsurgery (p = 0.0006). New arthritic complications are less common in Crohn's disease after resection of the ileocaecal area. This would be consistent with the hypothesis that luminal bacteria in this region are important in the pathogenesis of these complications.     

Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum.

We tested the efficacy of rifabutin and ethambutol in combination in healing severe recurrent Crohn's disease in the neoterminal ileum. Sixteen patients who had undergone an ileal resection with partial colectomy and ileocolonic anastomosis and who had severe recurrent lesions in the neoterminal ileum at baseline ileocolonoscopy were included in the study. The patients received rifabutin in a dose of 5 mg/kg together with ethambutol, 20 mg/kg. Ten patients were treated for 6 months; six patients dropped out because of adverse events. As no effect was observed after 6 months, five patients completed a 12-month therapy course. Follow-up ileocolonoscopy was performed at 3, 6, and 12 months. In none of the 10 patients who completed the 6-month trial and in none of the five patients who completed 12 months of therapy was endoscopic improvement of the lesions observed. In four patients the disease was clinically progressive, and two patients underwent a reresection after 6 and 8 months, respectively. This study shows that long-term therapy with rifabutin and ethambutol does not heal Crohn's disease in the neoterminal ileum and does not prevent recurrence of symptoms and complications.     

The Diagnostic Value of Serum Lysozyme Activity in Inflammatory Bowel Disease

Serum lysozyme (muramidase) activity was determined by the Lyso-Plate diffusion technic in 419 subjects consisting of normal persons and patients with Crohn's disease, ulcerative colitis, nonspecific diarrhea and various other disorders. Lysozyme activity in the normal subjects did not exceed 37.8 μg./ml. The values in the several groups of patients overlapped markedly with each other and with the normal range.
Approximately two-thirds (62.1%) of the 37 patients with Crohn's disease had values that were within the normal range. In about half (51.8%) of the patients with this disease in whom the process was clinically active, serum lysozyme activity was increased.
Of 10 patients with Crohn's disease who had undergone resection, heightened serum lysozyme activity was found only in the three patients in whom there was clinical evidence of recurrence of the disease.
It is concluded that serum lysozyme activity is not a dependable means of distinguishing Crohn's disease from ulcerative colitis or nonspecific diarrheas. The determination would appear to be of value, however, in helping to identify activity, recurrence, or extension of the disease in patients with Crohn's disease.     

Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn''s disease

BACKGROUND AND AIMS: New lesions of Crohn's disease occur early after ileal or ileocolonic resection and ileocolonic anastomosis. We performed a double blind controlled trial to evaluate the safety and tolerance of recombinant human interleukin 10 (IL-10; Tenovil) in subjects operated on for Crohn's disease. We also assessed the effect of Tenovil in preventing endoscopic recurrence 12 weeks after surgery. METHODS: Patients with Crohn's disease who underwent curative ileal or ileocolonic resection and primary anastomosis were randomised within two weeks after surgery to receive subcutaneous Tenovil 4 microg/kg once daily (QD) (n=22) or 8 microg/kg twice weekly (TIW) (n=21), or placebo (QD or TIW) (n=22). An ileocolonoscopy was performed after 12 weeks of treatment. RESULTS: Compliance was excellent. The most frequently observed adverse events were mild and moderate in severity and equally distributed across treatment groups. Thirty seven patients in the pooled Tenovil group and 21 patients in the pooled placebo group were evaluable by endoscopy. At 12 weeks, 11 of 21 patients (52%) in the placebo group had recurrent lesions compared with 17 of 37 patients (46%) in the Tenovil group (ns). The incidence of severe endoscopic recurrence was similar in both groups (9%). CONCLUSION: Tenovil treatment for 12 consecutive weeks in patients with Crohn's disease after intestinal resection was safe and well tolerated. No evidence of prevention of endoscopic recurrence of Crohn's disease by Tenovil was observed.     

T-cell activation in Crohn's disease. Increased levels of soluble interleukin-2 receptor in serum and in supernatants of stimulated peripheral blood mononuclear cells

Serum levels of soluble interleukin-2 receptor were determined in 29 patients with active and quiescent Crohn's disease. In addition, the ability of peripheral blood mononuclear cells of 23 of these patients to generate soluble interleukin-2 receptor following mitogenic stimulation was studied in vitro. Serum soluble interleukin-2 receptor concentrations of patients with active Crohn's disease (n = 19) were significantly elevated (757 +/- 438 U/ml) compared with levels in patients with inactive disease (n = 10; 412 +/- 120 U/ml) and healthy control individuals (n = 40; 375 +/- 102 U/ml; p less than 0.003 and p less than 0.0005, respectively). Serial determinations of serum soluble interleukin-2 receptor concentration in a follow-up of 11 hospitalized patients treated for highly active disease showed a decrease from 1252 +/- 494 U/ml to 527 +/- 193 U/ml (p less than 0.004) that corresponded to clinical improvement, as assessed by Crohn's disease activity index and a reduction of inflammatory parameters. In vitro phytohemagglutinin stimulation of peripheral blood mononuclear cells derived from patients with Crohn's disease resulted in elevated soluble interleukin-2 receptor production not only in patients with active disease (3987 +/- 2439 U/ml), but also in patients with inactive disease (3297 +/- 2282 U/ml), compared with the amount of soluble interleukin-2 receptor produced by mononuclear cells of healthy individuals (1523 +/- 1152 U/ml; p less than 0.005 and p less than 0.02, respectively). In addition, cultivation of mononuclear cells without mitogen resulted in higher soluble interleukin-2 receptor production in patients with active disease than in patients with inactive disease (p less than 0.02). However, patients suffering from active ulcerative colitis also had significantly increased serum levels of soluble interleukin-2 receptor (1080 +/- 400 U/ml) compared with the levels in patients with chronic disease (455 +/- 140 U/ml; p less than 0.0025). In addition, peripheral blood mononuclear cells derived from patients with ulcerative colitis produced significantly more soluble interleukin-2 receptor upon mitogenic stimulation with phytohemagglutinin (2314 +/- 936 U/ml), than cells from healthy controls (1523 +/- 1152 U/ml; p less than 0.05). The finding of elevated soluble interleukin-2 receptor serum levels in patients with active Crohn's disease and its increased production by mononuclear cells of patients with both active and inactive disease is a further example of an alteration of the immune system in this condition; however, this alteration can also be found in other inflammatory bowel diseases.     

Pediatric Crohn's disease: risk factors for postoperative recurrence

OBJECTIVE: Postoperative recurrence of Crohn's disease in adults has been extensively studied; however, the course of Crohn's disease after surgery in children has not been well defined. The aim of this study was to examine the postoperative course of pediatric Crohn's disease and the factors that may predict early postoperative recurrence. METHODS: We identified 100 resective surgeries in 79 children with Crohn's disease seen at the Children's Hospital of Philadelphia between 1978 and 1996. A retrospective, multivariable analysis of factors potentially influencing postoperative clinical recurrence was performed. Preoperative and postoperative height measurements were compared, and z scores were computed for height-for-age. Two-tailed t test was used for the analysis. RESULTS: Clinical recurrence rates were 17% at 1 yr, 38% at 3 yr, and 60% at 5 yr. Patients with colonic Crohn's disease had a significantly shorter postoperative recurrence-free interval (median 1.2 yr) than patients with ileocecal (median 4.4 yr) or diffuse disease (median 3.0 yr) (p = 0.01). On multivariable analysis, a high Pediatric Crohn's Disease Activity Index at the time of surgery (p = 0.01) and preoperative use of 6-mercaptopurine (6-MP) (p < 0.005) were also independently associated with higher postoperative recurrence rates. There was a significant improvement in z scores for height (p = 0.04) after surgery. CONCLUSIONS: In children undergoing resective surgery for Crohn's disease, high rates of postoperative Crohn's disease recurrence are associated with severe disease at the time of surgery, colonic Crohn's disease, and the preoperative use of 6-MP. Patients who require preoperative use of 6-MP are likely to suffer from a more aggressive disease and would benefit from postoperative 6-MP prophylaxis. Height growth was improved after intestinal resection for Crohn's disease.     

Circulating von Willebrand factor in inflammatory bowel disease.

Raised circulating von Willebrand factor is a recognised marker of vascular injury. To evaluate the role of vascular injury in the pathogenesis of inflammatory bowel disease, serum von Willebrand factor in Crohn's disease, ulcerative colitis, confirmed bacterial diarrhoea, and healthy subjects was measured. von Willebrand factor values were raised in 9/14 patients (p = 0.007) with active Crohn's disease, 15/28 (p = 0.0004) with inactive Crohn's disease, 16/23 (p = 0.0003) with active ulcerative colitis, 9/27 (p = 0.04) with inactive ulcerative colitis, and 15/17 (p = 0.0001) patients with bacterial diarrhoea. Serum von Willebrand factor was unrelated to disease activity in Crohn's disease but was significantly raised in active (p = 0.02) compared with inactive ulcerative colitis. In contrast to controls, the detection of von Willebrand factor from inflammatory bowel disease sera and that from fractured endothelial cells was significantly inhibited by the reducing agent, dithiothreitol, suggesting the presence of an additional dithiothreitol sensitive form of the molecule derived from injured endothelial cells in inflammatory bowel disease. That serum von Willebrand factor is raised in quiescent as well as active Crohn's disease is compatible with the proposal that vascular injury is a fundamental abnormality in this disorder. The raised von Willebrand factor values in active inflammatory bowel disease and bacterial diarrhoea could be caused by either vascular injury, occurring secondary to bowel inflammation, or to an acute phase response resulting from endothelial cell stimulation by mediators released during the inflammatory process. Raised circulating von Willebrand factor could contribute to the increased risk of thrombosis associated with active inflammatory bowel disease.     

Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn's disease: a randomised, double blind, placebo controlled GETAID trial

BACKGROUND AND AIMS: Early endoscopic recurrence is frequent after intestinal resection for Crohn's disease. Bacteria are involved, and probiotics may modulate immune responses to the intestinal flora. Here we tested the probiotic strain Lactobacillus johnsonii LA1 in this setting. PATIENTS AND METHODS: This was a randomised, double blind, placebo controlled study. Patients were eligible if they had undergone surgical resection of <1 m, removing all macroscopic lesions within the past 21 days. Patients were randomised to receive two packets per day of lyophilised LA1 (2 x 10(9) cfu) or placebo for six months; no other treatment was allowed. The primary endpoint was endoscopic recurrence at six months, with grade >1 in Rutgeerts' classification or an adapted classification for colonic lesions. Endoscopic score was the maximal grade of ileal and colonic lesions. Analyses were performed primarily on an intent to treat basis. RESULTS: Ninety eight patients were enrolled (48 in the LA1 group). At six months, endoscopic recurrence was observed in 30/47 patients (64%) in the placebo group and in 21/43 (49%) in the LA1 group (p = 0.15). Per protocol analysis confirmed this result. Endoscopic score distribution did not differ significantly between the LA1 and placebo groups. There were four clinical recurrences in the LA1 group and three in the placebo group. CONCLUSION: L johnsonii LA1 (4 x 10(9) cfu/day) did not have a sufficient effect, if any, to prevent endoscopic recurrence of Crohn's disease.