| Abstract|| |
Crohn disease is a chronic illness that affects the gastrointestinal tract from the mouth to the anus. Perianal Crohn develops in 31-94% of patients over the course of their illness. It affects the skin in the perianal area, the anal canal and can cause fistulae. It is diagnosed clinically and by other modalities like endoscopy, barium CT scan, endoscopic sonography and magnetic resonance image examination. The treatment of perianal Crohn disease is either medical or surgical. The current medical treatment will be reviewed in this article
Keywords: perianal Crohn disease
|How to cite this article:|
Al-Ghamdi AS. Medical treatment of perianal crohn disease. Saudi J Gastroenterol 2002;8:74-80
Crohn disease is a transmural granulomatous process that may involve any portion of the alimentary tract, from the mouth to the anus  . First described in 1913 by the Scottish surgeon Dalziel and described at 1932 by the American physician crohn  . Crohn disease is an inflammatory disorder of the bowel of unknown cause. It seems to result from stimulation of the intestinal immune cascade in genetically susceptible individuals. Although the specific antigen perpetuating this inflammatory response is unclear, over activation of the enteric immune and inflammatory pathways results in chronic mucosal damage 
Crohn disease involves predominantly the terminal ileum and, in most cases, stops abruptly at the ileocecal valve.
In the colon, it affects mainly the right side and may spare the rectum. Patchy or segmental disease can affect the transverse, descending, and sigmoid colon. In some cases, the rectum also may be diseased. The appendix frequently is involved, and perianal disease is present in as many as 25% of patients 
Perianal or anorectal disease is a primary feature of Crohn disease, with a prevalence of 8% to 90%, and The relative incidence ranges from 15% to 80% in the literature, typically is considered to afflict approximately one in three patients. More than half of patients with colonic involvement will have anal complications, whereas in less than 20% of patients with small-bowel disease, anal symptoms are likely to develop. The prevalence of perianal disease also has been found to be greater in blacks than in whites , .
| Clinical presentation|| |
Five percent of patients with Crohn disease present with anal lesions only, and most will develop intestinal symptoms. sometimes many years later  . Perianal disease develops in 31 % to 94% of patients over the course of their illness. Manifestations of perianal disease include skin involvement (maceration, erosions, skin tags, ulceration, and abscesses), lesions of the anal canal (fissures, ulcers. and stenosis), and fistulae. Approximately two thirds of patients with Crohn colitis have perianal fissures. Unlike ordinary anal fissures, those associated with Crohn disease typically are multiple, painless, and non midline in location. Fistulae develop in 20% to 40% of patients with Crohn disease. can be difficult to manage medically, and are one of the major reasons given for proctocolectorny , .
| Diagnosis|| |
Perianal Crohn can be diagnosed clinically. Early diagnosis of perianal disease complicating Crohn disease is essential. Delays in diagnosis increase the risk of anal sphincter destruction and may also lead to extension of the infection with the subsequent risk of overwhelming sepsis  . Endoscopy of the rectum is essential to identify the degree of inflammation in the rectum and to localize internal openings for a fistula or abscess  . Sinus tracts burrowing into the perirectal soft tissue can be demonstrated with barium, CT, endoscopic sonography and magnetic resonance (MR) image examinations  . Barium-enema examination often is complementary to colonoscopy in the workup of Crohn disease. Double-contrast barium-enema examination is superior to colonoscopy in the demonstration of the distribution of disease, fissures, fistulas, and subtle strictures and in viewing the terminal ileum  Barium studies are informative for complex high fistulas, and fistulography is helpful for more superficial tracts  . Although CT is slightly inferior to barium studies in demonstrating the presence of fissures and fistulas, CT is superior in demonstrating the inflammatory sequelae of these tracks. Anal endosonography and MRI have successfully detected anorectal abscesses and fistulas with variable, but often high accuracy  . The advantages of MR imaging are superior soft-tissue contrast, lack of ionizing radiation, and the ability for easy multiplanar imaging. The multiplanar capabilities of MR imaging allow its use for defining the course of perirectal fissures and fistulas  . In pregnant patients, MR imaging may be used as an alternative to CT. Transrectal sonography is better than CT but is probably inferior to MR imaging in defining the relationship of abscesses to the anal sphincter and levator ani muscles. Suspected abscesses can be aspirated for diagnosis and therapy using endoscopic sonography-guided fine-needle aspiration  . Hydrogen peroxide enhanced transanal ultrasound has proven superior to physical examination, fistulography, computed tomography and conventional ultrasound in demonstrating the fistula tract. Hydrogen peroxide was infused via a small catheter into the fistula  .
| Medical Treatment|| |
Many patients with anorectal Crohn disease have disease in other parts of the intestinal tract, which warrants an evaluation of the colon and small bowel. Treatment of active inflammation in the distal rectum with topical mesalamine or corticosteroids, or even immunomodulation, improves symptoms in the anus. Attention to perianal hygiene, including sitz baths, post-defecatory cleansing, and skin protection, also is important. Patients with perianal or fistulizing disease may be treated with metronidazole or ciprofloxacin. azathioprine or 6-MP, infliximab, or intravenous cyclosporine. Maintenance therapy may include a 5-ASA (although the effect is weak, particularly in the non postoperative setting), metronidazole, azathioprine or 6-MP, or infliximab. Data also exist that suggest benefit for use of infliximab for maintenance of remission in Crohn disease. Steroids, which are used commonly for intestinal Crohn flares, should not be used for fistulas. Reports indicate that steroids may retard the healing of internal fistulas and lead to abscess formation. Aminosalicylates are ineffective in closing fistulas in patients with Crohn disease ,
| Antibiotics|| |
Metronidazole has demonstrable effects for perianal CD  . Metronidazole, 10 to 20 mg kg/d, is an effective drug for many patients with perianal Crohn disease and started at a dose of 10 mg/kg/d and increased to a maximum of 20 mg/kg/d if no response occurs after one month. Complete healing was achieved in 561/6 who were maintained on therapy in one study. Because these high dosages may have to be maintained for prolonged periods in up to two thirds of the cases, patients should be made aware of potential side effects, particularly the occurrence of paresthesias, which are the major side effect of long-term metronidazole therapy, developing in one-half of all patients after a mean of six months of therapy. These usually are pedal and bilateral and can persist for up to two years after the drug is stopped. Metronidazole may have to be withheld and reintroduced later at lower doses. A 50% relapse rate follows cessation of metronidazole. Most patients respond to reinstitution of therapy. Minor side effects include metallic taste, dark urine, nausea, anorexia, headache, and reversible neutropenia. No carcinogenic or teratogenic effects have been seen. Ciprofloxacin, a fluoroquinolone antibiotic, has shown some promise as an adjunct to mesalazine, metronidazole, and steroids or immunosuppressants for the treatment of severe perianal disease or fistulae ,,,
| Immunomodulatory Therapy|| |
Both 6-mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are purine analogues are frequently used to treat perianal fistulas. Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6-mercaptopurine (6-MP) for significant perianal Crohn disease  . The two drugs are clinically equivalent and have the same side effect profile, including pancreatitis (5% to 15%), which occurs as a hypersensitivity reaction and is an indication for immediate discontinuation of the drug. Patients who develop pancreatitis should not be re-challenged with either drug, other common side effects include infections, neoplasm, bone marrow suppression and dug- induced hepatitis. The delayed onset of action requires approximately 3-6 months before the optimal therapeutic effect is achieved. The target dose for Azathioprine is 2-2.5 mg/kg and for 6-MP is 1-2 mg/kg. Patients are generally started at an initial dose of 50 mg and gradually increased to the target dosage.
Regular monitoring of the CBC (biweekly initially then monthly) is essential to avoid life-threatening neutropenia, and liver function should also be followed (every 3-6 months)  .
Cyclosporine has also been used effectively for treating patients with fistulizing Crohn disease. It is a potent immunosuppressant that inhibits IL-2 production from T-helper cells, IL-3, IL-4, gamma interferon, and tumor necrosis factor (TNF)-alpha, and indirectly inhibits B-cell activating factors and interferon-gamma by T-helper lymphocytes  . The clinical improvement will occur at dose of 4mg/kg/day within 1-2 weeks and was more than 80% in many studies  . Cyclosporine has significant toxicity, including nephrotoxicity, hypertension, seizures, peripheral neuropathy, and an increased risk of opportunistic infections such as Pneumocystis carinii pneumonia. Oral Cyclosporine is not particularly beneficial for either CD or UC  .
Some data suggest improved long-term benefit with the addition of azathioprine or 6mercaptopurine. thus supporting cyclosporine as a "bridge" until 6-mercaptopurine or azathioprine become effective. The overlapping is for more than four months after which the cyclosporine can be stopped  . Methotrexate (a folate inhibitor that works by interfering with DNA synthesis) have been used successfully to treat exacerbation of Crohn disease, it is used for treatment of perianal disease in one small study. A total of 16 of 33 patients with Crohn disease had fistulas who were treated with 25 mg/week intramuscularly, nine (56%) of the 16 patients had a significant response, four (25%) of whom showed complete closure, and five (31%) had significant improvement of their fistulas  . The main toxicity of methotrexate is hepatic fibrosis and bone marrow suppression. Liver function should be carefully monitored while on this drug. Normal liver enzymes can not role out liver fibrosis and liver biopsy can be used confirm it  .
Tacrolimus (FK-506, Prograf) is a macrolide antibiotic used for treatment of perianal Crohn and has a mechanism of action similar to cyclosporine with potency of 50 fold to 100 fold than cyclosporine it inhibits transcription of IL-2 by Thelper cells  . Many studies of tacrolimus in Crohn disease was done, the largest of these was published by Lowry and colleagues  . It involved 11 patients treated with oral tacrolimus at doses of 0.15 to 0.31 mg/kg. The mean blood level of the drug was 11. 1 ng/ml. All 11 patients experienced improvement, and seven (64%) had complete closure of all fistulas. Tacrolimus treatment was continued for a mean of 22 weeks with azathioprine or 6-mercaptopurine concomitantly for a maintenance. Eight of 11 patients (73%) had sustained improvement after tacrolimus treatment was discontinued. The Mayo group has used this study to demonstrate that FK506 in conjunction with surgical intervention and immunosuppression with azathioprine or 6-MP is efficacious in healing perianal fistulae in treatment-refractory perianal Crohn. Tacrolimus may be useful as a bridge for treating fistulae, followed by long-term treatment with other immunosuppressants  .
Side effect associated with tacrolimus include renal impairment hypertension: diabetes; nausea; paresthesias; headache; seizure; tremor; and an increased risk of infection especially if other immunosuppressive agents used concomitantly.
Mycophenolate Mofetil (MMF) (CellCept) is a purine-synthesis inhibitor in T and B lymphocyte that has potent immunosuppressive effects  It is a novel immunomodulator that may be effective in the treatment of chronic active and perianal Crohn disease  . It appears to have a quicker onset of action than either AZA or 6-MP. It seems that AZA still is the immunosuppressant of choice in chronic active CD, but MMF is a reasonable alternative in patients who do not tolerate AZA. Treatment of chronic active Crohn disease with MMF plus cortisone appears to be effective and well tolerated and should be considered in patients allergic to azathioprine or in whom azathioprine has failed ,,
In one study treatment with MMF in patients who are intolerant or non responder to AZA or MTX resulted in only 20% of success. Intolerance to MMF was observed in 25% of patients.  Another study was done by Hassard et al in which I 1 CD patients were treated with MMF after a failed course of 6-MP/AZA. Of 1 I patients who started MMFF four had early adverse reactions within 8 weeks and stopped the medication. Of the remaining seven patients who took MMF for at least 8 weeks, one had a complete response, two had a partial response and four had no response to the medication. In patients who failed 6-MP/AZA. MMF was of benefit in three of 11 patients with only one complete responder. This lower-than-expected response rate may indicate that patients who are resistant to 6-MP or AZA may also be resistant to MMF  . Side effects common to mycophenolate therapy are primarily gastrointestinal, including diarrhea, rash and nausea.
| Anti-tumor necrosis factor Alpha antibody therapy|| |
Tumour necrosis factor-alpha (TNF alpha) is a Proinflammatory mediator, which implicated in the pathogenesis of inflammatory bowel disease. TNF alpha is thought to play a central role in the immunopathology of Crohn disease, particularly since its levels are raised in all types of cells, tissues and secretory fluids of these patients and in animal models of the disease. In addition. TNF alpha has been found to modulate a number of different processes within the network of inflammatory reactions and therefore has become a target molecule for intervention studies  .
Therapies targeted to tumor necrosis factor alpha (TNF-alpha) include anti-TNF-alpha monoclonal antibodies (infliximab and CDP-57 1), TNF-binding neutralizing fusion proteins (etanercept), and TNF alpha production inhibitors (thalidomide )  .
| Infliximab|| |
Infliximab, is a murine-human chimeric monoclonal antibody to tumor necrosis factor alpha  . It antagonizes the biological activity of TNF-alpha by binding to it on macrophage and T-cell surfaces  . Clinical trials have shown infliximab to be effective in producing and maintaining a clinical response in patients with refractory, moderate to severe CD. Treatment helps promote healing of intestinal mucosa and closure of fistulas . It is now FDA approved for two indications: the treatment of severe CD defined as a high CDAI, and CD patients with enterocutaneous fistulas. It is administered as an intravenous infusion at a dosage of 5mg/kg. A one-time dose is used in patients with severe disease, and a series of three infusions at times 0, two weeks, and six weeks is administered in patients with fistulizing disease. Approximately two-thirds of patients will have a significant response within two weeks of the infusion, although it is unclear whether this response is sustained over the long-term  a placebo controlled study by present et al on infliximab was performed in 94 patients with fistulizing Crohn disease, of whom 85 (90%) had perianal fistulas. The primary end point was reduction in the number of draining fistulas of 50% or more and this was achieved in 62% of patients who received infliximab (5- and 10-mg/kg dose groups combined) and 26% of the placebo group. The median duration of response was three months for patients who had a 50% or greater reduction in the number of fistulas. Eleven percent of patients treated with infliximab developed a perianal abscess, possibly because the cutaneous end of the fistula tract closed before the rest of the fistula tract did so. This study assessed only the short-term benefits of infliximab on fistula closure , .
Short-term treatment of Crohn disease-associated fistulas with infliximab does not induce disappearance of fistulous tracts, irrespective of therapeutic response  . Infliximab may be given at eight-week intervals for maintenance or management of flare-ups. The recommended dosage is 5mg/kg i.v. infused over a two-hour period  . In initial clinical trials, the presence of human anti chimeric antibodies (HACA) in low titers was detected in approximately 13% of patients who received the drug. There is also a theoretical risk of lymphoma, although the number of reported malignancies (malignant melanoma, myeloma/plasmacytoma, and lymphoma) from the original trials was extremely low  infliximab is safe and beneficial in clinical practice for refractory Crohn disease  . The most frequent adverse effects are headache, nausea, fatigue and upper-respiratory tract infections  .
| CDP-571|| |
CDP571 is a humanized monoclonal IgG4 antibody targeting TNF-alpha that has shown benefit in patients with active Crohn disease . The molecule is humanized and consistent of approximately 95% human sequences and 5% murine sequences. As a consequence, CDP571 is less immunogenic than infliximab. The half-life of CDP571 is 145 h after infusion of 3mg/kg body weight  .
CDP571 is effective for treating active Crohn disease, steroid sparing, and possibly for closing fistulas and maintaining remission. Side effects occurring in patients treated with CDP571 include anti-idiotype antibodies, infusion reactions, and formation of autoantibodies  . In one placebo controlled trial by sand born et al, CDP571 was evaluated in 169 patient with moderate to severe Crohn disease for 24 weeks. Initially the patients received a single dose of 10mg/kg or 20mg/kg or placebo, then retreated with 10mg/kg or placebo every eight or 12 weeks to assess subsequent dosing interval. At the 2 nd week (CDAI > OR = 70) 45% responded compared with 27% placebo group. Patients appeared to benefit from retreatment with CDP571 over 24 weeks, but the results for secondary end points were statistically significant  .
| Thalidomide|| |
Thalidomide appears to be a potent inhibitor of TNF-alpha. The clinical effects of thalidomide in Crohn disease may be mediated by reduction of both TNF-alpha and IL-12  . Clinical studies have confirmed that previously refractory Crohn disease patients respond to thalidomide, and many enter clinical remission. Efficacy usually occurs within 4 weeks. Thalidomide also has steroid-sparing properties, and it is particularly useful in treating oral and fistulous complications of Crohn disease. Although it is usually tolerable, careful monitoring is recommended to prevent toxicities, such as birth defects and peripheral neuropathy (25%)  . Other problems include pruritus, dermatitis, hypertension, peripheral edema and constipation. In an open-label trial of thalidomide by Ehrenpreis and his group was performed in 22 patients with refractory Crohn disease (nine with luminal, 13 with fistulas). Eighteen patients received 200mg thalidomide at bedtime and four patients received 300mg at bedtime for 12 weeks. Fourteen patients completed 12 weeks and met the criteria for clinical response. Nine patients achieved clinical remission (three luminal, six fistula)  . The safety of thalidomide in treatment active and fistulizing Crohn disease still needs to be defined in more clinical trials.
| Etanercept|| |
It antagonizes the activity of TNF by binding to both membrane-bound and soluble forms of TNF. In one study by D'Haens et al at 1999, 10 patients were treated with s.c. injections of 25 mg Etanercept twice per week for 12 weeks. Clinical response was noted in 60% of patients by two weeks  . Another study done by Sandborn et al, where 43 patients with moderate to severe Crohn disease were enrolled in an 8-week placebo-controlled trial with s.c. injection of 25 mg Etanercept twice weekly and placebo. At the 4 th week, 39% of etanercept-treated patients had clinical response as compared with 45% of placebo treated patients (P = 0.763). The conclusion was, etanercept at dose of 25 mg twice per week is safe, but not effective for the treatment of patients with moderate to severe Crohn disease. Higher doses or more frequent dosing may be required to attain a response in patients with active Crohn disease  The common side effect of etanercept is injection site reaction, upper respiratory tract infection and headache.
Ongoing clinical trials have targeted interferon gamma and intracellular adhesion molecules (ICAM-1), as well as cytokines such as recombinant human interleukin-10 and interleukin-11. This relatively new category of "biologics" has been the fastest growing area of research in IBD in the past decade  .
| Hyperbaric Oxygen (HBO)|| |
HBO is administered in a hyperbaric chamber in which 100% oxygen is breathed at pressures greater than atmospheric. It should be considered in patients suffering from perianal Crohn disease who have failed to respond to conventional therapy. When 100% oxygen is breathed at an absolute pressure of 3 atm, the plasma oxygen content increases from 0.32 to 6.8 vol%. HBO is used to increase the oxygen tension within the tissue, this will kill anaerobic bacteria and improve leukocyte bactericidal activity, optimize fibroblast proliferation, collagen synthesis and capillary angiogenesis. Enhanced tissue oxygenation has a vasoconstrictive effect believed to reduce tissue edema  . In one study by Lavy and associates treated ten patients with refractory perianal Crohn disease with HBOT. Treatment was administered in a hyperbaric chamber at a pressure of 2.5 atm absolute. Each session lasted 90 min, and each course consisted of 20 daily sessions. Complete healing occurred in five patients after one to two courses. In an additional two, after three courses, I patient improved but did not heal, and two did not improve. No adverse effects were noted by any of the 10 patients. Followup of 18 months did not reveal any recurrence  . Another similar study using HBOT done by colombel et al in 10 patients with refractory Crohn disease, where they achieved a 60% response rate. In this study, two patients discontinued therapy because of adverse effects, which included psychological difficulties and bilateral tympanic perforation  .
Nutritional therapy like elemental diets are currently not used to treats perianal disease because the expense and the presence of alternative and more effective therapies. Setons. fistulotomies, and rectal mucosal advancement flaps are part of the surgical repertoire available to treat refractory perianal disease in patients with CD. A temporary loop ileostomy may help with healing in the patient with severe perianal disease and/or rectovaginal fistula and a small percentage of these patients may ultimately require proctectomy and permanent ileostomy .
| Conclusion|| |
The most important step in the management of perianal Crohn disease is to control the activity of the disease. Sepsis should be controlled by the drainage of abscess and by long term use of setons. Antibiotics are used as the primary therapy in the management of perianal Crohn with or without surgery. For more severe perianal disease combination therapy with antibiotics and immunomodulatory therapy with or without infliximab. along with conservative surgery will lead to healing in most patients. With advances in the understanding of the genetics of Crohn disease by molecular engineering many drugs will appear in future some of them still under trials and these may improve the quality of life of those patients with perianal Crohn disease.
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Abdullah Sa'eed Gozai Al-Ghamdi
Gastroenterologist, King Khalid University Hospital, P 0. Box 2925, Riyadh 1146 1
Source of Support: None, Conflict of Interest: None