Glucocorticosteroid therapy and steroid resistance in inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD) are diseases of unknown aetiology often referred to as inflammatory bowel diseases (IBD). Glucocorticosteroids (GCS) have been used since the 1950's to treat acute attacks of these diseases. Several independent studies have confirmed that 25-30 % of patients respond poorly or not at all to GCS treatment.

In this thesis it is demonstrated that steroid resistance in patients with UC severe enough to warrant hospitalisation is associated with shorter duration of disease and steroid treatment before admission. In particular, elevation of body temperature, persistence of diarrhoea, CRP elevation and passage of blood on day 3 of hospitalisation independently predict a high risk for colectomy within 30 days due to failure to respond to medical treatment.

A solution hybridisation technique was used for quantification of m-RNA levels of glucocorticoid receptors (GR) and their target gene Metallothionein Ila (MT Ila) in peripheral white blood cells. In colonic mucosa, receptor levels have been assessed at protein level by Western blotting. The levels of pro-inflammatory acting NFkappaB in colonic mucosa have also been analysed by Western blotting and DNA binding assessed with electrophoretic mobility shift-assay (EMSA).

In patients with UC peripheral white blood cells were found to have higher GR mRNA-levels than controls. Evaluating the hypothalamic pituitary adrenal axes, it was also demonstrated that patients with a history of steroid resistant UC after low dose dexamethasone treatment, down-regulated both basal and low-dose Synacthen stimulated S-cortisol more extensively than patients responding well to GCS-treatment at previous attacks. Lower levels of MT IIa were also found in patients with a history of steroid resistant UC as compared to responders.

Furthermore it was demonstrated that patients with UC responding well to GCS treatment had significantly higher levels of GR in inflamed rectal mucosa already after one week of treatment as compared to non-responders. Responders also had significantly higher mucosal levels of GR in remission compared to before treatment. DNA binding of NFkappaB, p65 in rectal mucosa was found to decrease as remission was obtained, but protein levels of the same tended to increase.

The GCS with least systemic effects available for treatment of CD today is budesonide, demonstrating 10-15 % systemic availability after oral administration. Rofleponide is a recently developed halogenated analogue of budesonide, characterised by a very high first pass metabolism and with oral systemic availability of only 0.5%. Tolerability and pharmacokinetics of rofleponide after oral administration in patients with CD in remission demonstrated that the drug was well tolerated. Single and repeated doses of 2 mg and a single dose of 6.4 mg of rofleponide suppressed p-cortisol on average by 25 % and 32% respectively. Steady state pharmacokinetics agreed well with single dose pharmacokinetics, and the data suggested dose linear pharmacokinetics. In a follow-up study of oral administration of 2 mg rofleponide to patients with active CD, pharmacokinetics did not differ from that of CD patients in remission and the average p-cortisol suppression after was 14%. The reduced cortisol suppression as compared to commercially available glucocorticosteroids, indicate a possibility for a better safety profile.

List of scientific papers

I. Lindgren SC, Flood LM, Kilander AF, Lofberg R, Persson TB, Sjodahl RI (1998). Early predictors of glucocorticosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis. Eur J Gastroenterol Hepatol. 10(10): 831-5.
https://pubmed.ncbi.nlm.nih.gov/9831403

II. Flood L, Lofberg R, Stierna P, Wikstrom AC (2001). Glucocorticoid receptor mRNA in patients with ulcerative colitis: a study of responders and nonresponders to glucocorticosteroid therapy. Inflamm Bowel Dis. 7(3): 202-9.
https://pubmed.ncbi.nlm.nih.gov/11515845

III. Flood L, Innala E, Lofberg R, Wikstrom AC (2004). Patients with ulcerative colitis responding to steroid treatment up regulate glucocorticoid receptor levels in colorectal mucosa. [Submitted]

IV. Flood L, Lofberg R, Sjodahl R, Seidegard J, Edsbacker S, Lundin P (2004). Rofleponide, a novel glucocorticosteroid. Safety and pharmacokinetics in patients with ulcerative colitis. [Manuscript]