Ulcerative colitis and Crohn's disease

In the past four years three excellent and comprehensive books on inflammatory bowel disease have been published.*RF 1-3* In a total of 1812 pages 156 contributors provide detailed accounts of the recent striking rise in the incidence of Crohn's disease but not ulcerative colitis in most developed countries; patients' genetic disposition (the dis-eases are apparently not HLA related); and clinical features, immunology, pathology, complications, and management options. Can there be much left to find out? Regrettably for the 120 000 or so patients with inflammatory bowel disease in Britain, from toddlers to octogenarians, the answer is yes. And despite inflam-matory bowel disease being unfashionable and attracting little research funding, there is a wealth of research going on.

Theories of the cause of inflammatory bowel disease abound. Current front runners include a range of types of immune dysregulation, such as abnormally vigorous stimulation of the gut immune system by products of the commensal flora, inappropriate activation of a single component among the many gut immune cells and mediators, or failure of an inhibitory signal that normally switches off a protective local inflammatory reaction. A rich new research seam has been opened with the discovery of strange new forms of colitis and enteritis in transgenic animals genetically engineered for deletion or altered expression of molecules such as cytokines, cytokine receptors, or T cell receptors.4

Several specific diseases have now been separated from the main body of inflammatory bowel disease, including campylobacter colitis, food protein sensitive colitis of infancy, collagenous colitis, and enteropathy caused by non-steroidal anti-inflammatory agents. Other small subsets of patients will probably be identified by continuing research, but the key issue is whether the two remaining enigmas, ulcerative colitis and Crohn's disease - the idiopathic inflammatory bowel diseases - are one condition or two.5 There is now abundant evidence that ulcerative colitis and Crohn's disease are completely different diseases. In ulcerative colitis several different agents may trigger susceptibility to a waxing and waning inflammatory process strictly confined to the superficial layers of the colonic mucosa. Crohn's disease seems to be a widespread (in some cases systemic) granulomatous disease, with important nutritional as well as gut manifestations. Exposure to the agent that initiates Crohn's disease probably occurs years before the condition is clinically expressed.

Nevertheless, ulcerative colitis and Crohn's disease share many features. They are both incurable. Their cardinal symptoms are abdominal pain, diarrhoea, urgency, faecal incontinence, rectal bleeding, and fatigue. During exacerbations there is laboratory evidence of inflammation, including mucosal production of IgG; occult gastrointestinal bleeding and protein losses; expansion of mucosal populations of T and B lymphocytes and macrophages; activation and luminal migration of neutrophils and eosinophils; and local secretion of many cytokines, particularly interleukin-1 and interleukin-8. Whole gut lavage - a new, relatively non-invasive procedure - has shown, however, that some or all of these features occur in patients with intestinal infections, abscesses, ischaemia, radiation colitis, ulcerating tumours, enteropathy caused by non-steroidal anti-inflammatory drugs, and the distal intestinal obstruction syndrome of cystic fibrosis*RF 6- 9* (unpublished research). Thus many characteristics of ulcerative colitis and Crohn's disease may be non-specific, resulting from rather than causing gut mucosal disease.

In clinical practice and in research on the treatment of Crohn's disease it is useful to separate, conceptually, the unknown intiating event (probably silent), inflammatory disease activity (correlating closely with symptoms), and indolent, virtually asymptomatic, destructive ulceration (leading to many serious complications).

Until the true cause of the disease is known all treatment is palliative. Usual forms of medical treatment, and new drugs being developed, simply suppress inflammatory disease activity and have little impact on the ulceration and fibrosis which are so destructive.10 Pharmaceutical companies should be encouraged to examine their portfolios for new agents and strategies for drug delivery that have the potential to heal these lesions, irrespective of their impact on inflammatory symptoms. Since current methods of monitoring the destructive lesions, such as colonoscopy, are invasive and insensitive, clinicians too must devise new ways of monitoring true healing of the gut in inflammatory bowel disease.

Why is there still so little knowledge about the causes of two such serious, common, and chronic diseases - and no sign of cure? In the new look National Health Service, there are defined standards for the amount and quality of care for patients with insulin dependent diabetes or chronic renal failure, but none for those with inflammatory bowel disease. Part of the explanation is that many doctors, nurses, other health professionals, and NHS managers are badly informed about chronic diarrhoeal diseases in general. On issues related to bowel function and disease, members of the public, journalists, and politicians too are more likely to react with embarrassment and avoidance than with understanding, sympathy, and constructive help.

The director of the National Association for Colitis and Crohn's Disease cannot recall having received a single five figure donation to support research in inflammatory bowel disease, so the £200 000 a year that the association distributes for research is raised almost entirely by members and their families. This year the association has been able to support only six of the 43 research applications submitted by potential investigators throughout Britain. The Crohn's in Childhood Research Association has not had funds to support any new research for two years. The Medical Research Council currently funds only one inflammatory bowel disease project, a study of mucin in ulcerative colitis. Against this background, the productivity and high international standing of British groups researching into inflammatory bowel disease is truly remarkable.