Abstract
Crohn’s disease is a relapsing GIT chronic inflammatory disease of unknown aetiology and no gender or race preference. Although the cause is unknown; however, the increased understanding of the inflammatory immune mechanisms leads to developing new treatment modalities. The aim of this essay is to provide a brief yet a comprehensive review on Crohn’s disease focusing on Crohn’s perianal disease, immune-suppressant drugs and the newly developed biological agents.
Introduction
Crohn’s disease is a relapsing chronic inflammatory disease of the gastrointestinal tract, which may involve any part but commonly affects the ileum. The inflammation of Crohn’s disease relates to that observed in other immune diseases as rheumatoid arthritis. In Crohn’s disease, the body recognizes proteins available in the environment (like bacteria, or food elements) as foreign proteins (antigen). Thus, developing the disease depends on the interaction between the host and the environmental antigen. Genetic factors are significant risk factors of the disease as shown by familial studies and studies on monozygotic twins. The most known gene is on chromosome 16 (NOD2/CARD15), which is responsible for the identification of luminal bacteria products and is essential for gastrointestinal mucosa defence.
Perianal disease in Crohn’s disease
Population-based studies varied in estimating the prevalence of perianal disease in patients with Crohn’s disease from 12 to 14% to 21-23 %. One of the reasons for these differences is the multiple features of perianal disease in patients with Crohn’s disease. The perianal disease may take the form of skin tags that vary in size up to the known elephant ears tags, it may represent features of haemorrhoides, perianal fissure, and anal ulcer. Perianal fistulae are either low or high based on their position in relation to the dentate line, anorectal abscess may either precede or complicate a fistula; besides, an anorectal fistula may extend to the vagina resulting in the rectovaginal fistula. Anorectal stricture or malignancy may complicate non-healing anorectal fistula. The causes of anorectal disease in Crohn’s disease are largely unknown but may result from the infected or inflamed anal gland. Alternatively, a fistula may result from the extension (penetration) of a fissure or an ulcer into the rectum or anal canal.
About diagnosis, the perianal disease may precede other features of Crohn’s disease, further, early diagnosis and management are essential since consequences like necrotising fasciitis are serious. Although many patients present with minor perianal problems as skin tags or haemorrhoides; yet, most commonly they present with features of perianal sepsis-like abscess formation from perianal to ischiorectal. Septic features commonly complicate obstructed fistula opening and are characterised by severe perianal pain in absence of significant clinical findings. Radiological imaging is the key to diagnosis; however, fistulography and pelvic CT scanning are not sensitive to delineate the fistula.
Therefore, external coil MRI is advised instead of internal coils to avoid pain, endo-anal ultrasonography is best used in patients with perianal pain or anorectal stenosis and is especially valuable to detect anorectal sphincter defects. Examination under anaesthesia remains an excellent diagnostic tool as it provides the clinician with anatomical diagnosis and be able to classify the disease. Treatment can be either medical or surgical; the medical treatment algorithm comprises early treatment of the underlying Crohn’s disease, hygienic procedures, bowel regulation, antibiotics, immunomodulators and infliximab. Surgical treatment of perianal Crohn’s disease may be an emergency as in abscess cases; otherwise, it should be borne in mind there is no curable treatment for Crohn’s disease. Therefore, the objective of surgery should be to improve symptoms and decrease the risk of complications like stricture formation or incontinence that may complicate aggressive surgery. Thus, a conservative surgery often results in better outcomes.
Immune-suppressant treatment of Crohn’s disease
The basic immune mechanism of Crohn’s disease is that it is a T-cell immune disorder. T-cells develop in the thymus gland where they undergo a receptor arrangement process, by which each T-cell become specifically responsive to a limited number of antigens. The disturbed immune mechanism in Crohn’s disease is these cells become responsive against commensal gut flora; therefore, immune-suppressant drugs are the mainstay of treatment.
The immune-suppressant drugs used for long-term or lifelong treatment are azathioprine and 6-mercaptopurine, which are specifically useful in perianal disease. Their serious side effects are mainly bone marrow depression, impairment of liver functions and pancreatitis. Therefore, before administering these drugs, the patient should have a blood count, abdominal ultrasonography, liver function tests and serum amylase. Methotrexate and cyclosporine are immune-suppressant drugs administered when the disease is resistant to other medications. However, both drugs may cause liver and kidney damage, hypertension and serious infection with cyclosporine causing specifically may cause a serious brain infection known as leuko-encephalopathy. Therefore, liver and kidney functions are advisable before treatment, besides, regular blood pressure measurements.
Corticosteroids are effective anti-inflammatory immune-suppressant agents but because of long-term use side effects like type 2 diabetes, hypertension, iatrogenic cataract, osteoporosis and increased risk for infection, they are not given for life or long-term treatment. They are reserved for moderate to severe cases where other medications fail to induce a remission usually for three to four months. The patient needs to do blood glucose level, x-rays to long bones in addition to thorough general examination before drug administration.
The following points to look for are the extra-intestinal features of Crohn’s disease; the commonest are episcleritis, osteoporosis, papulopustular skin lesions, aphthous ulceration and bronchiectasis. Therefore, a thorough general examination has to be done with a chest x-ray before deciding to administer an immune-suppressant agent.
Finally, as all these agents can be teratogenic or at least classified by the FDA as pregnancy class B agents (potentially teratogenic but with no documentation), a female patient with amenorrhoea must perform a pregnancy test before drug administration.
Biological agents: How useful they are
Biological therapeutic agents are medications that stimulate or re-establish the ability of the immune system to fight disease. Therefore, its action is to repair, or uplift the body defenses. They are classified according to the disease’s biological mechanism targeted into four categories. First is the human monoclonal anti-tumour necrosis factor (TNF) group, which can bind either to membrane-bound TNF of plasma cells or T-lymphocytes (TNF positive cells) causing cell apoptosis (death) like adalmumab. This drug is a human IgG1 antibody, therefore less antigenic than infliximab, which is a genetically engineered IgG1 chemric (75% human protein and 25% murine protein) monoclonal antibody against circulating TNF-alpha. This tumour necrosis factor is thought to play an important in both the initiation and progression of Crohn’s disease.
The second group is the cytokine inhibitors, the first example is the human anti-interleukin 12 (IL-12), interleukin-12 drive T-cells to T-helper (maximizes T-cell action); thus, remodels the inflammatory process. The third group is the drugs acting by selective adhesion molecule inhibition like natalizumab whose function is to neutralize alpha-4 integrin (a surface leucocytes receptor) responsible for adhesive interaction of the leucocytes to vascular endothelium. Thus, it prevents leucocytes migration to the intestinal lumen improving the inflammatory process. The last group is the CD3 monoclonal antibodies; vizilizumab is an example of this group whose action is to antagonize CD3 a T-cell receptor antigen involved in immune signal transfer. By this mechanism, it allows unprepared T-cells to proliferate and replace the disordered auto-reactive cells which are the principal cause of inflammation. Although most biological agents lack long-term safety data, however, evidence shows they result in fewer side effects than immune-suppressant medications. The drugs carry hope to Crohn’s disease patients because of therapeutic target specificity.
Step up and step-down treatment approach
Crohn’s disease categorization to mild, moderate and severe continued for decades with the main treatment objective being to induce a remission. With developments in treating ulcerative colitis evolved the concept of sequential Crohn’s disease treatment that is to induce remission and to maintain it. The concept of step up and step down (top-down) for treating Crohn’s disease evolved as an impact of introducing anti-TNF medication to clinical trials.
The basic concept of the step-up approach is to start treatment with traditional therapies like aminosalicylates being safer and well-tolerated in long-time treatment. When this fails, treatment shifts to steroids, in cases of failure or development of steroid dependence, and then treatment shifts to immune-suppressant drugs and anti-TNF medications. Step down (Top-down) suggests the opposite since anti-TNF drugs have the potential to control the disease and promote healing of the diseased mucosa; advocates of this approach suggest starting treatment with these agents. They have a point in the argument about cases with extra-intestinal Crohn’s disease features and cases associated with other autoimmune diseases like rheumatoid arthritis. To settle the debate, there is still a need for further clinical trials; many of them are going on.
Conclusion
Crohn’s disease is a relapsing chronic inflammatory gastrointestinal disease with no definite aetiology. It is characterised by the presence of an extra-intestinal feature, which may necessitate surgical treatment of perianal Crohn’s disease. The recent controversy in medical treatment is adopting a step up or top-down approach to treatment. Further research is still to decide the appropriate treatment strategy.
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