Conventional Therapy of Ulcerative Colitis: Corticosteroids

Study
Corticosteroid (starting dose)
Comparator
No. of patients
Disease extent
Duration
(weeks)
End-points
Remission
NNT
(95 % CI)
Intravenous
Meyers [6]
1983
Hydrocortisone
(300 mg daily)
Corticotropin (ACTH) 120 U/day
66
26 % sigmoid
48 % left sided
26 % pan
10 days
Clinical remission according to prior oral steroids
Prior steroids:
53 % hydrocortisone
25 % corticotropin
(p < 0.05)
No prior steroids:
27 % hydrocortisone
63 % corticotropin
(p = NS)
n/a
Oral—moderate–severe
Truelove and Witts [7]
1954
Cortisone
(100 mg OD in majority)
Placebo
210
Not reported
6
Clinical and hematological remission
16 % placebo
41 % cortisone (p < 0.001)
4 (2.7–7.3)
Hawthorne [8]
1993
Fluticasone propionate
(5 mg QD)
Prednisolone
(40 mg OD)
205a
Left sided or pan—numbers not stated
4
Investigators overall assessment of remission
28 % prednisolone
25 % fluticasone
(p = NS)
n/a
Oral—mild to moderate
Lennard-Jones [9]
1960
Prednisone
(40–60 mg OD, dose tapered)
Placebo
37
All distal
3–4
Clinical and endoscopic remission
17 % placebo
68 % prednisone
(p < 0.01)
2 (1.3–4.1)
Danish 5ASA Group [10]
1987
Prednisolone
(25 mg OD)
Mesalazine enema
(1 g OD)
123
All distal
2–4
Clinical and endoscopic response
77 % mesalazine
72 % prednisolone
(p = NS)
n/a
Angus [11]
1992
Fluticasone propionate
(5 mg QID)
Placebo
59b
44 % proctitis, 20 % sigmoid
36 % distal
4
Clinical and endoscopic remission
17 % placebo
13 % fluticasone propionate (p = NS)
n/a
Lofberg [12]
1996
Budesonide CR capsule
(10 mg OD)
Prednisolone (40 mg OD)
72
40 % left-sided
60 % extensive
9
Endoscopic remission
12 % prednisolone
16 % budesonide (p = NS)
n/a
Gross [13]
2011
Budesonide CR capsule
(9 mg OD)
Mesalazine
(1 g TDS)
343
55 % sigmoid
25 % left-sided 20 % pan
8
Clinical remission
54.8 % mesalazine
39.5 % budesonide (p = 0.52 for noninferiority)
n/a
D’Haens [14]
2010
Budesonide MMX
(9 mg OD)
Placebo
36
All left-sided
4
Clinical and endoscopic remission and/or reduction in CAI by ≥50 %
33.3 % placebo
47.1 % budesonide
(p = NS)
n/a
Sandborn [15]
2012
Budesonide MMX
(9 mg or 6 mg OD)
Mesalazine
(2.4 g OD)
or
Placebo
509
28 % sigmoid
29 % left sided
41 % extensive
2 % unknown
8
Clinical and endoscopic remission
7 % placebo
12 % mesalazine (p = NS)
13 % budesonide MMX 6 mg (p = NS)
18 % budesonide MMX 9 mg (p = 0.01)
budesonide MMX 9 mg
10 (5.5–45.3)
Travis [16]
2014
Budesonide MMX (9 or 6 mg OD)
Ileal-release (IR) budesonide
(9 mg OD)
or
Placebo
509
41 % sigmoid
39 % left sided
20 % extensive
8
Clinical and endoscopic remission
3 % placebo
10 % IR
7 % MMX 6 mg
15 % MMX 9 mg (p = 0.0008)
budesonide MMX 9 mg
9 (5.3–20.2)
Bossa [17]
2008
Prednisolone
(0.5 mg/kg daily dose)
DEEc (two intravenous infusions, 2 weeks apart)
or
Placebo
40
65 % distal
25 % left-sided
10 % pan
8
Endoscopic remission
10 % placebo
80 % prednisolone
75 % DEE
(p < 0.001)
Prednisolone: 2 (1–2.6)
DEE: 2 (1.1–2.6)
Rizzello
[18]
2002
Beclomethasone dipropionate
(5 mg OD) + mesalazine (3.2 g OD)
Placebo + mesalazine
(3.2 g OD)
119
71 % left-sided
29 % pancolitis
4
Clinical remission
34 % placebo
59 % beclomethasone (p = 0.008)
5 (2.4–14.7)
Van Assche
[19]
2015
Beclomethasone dipropionate
(5 mg OD)
Prednisone
(40 mg OD)
282
3 % proctitis, 43 % sigmoid 36 % left-sided
18 % pancolitis
4
Clinical and endoscopic response
66 % prednisone
65 % beclomethasone
(p = NS)
n/a
Rhodes [20]
2008
Prednisolone metasulfobenzoate [PM]
(20 mg or 30 mg BD)
Prednisolone
(40 mg, in two divided doses)
181
2 % proctitis
36 % sigmoid
30 % left-sided
25 % extensive
6 % unknown
24
Visual analog scale for assessment of symptoms at 2 and 6 months
Symptoms at 2 months:
6.9 cm prednisolone
7.4 cm PM 40 mg
6.3 cm PM 60 mg PM (p = NS)
n/a
aIncluded mild severity bseverity not stated cDEE = dexamethasone 21-P-encapsulated erythrocytes
Abbreviations: n/a not applicable, NS not significant, OD once daily, BD twice daily, TDS three times daily, QID four times daily
Table 39.2
Randomized controlled trials of rectally delivered corticosteroids in patients with mild–moderate ulcerative colitis
Study
Corticosteroid (starting dose)
Comparator
No. of patients
Disease extent
Duration
(weeks)
Criteria to define remission
Remission
NNT
(95 % CI)
Hanauer
[21]
1998
Budesonide
(0.5 mg, 2 mg or 8 mg OD)
Placebo
233
All distal
6
Clinical and endoscopic remission
8 % placebo
12 % 0.5 mg (p = NS)
27 % 2 mg (p ≤ 0.05)
35 % 8 mg (p ≤ 0.001)
2 mg: 6 (3.1–20.4)
Lindgren
[22]
2002
Budesonide
(2 mg OD)
Budesonide
(2 mg BD)
149
Proctitis and distal (not stated)
8
Clinical and endoscopic remission
54 % BD
51 % OD
(p = NS)
n/a
Sandborn
[23]
2015
Budesonidea
(2 mg BD)
Placeboa
546
(2 studies)
28 % proctitis,
71 % distal
1 % unknown
6
Clinical and endoscopic remission
24 % placebo
41 % budesonide
(p < 0.0001)
6 (4–10.6)
Bansky [24]
1987
Beclomethasone dipropionate
(0.5 mg OD)
Betamethasone phosphate
(5 mg OD)
16 (18 flares of colitis)
22 % rectum
56 % sigmoid
17 % descending
5 % transverse
20 days
Clinical, endoscopic, and histologic remission considered separately
Endoscopic remission:
33 % betamethasone
44 % beclomethasone
(p = NS)
n/a
Van der Heide
[25]
1988
Beclomethasone dipropionate
(1 mg OD)
Prednisolone disodium phosphate
(30 mg OD)
 18
All distal
4
Clinical, endoscopic, histologic response considered separately
Clinical and endoscopic response:
100 % prednisolone
40 % beclomethasone
(p = 0.01)
n/a
Halpern
[26]
1991
Beclomethasone dipropionate
(0.5 mg OD)
Betamethasone phosphate
(5 mg OD)
32 (40 flares of colitis)
All distal
4
Clinical, endoscopic, and histologic response considered separately
Clinical remission:
45 % betamethasone
60 % beclomethasone
(p = NS)
n/a
Mulder
[27]
1996
Beclomethasone dipropionate
(3 mg OD) ± mesalazine (2 g OD)
Mesalazine
(2 g OD)
 60
All distal
4
Clinical, endoscopic, and histologic response considered separately
Clinical response:
76 % mesalazine
70 % beclomethasone
100 % beclomethasone plus mesalazine (p < 0.01 vs either agent alone)
4 (2–10.1)
Campieri
[28]
1998
Beclomethasone dipropionate
(3 mg OD)
Prednisolone Na phosphate
(30 mg OD)
157
3 % proctitis
4 % sigmoid
93 % distal
4
Clinical, endoscopic, and histologic response considered separately
Clinical and endoscopic remission:
25 % prednisolone Na phosphate
29 % beclomethasone dipropionate (p = NS)
n/a
Biancone
[29]
2007
Beclomethasone dipropionateb
(3 mg od)
Mesalazineb
(2 g OD)
 99
All distal colitis
8
Clinical and endoscopic remission at week 4
28 % mesalazine
24 % beclomethasone dipropionate
(p = NS)
n/a
McIntyre
[30]
1985
Prednisolone metasulfobenzoate
(20 mg OD)
Prednisolone-21-phosphate
(20 mg OD)
 40
50 % proctitis
50 % sigmoid
2
Clinical, endoscopic, and histologic response considered separately
Clinical response:
70 % prednisolone -21-phosphate
75 % prednisolone metasulphobenzoate
n/a
Riley [31]
1989
Prednisolone metasulfobenzoate
(20 mg OD)
Sucralfate enema
(4 g OD)
 44
34 % proctitis
50 % sigmoid
16 % left-sided
4
Clinical, endoscopic, and histologic response considered separately
Resolution of rectal bleeding: 68 % vs 27 % (p < 0.02)
Endoscopic remission:
36 % vs 32 % (p = NS)
n/a
Cobden
[32]
1991
Prednisolone metabenzoate
(20 mg BD)
Mesalazine
(800 mg orally QD)
 37
38 % proctitis
51 % sigomoid
11 % left-sided
4
Clinical, endoscopic, and histologic response considered separately
Clinical, endoscopic, and histologic responses similar (p = NS)
n/a
Mulder
[33]
1988
Prednisolone Na phosphate
(30 mg OD)
Mesalazine
(3 g OD)
 29
All distal colitis
4
Clinical, endoscopic, and histologic response considered separately
Clinical response:
74 % mesalazine
79 % prednisolone
(p = NS)
n/a
O’Donnell
[34]
1992
Prednisolone Na phosphate
(20 g OD)
PASc
(2 g OD)
 53
All distal colitis
6
Clinical, endoscopic, and histologic response considered separately
Clinical remission:
23.8 % PAS
37.5 % prednisolone
(p = NS)
n/a
Sharma
[35]
1992
Prednisolone Na phosphate
(20 g OD)
PAS
(2 g OD)
 40
11 % proctitis
89 % sigmoid
4
Clinical, endoscopic, and histologic response considered separately
Similar clinical response (p = NS)
Endoscopic remission:
90 % PAS
40 % prednisolone (p < 0.01)
n/a
Campieri
[36]
1987
Hydrocortisone
(100 mg OD)
Mesalazine
(4 g OD)
 86
All left-sided colitis
2
Clinical, endoscopic, and histologic response considered separately
Greater improvement in clinical, endoscopic, and histologic response for mesalazine (p < 0.0005)
n/a
Bianchi Porro [37]
1995
Hydrocortisone
(100 mg OD)
Mesalazine
(1 g OD)
 52
All distal colitis
3
Clinical and endoscopic response considered separately
Similar clinical and endoscopic response between groups (p = NS)
n/a
aFoam enema bliquid or foam enema cpara-amino salicylic acid

Oral Therapy for Moderate to Severe Ulcerative Colitis

Oral corticosteroids are effective for the induction of remission in patients with moderate to severe ulcerative colitis [38], in milder disease that is refractory to sulfasalazine or mesalazine, and in patients who have responded to initial treatment with intravenous corticosteroids following hospitalization for acute severe disease. Prednisone and prednisolone are well absorbed after oral administration, with a high bioavailability (over 70 %). Absorption may be delayed, however, in patients with severe ulcerative colitis [39]. Although a daily dose of 40 mg prednisolone is more effective than 20 mg, doses above this threshold have not demonstrated incremental benefit, but are associated with increased adverse effects [40]. Single daily dosing is as effective as split-dosing and causes less adrenal suppression [41]. Both clinical and endoscopic response can be seen following 2 weeks of treatment with oral prednisolone [12, 20]. Those who have not responded by then are considered to have corticosteroid-refractory disease and should be treated with anti-tumor necrosis factor (anti-TNF) therapy , tacrolimus or intravenous corticosteroid therapy [42]. The optimal tapering regimen has not been determined but the dose is usually reduced over 8–12 weeks.

Oral Therapy with Low Systemic Bioavailability

Budesonide-MMX

Budesonide has an intrinsic potency, as measured by affinity to the glucocorticoid receptor, about 15 times higher than that of prednisolone [43]. It has been shown to be effective for ileocecal Crohn’s disease, with fewer side effects than prednisolone due to extensive first-pass metabolism in the liver [44]. Budesonide-MMX is a novel formulation that utilizes multimatrix technology to release the drug in the colon. It contains a gastro-resistant polymer coating that dissolves at a pH greater than 7, thereby delaying release during transit through the stomach and duodenum until the ileum is reached. A budesonide -containing lipophilic matrix then allows release of budesonide at a controlled rate throughout the colon [45]. In two trials, budesonide -MMX at a dose of 9 mg a day was shown to be well-tolerated and more effective than placebo for inducing remission in patients with mild–moderate ulcerative colitis [15, 16]. A small study of budesonide -MMX 10 mg in active extensive and left-sided ulcerative colitis showed similar efficacy to 40 mg of prednisolone with regard to endoscopic improvement. It may have a role in patients with disease that does not respond to mesalazine, before initiation of systemically acting corticosteroids.

Beclomethasone Dipropionate

The oral, prolonged-release formulation of beclomethasone dipropionate (Clipper) has an acid-resistant methacrylate film coating (Eudragit L100/55) that prevents the tablets from dissolving in the stomach, and a modified release core of hydroxypropyl methylcellulose (Methocel K4M) that dissolves at pH values below 6, allowing for release of the drug in the mid-distal ileum and colon [46]. Beclomethasone dipropionate is a prodrug with weak glucocorticoid receptor binding affinity, but it is hydrolyzed to its active metabolite, beclomethasone 17-monopropionate following contact with the gut mucosa. Beclomethasone 17-monopropionate is highly potent, with glucocorticoid receptor binding affinity approximately 80 times that of prednisolone [47]. As with budesonide , there is extensive first-pass metabolism. Its efficacy has been shown to be similar to that of mesalazine [48], and a recent trial has shown noninferiority with regard to clinical efficacy and safety of beclomethasone dipropionate 5 mg daily for 4 weeks followed by 5 mg on alternate days for 4 weeks, compared to oral prednisolone at an initial dose of 40 mg daily for 2 weeks then tapered by 10 mg a fortnight [19].

Prednisolone Metasulfobenzoate

Oral prednisolone metasulfobenzoate (Predocol ) has an acid-resistant coating (Eudragit L) that dissolves at a pH of 6 (corresponding to the mid-ileum) to release around 200 pellets. These pellets contain active drug in a controlled-release matrix, and spread throughout the colon [49]. Mucosal levels of prednisolone within the colon are similar to those achieved with conventional prednisolone , with minimal systemic absorption [50]. A randomized controlled trial of Predocol 40 mg daily for 6 months versus prednisolone at an initial dose of 40 mg daily for 2 weeks, tapering to stop at 8 weeks, showed similar efficacy between the groups, with fewer perceived steroid-related side effects in the Predocol group [20].

Topical Therapy

Topical corticosteroids are effective therapy for left-sided ulcerative colitis, with second-generation formulations (budesonide and beclomethasone dipropionate enemas) showing similar efficacies to topical mesalazine [51, 52]. Corticosteroids absorbed from the rectum (as opposed to the proximal gastrointestinal tract) do not undergo first-pass metabolism in the liver, and can result in adrenal suppression [53]. Studies of systemic bioavailability of topical corticosteroids in healthy subjects show high variability: from 2 % to 90 % of hydrocortisone administered as an enema was available systemically [54, 55]. The presence of rectal inflammation may reduce systemic absorption [56].
In active left-sided ulcerative colitis, budesonide enemas (2 mg, once a day) have shown similar endoscopic, histological and clinical response rates compared to both hydrocortisone foam (125 mg, once a day) and prednisolone (31.25 mg, once a day) enemas, but without the significant reduction in plasma cortisol levels seen with hydrocortisone [57] and prednisolone [58]. Beclomethasone dipropionate enemas (3 mg, once a day) also had a similar response compared with prednisolone enemas, again without the reduction in cortisol levels seen with prednisolone [28]. Budesonide foam enemas are better tolerated than budesonide liquid enemas and are just as effective [59].

Intravenous Therapy for Acute Severe Ulcerative Colitis

The optimum dose of corticosteroid for acute severe ulcerative colitis has not been established. However, hydrocortisone 300–400 mg intravenously every 24 h (or equivalent) is recommended based on clinical trial data, with an overall response rate of 67 % [60]. Again, higher doses are no more effective and lower doses are less effective. Therapy extending beyond 7–10 days provides no additional benefit [60]. The response to intravenous corticosteroids should be assessed objectively at day 3 to determine those who might need salvage therapy with ciclosporin or infliximab [61]. Predictors of poor response to medical therapy, with the need for early colectomy, include clinical markers (stool frequency), biochemical markers (elevated CRP, low albumin), radiological signs (colonic dilatation or mucosal islands on plain X-ray), and endoscopic appearance (severe ulceration) [62].

How to Manage Corticosteroid Withdrawal

Although they are effective agents for induction of remission of active ulcerative colitis, corticosteroids are not beneficial in maintaining remission [6365]. Short courses (<3 weeks) and low starting doses (<15 mg prednisolone ) of oral corticosteroids are associated with early relapse [40]. It is recommended that corticosteroids are tapered over several weeks, first to avoid rapid relapse, secondly, to allow the introduction or optimization of mesalazine, immunomodulators (thiopurines or methotrexate ), and biological therapy, and thirdly, to allow resumption of usual function of the hypothalamic–pituitary–adrenal axis. The most favorable regimen for corticosteroid tapering has not been determined, but a standardized taper can identify early those who are corticosteroid-dependent [66]. Arthralgia and myalgia can occur as corticosteroids are tapered. This usually responds to paracetamol and reassurance, but improvement can take several months and some patients need reintroduction of corticosteroids with a slower taper [67].

Corticosteroid Resistance

Up to one-third of patients with ulcerative colitis fail to respond to standard courses of corticosteroid therapy and have corticosteroid-resistant disease [61, 68]. This may be due to a superimposed pathogen, such as cytomegalovirus infection or Clostridium difficile toxin, which should be excluded. An association between glucocorticoid receptor polymorphisms and corticosteroid resistance in IBD has been postulated, but a meta-analysis of five studies involving 942 cases was underpowered to detect this [69].
Corticosteroid resistance may occur downstream in the glucocorticoid receptor-signaling pathway via inflammatory cytokines. Tumor necrosis factor α (TNF-α) decreases corticosteroid sensitivity in monocytes by downregulation of the glucocorticoid receptor [70], and in patients with ulcerative colitis, mucosal levels of this inflammatory cytokine, along with IL-6 and IL-8, are higher in corticosteroid-resistant patients [71]. Infliximab, a TNF-α blocker, is effective for corticosteroid-resistant disease [72], as too are the calcineurin inhibitors, ciclosporin and tacrolimus [73, 74]. Calcineurin participates in the synthesis of interleukin-2 (IL-2), which has been implicated in the development of corticosteroid-resistant T lymphocytes. However, a trial of basiliximab, a monoclonal antibody that binds to and blocks CD25 on activated T lymphocytes, inhibiting IL-2 binding and IL-2 mediated proliferation, did not show an increased effectiveness of corticosteroids for induction of remission in outpatients with moderate to severe, steroid-resistant ulcerative colitis [75].

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Jun 27, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Conventional Therapy of Ulcerative Colitis: Corticosteroids

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