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KP PP Ibd
KP PP Ibd
Review
Abstract:
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which includes Crohn’s disease
(CD) and ulcerative colitis (UC). These diseases have become important health problems. Medical therapy for IBD has advanced
dramatically in the last decade with the introduction of targeted biologic therapies, the optimization of older therapies, including
drugs such as immunomodulators and 5-aminosalicylic acid (5-ASA), and a better understanding of the mucosal immune system and
the genetics involved in the pathogenesis of IBD. The goal of IBD therapy is to induce and maintain remission. The current treatment
paradigm involves a step-up approach, moving to aggressive, powerful therapies only when milder therapies with fewer potential
side effects fail or when patients declare themselves to have an aggressive disease. This review focuses on the current treatments for
inflammatory bowel disease.
Key words:
inflammatory bowel disease (IBD), 5-aminosalicylates, corticosteroids, infliximab
Abbreviations: 5-ASA – 5-aminosalicylic acid, CD – Crohn’s is associated with a spectrum of extraintestinal mani-
disease, CDAI – Crohn’s disease activity index, CRP – C- festations, including arthritis, ankylosing spondylitis,
reactive protein, DHA – docosahexaenoic acid, DNBS – 2,4-
sclerosing cholangitis, uveitis, iritis, pyoderma gan-
dinitrobenzene sulfonic acid, EPA – eicosapentaenoic acid,
IBD – inflammatory bowel disease, IgE – immunoglobulin E, grenosum, and erythema nodosum. The pathogenesis
IL – interleukin, MMF – mycophenolate mofetil, NF-kB – nu- of IBD likely involves genetic, environmental, and
clear factor kappa B, SCG – sodium cromoglycate, TNF – tu- immunological factors [9, 16, 36]. Macrophages play
mor necrosis factor, UC – ulcerative colitis
a primary role in the formation of noncaseous epithe-
lioid granulomas in the intestinal mucosa. Activated
macrophages produce cytokines, such as TNF-a, in-
terleukins (IL-6, IL-8), and others [44]. Current drug
Introduction treatments aim to induce and maintain the patient in
remission and ameliorate the disease’s secondary ef-
Inflammatory bowel diseases (IBDs), which include fects, rather than modifying or reversing the underly-
Crohn’s disease (CD) and ulcerative colitis (UC), are ing pathogenic mechanism [21]. Corticosteroids, ami-
chronic inflammatory diseases of the gastrointestinal nosalicylates, and immunosuppressive agents, such as
tract and are characterized by chronic recurrent ul- azathioprine, are routinely used [24]. Other drugs,
ceration of the bowels [16]. IBD causes significant such as metronidazole and broad-spectrum antibiot-
gastrointestinal symptoms, including diarrhea, ab- ics, are helpful in some cases, while colestyramine,
dominal pain, bleeding, anemia, and weight loss. IBD sodium cromoglycate, bismuth and arsenical salts,
role in preventing relapses once remission has been tion; therefore, folate usually is given with sulfasa-
achieved. In general, newer 5-ASA preparations have lazine. The newer mesalamine formulations are gen-
similar therapeutic efficacies in UC with fewer side ef- erally well tolerated, and side effects are relatively
fects. Because they lack the dose-related side effects of infrequent and minor. Headache, dyspepsia, and skin
sulfapyridine, the newer formulations can be used to rash are the most common side effects. Diarrhea ap-
provide higher doses of mesalamine, which leads to pears to be particularly common with olsalazine (oc-
some improvement in disease control. To treat active curring in 10 to 20% of patients); this may be related
diseases, olsalazine is typically administered at a dose to its ability to stimulate chloride and fluid secretion
of 800 mg three times a day, and balsalazide is gener- in the small intestine. Nephrotoxicity, although rare, is
ally administered at a 1-g dose given four times a day. a more serious concern. Mesalamine has been associ-
The efficacy of 5-ASA preparations (e.g., sulfasa- ated with interstitial nephritis; while its pathogenic
lazine) in CD is less striking, with a modest benefit at role is controversial, renal function should be moni-
best in controlled trials. Sulfasalazine has not been tored in all patients receiving these drugs. Both sul-
shown to be effective in maintaining remission and fasalazine and its metabolites cross the placenta but
has been replaced by newer 5-ASA preparations. have not been shown to harm the fetus. Although they
Some studies have reported that both olsalazine and have not been studied as thoroughly, the newer formu-
balsalazide are more effective than a placebo in in- lations also appear to be safe during pregnancy [41].
ducing remission in patients with CD (particularly co-
litis), although higher doses than those typically used Corticosteroids
in UC are required. The role of mesalamine in mainte-
nance therapy for CD is controversial, and there is no The glucocorticoid properties of hydrocortisone and
clear benefit of continued 5-ASA therapy in patients prednisolone are the mainstay of IBD treatment. The
who achieve medical remission [6]. Because they preferred steroid is prednisolone, administered orally,
largely bypass the small intestine, prodrugs such as rectally or parenterally in emergency situations. Corti-
olsalazine and balsalazide do not have a significant costeroids can be used either alone or in combination
effect in CD of the small intestine. with a suitable mesalamine formulation to induce and
Topical preparations of mesalamine suspended in maintain remission in inflammatory bowel disease.
a wax matrix suppository or in a suspension enema are The incidence of adverse effects appears to increase
effective in active proctitis and distal UC, respectively when prednisolone doses are higher than 40 mg/day.
[64]. They appear to be superior to topical hydrocorti- An alternate-day regimen is helpful because it reduces
sone in this setting, with response rates of 75 to 90%. adrenal suppression. Azathioprine, with its steroid-
Mesalamine enemas (4 g/60 ml) should be used at bed- sparing property, may be introduced together with
time and retained for at least eight hours; the supposi- a lower dose of steroids [41]. The response to steroids
tory (500 mg) should be used two to three times a day in individual patients with IBD divides them into three
with the objective of retaining it for at least three hours. general classes: steroid-responsive, steroid-dependent,
Responses to local therapy with mesalamine may occur and steroid-unresponsive. Steroid-responsive patients
within three to 21 days; however, the usual course of improve clinically, generally within one to two weeks,
therapy is from three to six weeks. Once remission has and remain in remission as the dose of steroids is ta-
occurred, lower doses are used for maintenance. pered and discontinued. Steroid-dependent patients
Side effects of sulfasalazine occur in 10 to 45% of also respond to glucocorticoids but experience a re-
patients with UC and are primarily related to the sulfa lapse of symptoms as the steroid dose is tapered [1].
moiety. Some side effects are dose-related, including Steroid-unresponsive patients do not improve even
headache, nausea, and fatigue. These reactions can be with prolonged high doses of steroids. Approximately
minimized by administering the medication with 40% of patients are steroid-responsive, 30 to 40%
meals or by decreasing the dose. Allergic reactions in- have only a partial response or become steroid-
clude rash, fever, Stevens-Johnson syndrome, hepati- dependent, and 15 to 20% of patients do not respond
tis, pneumonitis, hemolytic anemia, and bone marrow to steroid therapy. Steroids are sometimes used for
suppression. Sulfasalazine reversibly decreases the prolonged periods to control symptoms in steroid-
number and motility of sperm but does not impair fe- dependent patients. However, failure to respond to
male fertility. It also inhibits intestinal folate absorp- steroids with prolonged remission (i.e., a disease re-
The packaging of these agents in a pH-sensitive coat- equally effective in both CD and UC. These drugs ef-
ing (similar to that used for 5-ASA preparations) of- fectively maintain remission in both diseases; they
fers the possibility of drug delivery to the small intes- may also prevent (or, more typically, delay) recur-
tine and right colon with few side effects [24]. rence of CD after surgical resection. The decision to
initiate immunosuppressive therapy depends on an ac-
Immunosuppressants curate assessment of the risk to benefit ratio.
For both azathioprine and mercaptopurine, the ini-
Several drugs initially developed for cancer chemo- tial dosage is 50 mg per day. A therapeutic benefit
therapy or as immunosuppressive agents in organ usually occurs at dosages of 50 to 100 mg per day for
transplants have been adapted for the treatment of mercaptopurine and 75 to 150 mg per day for azathio-
IBD. Immunosuppressant drugs can be an invaluable prine. Mild leukopenia suggests that the drug is effec-
adjunct therapy for the treatment of patients with in- tive and therefore more likely to benefit the patient. It
tractable inflammatory bowel disease or complex, in- is prudent to obtain a complete blood count every two
operable perianal disease. Although immunosuppres- weeks during the initial treatment phase in patients
sant agents have significant side effects, they are safer with active disease and every three months in patients
and better tolerated than long-term corticosteroid on maintenance therapy [31]. Drug-induced pancrea-
therapy. However, these agents should not be used in titis occurs in 3 to 5% of the patients, invariably dur-
young patients who are candidates for surgery or in ing the first six weeks of azathioprine or mercaptopu-
patients who are noncompliant and refuse to return for rine therapy [23]. Pancreatitis is a contraindication for
periodic monitoring. Before immunosuppressant ther- continued use of these agents. One large, retrospec-
apy is initiated, side effects and other treatment alter- tive review failed to find a significant association be-
natives should be discussed with the patient. At this tween azathioprine and the development of lym-
stage, it is best to set a definable goal, such as closure phoma or leukemia [8, 17].
of a fistula or tapering the patient off of corticoster- For more than 20 years, low-dose methotrexate
oids, and a minimum three-month time frame should therapy has been used in patients with intractable pso-
be set to reach that goal [41]. riasis and rheumatoid arthritis. Methotrexate was en-
Since the early 1970s, azathioprine and mercapto- gineered to inhibit dihydrofolate reductase, thereby
purine have been used to treat IBD. These drugs are blocking DNA synthesis and causing cell death. First
superior to the placebo, but their full effects may not used in cancer treatment, methotrexate was subse-
become apparent for as long as three months. quently recognized to have beneficial effects in auto-
Azathioprine and mercaptopurine are beneficial in 50 immune diseases such as rheumatoid arthritis and pso-
to 70% of patients with intractable perianal CD [1]. riasis. The anti-inflammatory effects of methotrexate
Less information is available about their effectiveness may involve mechanisms in addition to its inhibition
in treating UC, although they have been beneficial in of dihydrofolate reductase. One study showed that
patients with this disease. The cytotoxic thiopurine this treatment was beneficial in 70% of patients with
derivatives mercaptopurine (6-MP) and azathioprine severe IBD [14]. The response to methotrexate ap-
are used to treat patients with severe IBD or those peared to be more rapid than the response to mercap-
who are steroid-resistant or steroid-dependent [45]. topurine. Methotrexate is given weekly as an intra-
These thiopurine antimetabolites impair purine bio- muscular injection of 15 to 25 mg. Side effects are
synthesis and inhibit cell proliferation. Both are rare and include leukopenia and hypersensitive inter-
prodrugs; azathioprine is converted to mercaptopu- stitial pneumonitis. Hepatic fibrosis is the most severe
rine, which is subsequently metabolized to 6-thio- potential side effect of long-term therapy. Patients
guanine nucleotides, which are the presumed active with concomitant alcohol abuse and/or morbid obe-
moiety. These drugs are generally used interchangea- sity are more likely to develop hepatic fibrosis and
bly with appropriate dose adjustments; typically, therefore should not be treated with methotrexate. It is
azathioprine is administered at a dose of 2 to prudent to obtain a baseline chest radiograph and to
2.5 mg/kg and mercaptopurine is given at a dose of monitor the patient’s complete blood count, liver
1.5 mg/kg. Because of concerns of side effects, these function, and renal function every two weeks until the
drugs were used initially only in CD, which lacks patient is receiving oral therapy and every one to three
a surgical curative option. They now are considered months thereafter. Before methotrexate therapy is ini-
vated serum inflammatory maker CRP. Infliximab is a false-negative skin test has been noted in some pa-
a chimeric immunoglobulin (25% mouse, 75% hu- tients with CD, and some experts routinely perform
man) that binds to and neutralizes TNF-a, and it rep- chest radiographs to look for active or latent pulmo-
resents a new class of therapeutic agents for treating nary disease. Infliximab is also contraindicated in pa-
IBD [60]. Although many pro- and anti-inflammatory tients with severe congestive heart failure (New York
cytokines are generated in the inflamed gut in IBD, Heart Association classes III and IV) and should be
there is some rationale for targeting TNF-a because it used cautiously in class I or II patients. As with the
is one of the principal cytokines mediating the T01 immunosuppressant drugs, there are concerns about
immune response characteristic of CD. Infliximab the possible increased incidence of non-Hodgkin’s
(5 mg/kg infused intravenously at intervals of several lymphoma, but a causal role has not been established.
weeks to months) decreases the frequency of acute Finally, the significant cost of infliximab is an impor-
flare-ups in approximately two-thirds of patients with tant consideration for some patients [24, 41].
moderate to severe CD and facilitates the closing of Adalimumab is an anti-TNF agent similar to in-
enterocutaneous fistulas associated with CD [47]. Its fliximab and decreases inflammation by blocking
long-term role in CD is evolving, but emerging evi- TNF-a. In contrast to infliximab, adalimumab is
dence supports its efficacy in maintaining remission a fully humanized anti-TNF antibody (no mouse pro-
[48] and in preventing recurrence of fistulas [54]. Al- tein). Adalimumab is administered subcutaneously in-
though infliximab was specifically designed to target stead of intravenously, as in the case of infliximab.
TNF-a, it also may have more complex actions. In- Adalimumab is comparable to infliximab in effective-
fliximab binds membrane-bound TNF-a and may ness and safety for inducing and maintaining remis-
cause lysis of these cells by antibody-dependent or sion in patients suffering from Crohn’s disease (CD).
cell-mediated cytotoxicity. Thus, infliximab may de- Adalimumab is also effective in healing anal fistulas
plete specific populations of subepithelial inflamma- in patients with CD. Adalimumab is well tolerated
tory cells. These effects, together with its mean termi- and has been shown to be effective for patients who
nal plasma half-life of eight to 10 days, may explain cannot tolerate infliximab. The most common side ef-
the prolonged clinical effects of infliximab. fect is skin reactions at the site of injection, such as
The use of inflixamab as a biological response swelling, itching, or redness. Other common side
modifier raises several important considerations. Both effects include upper respiratory infections, sinusitis,
acute (fever, chills, urticaria, or even anaphylaxis) and and nausea. Rare cases of lymphoma and nervous sys-
subacute (serum sickness-like) reactions may develop tem inflammation have been reported with the use of
after infliximab infusion. Anti-double-stranded DNA adalimumab. Symptoms of nervous system inflamma-
antibodies develop in 9% of patients, but a frank tion may include numbness and tingling, vision dis-
lupus-like syndrome occurs only rarely. Antibodies to turbances, and weakness in the legs. Some patients
infliximab can decrease its clinical efficacy; strategies receiving adalimumab may rarely develop symptoms
to minimize the production of these antibodies (e.g., that mimic systemic lupus; these symptoms include
treatment with glucocorticoids or other immunosup- skin rash, arthritis, chest pain, or shortness of breath.
pressives) may be critical to preserving infliximab ef- These lupus-like symptoms resolve after cessation of
ficacy for either recurrent or chronic therapy [11]. drug treatment. In a randomized, double-blind,
Other proposed strategies to overcome the problem of placebo-controlled trial, adalimumab was more effec-
antibody resistance include increasing the dose of in- tive than the placebo in maintaining clinical remission
fliximab or decreasing the interval between infusions. for patients with moderate-to-severe CD through 56
Infliximab therapy is associated with the increased in- weeks. In this study, adalimumab demonstrated sus-
cidence of respiratory infections; of particular con- tained maintenance of clinical remission, improve-
cern in infliximab treatment is the potential reactiva- ments in quality of life, and reductions in hospitaliza-
tion of tuberculosis or other granulomatous infections tion during long-term treatment for CD, with no new
with subsequent dissemination. It is recommended safety concerns identified [43].
that candidates for infliximab therapy be tested for Certolizumab pegol is a monoclonal antibody directed
latent tuberculosis with purified protein derivatives, against TNF-a. More precisely, it is a PE (polyethylene)
and patients who test positive should be treated pro- gylated Fab’ fragment of a humanized TNF-inhibiting
phylactically with isoniazid. However, anergy with monoclonal antibody; this PE gylation increases the
and individual diets modified. Not all types of diar- given SCG orally (240 mg daily) for a period of two
rhea in the IBD patient are the same; therefore, it is to three years. During the course of two to three years
essential to tailor therapies according to the presumed of observation, 93% of the patients showed remission
etiologies. Antidiarrheal agents are not recommended maintenance due to oral SCG therapy [38].
in extremely ill patients and those with known hyper-
sensitivities or evidence of colonic obstruction or di- Bismuth salts
lation, fever, or abdominal tenderness. Concomitant
use of loperamide with diphenoxylate and atropine Bismuth subsalicylate citrate and bismuth chelate, ad-
should be avoided in early pregnancy. Loperamide or ministered as enemas, are effective treatments for UC.
diphenoxylate can be used to reduce the frequency of Bismuth salts inhibit sulfatase and sialidase enzymes,
bowel movements and relieve rectal urgency in pa- which are secreted by colonic bacteria, and contribute to
tients with mild disease; these agents are contraindi- the process of mucus degradation. Bismuth also demon-
cated in patients with severe disease because they strates cytoprotective properties through a mechanism
may cause patients to develop toxicity to megacolon that increases tissue prostaglandin levels. In a pro-
anticholinergic agents (e.g., dicyclomine hydrochlo- spective open study, 15 patients with UC who were
ride), which are used to reduce abdominal cramps, unresponsive to conventional therapy were treated
pain, and rectal urgency. As with the antidiarrheal with enemas containing bismuth subsalicylate (700 or
agents, they are contraindicated in severe disease or 800 mg daily). Nine out of the 15 patients showed
when obstruction is suspected. Codeine, diphenoxy- a significant clinical response, and six went into com-
late, and loperamide should be used cautiously to treat plete clinical remission after eight weeks of treatment.
diarrhea and abdominal cramping in inflammatory Sigmoidoscopic appearances of the rectal mucosa
bowel disease because their use may mask inflamma- showed improvement in nine out of 15 patients at two
tion, infection, obstruction, or colonic dilatation, thereby weeks, and 11 out of 15 patients at eight weeks. The
delaying an accurate diagnosis. mucosa appeared normal in six out of 15 patients at
Cholestyramine can be used to prevent bile salt- eight weeks. A reduction in the oral prednisolone dos-
induced colonic secretions in patients who have under- age from a median of 15 mg daily (range 10 to
gone limited ileocolic resections. Following ileal resec- 35 mg daily) to 6 mg daily (range 0 to 18 mg daily)
tion, colestyramine has been used in CD to decrease di- was also shown to be effective after eight weeks of
arrhea associated with bile-acid malabsorption caused treatment; five patients were no longer taking oral
by the decrease in the small bowel absorptive surface steroids at this time. Rectal bismuth subsalicylate ap-
area and the cathartic effect of bile salts on the colon. pears to be an effective therapy in UC and controlled
At doses of up to 4 g three times a day, it inhibits bile- trials are now required. Similarly, arsenic salts, par-
acid stimulated secretion of water and electrolytes. ticularly acetarsol in the form of 250 mg supposito-
ries, have been used successfully to treat 172 patients
Sodium cromoglycate with ulcerative proctitis, but their toxicity limits their
use. Acetarsol is bactericidal and chemically similar
Sodium cromoglycate (SCG) reduces degranulation to bismuth, which may account for its method of ac-
of mast cells by inhibiting the passage of calcium ions tion [50].
across cell membranes, a process essential for the re-
lease of inflammatory mediators from mast cells. In- Thalidomide
testinal lesions contain mast cells, macrophages, and
eosinophils, and rectal biopsies show large numbers The use of thalidomide has been restricted to moni-
of IgE plasma cells in the lamina propria. SCG was tored refractory cases of CD [38]. It acts as a TNF-a
applied intrarectally for the treatment of UC in 39 pa- inhibitor and probably stabilizes lysosomal mem-
tients with an active pathological process. The drug branes. Additionally, at therapeutic doses, thalidomide
was insufflated by means of a rectoscopic tube at inhibits the formation of superoxide and hydroxyl radi-
a dosage of 200 mg daily for 15 days. Complete re- cals, which are potent oxidants capable of causing tis-
mission of the disease was achieved in 97% of pa- sue damage. Thalidomide treatment (200 mg/kg per
tients within two weeks of the administration of the oral) reverses the development of experimental colitis
drug. As a maintenance treatment, the patients were induced by DNBS in mice [39]. This evidence may
Fish liver oils, which contain EPA and DHA, have Probiotics are a mixture of putatively beneficial lyo-
been used with some success in the treatment of both philized bacteria that are given orally. Although pro-
UC and CD. UC is accompanied by an increased level biotics are a promising alternative to more conven-
of leukotriene B4 in the lining of the colon. Fish oils tional therapies for inflammatory bowel disease, their
are known to inhibit the synthesis of leukotrienes. It role in treating IBD requires further evaluation. In one
has therefore been postulated that fish oils might be study, they diminished the occurrence of pouchitis,
beneficial in the treatment of UC. One study evalu- a common inflammatory condition that occurs in sur-
ated the responses of 11 male patients aged 31 to 74 gically created ileal reservoirs after total proctocolec-
years who had been diagnosed with UC [37]. The pa- tomy for the treatment of UC [19]. Probiotics reside
tients were randomized into two groups with one in the gut and have been found to be effective in man-
group receiving 15 fish oil capsules (providing 2.7 g aging UC. Additionally, they help to control the
of EPA and 1.8 g of DHA daily); the other group re- number of potentially harmful bacteria, reduce in-
ceived placebo capsules (olive oil). After three flammation, and improve the protective mucus lining
months on the supplements, all participants under- of the gut [10]. Probiotics are among the more popu-
went a two-month wash-out period and were then as- lar remedies because they are without significant side
signed to the opposite treatment from what they had effects and appear to be safe [26]. In one study, 34
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