30 Medical management of ulcerative colitis

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30 Medical management of ulcerative colitis

WILLIAM J. SANDBORN

Introduction

The optimal medical treatment of patients with ulcerative colitis (UC) requires that the treating physician obtain a history and perform any neces- sary diagnostic procedures, and then prescribe an appropriate medication regimen based on a knowl- edge of clinical pharmacology and the evidence from controlled clinical trials. This chapter will review the results from clinical trials that assessed the efficacy of medications used to treat UC and then provide an integrated therapeutic approach to the medical treat- ment of specific disease settings for patients with UC.

Pretreatment evaluation of the patient

Prior to initiating or altering the medical treatment regimen of patients with UC, the physician should evaluate the patient [1]. This evaluation begins with a medical history to determine the age of onset, the duration of disease, the extent of disease, the disease course over time, prior and current medication use (including duration and dose), and the symptoms currently being experienced by the patient. At the time of diagnosis the patients should undergo colonoscopy with mucosal biopsy and small bowel X-ray to provide a baseline characterization of the UC and to exclude Crohn's disease (CD). Infectious and medication-associated causes of colitis should be excluded. In patients with an estabhshed diagnosis of UC it is useful to repeat these tests when patients relapse and fail to respond to empiric therapy with 5- aminosalicylates and/or corticosteroids, prior to instituting immune modifier therapy or referring the patient for surgery. Adherence to this methodical approach allows the treating physician to make observations that would lead to a change in therapy such as: a change in the proximal extent of colitis;

endoscopic findings of severe colitis; features that are more compatible with a diagnosis of CD; infectious

Pancolitis

Figure 1. Distinguishing the various states of ulcerative GOlitis - proctitis, proctosigmoiditis, left-sided colitis, and pancolitis - depends on both the degree of mucosal inflammation and the extent of colonic mucosal involvement. (Reprinted with permission from: Miner PB, Peppercorn MA, Targan SR. A rational approach to 5-aminosalicylic acid therapy in ulcerative colitis. Hosp Pract 1993; 2a(Suppl 3): 3-24.)

colitis or medication-associated colitis; and patients with UC in endoscopic remission who may be experiencing symptoms of concomitant irritable bowel syndrome.

Classification of the patient according to the anatomic extent of involvement is shown in Fig. 1 [2]. Determining the extent of involvement is important because many 5-aminosalicylate-based medications and corticosteroid preparations are delivered topically, and do not distribute uniformly throughout the colon at a high concentration. The expected sites of drug delivery for various topically delivered 5-aminosalicylate formulations are shown in Table 1 [3]. Suppositories can be expected to release medication only in the rectum (approxi- mately the last 10 cm of the colon) [4, 5]. Enemas will reach the ascending colon/splenic flexure in approxi- mately 80-90% of patients (Fig. 2) [6-13].

Stephan R. Targan, Fergus Shanahan and Lor en C. Karp (eds.), Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 605-629.

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Table 1.5-Aminosalicylate preparations

Proprietary

Generic name name Formulation

Daily dose

Sites of delivery Active Maintenance Indication Mesalamine

Mesalamine

Olsalazine

Sulfasalazine

Balsalazide

Rowasa Salofalk

Rowasa Canasa

Asacol

Salofalk Mesasal Claversal

Pentasa

Dipentum

Azulfadine

Colazide Colazal

Enema suspension

Suppository

Eudragit-s-coated tablets (release at pH ^ 7 . 0 )

Mesalamine in a sodium /glycerine buffer coated with Eudragit-I (release at pH ^ 6 . 0 )

Ethylcellulose-coated microgranules (time and pH-dependent release)

5-ASA dimer linked by azo-bond

5-ASA linked to sulfa- pyridine by azo-bond

5-ASA linked to inert carrier by azo-bond

Distal to splenic flexure

Rectum

Terminal ileum, colon

Distal jejenum, proximal ileum

Duodenum, jejenum, ileum, colon

Colon

4g

1-1.5 g

1.6-4.8 g

1.5-4 g

2 - 4 g

2 - 3 g

2 - 4 g

2-6.75 g

1-4 g

0.5-1 g

0.8-4.8 g

0.75-4 g

1.5-4

i g

2 - 4 g

2-6.75 g

Active distal UC, remission

maintenance distal UC

Active proctitis, remission

maintenance distal UC

Active UC, remission maintenance UC

Active UC, maintenance UC

Reprinted after modification with permission from: Loftus EV, Sandborn WJ. Drug therapy for inflammatory bowel disease. Contemp Intern Med 1 9 9 5 ; 7 : 2 1 - 3 4 .

The Truelove and Witts classification can be used to determine whether patients have mild to moder- ately active or severely active UC (Table 2) [14]. This assessment of disease severity is important in deter- mining whether or not to hospitalize the patient and whether steroid therapy is mandatory. Other disease activity indexes such as the Sutherland Index or the Mayo Index are more useful for distinguishing patients with remission, mildly active disease, and moderately active disease for the purposes of asses- sing efficacy of sulfasalazine and other 5-amino- salicylate-based medications (Table 3) [15, 16].

Goals of treatment

The primary goals of medical therapy are to induce and then maintain significant clinical improvement or remission, resulting in a reduction or resolution of

the signs and symptoms of active UC. Secondary goals, which often occur in parallel with clinical changes, are induction of endoscopic improvement and remission. The efficacy of various medical therapies in achieving these endpoints in patients with UC is reviewed in the following sections.

5-Aminosalicylate-based medications

Sulfasalazine, oral mesalamine (Pentasa, Asacol,

Salofalk, Mesasal, Claversal) rectal mesalamine

(Rowasa, Canasa, Salofalk, Pentasa), olsalazine,

and balsalazide are all drugs that deliver 5-amino-

salicylate to the colon (Table 1) [3]. The clinical

pharmacology of these medications is reviewed in

detail elsewhere in this book.

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Figure 2. The individual colonic spread of radiolabeled low-viscosity 100 ml budesonide enemas in five patients with distal ulcerative colitis 15 min after administration. The filled areas of the colon represent areas where radioactivity was found. Modified with permission from: Nyman-Pantelidis M, Nillson A, Wagner GW, Borga 0. Pharmacokinetics and retrograde colonic spread of budesonide enemas in patients with distal ulcerative colitis. Aliment Pharmacol Ther 1994; 8: 617-22.

Table 2. Truelove and Witts criteria for evaluating the severity of ulcerative colitis*

Variable Mild disease Severe disease Fulminant disease

Stools (number/day) Blood in stool Temperature (°C) Pulse (beats/min) Hemoglobin

Erythrocyte sedimentation rate (mm/h) Colonic features on X-ray

Clinical signs

<4 Intermittent

Normal Normal Normal

^30

>6 Frequent

> 3 7 . 5

>90

< 75% of normal value

>30 Air, edematous wall,

thumbprinting Abdominal tenderness

>10 Continuous

> 3 7 . 5

>90 Transfusion required

>30 Dilatation

Abdominal distention and tenderness

*Moderate disease includes features of both mild and severe disease.

Reprinted with permission from: Truelove SO, Witts LT. Cortisone in ulcerative colitis: final report on a therapeutic trial. Br Med J 1955; 2 : 1 0 4 1 - 8 .

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Table 3. Mayo scoring system for assessment of ulcerative colitis activity

Stool frequency*

0 = Normal no. stools for this for this patient 1 = 1 - 2 stools more than normal

2 = 3 - 4 stools more than normal 3 = 5 or more stools more than normal

* Each patient served as his or her own control to establish the degree of abnormality of the stool frequency

Rectal bleeding**

0 = No blood seen

1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passed

** The daily bleeding score represented the most severe day of bleeding

Findings of flexible proctosigmoidoscopy 0 = Normal or inactive disease

1 = Mild disease (erythema, decreased vascular pattern, mild friability)

2 = Moderate disease (marked erythema, absent vascular pattern, friability erosions) 3 = Severe disease (spontaneous bleeding, ulceration

Physician's global assessment***

0 = Normal 1 = Mild disease 2 = Moderate disease 3 = Severe disease

*** The physician's global assessment acknowledged the three other criteria, the patient's daily record of abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the patient's performance status

A total Mayo ulcerative colitis activity score of 0 - 2 points indicates remission/minimally active disease; a score of 3-5 points indicates mildly active disease; a score of 6 - 1 0 points indicates moderately active disease; and a score of 11-12 may indicate moderate or severe disease, depending on the patient's Truelove and Witt's score. Reprinted with permission from: Schroeder KW, Tremaine WJ, llstrup DM. Coated oral 5- aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. N Engl J Med 1987; 317:1625-9.

Sulfasalazine

In 1942 Svartz reported on both the therapeutic results and the toxic effects of a novel sulfanilamide preparation, sulfasalazine, in patients with UC [17].

Sulfasalazine is composed of 5-aminosalicylate linked to sulfapyridine by a diazo bond. Placebo- controlled trials demonstrated that sulfasalazine administered orally at doses of 2-6 g/day or as a 3 g enema was effective in inducing remission in patients with mildly to moderately active UC and ulcerative proctitis [18-21]. Studies comparing sulfasalazine with a combination of low-dose oral and rectal steroids for active UC concluded that steroid therapy acted more rapidly, and perhaps was more effective, than sulfasalazine [22, 23]. Additional placebo-con- trolled trials demonstrated that sulfasalazine at doses of 2-4 g/day was effective in maintaining remission in patients with UC, and that the 4 g dose was more effective whereas the 2 g dose was better tolerated [24-26]. One placebo-controlled trial failed to demonstrate a maintenance benefit [27]. Com-

parative studies of sulfasalazine versus a high-fiber diet or mast cell stabilizers such as cromoglycate also showed maintenance benefits for sulfasalazine [28- 31]. Approximately 10-20% of orally administered sulfasalazine is absorbed systemically with the remainder passing unaltered to the colon [32]. Sulfa- salazine undergoes metabolism in the colon by bacterial azoreductase enzymes to 5-aminosalicylate and sulfapyridine [33, 34]. The active moiety of sulfasalazine was determined to be the poorly absorbed molecule 5-aminosalicylate and not the well-absorbed molecule sulfapyridine [32, 35-38].

Adverse events occurring in patients with inflam-

matory bowel disease (IBD) treated with sulfa-

salazine include: headache, epigastric pain, nausea

and vomiting, cyanosis, skin rash, fever, hepatitis,

a u t o i m m u n e hemolysis, transient reticulosis,

aplastic anemia, leukopenia, agranulocytosis, folate

deficiency, pancreatitis, systemic lupus erythema-

tosus, sulfonamide-induced toxic epidermal necro-

lysis, Stevens-Johnson syndrome, pulmonary

dysfunction, and male infertility [39, 40]. For the

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most part the side-effects from sulfasalazine can be attributed to the systemic absorption of sulfa- pyridine, and they occur more commonly in patients who are genetically predisposed to 'slow' acetylation of sulfapyridine to A^-acetylsulfapyridine in the liver [39]. Headache, nausea and vomiting, and epigastric pain often appear to be related to the sulfasalazine dose, and it is frequently possible to desensitize patients by discontinuing sulfasalazine for 1-2 weeks, and then restarting at 0.125-0.25 g/day and increasing by 0.125 g/week up to a maintenance dose of 2 g/day [40]. Sulfasalazine therapy may also lead to a paradoxical worsening of diarrhea in patients with UC [41].

Rectal mesalamine (5-aminosalicylate)

After it was demonstrated that mesalamine (5-ami- nosalicylate; 5-ASA) was the active moiety of sulfa- salazine (discussed above), oral and rectal drug delivery systems were devised to avoid absorption of mesalamine in the proximal small intestine, instead targeting the colon as the site of drug release.

Placebo-controlled trials demonstrated that mesala- mine administered rectally as a suspension enema at doses of 1-4 g/day or as a suppository at doses of 0.5-1.5 g/day was effective in inducing remission in patients with mildly to moderately active left-sided UC, ulcerative proctosigmoiditis, and ulcerative proctitis [4, 15, 42-44]. There does not appear to be a dose response across this range of mesalamine doses [42, 45]. Studies comparing novel foam or suppository formulations of mesalamine to standard mesalamine enemas or suppositories have shown equivalent results [46-48]. Relatively small studies comparing rectally administered 5-ASA with rectal steroids demonstrated similar efficacy rates [49-59].

However, a meta-analysis suggested that rectally administered mesalamine is superior to rectal ster- oids for inducing remission [45]. Other small com- parative studies have suggested that rectally adminis- tered mesalamine is equivalent to oral sulfasalazine, 4-aminosalicylate, and bismuth but not sucralfate [22, 23, 60-63]. A comparison of oral mesalamine 2.4 g/day, rectal mesalamine 4 g/day, and a combina- tion of the two therapies demonstrated a benefit for rectal mesalamine and combination therapy [64].

Whether this result represents a mesalamine dose response or an advantage for rectal delivery of mesalamine is unclear. Additional placebo-con- trolled trials d e m o n s t r a t e d that mesalamine administered rectally as 1 or 4 g enemas or 0.5 or 1 g

suppositories was effective in maintaining remission in patients with left-sided UC, distal UC, and ulcera- tive proctitis [65-69]. There is little evidence of a mesalamine dose response in maintenance therapy, but more frequent dosing intervals (twice-daily suppositories or daily enemas) are associated with lower relapse rates than less frequent dosing intervals of once-daily suppositories or enemas every second or third night [66, 68, 70]. Comparative studies suggest that rectal mesalamine 4 g is superior to oral mesalamine 1.5 or 2 g and that rectal mesalamine 4 g in combination with oral mesalamine 1.6 g is super- ior to monotherapy with oral mesalamine 1.6 g for maintaining remission [71-73]. It is unclear whether this represents a dose response or an advantage for rectal delivery of mesalamine.

Oral mesalamine (5-ASA)

Placebo-controlled trials demonstrated that oral mesalamine administered at doses of 1.6-4.8 g/day (Asacol 1.6-4.8 g/day, Pentasa 2-4 g/day) was effec- tive in inducing remission in patients with mildly to moderately active UC [16, 74-76]. Meta-analyses indicate that a dose response for oral mesalamine probably exists [77, 78]. Comparative studies have demonstrated that oral mesalamine at doses of 0.8- 4.0 g/day has comparable efficacy to sulfasalazine 2.0-4.0 g/day, but that side-effects occur more frequently in sulfasalazine-treated patients [79-81].

Additional placebo-controlled trials demonstrated that oral mesalamine at doses of 0.8-4.0 g/day was effective in maintaining remission in patients with UC [82, 83]. Comparative studies of oral mesalamine versus sulfasalazine demonstrated comparable efficacy for maintaining remission in UC, again with fewer side-effects for oral mesalamine [84-88]. More recent comparative studies for maintaining remis- sion in patients with UC have suggested that oral mesalamine may be equivalent to dietary fiber and probiotic bacteria [88-91].

Olsalazine

Olsalazine is a dimer, composed of two 5-ASA

molecules linked by a diazo bond. Placebo-con-

trolled trials demonstrated that olsalazine adminis-

tered orally at doses of 0.75-3 g/day or rectally as a 1

g enema was not consistently effective in inducing

remission in patients with mildly to moderately

active UC, due to a higher than expected dropout

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rate in olsalazine-treated patients for worsened diarrhea [92-97]. The worsened diarrhea is a result of ileal secretion [98]. In contrast to the placebo- controlled trials, studies that compared olsalazine with sulfasalazine for active UC for the most part concluded that the two agents had comparable efficacy [99-102]. Additional placebo controlled trials demonstrated that olsalazine at doses of 1-2 g/day was effective in maintaining remission in patients with UC [103, 104]. Comparative studies of olsalazine against oral mesalamine and sulfasalazine demonstrated similar efficacy for maintenance of remission in patients with UC [105-110].

Balsalazide

Balsalazide is composed of 5-ASA Hnked to an inert carrier molecule by a diazo bond. A comparative study of balsalazide 6.75 g/day with oral mesalamine (Asacol) 2.4 g/day in patients with active UC demon- strated similar efficacy [112]. Maintenance studies in patients with UC demonstrated that balsalazide 4 g/

day was more effective than 2 g/day, balsalazide 3 g/

day had similar efficacy to balsalazide 6 g/day and to oral mesalamine (Asacol) 1.2 g/day, and balsalazide 2 g/day had similar efficacy to sulfasalazine 2 g/day in maintaining remission [111, 113-115].

Toxicity of mesalamine, olsalazine, and balsalazide

Adverse events attributable to 5-ASA occur infre- quently in patients with IBD treated with mesala- mine, olsalazine, and balsalazide. Rare but serious events include pulmonary toxicity, pericarditis, hepatitis, and pancreatitis [116-119]. Interstitial nephritis has been reported in patients treated with mesalamine but whether the mesalamine causes the renal lesion is unclear [120-123]. Several studies have demonstrated that renal tubular proteinuria may be related to the disease activity of the IBD [124, 125].

Hanauer et al. reported on the safety of Asacol in 2940 patients with UC at doses up to 7.2 g/day for up to 5.2 years and concluded that there were no clinically significant dose or duration effects on renal function [126]. A minority of patients will experience worsening diarrhea and abdominal pain due to a hypersensitivity reaction to 5-ASA, and treatment with olsalazine will lead to an ileal secretory diarrhea in some patients, as discussed above [127].

Corticosteroid-based medications

Cortisone is produced by the adrenal cortex, and prednisone must be activated in the liver to hydro- cortisone and prednisolone, respectively. Predniso- lone and methylprednisolone have the same gluco- c o r t i c o i d and a n t i - i n f l a m m a t o r y activity as hydrocortisone but less mineralocorticoid activity.

Rectal administration of hydrocortisone, predniso- lone, methylprednisolone, and betamethasone; oral administration of cortisone, prednisone, and prednisolone; and intravenous administration of prednisolone, methylprednisolone, and cortico- tropin are all methods of delivering corticosteroids for a systemic effect (Table 4). In contrast to systemically administered corticosteroids, rectal administration of beclomethasone, tixicortol, budesonide, and prednisolone metasulfobenzoate;

and oral administration of fluticasone and controlled colonic release budesonide are all methods of deliver- ing corticosteroids directly to the colon for a non- systemic effect (Table 4). Topical administration of beclomethasone, fluticasone, tixocortol, or bude- sonide to the colon results in a predominantly non- systemic effect because these newer corticosteroids have high affinities for the glucocorticoid receptors and undergo extensive first-pass hepatic metabolism.

Topical administration of prednisolone metasulfo- benzoate and tixocortol to the colon results in a predominantly non-systemic effect because they are poorly absorbed.

Oral corticosteroids (systemic effect)

In 1954 and 1955 Truelove and colleagues reported

the preliminary and final results of a placebo-con-

trolled trial which demonstrated that a tapering dose

of cortisone beginning at 100 mg/day was effective in

inducing remission in patients with mildly to severely

active UC [14, 128]. Studies comparing sulfasalazine

with a combination of low-dose oral and rectal

steroids for active UC concluded that steroid therapy

acted more rapidly, and perhaps was more effective,

than sulfasalazine [22, 23]. A dose-ranging study

demonstrated that prednisone 40-60 mg/day was

more effective than 20 mg/day, and that 60 mg/day

was no more effective than 40 mg/day but resulted in

a greater frequency of side-effects [129]. A subse-

quent study demonstrated that a single daily dose of

prednisone 40 mg was equally effective as prednisone

10 mg four times daily [130]. Placebo-controlled

trials of cortisone 25 mg twice daily and prednisone

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Table 4. Rectal corticosteroid preparations

Generic name

Hydrocortisone acetate Hydrocortisone

Hydrocortisone acetate

Hydrocortisone acetate + pramoxine hydrochloride (local anesthetic)

Prednisolone phosphate

Betamethasone valerate

Prednisolone metasulpho- benzoate

Tixocortol pivalate

Budesonide

Proprietary name

Anusol-HC 25 mg Cortenema

Cortifoam

Colifoam*

Proctocort

Proctofoam HC

Predsol enema*

Betnesor

Predenema*

Predfoam*

Rectovalone*

Entocort enema*

Formulation

Suppository 25 mg

Enema 100mg/60ml

Foam 80 mg/

900 mg foam

Foam

125 ml/5 ml foam

Suppository 30 mg

Topical aerosol 1% hydrocortisone

(approx. 7 mg) 1 % pramoxine

(approx. 7 mg)

Enema 20mg/100ml

Enema 5mg/100ml

Enema 20mg/100ml

Foam

20 mg/20 ml foam

Enema 250mg/100ml

Enema 2mg/100ml

Sites of delivery Rectum

Distal to splenic flexure Distal rectum

Distal to splenic flexure Rectum

Anus, distal rectum

Distal to splenic flexure

Site and mechanism of action Systemic

Systemic

Non-systemic:

poorly absorbed

Non-systemic:

poorly absorbed

Non-systemic:

poorly absorbed and first pass metabolism

Non-systemic:

first pass metabolism

Daily dose (mg) 5 0 - 1 0 0

100

8 0 - 1 6 0

125-250

6 0 - 1 2 0

7 - 2 8

20

5

20

250

2

Indication Active proctitis

Active distal UC

Active proctitis in the distal rectum Active distal UC

Active proctitis

Active procitis

Active distal UC

*lndicates not available in the United States.

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at doses of 15 mg/day or 40 mg every other day failed to demonstrate a maintenance benefit for oral corticosteroids [131-133].

Intravenous corticosteroids and corticotropin (ACTH)

Patients with severe UC and those refractory to oral coticosteroids are hospitaHzed and treated with intravenous corticosteroids. The rationale for this practice is altered corticosteroid absorption and metabolism in patients with UC. Oral administration of a 40 mg dose of prednisolone resulted in a lower peak and a slower rate of decrease in the plasma concentration of prednisolone in patients with severe UC compared with the time versus concentration curve observed in healthy volunteers; although total prednisolone absorption was similar [134]. In con- trast, intravenous administration of prednisolone to patients with UC resulted in serum concentrations similar to volunteers [135]. Continuous infusion of prednisolone resulted in greater mean serum concentrations over time compared to bolus intra- venous dosing; and both intravenous dosing strate- gies resulted in greater mean serum concentrations than oral dosing [135]. Uncontrolled studies have reported that approximately 60% of patients hospi- talized for severe UC will respond to intravenous corticosteroid therapy [136-138]. Dosing strategies have included prednisolone 60 mg/day in four divided doses [136], betamethasone 3 mg twice daily [138], and hydrocortisone 300-400 mg/day [139- 141]. Methylprednisolone 40-60 mg/day is preferred by many clinicians because it has minimal miner- alocorticoid effect. There was no apparent advantage in increasing the dose of methylprednisolone to 1000 mg/day [142]. No placebo-controlled trials of intra- venous corticosteroid therapy for severe UC have been performed.

A comparative study of intramuscular corticotro- pin (adrenal corticotropin hormone, ACTH) 80 U/

day and cortisone 200 mg/day demonstrated a simi- lar overall benefit in patients with active UC and in the subgroup of patients with a first attack, with a possible advantage for corticotropin in patients in patients with a relapse of established colitis [131].

Subsequent studies in patients with severe UC showed that overall the response to corticotropin 80-120 U/day is similar to hydrocortisone 300-400 mg/day, with trends toward better response to hydro- cortisone in patients recently treated with cortico-

steroids and better response to corticotropin in patients not recently treated with corticosteroids [139-141].

Rectal corticosteroids (systemic effect)

Hydrocortisone, prednisolone, methylprednisolone, and betamethasone administered directly to the rectum as enemas or suppositories are well absorbed (similar to oral dose) [143, 144] and can result in suppression of the adrenal axis [49, 145-148]. Pla- cebo-controlled trials have demonstrated efficacy for rectal administration of hydrocortisone 100 mg and prednisolone 5 mg in patients with active ulcerative proctitis or proctosigmoiditis [149-151]. Relatively small studies comparing rectally administered 5- ASA with rectal hydrocortisone 100-178 mg/day or prednisolone 20-30 mg/day, demonstrated similar efficacy rates in patients with active ulcerative procti- tis or proctosigmoiditis [49-57, 59, 152, 153]. How- ever, a meta-analysis suggested that rectally adminis- tered mesalamine is superior to rectal steroids for inducing remission [45]. Other small comparative studies have suggested that rectally administered hydrocortisone 100 mg, prednisolone 20-30 mg, or betamethasone 5 mg is equivalent to oral prednisone, oral sulfasalazine, and rectal 4-aminosalicylate, sodium cromoglycate, hydrocortisone foam 100 mg, and Ridogrel in patients with active ulcerative proc- titis or proctosigmoiditis [23, 154-160]. Rectal hydrocortisone 100 mg every 2 nights each week for 6 months did not demonstrate a maintenance benefit compared with placebo [149].

Rectal corticosteroids (non-systemic effect) Placebo-controlled trials demonstrated that budeso- nide administered rectally in a suspension enema at doses of 2-8 mg/day was effective in inducing remis- sion in patients with mildly to moderately active left- sided UC, ulcerative proctosigmoiditis, and ulcera- tive proctitis; a 0.5 mg/day dose was not effective [48, 161-164]. Relatively small studies comparing rect- ally administered budesonide 2.0-2.5 mg/day with other rectal steroids (methylprednisolone 20 mg, prednisolone 25-31 mg, hydrocortisone 100-125 mg) demonstrated similar efficacy rates [147, 148, 163, 165-167]. Similarly, relatively small studies comparing rectally administered budesonide 2 mg/

day with rectal 5-ASA 1-4 g/day demonstrated

similar efficacy rates [58, 168]. Other small compara-

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tive studies have demonstrated that rectally adminis- tered non-systemic corticosteroids (prednisolone metasulfobenzoate 20 mg, beclomethasone 0.5-3 mg, tixocortol 250 mg) are equivalent to oral pre- dnisolone, oral 5-ASA, rectal betamethasone 5 mg, rectal hydrocortisone 100 mg, rectal prednisolone 30 mg, rectal 5-ASA, and Ridogrel but not sucralfate [59, 157, 169-174]. Rectal budesonide 2 mg 2 nights each week for 6 months did not demonstrate a maintenance benefit compared with placebo [164].

Oral corticosteroids (non-systemic effect) A placebo-controlled trial demonstrated that oral fluticasone 20 mg/day was not ejffective in inducing remission in patients with mildly to moderately active distal UC [175]. A study comparing oral fluticasone 20 mg/day with prednisolone 40 mg/day tapered to 10-20 mg/day in patients with active UC showed a greater benefit and more rapid response in the prednisolone group [176]. A comparative study of controlled colonic release budesonide 10 mg and prednisolone 40 mg/day and tapered to 0 mg demon- strated similar response rates in the two groups, with fewer side-effects in the budesonide group [177].

Toxicity of corticosteroids

Corticosteroid toxicity occurred frequently in patients with active CD treated with prednisone at an initial dose of 60 mg/day tapered over 17 weeks.

Toxicities observed included a moon face in 47%, acne in 30%, infection in 27%, ecchymoses in 17%, hypertension in 15%, hirsutism in 7%o, petechial bleeding in 6%, and striae in 6% [178]. A similar short-term toxicity profile can be expected in patients with UC.

Prolonged corticosteroid therapy at low to inter- mediate doses (doses frequently utilized in patients with steroid-dependent UC) is associated with the potential for multiple serious side-effects [179].

Hypertension occurs in up to 20% of patients [180].

New-onset diabetes mellitus requiring initiation of hypoglycemic therapy occurs at a frequency 2.23 times greater than in the general population [181].

Infection occurs at a frequency of 13-20%o [182].

Osteonecrosis occurs at a frequency of approxi- mately 5% [183]. The frequency of steroid-associated osteoporosis may be as high as 50% [184]. Neuro- logic side-effects occur often and can include myo- pathy at a frequency of 7%o and psychosis at a

frequency of 3-5%) [185]. Ophthalmologic side- effects also occur often and can include cataracts at a frequency of 22%) (dose-dependent) and glaucoma (frequency unclear, response genetically determined) [186, 187]. These frequencies of side-effects from prolonged exposure to corticosteroids were generally confirmed in a study of patients with UC who had undergone colectomy for medically refractory dis- ease [188].

Immune modifer medications

The antimetabolites 6-mercaptopurine (Purinethol), its pro-drug azathioprine (Imuran), and metho- trexate; the calcineurin inhibitors cyclosporine (San- dimmune, Neoral) and tacrolimus (FK506, Prograf);

and the T-cell inhibitor mycophenolate mofetil (Cell- cept) are all medications with immune modifier activity. The clinical p h a r m a c o l o g y of these medications is reviewed in detail elsewhere in this book.

Azathioprine and 6-mercaptopurine

The first uncontrolled reports of the treatment of UC with 6-mercaptopurine (6-MP) and azathioprine (AZA) date back to the early 1960s [189-191]. A placebo-controlled trial of AZA 2.5 mg/kg per day in combination with a tapering dose of corticoster- oids in 80 patients with active UC showed no benefit at 1 month and a trend toward a benefit at 1 year that was not significant [192, 193]. A comparative study of AZA 2.5 mg/kg per day versus sulfasalazine 65 mg/kg per day in patients with active UC showed similar efficacy for the two agents [194]. Two small placebo-controlled trials suggested that AZA at 1.5 mg/kg per day and 2.0-2.5 mg/kg per day was steroid-sparing in patients with steroid-dependent UC [195, 196]. Finally, a placebo-controlled with- drawal trial in patients maintained with AZA 100 mg/day demonstrated a maintenance of remission benefit [197]. These studies have been supplemented by five recently published open series of AZA and 6- M P therapy for U C [198-202]. Overall, these controlled and uncontrolled studies demonstrate that 6-MP and AZA are effective for steroid-sparing and maintenance of remission, and probably for inducing remission in patients with chronically active and treatment-refractory UC.

Adverse events occurring in patients with IBD

treated with 6-MP and AZA include: pancreatitis

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(3%); fever, rash, arthralgias, malaise, nausea, diarrhea, leukopenia (2-5%); thrombocytopenia, infection, and hepatitis [203-205]. It appears that there is not an increased risk of malignancy when AZA/6-MP is used as a monotherapy in IBD, and in three large series only one lymphoma occurred in

1308 patients [203, 206, 207].

Methotrexate

Two uncontrolled reports of the treatment of UC with methotrexate date occurred in the late 1980s and early 1990s [208, 209]. These studies suggested that intramuscular methotrexate 25 mg/week might be beneficial whereas oral methotrexate 15 mg/week appeared less promising. In patients with CD these uncontrolled observations regarding dose response and route of administration have been substantiated, with placebo-controlled trials demonstrating effi- cacy for intramuscular methotrexate 15-25 mg/week but not for oral methotrexate 12.5-15 mg/week [210-213]. In patients with UC a single placebo- controlled trial of oral methotrexate 12.5 mg/week did not demonstrate efficacy for either inducing or maintaining remission [214]. Whether intramuscular or subcutaneous methotrexate at doses of 15-25 mg/

week would be effective for patients with UC is unknown, although the uncontrolled study discussed above is encouraging [208]. Based on the currently available evidence, patients with UC should not be treated with methotrexate.

Cyclosporine

The use of oral cyclosporine for UC was first reported in 1984 [215]. Subsequently multiple uncon- trolled studies have reported a beneficial effect of cyclosporine administered at relatively high doses (5-15 mg/kg per day orally or 2-7 mg/kg per day intravenously) in patients with severe UC unrespon- sive to intravenous corticosteroids [216-221]. A placebo-controlled trial demonstrated that the addi- tion of intravenous cyclosporine administered at a dose of 4 mg/kg per day as a continuous infusion to intravenous corticosteroids was effective for indu- cing remission in patients with severe steroid-refrac- tory UC (82% versus 0% response) [222]. However, only 45% of the patients treated with cyclosporine had avoided colectomy after 6 months of follow-up [223], an observation confirmed by other uncon- trolled studies [217-219, 224]. Maintenance therapy

with AZA or 6-MP in patients with UC who require treatment with cyclosporine appears to reduce the rate of relapse and colectomy [217, 225, 226]. Two more recent controlled trials have demonstrated that monotherapy with intravenous cyclosporine 4 mg/

kg per day has efficacy comparable to intravenous corticosteroids or intravenous corticosteroids combined with intravenous cyclosporine in patients with active refractory UC [227, 228]. Overall, these studies demonstrate that intravenous cyclosporine is effective in inducing remission in patients with severe, steroid-refractory UC, but that the benefit is of limited duration unless AZA or 6-MP is initiated for maintenance of remission. Uncontrolled pilot studies of low-dose cyclosporine enemas suggested a potential beneficial effect in patients with active left- sided UC [229-232], but a placebo-controlled trial was negative [233].

Adverse events occurring in patients with IBD treated with cyclosporine include: hypertension, headaches, paresthesias, seizures, gingival hyperpla- sia, hypertrichosis, anaphylaxis, opportunistic infec- tion, and renal insufficiency [217, 221, 234, 235].

There is an increased risk of opportunistic infection in patients with IBD treated with intravenous cyclo- sporine combined with corticosteroids and AZA or 6-MP; Pneumocystis carinii pneumonia, invasive apergillosis, lung abscess, mycotic aneurysm, and overwhelming sepsis have all been reported, with death rates ranging from 1% to 2% in larger series [217, 234-237]. There does not appear to be an increase in perioperative morbidity or mortality in patients with UC who receive intravenous cyclo- sporine and then require colectomy within a short period of time [238]. Another study reported that 20% of 99 patients with IBD treated with intravenous cyclosporine had a decrease in estimated renal function greater than 30% [239]. Results from a previous study suggest that patients with auto- immune diseases treated with intravenous cyclo- sporine have a significant likelihood of having histo- logic evidence of irreversible nephrotoxicity on renal biopsy (which to date has not been performed in patients with IBD) [240].

Tacrolimus

Small uncontrolled case series have suggested that tacrolimus may be beneficial in patients with refrac- tory UC [241-243]. To date no controlled trials of tacrolimus have been performed in patients with UC.

Given the similarities in mechanism of action to

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cyclosporine, it is reasonable to believe that tacro- limus would have similar efficacy and toxicity as cyclosporine in this patient group.

Mycophenolate mofetil

A small controlled trial reported that mycophenolate mofetil 15 mg/kg per day had similar efficacy as azathioprine 2.5 mg/kg per day in patients with chronically active CD [244]. In contrast, a small controlled trial of mycophenolate mofetil 20 mg/kg per day versus AZA 2.0 mg/kg per day in patients with chronically active UC demonstrated a superior outcome with azathioprine [245]. Similarly, an uncontrolled study did not report a benefit with mycophenolate in patients with UC [246]. Based on the currently available evidence, patients with UC should not be treated with mycophenolate mofetil.

Miscellaneous agents

4-Aminosalicylate (4-ASA)

4-Aminosalicylate (para-aminosalicylate, PAS) is an isomer of 5-ASA, the active component of sulfa- salazine. Controlled trials with oral or rectal enema formulations of 4-ASA have shown superiority to placebo and equivalence to corticosteroids and 5- ASA [61, 154, 247-252].

Nicotine

Epidemiologic studies have demonstrated that non- smokers are at increased risk to develop UC. There are multiple potential mechanistic explanations for this beneficial effect [253]. Two placebo-controlled trials of transdermal nicotine patches reported that the highest tolerated dose of nicotine (up to 25 mg/24 h and 22 mg/24 h, respectively) was effective in patients with active UC [254, 255]. Similarly, a controlled trial of transdermal nicotine at the highest tolerated dose (up to 25 mg/16 h) showed equiva- lence to prednisolone for active UC [256]. A con- trolled trial using a lower dose of transdermal nicotine (15 mg/16 h) for maintenance of remission was negative [257]. Two uncontrolled studies of nicotine enemas for active distal UC reported a beneficial clinical effect and a reduction in both blood concentrations of nicotine (by first-pass hepa- tic metabolism of nicotine) and side-effects [258, 259]. Side-effects from transdermal nicotine occur

frequently and include contact dermatitis, nausea, vomiting, headaches, sleep disturbance, diaphoresis, tremor, and lightheadedness [253-255].

Heparin

The inflammatory bowel diseases have been asso- ciated with a hypercoagulable state, and heparin has been proposed as a potential therapy in UC both for its anticoagulant and anti-inflammatory effects [260]. Four uncontrolled trials have suggested that both intravenous and subcutaneous heparin may be of benefit in patients with active UC [261-264]. A placebo-controlled trial of subcutaneous porcine heparin 10 000 units two or three times daily in patients with active UC reported a response rate of 42% for the heparin group and 19% for the placebo group [265]. Paradoxically, heparin appears to improve active UC rather than to exacerbate bleed- ing from the friable and ulcerated colonic mucosa.

Anti-tumor necrosis factor oc antibody

Placebo-controlled trials have demonstrated that the mouse/human chimeric monoclonal antibody to tumor necrosis factor (TNF)-oc, infliximab, and the humanized antibody to TNF, CDP571, are effective for the treatment of CD [266-269]. Two small studies conducted in patients with active UC have suggested a potential beneficial effect [270, 271]. Use of anti- TNF-oc antibodies for the treatment of UC in clinical practice is premature at the present time.

Stiort-chain fatty acids

Luminal «-butyrate and other short-chain fatty acids (SCFA) produced by bacterial carbohydrate fermen- tation are the major luminal source of energy for colonocytes, and colonocytes from patients with UC may have reduced capacity to oxidize SCFA [272].

Two small and poorly designed controlled trials

suggested that SCFA enemas may be beneficial in

active distal UC [273, 274]. Subsequently, four pla-

cebo-controlled trials with larger sample sizes have

been conducted [275-278]. Two of two studies com-

paring butyrate enemas to placebo [275, 276], and

two of three studies comparing SCFA enemas to

placebo [276-278] failed to demonstrate efficacy in

patients with active left-sided UC.

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Fish oil

Fish oil (eicosapentanoic acid and docosahexenoic acid) inhibits 5-lipoxygenase and other enzymes involved in arachidonate metabolism. A small controlled trial suggested that fish oil may be of benefit in patients with active UC [279]. However, three large controlled trials with adequate sample sizes did not demonstrate clinical efficacy of fish oil compared with placebo in patients with active UC [280, 281] or for maintenance of remission [282].

These negative clinical results were observed in spite of the finding that fish oil did result in a significant decrease in colonic luminal concentrations of leuko- triene B4 [280].

Antibiotics

Given the attractive but unsubstantiated hypothesis that UC may be a specific infectious colitis, studies evaluating treatment with antibiotics were logical. A controlled trial of oral tobramycin in patients with mild to moderately active UC demonstrated efficacy but there was no maintenance benefit [283, 284].

Only one of two placebo-controlled trials of oral ciprofloxacin in patients with active UC demon- strated efficacy [285, 286]. Controlled trials of oral vancomycin [287], intravenous metronidazole [288], and intravenous tobramycin and metronidazole [289] in patients with severely active UC demon- strated no clinical benefit compared with placebo.

Based on the nearly uniform negative outcome of these studies, antibiotics have no role in the treat- ment of UC except in the case of a documented or suspected co-existing infection with a specific infectious organism.

Ziieuton and ottier ieul(otriene inhibitors

Initial studies suggested that compounds which act to inhibit 5-lipoxygenase might be of benefit in patients with UC [290, 291]. However, larger con- trolled trials with adequate sample sizes were nega- tive [292-295]. The Merck compound MK-591 resulted in a significant decrease in colonic luminal concentrations of leukotriene B4 but did not demon- strate clinical efficacy when compared with placebo in patients with mild to moderately active UC [292].

There was a trend toward clinical benefit for ziieuton compared with placebo in patients with mild to moderately active UC, but the results did not reach statistical significance [293, 294]. Ziieuton was less

eff'ective than 5-ASA 1.6 g/day and similar to placebo for maintaining remission in patients with UC [295].

Anti-piateiet-activating factor agents

Platelet-activating factor is elevated in the stool and mucosa of patients with UC. Randomized, double- blind placebo-controlled trials have not demon- strated that antibodies directed against platelet-acti- vating factor are effective in the treatment of moder- ately or severely active UC [296, 297].

Bismuth

Bismuth compounds have both antidiarrheal and antibacterial properties. Uncontrolled studies of bismuth subsalicylate enemas [298] and tripotassium dicitrato bismuth enemas [299] suggested benefit in patients with mild to moderately active distal UC.

These observations were confirmed by a small con- trolled trial comparing bismuth citrate enemas to 5- ASA enemas that demonstrated equivalence in patients with mild to moderately active distal UC [62]. Systemic absorption of bismuth after rectal administration was minimal.

Interferon

Because of the probable central role of the immune system in the pathogenesis of UC, it seems reason- able to evaluate the potential efficacy of the inter- ferons (alpha, beta, and gamma) as a therapy. Inter- feron-alpha has been used in a pilot study to treat patients with mild to moderately active UC with reported success [300].

Interieul(in-10

Interleukin-lO is a cytokine produced by T-helper type 2 cells, B cells, monocytes, and macrophages that has multiple immune modifier effects. A small controlled trial of recombinant human interleukin-

10 (rhuIL-10) (Schering Plough Research Institute,

Kenilworth, NJ) in patients with mild to moderately

active CD demonstrated a modest beneficial effect

[301]. A placebo-controlled trial of interleukin-10 in

94 patients with mild to moderately active UC was

negative [302].

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Lidocaine/ropivacaine

Topical anesthetic agents including both lidocaine and ropivacaine may have anti-inflammatory effects.

Uncontrolled studies of 2% lidocaine enemas [303, 304] and ropivacaine gel enemas [305] have been reported to be of benefit in patients with mild to moderately active distal UC. A placebo-controlled trial in this same patient group has been completed, but to date the results have not been made available.

Systemic absorption of these agents after rectal administration is minimal.

Probiotic bacteria

Probiotic bacteria may be of benefit in patients with U C and pouchitis. Two controlled studies have reported that E. coli Nissle is therapeutically equiva- lent to 5-ASA for maintaining remission in patients with UC [90, 91]. These trials were not statistically powered to demonstrated equivalence. A placebo- controlled trial is needed to determine if probiotic therapy is a useful treatment modality for UC.

Treatment indications and

algoritiim and specific treatment approaclies

The indications for therapy in patients with UC are summarized in Table 5 and a suggested treatment algorithm is proposed in Fig. 3. The specific approaches to the medical treatment of patients with proctitis/distal UC, extensive UC, refractory UC, and severe UC are each reviewed separately below.

Proctitis/distal ulcerative colitis

The treatment of patients with mildly to moderately active proctitis/distal UC may include rectal therapy, oral therapy, or a combination of both. Patient preferences with regard to rectal therapy for induc- tion of remission must be considered. Rectal mesa- lamine may be more efficacious than orally adminis- tered mesalamine [64)]or rectally administered corticosteroids [45]. Thus, for patients who will accept rectal therapy, mesalamine suppositories (500 mg b.i.d.) for proctitis and mesalamine enemas (1 g or 4 g nightly) for distal colitis are the treatment of choice. For patients who prefer oral therapy, oral mesalamine 2.0-4.8 g/day, sulfasalazine 2-4 g/day, and balsalazide 6.75 g/day are all equivalent first-line treatments [77, 78, 112]. Olsalazine should be

Table 5. Ulcerative colitis: indications for treatment

Drug Sulfasalazine Rectal mesalamine Oral mesalamine Olsalazine Balsalazide

Rectal corticosteroids Oral corticosteroids Intravenous corticosteroids Azathioprine/6-mercaptopurine Cyclosporine

Transdermal nicotine

Mildly to moderately active Distal

Yes Yes Yes No' Yes Yes Yes No No No No

Extensive Yes No Yes No' Yes No Yes No No No No

Refractory Yes' Yes' Yes' No' Yes' Yes' Yes' Yes^

Yes No Yes

Severely active

No'' No^

No^

No' No^

Yes' No Yes No Yes No

Remission maintenance Distal

Yes Yes Yes Yes Yes No No No Yes No No

Extensive Yes No Yes Yes Yes No No No Yes No No typically continued as a carryover of treatment for mildly to moderately active disease when additional agents are added.

h"ypically discontinued because of the possibility of intolerence to sulfasalazine, mesalamine, or balsalazide.

'Diarrhea occurs frequently at higher doses in patients with active ulcerative colitis.

'Adjunctive therapy to intravenous corticosteroids.

^Some patients who fail oral corticosteroids will respond to hospitalization with intravenous administration of corticosteroids.

Reprinted after modification with permission from: Loftus EV, Sandborn WJ. Drug therapy for inflammatory bowel disease. Contemp Intern Med 1 9 9 5 ; 7 : 2 1 - 3 4 .

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Severe colitis

IV steroids (hydrocortisone, 300 mg/d or the equivalent) plus topical hydrocortisone

Mild-to-moderate distal colitis

(proctitis, left-sided colitis) 5-ASA enemas or suppositories;

active doses

Mild-to-moderate extensive colitis

Sulfasalazine or oral 5-ASA active doses . Maintenance ^_

doses Topical hydrocortisone

(hs or bid)

Consider maintenance - ^ with sulfasalazine or

rectal/oral 5-ASA Oral corticosteroids

^ (for example, prednisone, 40-60 - ^ mg/d tapered over 4-12 wk)

No response in 7-10 d, surgery or IV cyclosporine

at referral center

Maintenance with sulfasalazine or oral 5-ASA Azathioprine, 1.5-2.5 mg/kg/d, or

6-mercaptopurine, 1.5 mg/kg/d

•f response - no response

Maintenance with Azathioprine or 6-mercaptopurine Surgery

Figure 3. Suggested treatment guidelines for ulcerative colitis are offered in this algorithm. Reprinted after modification with permission from: Loftus EV, Sandborn WJ. Drug therapy for inflammatory bowel disease. Contemp Intern Med 1995; 7: 21-34.

avoided due to a high frequency of diarrhea in patients with active UC.

Sulfasalazine therapy is associated with more side effects but is less expensive than oral mesalamine or balsalazide. In one study the combination of mesala- mine enemas 4 g/day and oral mesalamine 2.4 g/day was more effective than either agent alone [64] and another study demonstrated that combination ther- apy results in greater colonic tissue concentrations of 5-ASA [306]. Based on these data, many clinicians use rectal and oral mesalamine in combination to induce remission and then continue the oral mesala- mine for maintenance of remission. In patients who fail to respond to oral or rectal mesalamine, sulfa- salazine, or balsalazide, rectal corticosteroids can be tried. When all of these treatment approaches are ineffective, then oral prednisone is added to the other

oral and rectal therapies. The preferred initial prednisone dosing regimen is 40 mg/day adminis- tered as a single dose. The optimal tapering strategy has not been determined, but experienced clinicians will typically treat the patient with prednisone 40 mg/day for 2-4 weeks, then taper by 5 mg/week to a daily dose of 20 mg/day, then slow the taper to 2.5 mg/week until prednisone is discontinued.

Once the patients have achieved clinical remission,

a long-term maintenance of remission strategy must

be undertaken to avoid relapse. Again, patient pre-

ferences with regard to rectal therapy must be con-

sidered. Rectal mesalamine may be more efficacious

than orally administered sulfasalazine or mesala-

mine for maintaining remission [71, 72]. Again, for

patients who will accept rectal therapy, mesalamine

suppositories (500 mg once or twice daily) for

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proctitis and mesalamine enemas (4 g nightly, every other night or every third night) for distal colitis are the treatment of choice. For patients who prefer oral therapy, oral mesalamine 1.6-4.8 g/day, sulfasala- zine 2-4 g/day, olsalazine 1.0 g/day, and balsalazide 3.0-6.75 g/day are all equivalent first-line mainte- nance treatments [77, 78, 113]. Sulfasalazine therapy is associated with more side-effects but is less expen- sive than oral mesalamine, olsalazine, or balsalazide.

In one study the combination of mesalamine enemas 4 g/day and oral mesalamine 1.2 g/day was more effective than oral mesalamine alone [73]; however, most patients find maintenance with both oral and rectal mesalamine unacceptable. There is not agree- ment among expert clinicians as to whether patients should taper rectal mesalamine to the least frequent effective dose interval, or oral mesalamine, sulfa- salazine, olsalazine, or balsalazide to the lowest effective dose; or instead continue maintenance ther- apy with the same dose interval or dose required to induce remission. The former strategy is less expen- sive and may improve patient compliance by reducing the amount and frequency of medication administered, whereas the latter strategy may result in effective maintenance of remission in a larger proportion of patients. Rectal corticosteroids are not effective for maintaining remission and should not be used for that indication. Clinical trials have not demonstrated that oral corticosteroids at low to moderate doses are effective for maintaining remis- sion. Nevertheless, some patients who respond to higher doses of prednisone will relapse with steroid tapering and can be maintained nearly asympto- matic by increasing the prednisone dose back to 15- 25 mg/day These patients are classified as 'steroid- dependent'. Because of the toxicity associated with long-term corticosteroid therapy, this is not an acceptable form of maintenance therapy and such patients should be treated for refractory disease as described below.

Extensive ulcerative colitis

Oral administration of medications that deliver 5- ASA to the colon is the treatment of choice in patients with mildly to moderately active extensive UC. Oral mesalamine 2.0-4.8 g/day, sulfasalazine 2 - 4 g/day, and balsalazide 6.75 g/day are all equivalent first-line treatments [77, 78, 112]. Sulfasalazine ther- apy is associated with more side effects but is less expensive than oral mesalamine or balsalazide.

Olsalazine should be avoided due to a high frequency

of diarrhea in patients with active UC. There appears to be a dose response for oral medications that deliver 5-ASA [77]. There is not agreement among expert clinicians as to whether the preferred strategy is to begin with the lowest dose proven to be effective for active disease, increasing the dose in those patients who fail to respond; or rather to begin with the maximally tolerated dose and then titrate the dose downward when the patient comes into clinical remission. When treatment with one of these agents at an optimal dose has failed, then oral prednisone is added to the oral mesalamine, sulfasalazine, or balsalazide. The preferred initial prednisone dosing regimen is 40 mg/day administered as a single dose, with tapering as described above for proctitis/distal UC.

Once the patients have achieved clinical remission, a long-term maintenance of remission strategy must be undertaken to avoid relapse. Oral therapy with a drug that delivers 5-ASA to the colon is the treatment of choice. Oral mesalamine 1.6-4.8 g/day, sulfasala- zine 2-4 g/day, olsalazine 1.0 g/day, and balsalazide 3.0-6.75 g/day are all equivalent first-line mainte- nance treatments [77, 78, 113]. Sulfasalazine therapy is associated with more side-effects but is less expen- sive than oral mesalamine, olsalazine, or balsalazide.

As described above for patients with proctitis/distal UC, there is not agreement among expert clinicians as to whether patients with extensive UC should taper oral mesalamine, sulfasalazine, olsalazine, or balsalazide to the lowest effective dose; or instead continue maintenance therapy with the same dose required to induce remission. Clinical trials have demonstrated that oral corticosteroids at low to moderate doses are not effective for maintaining remission. As discussed above for proctitis/distal UC, treatment with prednisone 15-25 mg/day in patients with extensive UC who are 'steroid-depen- dent' is not acceptable because of the toxicity associated with long-term corticosteroid therapy.

Such patients should be treated for refractory disease as described below.

Refractory ulcerative colitis

Patients with mildly to moderately active UC who

fail to respond to oral prednisone at a dose of 40-60

mg/day in combination with mesalamine, sulfasala-

zine, or balsalazide can be considered to have refrac-

tory UC. One potential approach to treatment is

hospitalization for intravenous administration of

corticosteroids. The rationale for this treatment

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approach is a clinical trial that demonstrated greater mean serum prednisolone concentrations with intra- venous compared to oral dosing [135].

The mainstay of treatment in patients who have failed combination therapy with maximal doses of oral and rectal mesalamine and oral corticosteroids is AZA or 6-MP. The prodrug AZA is approximately 50% 6-MP by molecular weight, requiring a conver- sion factor of 2 to convert a dose of AZA to a therapeutically equivalent dose of 6-MP. The doses of AZA and 6-MP shown to be effective for UC and CD in controlled trials range from 100 mg/day to 3.0 mg/kg per day. For patients with normal AZA and 6- MP metabolism (based on normal thiopurine methyltransferase (TPMT) activity), a starting AZA dose of 2.0-2.5 mg/kg per day or 6-MP dose of 1.0- 1.5 mg/kg per day is recommended (see Chapter 25 on Clinical pharmacology for further details).

Patients with decreased TPMT activity should have their starting AZA or 6-MP dose reduced by 50% to 1.0-1.25 mg/kg per day and 0.5-0.75 mg/kg per day, respectively. Patients with absent TPMT activity should not be treated with AZA or 6-MP. AZA and 6-MP are slow-acting antimetabolite drugs, requir- ing at least 1-2 months and perhaps 3-4 months to reach the full clinical effect. Thus, concomitant therapy with corticosteroids should not be tapered below a dose of 15-20 mg/day for 2-3 months in patients who are beginning AZA or 6-MP. Concomi- tant therapy with mesalamine, sulfasalazine, olsala- zine, or balsalazide is continued in most cases.

Measurement of a total leukocyte count every 1-2 months as long as patients are receiving AZA or 6- MP is mandatory to monitor for leukopenia. Indica- tions for treatment with AZA or 6-MP in patients with UC include: induction of remission in steroid- refractory disease; steroid sparing in steroid-depen- dent disease; and maintenance of remission in patients who have failed maintenance therapy with high-dose mesalamine, sulfasalazine, olsalazine, or balsalazide.

Transdermal nicotine may be of benefit as an alternative to AZA or 6-MP in patients with active UC refractory to mesalamine, sulfasalazine, olsala- zine, balsalazide, and corticosteroids. Because non- smokers frequently experience side-effects from nicotine when initally beginning therapy, a dose escalation strategy in which patients are treated with 7 mg/day of transdermal nicotine for 1 week, then 14 mg/day for 1 week, then 21 mg/day is recommended.

Clinical trials have demonstrated efficacy for trans- dermal nicotine over 4-6 weeks of treatment. The

role of maintenance therapy with transdermal nico- tine beyond 6 weeks is unknown.

Severe ulcerative colitis

Severe UC is defined using the Truelove and Witts criteria' (Table 1) [14]. Toxic (fulminant) colitis is defined as the sudden extension of mucosal inflam- mation through all layers of the colonic wall to the serosa and presents clinically as focal visceral tender- ness to deep palpation. Megacolon is defined as dilation of the colon (5-6 cm or more) demonstrated by X-ray and presents clinically as abdominal disten- sion, decreased or absent bowel sounds, and in some cases decreased stool frequency. Approximately 10%

of all patients with UC will develop a severe flare at some point in their disease course, whereas only 1- 2% progress to toxic (fulminant) colitis and/or mega- colon. The mortality for severe UC is 2%, but remains approximately 30% for toxic (fulminant) colitis.

In patients with severe or toxic colitis, hospitaliza- tion is mandatory. The treatment regimen outlined by Truelove and Jewell, consisting of intravenous fluids, electrolyte supplements, bowel rest, transfu- sion if indicated, intravenous antibiotics, intrave- nous corticosteroids, and rectal corticosteroids, remains in use today [136], although controlled trials have demonstrated that intravenous antibiotics are not of benefit. Sixty percent of patients treated with this regimen will be symptom-free by the end of 5 days, 15% will have significant improvement, and 25% will not improve and should be treated with cyclosporine or surgery.

Most patients hospitalized with severe UC should continue to receive a normal diet. Two randomized controlled trials have demonstrated that bowel rest does not affect the outcome of severe UC in patients treated with intravenous prednisone [307, 308].

Patients with toxic colitis or megacolon should be made nil per os because of the potential for eminent surgical intervention. Peripheral or central intrave- nous nutrition should be instituted if there is evidence of malnutrition. The goal of intravenous nutrition is to replace nutritional deficits rather than for any primary therapeutic benefit.