SOME GENETIC PREDISPOSITION IS SEEN.
Medical Care: The care of a patient with IBD can be either medical or surgical in nature, or commonly a combination of both. The medical approach for patients with IBD is symptomatic (flaring) care and generally follows a step-wise approach to medication therapy, with progression of the medical regimen until a response is achieved. Whether patients whose disease is in remission benefit from continuing to take aminosalicylate is controversial. In persons with Crohn disease, earlier data suggested that postoperative recurrences are decreased in frequency and severity, although later data suggest that this preventive effect may not apply to flares of this IBD.
" The first step in medication therapy is usually aminosalicylates; no advantage has been demonstrated for any particular agent for either ulcerative colitis or Crohn disease. For Crohn disease, metronidazole or ciprofloxacin is occasionally used, particularly for perianal disease or an inflammatory mass.
" If the IBD fails to respond to aminosalicylates, the second step is corticosteroids. Corticosteroids tend to provide rapid relief of symptoms and a significant decrease in inflammation, but they are limited by their adverse effects, particularly for prolonged use. The consensus regarding treatment with corticosteroids is that they should be tapered as rapidly as possible. Corticosteroids do not have a role in maintaining remission.
" If patients have difficulty reducing the dose of corticosteroids, have IBD that is refractory to corticosteroid therapy, or have frequent flares that require corticosteroid therapy, the third step for medication is one of the immunomodulatory agents, either 6-MP or azathioprine. These agents are not used for acute flares because the time from the initiation of treatment to the onset of significant action may be as long as 2-3 months. Response to these agents may be dose dependent; monitoring of blood counts is required to protect the patient from the hematological toxicity associated with these agents. Some authors suggest earlier use of these agents.
" An alternative third step is available for persons with IBD. This alternative is infliximab, a monoclonal antibody against tumor necrosis factor (TNF)- . Administer this agent by intravenous infusion. This medication is generally administered in 3 doses over 6 weeks (at weeks 0, 2, and 6) followed by a maintenance regimen. Administering the drug every 8 weeks has been demonstrated to be effective for maintaining remission.
o The practitioner is advised to have the patient seek insurance approval for the administration of this medication because it is extremely expensive (typically, several thousand dollars per dose). Infliximab has an excellent response rate for Crohn disease (>80%); its response rate for ulcerative colitis is clearly less (approximately 50%).
o As of July 2005, the medications approved by the US Food and Drug Administration (FDA) for the treatment of Crohn disease are prednisone, budesonide, and infliximab. Infliximab was recently approved by the FDA for ulcerative colitis (August 2005).
" The final step for the treatment of IBD involves agents that have less well-demonstrated levels of efficacy but have been shown to be useful in some subsets of patients. For Crohn disease, methotrexate at 12.5-25 mg/wk may fall into this category. For ulcerative colitis, cyclosporine A (usually started intravenously for overwhelming disease) and nicotine patches fall into this category. Finally, a number of clinical trials of biological agents and diets are being conducted and may demonstrate efficacy in persons with IBD.
Surgical Care: The approach to surgical treatment of IBD varies depending on the disease. Most important, ulcerative colitis is a surgically curable disease because the disease is limited to the colon. However, Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus; thus, surgical resection is not curative. On the contrary, excessive surgical intervention can leave the patient with a crippling short bowel syndrome. Situations arise in Crohn disease in which surgical intervention without resection can be used to defunctionalize the colon in order to possibly allow healing of distal disease.
" Surgery for ulcerative colitis
o Surgical intervention for ulcerative colitis is curative for colonic disease and potential colonic malignancy. The indications for colectomy are (1) inflammation that is difficult to control, (2) early changes found during surveillance (high-grade dysplasia, low-grade dysplasia in some instances), (3) strictures, (4) significant adverse medication effects, and/or (5) an unacceptable quality of life referable to the ulcerative colitis.
o The surgical options for ulcerative colitis vary. While segmental resection is rarely performed, total proctocolectomy is common. Total proctocolectomy with ileostomy creation is the simplest procedure with the lowest overall complication rate. A variation on this is the continent ileostomy or Koch pouch. This procedure creates an ileal reservoir that can be emptied with catheterization several times per day. However, incontinence from the pouch may necessitate use of an ileostomy bag. A colectomy may be performed, leaving a few centimeters of rectum intact; this ensures anal continence, but continued malignancy surveillance is needed for any colonic mucosa that remains and the remaining diseased rectal mucosa can continue to be problematic from a symptomatic standpoint.
o The most technically demanding option is ileal pouch/anal anastomosis (IPAA). In this multistage procedure, a diverting ileostomy is performed and an ileal pouch is created and anastomosed directly to the anus, with complete removal of the rectal mucosa. After the ileoanal anastomosis is healed, the ileostomy is taken down and flow through the anus is reestablished. The major complications of this procedure are anal incontinence and impotence. Occasionally, postoperative pouchitis is a problem. If the diagnosis is incorrect and this procedure is performed on a patient with colonic Crohn disease, the likelihood of disease recurrence at the ileoanal anastomosis is high, which requires takedown, ileostomy creation, and loss of additional small bowel. When performed by a surgeon skilled in this technique, it offers an excellent option for younger patients with ulcerative colitis and concerns about body image.
" Surgery for Crohn disease
o Surgery in Crohn disease is most commonly performed for complications of the disease (ie, strictures, fistulae, bleeding) rather than for the disease itself.
o The most straightforward surgery for Crohn disease is the segmental resection, in which a segment of intestine with active Crohn disease or a stricture is resected and the remaining bowel is reanastomosed. This surgery requires margins of resection; in general, as little bowel as possible is resected because the risk of disease recurrence is significant.
o In patients with a very short cicatrix (scar tissue) stricture, a bowel-sparing stricturoplasty can be performed. In this procedure, a longitudinal incision is made across the stricture and then the incision is repaired with a vertical suture. All mucosa is spared, and the obstruction is relieved. As many as 6-8 stricturoplasties can be performed in a single operative session. Stricturoplasty is associated with a 6-8% septic complication rate (2-3% of patients require reoperation); this can generally be prevented with optimal preoperative management to control the inflammatory component of the stricture before surgical intervention.
o Ileorectal or ileocolonic anastomosis is an option available to some patients who have distal ileal or proximal colonic disease. This is a variation on the simple segmental resection.
o In patients with severe perianal fistulae, a diverting ileostomy or colostomy is a surgical option. In this procedure, the distal colon is defunctionalized and a temporary ileostomy or colostomy is created. The defunctionalized rectum is allowed to heal, and the ileostomy or colostomy is then taken down 6 months or a year later. Many patients who pursue this option choose to forego reanastomosis after experiencing a stoma and a consequent improvement in quality of life. Approximately 50% of patients who have the reanastomosis performed have recurrences of perianal disease.
Symptomatic enteroenteric fistulae are generally resected, although recurrence is common. Postoperative medical therapy is often used to prevent recurrence, although data are lacking on efficacy.
Diet: No known dietary substances cause activation of IBD. Diet may influence intestinal inflammation in persons with Crohn disease, but it does not play a role in influencing inflammation in those with ulcerative colitis.
" Lactose intolerance is common in persons with Crohn disease or ulcerative colitis and some patients with other types of IBD.
" Diet has been well demonstrated to have little or no influence on inflammatory activity in persons with ulcerative colitis. However, diet may influence symptoms. For this reason, patients are often advised to make a variety of diet modifications, especially the adaptation of a low-residue diet. Evidence does not support a low-residue diet as beneficial in the treatment of ulcerative colitis, although it might decrease the frequency of bowel movements.
" Unlike in persons with ulcerative colitis, diet can influence inflammatory activity in persons with Crohn disease. Nothing by mouth (status NPO) can hasten the reduction of inflammation, as might the use of a liquid or predigested formula for enteral feeding. Although a meta-analysis in 1993 demonstrated that steroids were superior to liquid diet alone for Crohn disease, a liquid diet seemed superior to a regular diet for reducing inflammation. The problem with using enteral liquid diets, especially the predigested formulations, is that palatability limits the intake of adequate energy (calories) to meet patient requirements. Parenteral alimentation may be needed.
Activity: Generally, patients do not need to limit activity when IBD is quiescent. Even during flares of disease activity, activity is limited only by the extent of fatigue and the abdominal pain or diarrhea the patient is experiencing.
" Abdominal pain may limit the ability of the patient to work productively during flares of disease. When abdominal pain persists beyond medical therapy-induced resolution of the active inflammation, other causes of pain must be considered, including nephrolithiasis, abscess, stricture, irritable bowel syndrome, and psychiatric disease.
" In most instances, diarrhea limits activity primarily because of the lack of immediate access to toilet facilities in many locations and/or occupations. This can often be resolved with employers. Occasionally, dehydration may be an issue, requiring intravenous hydration or the use of oral rehydration solutions.
While several drugs have been used successfully for the treatment of IBD for many years, medical treatment has advanced rapidly. The medications used are broken down into several classes based on the chemical similarities of the individual agents and similarities in the mechanisms of action. A step-wise approach may be taken. With this approach, the most benign (or temporary) drugs are used first. As they fail to provide relief, drugs from a higher step are used.
The aminosalicylates and symptomatic agents are step I drugs under this scheme; the antibiotics are a step IA, given the limited situations in which they are used. The corticosteroids constitute the step II drugs to be used if the step I drugs fail to adequately control the IBD. The immune-modifying agents are step III drugs and are used if corticosteroids fail or are required for prolonged periods. Infliximab is also a step III drug that can be used in some situations in patients with Crohn disease and ulcerative colitis. The experimental agents are step IV drugs and are used only after the previous steps fail and, then, are administered only by physicians familiar with their use.
Note that drugs from all steps may be used additively; in general, the goal is to wean the patient off steroids as soon as possible to prevent long-term adverse effects from these agents. Opinions differ regarding the use of certain agents in this step-wise approach.
Step I (aminosalicylates)
The 5 oral aminosalicylate preparations available for use in the United States are sulfasalazine (Azulfidine), mesalamine (Asacol, Pentasa), balsalazide (Colazal), and olsalazine (Dipentum). Enema and suppository formulations are also available. All of these are derivatives of 5-aminosalicylic acid (5-ASA); the major differences are in the mechanism of delivery. Some of these also have unique adverse effects that other agents of this class lack. All of the aminosalicylates are useful for treating flares of IBD and for maintaining remission. None of the aminosalicylates has been proven to have greater efficacy for the treatment of ulcerative colitis or Crohn disease over any of the others. All of them are clearly more effective in persons with ulcerative colitis than in persons with Crohn disease; in persons with Crohn disease, the primarily utility is for colonic disease.
Step IA (antibiotics)
The antibiotics metronidazole and ciprofloxacin are the most commonly used antibiotics in persons with IBD. Antibiotics are used only sparingly in persons with ulcerative colitis because ulcerative colitis increases the risk of developing antibiotic-associated pseudomembranous colitis. When used in persons with ulcerative colitis, antibiotics are most commonly administered in the perioperative setting. However, in persons with Crohn disease, antibiotics are used for a variety of indications, most commonly for perianal disease. They are also used for fistulae and inflammatory masses in the abdomen, and they may have some efficacy in treating ileitis. The antibiotics have potential adverse effects, including nausea, anorexia, diarrhea, and monilial (candidal) infections; peripheral neuropathy can be observed in association with metronidazole use and, when present, requires discontinuation of therapy with that drug.
Step II (corticosteroids)
Corticosteroids are rapid-acting anti-inflammatory agents used in the treatment of IBD. Indications are for acute flares of disease only; corticosteroids have no role in the maintenance of remission. Corticosteroids may be administered by a variety of routes depending on the location and severity of disease; they may be administered intravenously (ie, methylprednisolone, hydrocortisone), orally (ie, prednisone, prednisolone, budesonide, dexamethasone), or topically (ie, enema, suppository, or foam preparations).
Intravenous corticosteroids are often used for patients who are severely ill and hospitalized; few data have been published on the optimum dosage of intravenous (or oral form) corticosteroids. The generally used upper ends of dosing are methylprednisolone at 40 mg intravenously every 6 hours or hydrocortisone at 100 mg intravenously every 8 hours. Some situations mandate a higher initial intravenous dose, but many practitioners start hospitalized patients at lower intravenous doses.
In general, once a clinical response is observed (typically within a 1-2 d, occasionally longer), the dose of the intravenous corticosteroid can be tapered. Before hospital discharge, conversion to an oral corticosteroid is made; further dosage tapering can be accomplished in an outpatient setting. When oral corticosteroids are used, dosing is highly variable and few data have been published to guide optimal dosing. The most common range for moderate flares of IBD is prednisone at 10-40 mg/d; for more severe flares, the higher end of the range is used (occasionally even higher doses are used). Again, once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can only occasionally tolerate a relatively rapid taper after a response is achieved; occasionally, a very prolonged steroid taper is necessary to prevent relapse. When the latter situation occurs, consider the use of alternative drugs (immune modifiers or anti-TNF therapy).
Topical corticosteroids are used in persons with distal colonic disease in a manner similar to topical mesalamine; the major difference is that even though topical mesalamine may be used to help maintain remission, topical corticosteroids are used for active disease and have only a small role in the maintenance of remission. The potential complications of corticosteroid use are multiple and include fluid and electrolyte abnormalities, osteoporosis, aseptic necrosis, peptic ulcers, cataracts, neurologic and endocrine dysfunctions, infectious complications, and occasional psychiatric disorders (including psychosis). Patients who are taking corticosteroids, especially for longer than a few weeks, must be warned about the associated complications; this discussion should be documented in the medical record. Some recent data assert that some agents used for osteoporosis prevention and treatment (eg, the bisphosphonates) are useful for preventing the bone loss associated with corticosteroid use.
Step III (immune modifiers)
The immune modifiers 6-MP and azathioprine are used in patients with IBD in whom remission is difficult to maintain with the aminosalicylates alone. Immune modifiers work by causing a reduction in the lymphocyte count, and because of that mechanism of action, their onset of action is relatively slow (typically 2-3 mo). They are used most commonly for their steroid-sparing action in persons with refractory disease; they are also used as primary treatment for fistulae and the maintenance of remission in patients intolerant of aminosalicylates. Use of these agents mandates monitoring of blood parameters; they can cause significant neutropenia or pancytopenia that would warrant a dose reduction or discontinuation. Routine CBC counts with differentials and platelet counts are checked monthly, and LFTs can be performed intermittently. After a year of stable dosing with no difficulties with blood counts (except the expected lymphopenia), the intervals between blood count monitoring can be increased.
The cytopenic effect is typically dose dependent, although some patients are more sensitive than others. Typical dosing of the immune modifiers (either 6-MP or azathioprine) is 1-2 mg/kg/d. If needed, the dose can be increased to the point when cytopenia occurs; obviously, at higher doses, closer monitoring is warranted. Blood tests are available to measure metabolite levels, but the results have not been shown in independent studies to have any correlation with clinical efficacy. These blood tests for monitoring toxicity offer little advantage (but much greater expense) over monitoring CBC counts and LFT results.
Other adverse effects of the immune modifiers include fever, rash, infectious complications, hepatitis, pancreatitis, and bone marrow depression. The most common reason for discontinuing the immune modifiers within the first few weeks is the development of abdominal pain; occasionally, a biochemically demonstrable pancreatitis occurs.
Concerns have been raised about the development of malignancy in patients taking azathioprine and 6-MP. Because the population that requires these medications is already at higher risk for the development of malignancy, the author believes that the available data on the use of azathioprine or 6-MP are insufficient and do not demonstrate a significant increase in the risk of malignancy.
An additional step III agent works by a different mechanism. Infliximab (Remicade) is an anti-TNF-alpha monoclonal antibody administered by infusion for the treatment of Crohn disease. Infliximab is currently FDA approved for both ulcerative colitis and Crohn disease, although it does appear to have a higher efficacy rate in the latter. Infliximab is generally administered as infusions of 5 mg/kg for the treatment of moderate-to-severe IBD. It is administered as 3 separate infusions of 5 mg/kg at weeks 0, 2, and 6, often followed by doses every 8 weeks for maintenance of remission. For Crohn disease, the response rate is 80% and the induction of remission rate is 50% after a single dose; with multiple dosing, higher rates of remission are attained. For ulcerative colitis, the response rates are 50-70%.
Infliximab is also indicated for the treatment of fistulizing Crohn disease; for this indication, the fistula responds (closes) in 68% of patients treated with infliximab, although 12% develop an abscess. The response can be maintained by continuing regular dosing (ie, every 8 wk) after the induction dose.
The adverse effects of infliximab commonly include hypersensitivity and flulike symptoms; the latter can often be avoided by pretreatment with acetaminophen and diphenhydramine. Rare reports of lupuslike reactions and lymphoproliferative malignancies have been reported, although whether the malignancies are related to the drug or to the underlying disease process remains uncertain.
Step IV (experimental treatments)
Generally, use these agents as part of an experimental protocol or in a setting in which the toxicities of the agents can be rapidly recognized and managed. Examples of some agents are provided, but a review of the literature is warranted before using them. In most cases, some subsets of patients respond; in general, large placebo-controlled trials have not yet established efficacy for these agents for the treatment of IBD.
Various experimental agents tend to be more disease-specific, ie, an agent works for Crohn disease but not ulcerative colitis, or vice versa. Experimental agents used in persons with Crohn disease include methotrexate (12.5-25 mg/wk orally or intramuscularly), thalidomide (50-300 mg/d orally), and interleukin 11 (1 mg/wk subcutaneously). Experimental agents used in persons with ulcerative colitis include cyclosporine A at a dose of 2-4 mg/kg/d intravenously (measure level; convert to oral dosing at 2-3 times the intravenous dose), nicotine patch (14-21 mg/d via topical patch), butyrate enema (100 mL per rectum twice daily), and heparin (10,000 U subcutaneously twice daily). Multiple contraindications, interactions, and precautions are associated with these drugs.
Symptomatic treatments
Because patients report symptoms (eg, diarrhea, spasm/pain, epigastric discomfort) and not inflammation per se, symptomatic relief is appropriate when indicated. This includes therapy with antidiarrheal agents, bile acid-binding agents, antispasmodics, and acid suppressants, as needed. These medications are not without complications, and caution is necessary.
DRUG TEATMENT :
1. AMINOSALICYLATES :
- SULFASALAZINE
- MESALAMINE
- BALSALAZIDE
- OLSALAZINE
2. ANTIBIOTICS :
- METRONIDAZOLE
- CIPROFLOXACIN
3. CORTICOSTEROIDS :
- HYDROCORTISONE
- PREDNISONE
4. IMMUNOMODULATORS :
- AZATHIOPRINE
- 6- MERCAPTOPURINE
5. ANTI-TUMOR NECROSIS FACTOR AGENTS :
- INFLIXIMAB
5. H-2 RECEPTOR ANTAGONISTS / PROTON PUMP INHIBITORS :
- CIMETIDINE
- RANITIDINE
- FAMOTIDINE
- NIZATIDINE
- OMEPRAZOLE
- RABEPRAZOLE
- LANSOPRAZOLE
- ESOMEPRAZOLE
- PANTOPRAZOLE
6. ANTIDIARRHOEAL AGENTS :
- LOPERAMIDE
- DIPHENOXILATE & ATROPINE ( LOMOTIL )
- CHOLESTYRAMINE
7. ANTISPASMODIC AGENTS :
- IDCYCLOMNE