Diether Ludwig

Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506)

Objective:Steroid treatment failure in acute Crohns disease and ulcerative colitis frequently necessitates surgical intervention. Several alternative therapeutic strategies have been raised. The most promising so far has been intravenous cyclosporine, but the results in the long term have been discouraging. We assessed the efficacy and safety of the new macrolide immunomodulator tacrolimus as an alternative to cyclosporine A.Methods:Eleven patients with steroid-refractory disease (six ulcerative colitis, two indeterminate colitis, two Crohns disease, one pouchitis) and severe activity according to the Truelove and Witts criteria or Crohns disease activity index > 150, respectively, were eligible for the study. All patients were treated with intravenous tacrolimus for 7–10 days followed by oral treatment over a median period of 7 months (range 0.25–16). Azathioprine and mesalamine were given concomitantly. Steroids were tapered according to clinical activity.Results:Seven of 11 patients achieved remission rapidly, whereas a modest improvement was noted in two. Only two patients required an early and one a delayed colectomy. Moreover, a rectovaginal fistula closure in a case of Crohns disease and an improvement of pouchitis was observed. A tapering to low dose steroids was possible during oral tacrolimus therapy in all nine responders and remission was maintained in five of them (mean follow-up 9.2 months). The drug was well tolerated and side effects were managed conservatively.Conclusion:Tacrolimus induced rapid remission in steroid resistant inflammatory bowel disease in the majority of cases. It appears to be an effective treatment modality that may be superior to cyclosporine with respect to maintenance of remission.

Response of refractory colitis to intravenous or oral tacrolimus (FK506)

Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis. FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to 0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started orally at this dose in a second group (n = 20). Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients, followed by a dose reduction of FK506. Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety. Primary objectives were the induction of remission (Truelove index of mild) and colectomy-free survival. Treatment lasted for a mean of 7.6 months, and the mean observation period was 16.2 months. Eighteen of 38 patients improved within 14 days, and a complete remission was achieved in 13 patients after 1 month. A colectomy within 1 month was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half of the patients with a minimum follow-up of 2 years required a colectomy. Intravenous and per oral administration were equally safe and effective. The most frequent adverse events included tremor, hyperglycemia, hypertension, and infection, but none were severe. Renal impairment was rare and subsided upon drug withdrawal. In conclusion, FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration.

ALTERATIONS IN PULMONARY FUNCTION IN INFLAMMATORY BOWEL DISEASE ARE FREQUENT AND PERSIST DURING REMISSION

OBJECTIVES:Information on the occurrence and frequency of pulmonary involvement in patients with inflammatory bowel disease (IBD) is inconsistent. The aim of this prospective study was to determine the frequency and type of pulmonary dysfunction in patients with IBD.METHODS:Sixty-six patients with IBD (35 with Crohns disease [CD] and 31 with ulcerative colitis [UC]) and 30 control patients were investigated with respect to the following pulmonary function tests: forced expiratory volume in 1 s (FEV1), inspiratory vital capacity (IVC), Tiffeneau value (FEV1/IVC), and lung CO transfer capacity (Dlco). Disease activity in IBD patients was assessed by the CD activity index for CD and the Truelove index for UC, respectively. Smoking habits and medication were documented in every patient.RESULTS:Fourteen of 36 CD patients (39%) and 14 of 31 UC patients (45%) but only one of the controls exhibited at least one pathological (<80% of predicted value) pulmonary function test. In both CD and UC lung function tests were significantly decreased in comparison to the control group. This could be shown for FEV1 (−14% of predicted value in CD and −17% in UC, p < 0.01), IVC (−10% in CD and −12% in UC, p < 0.05), and Dlco (−20% in CD and −31% in UC, p < 0.01) without significant differences between both disease entities. The impairment of pulmonary function tests was more pronounced in patients with active disease than in those with inactive disease (FEV1, 81.4% vs 93.4% predicted, p < 0.02; IVC, 84.4% vs 93.7%, p < 0.05; Dlco, 80.4% vs 95.8%, ns).CONCLUSIONS:IBD patients show significantly decreased lung function tests in comparison to healthy controls. The impairment in active disease exceeded that during remission.

Mucosal cytokine expression, cellular markers and adhesion molecules in inflammatory bowel disease

OBJECTIVE To relate proinflammatory cytokines to leukocyte surface markers and adhesion molecules in the same paraffin-embedded biopsy specimen in inflammatory bowel disease (IBD) of varying activity. METHODS Biopsies of seven cases of Crohns disease, seven patients with ulcerative colitis, one case of intestinal infection and six control subjects were studied. We performed in situ hybridization on sections of tissue using probes specific to interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF alpha). Leucocyte markers and adhesion molecules were investigated in subsequent slides of selected specimens by immunohistochemistry. RESULTS Cytokine mRNA was found in large numbers of cells throughout the inflamed intestine but also in some macroscopically unaffected tissue specimens. Transcripts were predominantly located within the lamina propria where immunohistochemistry of parallel sections revealed numerous macrophages and the presence of endothelial adhesion molecules. The expression of the different cytokines was closely related to each other and to histological but not to macroscopic (endoscopic) activity. CONCLUSIONS The synthesis of IL-1beta IL-6 and TNF alpha mRNA is coordinately regulated. Cytokine production is located mostly in the lamina propria at sites that are rich in macrophages and show abundant staining of vascular adhesion molecules. This cascade of immune events is related to inflammatory cell infiltration in both Crohns disease and ulcerative colitis.

Enhanced intestinal expression of heat shock protein 70 in patients with inflammatory bowel diseases.

Heat shock protein (Hsp) 70 is stress-inducibleand exhibits both protective and antigenic properties.This study investigated the mucosal expression of theconstitutive (Hsp70c) and inducible form (Hsp70i) as well as antibodies against human Hsp70 ininflammatory bowel disease and controls. Biopsies wereassessed by immunoblot and immunofluorescence, resectionspecimens by immunohistochemistry, and mucosal antibody content by isoelectric focusing.Compared to controls, expression of Hsp70 was enhancedin ulcerative colitis (P < 0.05), less so in Crohnsdisease and infectious colitis. Strong epithelial staining was found for Hsp70c and Hsp70i inboth diseases. Mucosal and submucosal mononuclear cellsshowed enhanced Hsp70c expression in Crohns disease andto a lesser degree in ulcerative colitis. Antibodies of isotypes A or M were detected in nearly allpatients and controls. The different pattern of Hsp70expression in Crohns disease compared to ulcerativecolitis points to a distinct protective andimmunological function, whereas a role in autoimmunity seemsunlikely.

Mesenteric blood flow is related to disease activity and risk of relapse in Crohn's disease: a prospective follow-up study

Objective:The diagnostic significance of increased splanchnic blood flow in Crohns disease is unclear. This prospective study was therefore undertaken to define the role of Doppler sonography in the assessment of disease activity and in the prediction of early relapse.Methods:Splanchnic flowmetry was performed in 59 patients with Crohns disease and 20 healthy volunteers during fasting and 30 min after ingestion of a standardized meal. Twenty-one patients measured during the active state and in clinical remission were followed-up for 6 months. Hemodynamic parameters of the superior and inferior mesenteric arteries and the portal vein were related to clinical (Crohns disease activity index [CDAI]), laboratory (C-reactive protein), and endoscopic (Crohns Disease Endoscopic Index of Severity) parameters of disease activity.Results:The postprandial mean velocity of the superior mesenteric artery correlated closest with clinical activity (CDAI, p < 0.005) and C-reactive protein (p < 0.01), but was unrelated to endoscopic activity. All patients in remission after 6 months (9/9) showed an increase in postprandial pulsatility index of the superior mesenteric artery, compared with an initial measurement during active disease (+28%). In contrast, the majority of patients with later relapse or surgery (11/12) had decreased pulsatility index during initial remission (−20%). The positive predictive value of this index for maintenance of remission was 0.82.Conclusion:Postprandial flow measurements in the superior mesenteric artery are closely related to clinical but not endoscopic disease activity in patients with Crohns disease. The repeated measurement of the postprandial pulsatility index allows estimation of the risk of recurrence.

Elevated serum thrombopoietin and interleukin-6 concentrations in thrombocytosis associated with inflammatory bowel disease.

Reactive thrombocytosis is a typical feature in inflammatory bowel disease (IBD). The question arose as to whether the normal negative feedback regulation of the concentration of thrombopoietin (TPO) in blood was altered in IBD patients. We measured serum immunoreactive TPO in 30 patients with active IBD, 29 patients with inactive IBD, and 56 healthy controls. The results were related to platelet and leukocyte counts and to the serum concentration of interleukin 6 (IL-6). Patients with active IBD exhibited significantly increased TPO levels (medians 112 pg/ml vs. 90 pg/ml in controls, p < 0.05) in association with thrombocytosis (428 platelets/nl blood vs. 241 platelets/nl blood in controls), leukocytosis, and increased IL-6 levels (12.9 pg/ml vs. 2.5 pg/nl in controls). In patients with inactive IBD, only platelets (322/nl) and leukocytes were above normal. Although the observation of increased TPO and IL-6 levels provides an explanation for the occurrence of thrombocytosis in IBD, the pathogenetic mechanisms underlying the elevated TPO level still need to be identified.

The postprandial portal flow is related to the severity of portal hypertension and liver cirrhosis

BACKGROUND/AIMS Diminished postprandial portal hyperemia has been demonstrated by echo-Doppler flowmetry in patients with liver cirrhosis, but its diagnostic role is unclear. This prospective study was therefore undertaken in patients with varying severity of portal hypertension and degree of liver cirrhosis. METHODS Portal flowmetry was performed in 66 patients with cirrhosis and 20 healthy volunteers during fasting and 30 min after ingestion of a standardized meal. Hemodynamic parameters were related to the degree of esophageal varices, variceal bleeding, portal hypertensive gastropathy and Child-Pugh score. RESULTS The postprandial portal blood velocity increment was low in patients with esophageal varices of any degree (22-24%), compared to patients without varices (49%, p<0.01) and healthy controls (65%, p<0.001), but was not different in patients with or without variceal bleeding (22% vs. 20%). In contrast, the congestion index (CI; ratio of portal vein cross-sectional area and portal blood velocity) pre-/postprandial decreased in the bleeding group only (CI pre/ CI post 1.30+/-0.23 (no bleeding) vs. 0.86+/-0.29 (bleeding); p<0.01). Portal hypertensive gastropathy was not related to any of the portal flow parameters. The portal blood velocity increment was comparable in controls (65%) and patients with Child-Pugh class A cirrhosis (56%), but lower in patients with class B (32%) and class C cirrhosis (15%, p<0.05 vs. class A). Also, there was no postprandial decrease in congestion index in patients with the most severe cirrhosis (p<0.01 class C vs. class A and B). CONCLUSIONS The postprandial rise in portal flow is inversely related to the severity of portal hypertension and liver cirrhosis, and may be a valuable parameter with respect to the risk of variceal bleeding.

Mesenteric blood flow is related to disease activity and risk of relapse in ulcerative colitis: a prospective follow up study.

BACKGROUND The diagnostic significance of increased splanchnic blood flow in ulcerative colitis is unclear. This prospective study was therefore undertaken to define the role of Doppler sonography in the assessment of disease activity and in the prediction of early relapse. SUBJECTS/METHODS Splanchnic flowmetry was performed in 76 patients with ulcerative colitis (47 with active disease and 29 in remission), six with infectious colitis, and 13 healthy controls during fasting and 30 minutes after ingestion of a standardised meal. Twenty seven of the patients with ulcerative colitis and all patients with infectious colitis were investigated during the active state as well as in clinical remission and followed up for six months. Flow velocity and pulsatility index (PI) of the superior (SMA) and inferior (IMA) mesenteric arteries and the portal vein were related to clinical (Truelove index), laboratory (C-reactive protein), and endoscopic (Sutherland index) parameters of disease activity. RESULTS The mean flow velocity of the IMA correlated closest with clinical activity (Truelove, r = 0.41, p<0.005), the PI with C-reactive protein (r = 0.30, p<0.05), and endoscopic activity (r = 0.45, p<0.001). All patients in remission after six months (14/14) or with infectious colitis (6/6) showed an increase in PI of the IMA compared with the initial measurement during active disease (mean increase for ulcerative colitis +36% and for infectious colitis +77%). In contrast, most patients with later relapse or surgery (11/13) had decreased PI during initial remission (mean decrease −12%). The positive predictive value of this index for maintenance of remission was 0.77. Flow variables of the SMA and portal vein displayed weaker correlations. CONCLUSIONS Flow measurements in the IMA are closely related to clinical and endoscopic disease activity in patients with ulcerative colitis. Repeated measurement of the PI allows estimation of the risk of recurrence.

Helminths as Governors of Inflammatory Bowel Disease

The incidence of the inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn′s disease (CD) markedly increased in industrialised countries during the past decades. In contrast to these countries where helminthosis are rare, IBD is still uncommon in global areas where most people carry worms. Thus lack of exposure to parasites may critically contribute to the risk of IBD. In a recent article in Gut, Summers et al. demonstrated efficacy of treatment with Trichuris suis in active CD (Gut 2005;54:87-90). Trichuris suis was additionally shown to be effective in UC in a randomized trial carried out by the same group. Both studies did not address mechanisms of action. Here we present a real life scenario, which supports the impact of helminths in the prevention of IBD, and provide a rationale for the mechanisms of action.