TREATMENT

Adverse Events of IBD TherapiesMaria Lia Scribano, MD

Medical treatment of Crohn’s disease (CD) and ulcerativecolitis (UC) includes a variety of drugs: aminosalicylates,

corticosteroids, antibiotics, immunosuppressors, and biologicalagents (anti-TNF [tumor necrosis factor]). Each kind of medi-cation has found a role in the therapy of these diseases, and thefirst objective in the treatment of patients is to maximize theefficacy of drugs, while minimizing their toxicity.

AminosalicylatesLarge clinical trials have shown that sulfasalazine

(SASP), a compound of 5-aminosalicylic acid (5-ASA, me-salamine) and sulfapyridine (SP), is more effective than pla-cebo in the treatment of patients with active inflammatorybowel disease (IBD). However, SASP therapy is accompa-nied by a relatively high incidence of side effects, mainlyconnected with SP, ranging from 10%–45% of treated pa-tients. The most common side effects are related to intoler-ance and include headache, nausea, dyspepsia, myalgias, andarthralgias. Skin rash, megaloblastic anemia, and fever,which are hypersensitivity reactions, can rarely occur also asa reaction to the mesalamine component. Reversible spermabnormalities are quite common in males.

The appearance of side effects and the uncertain effi-cacy of SASP when the disease is limited to the smallintestine have led to the elaboration of new products made upexclusively from 5-ASA. Several oral preparations of 5-ASAare available with good tolerability. In fact, only 10%–20% ofpatients intolerant to SASP show the same adverse eventswith mesalamine. Many side effects of 5-ASA, such as diar-rhea, headache, nausea, dyspepsia, skin rash, are not severe,but can be the cause of drug interruption.1 Diarrhea is re-ported with an incidence of between 4% and 6% and it isparticularly frequent with olsalazine (Dipentum), a formula-tion composed of 2 molecules of 5-ASA. Renal toxicity andpancreatitis are fortunately rare, but worrying.

CorticosteroidsThe toxic effects of corticosteroids are well known.2

During treatment of active CD, steroid-related adverse eventshave been reported in 55% of patients treated with pred-

nisolone 40 mg daily. The occurrence and severity of mostside effects are related to the dose and duration of treatment.Steroids can cause complications involving nearly every bodysystem. Common findings include fluid retention, acne, moonface, abdominal striae, weight gain, hypertension, hypergly-cemia, glaucoma, cataracts, and emotional disturbances.Musculoskeletal complications, such as osteoporosis, osteo-necrosis, and myopathy, are important side effects. Bone lossis a frequent and serious complication that occurs particularlyrapidly, within a few weeks to months after administration.Corticosteroid therapy also increases the risk of infections.

Because of the high rate of side effects produced by theclassical corticosteroids, new glucocorticoid derivatives, suchas budesonide, which act locally in the mucosa and have littlesystemic activity, have been introduced. Several controlledstudies have established the clinical value of budesonide inactive CD and have reported fewer steroid-related side effectsin the patients on budesonide compared to patients treatedwith systemic corticosteroids .

AntibioticsMany experimental and clinical data support an in-

volvement of intestinal flora in the pathogenesis of IBD and,consequently, antibiotics are employed in the treatment ofthese diseases.

Metronidazole, active against parasites and anaerobic bac-teria, is the most widely used antibiotic, especially in treatingperianal CD. However, the side effects of metronidazole remainof concern.3 Apart from short-term side effects in around 50% oftreated patients (gastrointestinal intolerance, metallic taste, reac-tion to alcohol), polyneuropathy secondary to metronidazolelimits long-term use. Side effects are generally reversible withdiscontinuation of the drug, except for the neuropathy that oc-casionally persists despite cessation.

Another antibiotic used in IBD is ciprofloxacin, a quin-olone derivative with a selective suppressive effect on theintestinal microflora. This antibiotic is better tolerated in theshort-term, but is associated with tendonitis and Achillestendon rupture, especially with concomitant steroids. Themost frequent side effects reported are of gastrointestinalorigin; skin reactions and an increase in transaminase levelhave been also described.

An interesting antibiotic recently introduced in the man-agement of IBD is rifaximin, a rifamycin derivative with a largeantimicrobial spectrum, characterized by a negligible intestinal

From the Gastroenterology Operative Unit, Azienda Ospedaliera S. Cam-illo-Forlanini, Rome, Italy.

Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc.DOI 10.1002/ibd.20702Published online in Wiley InterScience (www.interscience.wiley.com).

S210 Inflamm Bowel Dis ● Volume 14, Number S2, A Clinician’s Guide to IBD

absorption—less than 1% of the oral dose is excreted in theurine—conferring on it an excellent safety profile.

ImmunosuppressorsThe immunosuppressive agents azathioprine (AZA)

and its metabolite 6-mercaptopurine (6-MP) are used in pa-tients with steroid-dependent or refractory IBD. Cochraneand Pearson meta-analysis have shown that adverse events ofthese drugs cause withdrawal from the studies in 9% ofpatients. The adverse events can be divided as either non-dose-dependent (allergic/idiosyncratic) or dose-dependent.About 5%–10% of patients present allergic reactions, whichgenerally occur within the first month of treatment. These arepancreatitis, nausea, arthralgias, malaise, fever, abdominalpain, and skin rash. Some patients who report an allergicreaction to AZA can be successfully rechallenged with 6-MP,but that is not recommended for patients who report a pan-creatitis. The most common dose-dependent adverse event ismyelosuppression, generally manifested as leukopenia. Thewide range of frequency reported in the literature, from 2.2%to 15% of patients, is due to the different definitions ofleukopenia (�2000 versus �4000 mm3). Leukopenia maydevelop at any time during treatment, increasing the risk ofinfections, but generally responds to dose reduction or dis-continuation. Another relevant dose-dependent adverse eventis hepatic toxicity. The relationship between these drugs andlymphoma remains a controversial aspect. The risk of lym-phoma related to thiopurines appears to be small. However, ameta-analysis of 6 studies reported a 4-fold increase in theincidence of lymphoma in IBD patients treated with AZA or6-MP.4 The increased risk could be a result of the therapy, theseverity of the underlying disease, or a combination of the 2.

Methotrexate (MTX) is an immunosuppressor gener-ally used in patients with CD who are refractory or intolerantto the purine antimetabolites. The most frequent side effectsreported with the relatively low doses employed in CD arenausea, vomiting, stomatitis, and leukopenia. Serious com-plications of therapy can be hepatic fibrosis and hypersensi-tivity pneumonitis. MTX is contraindicated in pregnancybecause of severe side effects on both the fetus and the courseof the pregnancy.

Cyclosporin (CsA) is a potent immunosuppressiveagent with a prompt onset of action, mainly used in thetreatment of patients with severe UC refractory to steroidtherapy. The most common side effects reported in patientswith IBD treated with CsA include nephrotoxicity, opportu-nistic infections, hypertension, tremor, gingival hyperplasia,and seizures. Dose reduction is recommended in patients withlow serum cholesterol levels or who present adverse events.

Anti-TNF TherapyTNF-�, a proinflammatory cytokine involved in im-

mune regulation, plays a pivotal role in the inflammatory

cascade in IBD. The advent of biological therapies directedagainst TNF has initiated a new therapeutic era.

More safety data of patients treated with infliximab andadalimumab for IBD, rheumatoid arthritis, and other condi-tions are available, while the reported experience with Cer-tolizumab pegol is limited.

Infections are the main safety concern. Easily treatedupper respiratory tract and urinary tract infections occurcommonly with anti-TNF agents. However, more seriousinfections such as pneumonia, tuberculosis, sepsis, opportu-nistic fungal infections, and viral infections have been ob-served following their use. TNF antagonists should not begiven to patients with an active infection and all patients mustbe screened for latent tubercular infection before anti-TNFtherapy is initiated. Data from the large TREAT registrysuggest that the increased risk for serious infections in pa-tients treated with infliximab may be due to the severity ofCD in these patients and to the concomitant use of cortico-steroids and immunosuppressive drugs.5

The risk of lymphoma and malignancy has not beenconfirmed in the TREAT registry and an Italian study showedthat the risk of neoplasia in CD patients who had receivedinfliximab was comparable with CD patients never treatedwith infliximab. Recently, however, an association betweenthe use of infliximab along with thiopurines and the devel-opment of a rare, aggressive form of non-Hodgkin lym-phoma, classified as hepatosplenic T-cell lymphoma, hasbeen reported in young patients with IBD.

The formation of antibodies to infliximab may lead toacute and delayed infusion reactions and loss of response totreatment. The incidence of antibody formation can be reducedby scheduled maintenance therapy rather than episodic or on-demand administration, by concomitant use of immunosuppres-sive drugs, and by premedication with corticosteroids. Antibodyformation has been also reported with adalimumab, but it wasnot associated with an increase of side effects.

Other adverse events observed with the use of anti-TNFdrugs are liver function abnormalities, skin lesions, worsen-ing of congestive heart failure, rare hematologic events, andnew onset or exacerbation of demyelinating disorders.

REFERENCES1. Loftus EV, Kane SV, Bjorkman D. Systematic review: short-term ad-

verse effects of 5-aminosalicylic agent in the treatment of ulcerativecolitis. Aliment Pharmacol Ther. 2004;19:179–189.

2. Singleton JW, Law DH, Kelley ML Jr, et al. National CooperativeCrohn’s Disease Study: adverse reactions to study drugs. Gastroenter-ology. 1979;77:870–882.

3. Prantera C, Zannoni F, Scribano ML, et al. An antibiotic regimen for thetreatment of active Crohn’s disease: a randomized, controlled clinical trial ofmetronidazole plus ciprofloxacin. Am J Gastroenterol. 1996;91:328–332.

4. Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphomaamong inflammatory bowel disease patients treated with azathioprineand 6-mercaptopurine. Gut. 2005;54:1121–1125.

5. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections andmortality in association with therapies for Crohn’s disease: TREATregistry. Clin Gastroenterol Hepatol. 2006;4:621–630.

Inflamm Bowel Dis ● Volume 14, Number S2, A Clinician’s Guide to IBD Adverse Events of IBD Therapies

S211