Disease association of antibodies to human and mycobacterial hsp70 and hsp60 stress proteins.

Structural homology between microbial and human stress proteins has been postulated to be a basis for autoimmunization in chronic inflammatory diseases. Therefore, we estimated by ELISA titration the antibody levels to mycobacterial (M) and human (H) recombinant hsp70 and M-hsp65 heat-shock proteins in sera of patients with Crohn's disease (n = 29), ulcerative colitis (n = 20) and nontuberculous mycobacterial disease of the lungs (n = 20). Antibodies to H-hsp60, separated by two-dimensional gel electrophoresis, were tested in six sera of each group of patients. In Crohn's disease, antibody titres to the M-hsp65 antigen without detectable H-hsp60 binding were significantly elevated in 52% of the patients. In contrast titres to both M-hsp70 and H-hsp70 were demonstrable and correlated, but increased over control values only in four (14%) patients. The antibody pattern in ulcerative colitis was found to be quite different: anti-H-hsp60 binding was demonstrable in most patients, although anti-M-hsp65 titres were not elevated. Furthermore, 25% of patients had significantly elevated titres to M-hsp70, but not to H-hsp70. In non-tuberculous mycobacterial pulmonary disease, about 50% of patients had elevated titres to both hsp65 and hsp71 mycobacterial antigens but not to the corresponding human proteins; patients with Mycobacterium xenopi infection had the highest titres in this group. These results demonstrate the existence of distinct disease-associated patterns in the human antibody response to stress protein antigens. However, these data are not sufficient to imply sensitization with mycobacteria in patients with inflammatory bowel diseases, since certain epitopes of heat-shock proteins are shared by several bacterial genera.     

Antibiotic Use in Crohn’s Disease

On the assumption that bacteria in the gut may be a cause of symptoms and/or complications of Crohn's disease, various antibiotics are efficaciously employed in some affected patients. However, we do not know exactly why and how they are helpful. A possible explanation is that one or several bacterial species may have a primary role in the aetiology of Crohn's disease, but this is not supported by the data in our possession. Another hypothesis is that intestinal bacteria may cause flare-up of the disorder, either by inducing intestinal lesions or by an interaction with the immune system, but we know today that specific pathogens can cause flares only in a minority of cases. On the contrary, there is considerable evidence that the intestinal microflora and its products may amplify and perpetuate inflammation in Crohn's disease. Despite the fact that few controlled trials have been conducted, and have shown inconclusive results, antibiotics are widely employed for improving symptoms and for inducing remission of active phases. At present, a combination of metronidazole and ciprofloxacin, active against many enteric bacteria, has proved to be effective in the treatment of Crohn's disease complications. This therapy also seems to be effective in acute flares as an alternative to, or in combination with, corticosteroids.     

Use of antibiotics in the treatment of Crohn’s disease

Many data coming from animal models and clinical observations support an involvement of intestinal microbiota in the pathogenesis of Crohn’s disease(CD). It is hypothesized in fact,that the development of chronic intestinal inflammation is caused by an abnormal immune response to normal flora in genetically susceptible hosts.The involvement of bacteria in CD inflammation has provided the rationale for including antibiotics in the therapeutic armamentarium.However, randomized controlled trials have failed to demonstrate an efficacy of these drugs in patients with active uncomplicated CD,even if a subgroup of patients with colonic location seems to get benefit from antibiotics. Nitroimidazole compounds have been shown to be efficacious in decreasing CD recurrence rates in operated patients,and the use of metronidazole and ciprofloxacin is recommended in perianal disease.However,the appearance of systemic side effects limits antibiotic long-term employment necessary for treating a chronic relapsing disease.Rifaximin,characterized by an excellent safety profile,has provided promising results in inducing remission of CD.     

Crohn's disease and mycobacteria: two cases of Crohn's disease with high anti-mycobacterial antibody levels cured by dapsone therapy

Five patients with Crohn's colitis or ileocolitis (CD) refractory to conventional therapy were enrolled in an open trial with dapsone (100 mg/day). This therapy was apparently effective in two out of five patients. In these patients we observed a clinical improvement after one month of therapy and, in the first patient, a complete healing of all the cutaneous and rectal ulcers. In the two responders antibody levels to a soluble extract of M. paratuberculosis (MPSE) were significantly greater than in the three non-responders (P = 0.03); in the first patient, moreover, there was a rise of 39% in antibody titres following the treatment. This rise in antibody levels, that might be expected following death of the pathogen and release of antigen, is similar to that observed after treatment of tuberculosis. Our data suggest that a mycobacterial species or another pathogen that cross-react with those of MPSE, sensitive to dapsone, may in a subset of cases be responsible for the development of CD. This is the first report of clinical cure with an agent active against specific bacterial species, associated with immunologic confirmation of a response.     

Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn's disease: a randomised controlled trial with Lactobacillus GG

BACKGROUND AND AIMS: Experimental studies have shown that luminal bacteria may be involved in Crohn's disease. Probiotics are a possible alternative to antibiotics. The aim of this randomised placebo controlled study was to determine if Lactobacillus GG, given by mouth for one year, could prevent Crohn's recurrent lesions after surgery or to reduce their severity. METHODS: Patients operated on for Crohn's disease in whom all of the diseased gut had been removed were randomly allocated to receive 12 billion colony forming units of Lactobacillus or identical placebo for one year. Ileocolonoscopy was performed at the end of the trial or at the onset of symptoms. Endoscopic recurrence was defined as grade 2 or higher of Rutgeerts scoring system. RESULTS: Eight of 45 patients were excluded from the trial (three for non-compliance and five for protocol violations). Clinical recurrence was ascertained in three (16.6%) patients who received Lactobacillus and in two (10.5%) who received placebo. Nine of 15 patients in clinical remission on Lactobacillus (60%) had endoscopic recurrence compared with six of 17 (35.3%) on placebo (p=0.297). There were no significant differences in the severity of the lesions between the two groups. CONCLUSIONS: Lactobacillus GG seems neither to prevent endoscopic recurrence at one year nor reduce the severity of recurrent lesions.     

Psychological Stress and Disease Activity in Ulcerative Colitis: A Multidimensional Cross-sectional Study

Objectives: It is not known whether any link exists between life stress and disease activity in ulcerative colitis; attempts to demonstrate one have been complicated by recall bias, distressing psychological consequences of disease, psychogenic symptom exaggeration, and an irritable bowel component of inflammatory bowel disease symptoms. We therefore studied the relationship between psychological measures and two different aspects of ulcerative colitis activity. Methods: The relation of perceived stress, depression, state anxiety, trait anxiety, and life events with endoscopic appearance of the rectal mucosa was studied "blind" in 46 asympto-matic outpatients with known ulcerative colitis. The same measures were then examined in relation to subjective activity, comparing the group in clinical remission with 32 ulcerative colitis outpatients who reported symptoms. Results: Among asymptomatic patients, the level of stress over the past 2 yr on the General Perceived Stress Questionnaire was higher in the 11 with mucosal abnormalities than in the 35 with a normal rectal mucosa ( p = 0.004). Among the entire population, symptomatic patients were more likely to recall major life events in the previous 6 months than the asymptomatic group ( p = .02). Adjustment for smoking and for duration of remission did not substantially alter these findings. Conclusions: Life stress is associated with both objective and subjective aspects of activity in ulcerative colitis. Although the association of life events with reported symptoms may be subject to recall bias, the association of perceived stress with rectal mucosal abnormalities in asymptomatic patients is strongly suggestive of a true link between psychological factors and ulcerative colitis activity.     

Antimycobacterial Therapy in Crohn's Disease: Results of a Controlled, Double-Blind Trial with a Multiple Antibiotic Regimen

Several recent reports have suggested an association of atypical mycobacteria with Crohn's disease. Objectives: The goal of this double-blind, placebo-controlled trial was to determine the efficacy of treatment with antimycobacterial drugs in maintaining clinical remission and in reducing active infiammatory lesions. Methods: Forty patients (15 male) with refractory, steroid-dependent Crohn's disease were randomized to receive 2 months of tapering steroids plus either a 9-month regimen of ethambutol, clofazimine, dapsone and 1-day dose only of rifampicin (n = 22), or identical placebo. Results: Three patients (two on active drug) were unable to discontinue steroids, and one patient on active drug was withdrawn for side effects during the first 2 months. Three of the remaining 19 patients on active drug relapsed during the study period, compared with 11 of 17 on placebo (log likelihood ratio = 4.6; p = 0.03). Another patient was withdrawn in remission at 5 months for anemia related to dapsone. Nine patients whose disease relapsed or persisted on placebo were crossed over to active drug; five achieved sustained remission, two failed, and two were withdrawn for side effects. Substantial endoscopic or radiologic healing did not occur. Conctusion: This study suggests that the treatment regimen with rifampicin, ethambutol, clofazimine, and dapsone is effective in relief of symptoms and maintenance of remission in some Crohn's disease patients.     

Relationship between clinical and laboratory parameters and length of lesion in Crohn's disease of small bowel

The correlation of 22 commonly used clinical and laboratory abnormalities with linear extent of the lesion was studied in 70 patients with Crohn's ileitis, 16 of whom had inactive disease and 54 active disease. Extent was measured radiologically using a well-validated double-contrast technique. In the patients with active disease, lesion length was significantly correlated with weight loss, serum albumin, total protein, and serum iron. In the group without active inflammation, pain and abdominal mass were significantly correlated with lesion extent. No correlation was found between linear extent of lesion and the following: an index of inflammatory activity (New Crohn's Disease Activity Index), several acute-phase reactants, and the components of the complete blood count. Only total protein and serum iron had a significant regression coefficient following a procedure of stepwise regression. No mathematical model was found capable of satisfactorily predicting the length of lesion.This study was supported by CNR grant 81.00039.04.     

Life events, personality, and physical risk factors in recent-onset duodenal ulcer. A preliminary study.

To clarify the interactions between stressful life events and other risk factors in the development of duodenal ulcer disease, we studied 33 patients with active ulcer, symptomatic for less than or equal to 6 months and untreated during the previous year, using the Paykel Interview for stressful life events, the Minnesota Multiphasic Personality Inventory (MMPI), and Zung's Anxiety and Depression scales. MMPIs were abnormal in 64% of the patients, and 61% showed some degree of depression. The 16 patients whose symptoms had been preceded by severe stress and more pathological MMPIs, especially on paranoia and dependency scales; were more depressed; and had used less nonsteroidal anti-inflammatory drugs than those without (p less than 0.05). They were somewhat more likely to be single, to be of low social class, and to have recently increased use of cigarettes, alcohol, or coffee (though their absolute level of alcohol consumption was low). Anxiety levels did not differ between stress and nonstress groups. Correspondence analysis yielded four clusters of patients, characterized by (a) alcohol/cigarette use, personality disorder, chronicity; (b) early onset, neurosis; (c) depression, life events; (d) late onset, psychosocial stability. The analysis changed little according to whether life events were or were not considered in cluster formation. We conclude that ulcer patients who become ill under stress from a distinct subgroup, that depressed mood and stress-related increases in use of alcohol and cigarettes may mediate between stress and ulcer formation, and that life events are a quantitatively minor factor in ulcerogenesis.