To determine the prognostic importance of microscopic rectal inflammation we followed up The macroscopic appearances of the rectal mucosa were graded using well established criteria.7 Only patients with normal mucosal appearances or erythema were included in the study. Those with contact bleeding, spontaneous bleeding, or ulceration were specifically excluded as most of these patients have pronounced histological features of inflammation.5Only patients taking either oral sulphasalazine or oral mesalazine as sole maintenance treatment were recruited. Those taking other drugs known to have an effect on colitis activity were excluded. No patient had received either oral or rectal steroids within four weeks of inclusion. HISTOLOGICAL ASSESSMENTAt the time of sigmoidoscopy a mucosal biopsy specimen was taken from the anterior rectal wall between 5 and 10 cm from the anal margin. Biopsy specimens were fixed in formalin, embedded in paraffin, and 5 micron sections were stained with haematoxylin and eosin. Sections were then coded and graded independently by two histopathologists who had no knowledge of the patients.Six histological features were assessed: the acute inflammatory cell infiltrate (polymorphonuclear cells in the lamina propria), crypt abscesses (Fig 1), mucin depletion (Fig 2), surface epithelial integrity, the chronic inflammatory cell infiltrate (round cells in the lamina propria), and crypt architectural irregularities.8 Each feature was graded on a four point scale corresponding to none, mild, moderate, or severe. The final grade being the mean of the two independent assessments. PATIENT FOLLOW UPPatients attended for clinical review at three, six, nine, and 12 months or at any other time if they wished. Throughout the study patients were asked to report promptly with symptomatic deterioration. Sigmoidoscopy was then undertaken and a stool culture performed. Colitis relapse was confirmed if the macroscopic appearance of the rectal mucosa had become haemorrhagic and the stool culture was negative.All results are expressed as median and range unless otherwise stated. Relapse data were analysed using the X2 test with Yates's correction.

Transdermal nicotine alone was no better than placebo in the maintenance of remission of ulcerative colitis, and premature withdrawal due to side effects was more common in the nicotine group.

To determine the factors responsible for ulcerative colitis relapse a cohort of 92 patients (18 to 78 years, 50 men) with clinically inactive disease have been We have therefore followed a cohort of patients with quiescent colitis in order to study: (a) the clinical features that may predict relapse; (b) the events preceding relapse; and (c) the timing of ulcerative colitis relapse. We have also undertaken a retrospective case note analysis to assess the timing of onset of first attack of ulcerative colitis.

SUMMARY Oral formulations of 5-aminosalicylic acid (mesalazine) appear less toxic than sulphasalazine. We have therefore compared sulphasalazine, low dose mesalazine and high dose mesalazine in the treatment of mild to moderate relapse of ulcerative colitis. Sixty one patients (32 men, aged 20-78 years) were randomly allocated to sulphasalazine 2 g daily, mesalazine 800 mg daily, or mesalazine 2.4 g daily in a double blind, double dummy, four week trial. Groups were comparable for age, sex, extent of disease, and pretrial sulphasalazine intake. Four patients were unable to complete the study because of treatment failure (two taking sulphasalazine and two high dose mesalazine). A further two patients taking sulphasalazine developed side effects necessitating withdrawal. Within treatment comparisons revealed significant improvement of: sigmoidoscopic grade in the sulphasalazine group; rectal bleeding, sigmoidoscopic and histological grade in the low dose mesalazine group; stool frequency, rectal bleeding and sigmoidoscopic grade in the high dose mesalazine group. Greater improvement in rectal bleeding (p<005) and sigmoidoscopic appearances (p<005) occurred in patients taking high dose mesalazine than in those taking sulphasalazine. In two patients taking high dose mesalazine minor rises of plasma creatinine concentrations occurred, suggesting the need to monitor renal function.Although the main value of sulphasalazine (SSZ) is in the maintenance of ulcerative colitis remission'-3 it is also of benefit in active disease.' Many patients, however, are unable to take the drug as side effects are common, particularly at high doses.' As most of these side effects are similar to those seen with sulphonamide drugs and as they correlate well with plasma sulphapyridine concentrations it seems likely that the sulphapyridine component of SSZ is responsible for much of the drug's toxicity.' Therapeutic activity, on the other hand, seems to reside in the 5-aminosalicylic acid (5-ASA) component of SSZ.`'4Unfortunately, 5-ASA is unstable in gastric acid and is rapidly absorbed from the small intestine.`As

Impaired absorption of sodium (Na+) and water is a major factor in the pathogenesis of diarrhoea in ulcerative colitis (UC). Electrogenic Na+ absorption, present mainly in human distal colon and rectum, is defective in UC, but the molecular basis for this is unclear. The effect of UC on the expression of apical Na+ channels (ENaC) and basolateral Na+, K+-ATPase, the critical determinants of electrogenic Na+ transport, was therefore investigated in this study. Sigmoid colonic and/or proximal rectal mucosal biopsies were obtained from patients with mild to moderate UC, and patients with functional abdominal pain (controls). ENaC subunit expression was studied by immunohistochemistry, western blot analysis, and in situ hybridization, and Na+, K+-ATPase isoform expression was studied by immunohistochemistry, western blotting, and northern blot analysis. UC was associated with substantial decreases in the expression of the ENaC beta- and gamma-subunit proteins and mRNAs, whereas the decrease in ENaC alpha-subunit protein detected by immunolocalization was less marked. The levels of expression of Na+, K+-ATPase alpha1- and beta1-isoform proteins were also lower in UC patients than in controls, although there were no differences in Na+, K+-ATPase alpha1- and beta1-isoform mRNA levels between the two groups. Taken together, these results show that UC results mainly in decreased expression of the apical ENaC beta- and gamma-subunits, as well as the basolateral Na+, K+-ATPase alpha1- and beta1-isoforms. In conclusion, these changes provide a basis for the low/negligible levels of electrogenic Na+ absorption seen in the distal colon and rectum of UC patients, which contribute to the pathogenesis of diarrhoea in this disease.

No abstract

Distal ulcerative colitis can be treated with oral or rectal mesalazine, or both. A foam enema preparation has been developed and its efficacy investigated. The aim of this study was to evaluate the efficacy and safety of mesalazine foam enemas compared with prednisolone foam enemas in the treatment of patients with acute distal ulcerative colitis. Patients aged over 18 years presenting with a relapse of distal ulcerative colitis were randomly allocated treatment with mesalazine foam enema (n = 149 evaluable patients) and prednisolone foam enema (n = 146 evaluable patients) for four weeks. A randomised multicentre investigator blind parallel group trial was conducted. It was found that after four weeks of treatment, clinical remission was achieved by 52% of mesalazine treated patients and 31% of patients treated with prednisolone (p < 0.001). There was a trend in favour of more patients in the mesalazine group achieving sigmoidoscopic remission (40% v 31%, p = 0.10). Histological remission was achieved by 27% and 21% of patients receiving mesalazine and prednisolone respectively. Symptoms improved in both treatment groups. Significantly more mesalazine patients had no blood in their stools after four weeks of treatment (67% v 40%, p < 0.001). Prednisolone treated patients had significantly fewer days with liquid stools than mesalazine patients, with a median of 0 and 1 days respectively by week 4 (p = 0.001). In this study mesalazine foam enema was superior to prednisolone foam enema with regards to clinical remission, this was supported by favourable trends in sigmoidoscopic and histological remission rates. Both treatments were well tolerated.

Mesalazine has structural similarities to aspirin and phenacetin and is nephrotoxic when given intravenously in high doses to rats. A number of cases of nephrotoxicity has been reported recently in patients taking oral mesalazine. Sensitive indicators of renal function in a group of patients maintained on long term, delayed release mesalazine and a comparable group on sulphasalazine have been studied. Sixty two patients (32 men, aged 28-82 years) with quiescent colitis were studied. Thirty four had been maintained on delayed release mesalazine 1-6 (0.8-2.4) g/day for 2-9 (0.5469) years and 28 on sulphasalazine 2 (2-3) g/day. Groups were comparable for age, sex, disease duration, and disease extent. Renal function was assessed by: urine microscopy; creatinine clearance; the urinary excretion of two markers of glomerular toxicity, albumin and transferrin; and the urinary excretion for two markers of tubular toxicity, N-acetyl-P-D-glucosaminidase (NAG) and almicroglobulin. There were no significant differences in renal function between the two treatment groups. Furthermore, no correlations were found between measures of renal function and either cumulative mesalazine dose or mesalazine treatment duration. In this study, long term maintenance treatment with delayed release mesalazine was no more nephrotoxic than continued treatment with sulphasalazine. (Gut 1992; 33: 1348-1352 The effect of mesalazine treatment on renal function has been a particular concern as mesalazine has structural similarities to aspirin and phenacetin, both of which have been implicated in analgesic nephropathy.3 Chronic sulphasalazine treatment does not seem to be nephrotoxic but the systemic absorption of 5-ASA from sulphasalazine is relatively low.4 Delayed release mesalazine formulations release their contents rapidly in the distal small intestine and proximal colon. Plasma concentrations of 5-ASA may therefore be higher in patients taking delayed release mesalazine than in patients taking equivalent doses of sulphasalazine.' In addition, freedom from sulphapyridine related side effects allows high dose treatment, further increasing the potential for dose related nephrotoxicity. We have therefore studied sensitive indicators of renal function in patients maintained on long term, delayed release mesalazine and a comparable group maintained on sulphasalazine. Methods PATIENT SELECTION AND ASSESSMENTPatients were selected from a computerised database of 222 patients with chronic ulcerative colitis attending Leigh Infirmary. Of these, 44 had been taking delayed release mesalazine as the sole maintenance treatment for at least six months. For each patient taking mesalazine a computer matched patient taking sulphasalazine was also selected. All pairs were matched for age. (within five years), sex, disease duration (within five years), and disease extent.Patients were invited to participate by letter and those who consented attended for outpatient review. Patients with symptoms of active colitis in the four weeks before attendance and t...