Crohn’s Disease and Perianal Manifestations

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Table of Contents

Abstract
Introduction
Perianal Crohn’s disease
Immune-suppressive agents pre-therapy patient workup
Biological agents to treat Crohn’s disease
Step up and top-down (step down) approaches
Conclusion
References

Abstract

Crohn’s disease is a relapsing idiopathic chronic inflammatory disease affecting the gastrointestinal tract, commonly the ileum. A debilitating disease has serious physical and psychological health outcomes. New biologic agents carry the hope of effectively treating the disease; however, their safety profile still needs further research. The aim of this essay is to provide a brief review on Crohn’s disease highlighting perianal manifestations, patient work up before administering immune-suppressant drugs and the new biological agents.

Introduction

Crohn’s disease is an idiopathic chronic inflammatory disease of the gastrointestinal tract characterised by remissions and relapses. Its incidence varies in different parts of the world being more common in North America and Europe than in Africa and Asia. Many factors are blamed for its aetiology, environmental like smoking, diet, oral contraceptive, and non-steroidal anti-inflammatory drugs.

Bacteria, immunologic deregulation and genetic factors are also to blame; however, it appears that interaction of all factors combine together is more likely to cause the disease. The disease is 2-4 times more common in Jews, with an increased risk of Ashkenazi Jews among the Jewish population, and the white race preference over Africans has to lead to the conclusion that genetic factors are at least partly responsible for the disease.

Despite that, the disease never shows typical Mendelian distribution, the most likely responsible gene (NOD2/CARD 15) located on chromosome 16, which is responsible for the identification of luminal commensal bacteria products and is significant for gastrointestinal mucosa defence mechanisms¹.

Perianal Crohn’s disease

Perianal Crohn’s disease lesions occur in an area rich in lymphoid tissue especially around the ducts of anal glands. This is an area of slow transit of faecal material; thus, liquid faeces may pass through anal glands ducts interacting with local lymphoid tissue resulting in perianal lesions. Perianal Crohn’s disease can be classified as primary where the same disease process (idiopathic chronic inflammatory immune-mediated) is responsible for the perianal disease and thus reflect the disease activity.

Examples of primary perianal disease are Crohn’s fissures, ulcers and the ulcerated pile complex of Crohn’s disease, Crohn’s ulcers may be aggressive to extend to the vagina (rectovaginal fistulae). Secondary perianal Crohn’s lesion result as a mechanical or infective complication of the primary lesions, examples are perianal abscesses and fistulae secondary to deep ulcers, non-healing ulcers secondary to faecal contamination and anal strictures.

The third group is incidental perianal Crohn’s disease, which does not relate to the original disease like piles. Provided the disease is under control, 50% of fissures and intra-sphincteric fistulae heal either spontaneously (hygiene and medical treatment) or by simple surgical procedures like fistulotomy. However, the prognosis of fistulae with deep ulcers is poor as fistulae may be complicated with sepsis, sphincter destruction and incontinence².

History and physical examination are usually sufficient to establish a diagnosis, examination under anaesthesia may be necessary when perianal sepsis (abscess) is suspected because of severe tenderness and pain. Imaging techniques, ultrasound and endoscopy are helpful to locate disease not evident by examination, number, location and extent of perianal fistula (e) or their relationship to the anal sphincter. Endoscopy is helpful to diagnose active disease and to take a biopsy, x-rays with contrast media and fistulography can localise fistulae but do not determine their relationship to the sphincter.

Pelvic CT may be useful to diagnose abscesses but is not as accurate as MRI in diagnosing fistulae. Transperineal ultrasonography may be informative and avoids the pain produced by transrectal ultrasonography, being relatively a new technology further experience is needed to judge its efficacy³.

Treatment of perianal Crohn’s disease requires a multidisciplinary approach, medical treatment with antibiotics, immune-suppressant agents and infliximab combined with surgery, which may be an emergency to drain an abscess. Surgical treatment for fistulae or deep ulcers has to be conservative to avoid unnecessary complications like damage to the sphincter. A nutritionist may join the team for controlling the disease³.

Immune-suppressive agents pre-therapy patient workup

Crohn’s disease needs long-term treatment because of the relapsing nature of the disease. Medical treatment aims at inducing and maintaining remission, patients relapsing within 6-12 months after initial treatment often need long-term immunosuppressant medications. The most frequently used drugs are azathioprine, 6-mercaptopurine, methotrexate and cyclosporine⁴.

Pre-long-term immunosuppressant therapy workup aims at disease assessment and patient condition in the lights of the toxicity of drug (s) use plan. Disease assessment investigations include besides complete history and physical examination, complete blood counts, blood chemistry, inflammatory markers, G.I.T endoscopy, and radiological imaging. Pre-therapy investigations target the possible medication side effects⁵.

Before azathioprine or 6-mercaptopurine therapy, thiopurine methyltransferase enzyme should be assessed because patients with low enzyme levels are prone to bone marrow suppression⁶. The most significant side effects for these two drugs are dose-related bone marrow depression and hepatotoxicity; therefore, hepatic aminotransferases levels and complete blood count should be done before treatment. For methotrexate, the side effects are usually mild but leucopoenia, hepatotoxicity and interstitial pneumonitis may develop. Therefore, an x-ray chest, complete count and liver function test are advisable before starting treatment⁷.

For cyclosporine, hepatic toxicity, renal impairment, hypertension, fungus-caused pneumonia (carinii pneumonia) and opportunistic fungus infection are reported with varying incidence up to 51% of cases. Therefore, hepatic and renal function tests, chest x-rays, complete blood count are advisable⁸.

Biological agents to treat Crohn’s disease

Biological agents are drugs that modify the biological response of the immune system restoring the function of the deregulated T-lymphocytes or acting specifically on one disease mechanism. Scholmerich⁹ classified these drugs according to their mechanisms of action into six groups. First are drugs that inhibit pro-inflammatory cytokines like TNF (tumour necrosis factor) inhibitors and TNF antibodies, second are drugs that inhibit T-cells proliferation like interleukin-12 antibodies. Third are drugs that inhibit leucocytes trafficking and adhesion to vascular endothelium like alpha-4 integrin antibodies, fourth are growth factors and hormones like keratinocyte growth factors. Fifth are immuno-stimulating factors like G-CSF (filgrastim) and finally immuno-modulator group like interferon-alpha⁹.

Most of these drugs are on a clinical trial with only four drugs approved by the FDA until the end of 2008; therefore, the following discussion will focus on these drugs¹⁰. First is cetrolizumab, which is indicated to induce and maintain remission in patients with moderate to severe Crohn’s disease who showed unsatisfactory response to traditional treatment. The drug is a TNF-alpha blocking agent composed of a humanized antibody fragment conjugated to a glycol polymer.

Since TNF-alpha is a cytokine pro-inflammatory cytokine whose function is to initiate and maintain intestinal inflammation, the drug is capable of reducing the disease clinical features effectively. Although the drug did not show neutrophils degranulation, yet, its prolonged use carries a high risk of fungus and TB infections. The second drug is infliximab, which the FDA approved in 1998. Besides the mechanism of action described for cetrolizumab, infliximab causes activated T-lymphocytes apoptosis, which is the cause of the inflammatory process.

As the case with cetrolizumab, infliximab may cause an increased risk of serious infections like TB. In addition, being a hybrid (chimeric) monoclonal antibody (75% human and 25% mouse) there is a risk of hypersensitivity reactions on administration. Further, the drug is contraindicated in heart failure patients. Third is adalmumab, which is a genetically engineered humanised IgG1 monoclonal antibody that neutralizes TNF, besides it causes apoptosis of transmembrane positive TNF T-Helper cells. As with the other two drugs, there is a high risk of developing serious infections on long-term use.

Finally, is natalizumab, which is a genetically engineered humanised IgG4 monoclonal antibody neutralising alpha 4-integrin that is a surface antigen on leucocytes (except neutrophils). Thus, the drug inhibits the alpha-integrin 4 mediated adhesion of leucocytes to vascular endothelium decreasing their migration to the intestinal lumen. The most serious complication is multifocal leucoencephalopathy (opportunistic viral brain infection that might lead to death or severe disability)¹⁰.

Despite the high risk of serious infections with long-term use of these medications, yet they reduce the clinical features significantly, which helps restoring social integration of the patient and participation in school, work or leisure activity¹¹.

Step up and top-down (step down) approaches

The views of step up and top-down approaches to treat Crohn’s disease are two different concepts. Figure 1 represents the difference in treatment plans¹². In the top-down approach, patients are treated early with biological agents seeking earlier recovery and social integration of patients. However, the main concern of this approach is the higher incidence of serious infections like TB and fungus infections.

In the step-up approach, treatment starts with 5-ASA, steroids, and steroid-dependent or failing treatment, therapy escalates to biological agents. The controversy represents the uncertainty of an ideal treatment strategy for Crohn’s disease. Therefore, some authorities suggested a midway strategy called the accelerated step-up approach, its basis is weighing the benefits and harms in the light of each patient’s status that is to stratify patients according to the risk and tailor a treatment plan individually¹³.

Figure (1): Step up and top down concepts for treatment of Crohn’s disease. Adapted from Etchevers et al, 2008

2) Top-down approach to treatment;
1) Step up approach to treatment.

Conclusion

Crohn’s disease is a chronic inflammatory gut disease that causes high morbidity and affects the social integration of patients. New treatment developments are effective; however, there is still a need for long-term trials to demonstrate safety and efficacy. Controversies about treatment concepts should direct researchers towards a common treatment strategy.

References

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Rutgeerts P. Review article: treatment of perianal fistulising Crohn’s disease. Aliment Pharmacol Ther. 2004; 20(suppl 4): 106-110
Khaikin M, Chowers Y and Zmora O. Perianal Crohn’s Disease. IMAJ. 2007; 9: 163-168
Vermeire S, Van Assche G and Rutgeerts, P. In Bernstein C (editor). Inflammatory Bowel Disease Year Book (volume3). London: Remedica Publishing Limited 2006; 91-93
Lichtenstein GR, Hanauer SB and Sandborn WJ. Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2009; 104: 465-483
Holme SA, Duley JA, Sanderson J et al. Erythrocyte thiopurine methyltransferase assessment prior to azathioprine use in the UK. Q J Med. 2002; 95: 439-444
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Carter MJ, Lobo AJ, Travis SPL et al. Guidelinelines for the management of inflammatory bowel disease in adults. Gut. 2004; 53(suppl V): v1-v16
Scholmerich J. Biological therapies. In Bernstein C (editor). Inflammatory Bowel Disease Year Book (volume3). London: Remedica Publishing Limited 2006; 111-134
Floyd JH. Current Treatment of Crohn’s Disease with an emphasis on the Biological Agents. cjhp. 2008; 8-17
Kogan A. Evidence-Based Update on Treatment Armamentarium for Crohn’s Disease. Journal of Managed Care. 2007; 10(3): 36-42
Etchevers MJ, Aceituno M and Sans M. Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease. World Gastroenterol J. 2008; 14(36): 5512-5518
Shergill, AK and Terdiman P. Controversies in the treatment of Crohn’s disease: The case for an accelerated step-up treatment approach. World Gastroenterol J. 2008; 14(17): 2670-2677

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