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This is some good info on these:Sorry it's longDigestive Disease WeekDay 3 - May 18, 1999 Is It Time to Rethink Our Approach to Newly DiagnosedCrohn's Disease?Gary R. Lichtenstein, MD and Richard P. MacDermott, MD In an American Gastroenterological Association clinical symposium on the role of immunomodulators for new onset Crohn's disease, Dr. Bruce Sands of Massachusetts General Hospital outlined the problems with our current "step-up approach" to Crohn's disease treatment.[1] The step-up approach is additive and often leads to a complex medical regimen. Furthermore, Dr. Sands pointed out that drugs which are ineffective are nevertheless continued. Dr. Sands stated that despite our current available medical therapy, the rate of surgery early in the course of Crohn's disease is high. Finally, he noted that we are unable to predict a specific response any given individual may have to therapy. Dr. Sands then proceeded to review the current status of medical therapy for new onset Crohn's disease. Azulfidine Since initially used to treat individuals with inflammatory bowel disease (IBD) in the 1930s, azulfidine has been the cornerstone of medical therapy in this setting. Azulfidine appears to provide benefits in patients with colonic (ie, ileocolonic and colonic) Crohn's disease, but not in those with small bowel disease alone. Thus, the site of disease activity is important to know when administering azulfidine. These data are derived from the National Crohn's Disease Cooperative Study and the European Cooperative Crohn's Disease Study where a sum total of over 500 patients were assessed with active Crohn's Disease. Doses of azulfidine ranging from 3 to 5 grams daily were more effective than placebo in these patient populations. Although azulfidine and steroids have been widely used for ulcerative colitis and Crohn's disease for many years, recent clinical studies have clarified new approaches to IBD management strategies. Mesalamine Specifically designed mesalamine products have been developed in order to provide new ways of delivering 5-aminosalicylic acid (5-ASA) topically to specific sites of intestinal inflammation. The oral mesalamine agents have also been proven effective in individual patients with Crohn's disease. The oral 5-ASA preparations are more effective in small bowel (ileal) Crohn's disease than large bowel Crohn's disease. Mesalamine compounds have also been shown to maintain remission in Crohn's disease. Mesalamine agents are often not as effective in Crohn's disease as in ulcerative colitis, perhaps because they are topically delivered to the mucosa. Recent observations have clearly demonstrated that oral mesalamine agents are able to prevent or delay both endoscopic and clinical recurrences of Crohn's disease following resection and anastomosis. Use of 5-ASA for the prevention of the recurrence of Crohn's disease following surgical resection has been evaluated using both endoscopic and clinical endpoints. Mucosal aphthous ulcerations, consistent with early Crohn's disease, can be observed by colonoscopy in up to 90% of patients 1 year after surgical resection. Studies have been carried out using oral 5-ASA products to determine if endoscopic recurrence can be prevented. Blinded control trials have convincingly demonstrated that oral 5-ASA will reduce the endoscopic recurrence rate of Crohn's disease post surgery. 5-ASA has also been observed to decrease the clinical (symptomatic) recurrence rate with the highest rate of prevention of clinical recurrence being in patients with large bowel or small bowel plus large bowel Crohn's disease (with less effect observed in patients with disease of the small bowel only). Metronidazole Experimental and clinical evidence suggests that bacterial flora may play a role in the pathogenesis of IBD. Antibiotics, including metronidazole and ciprofloxacin, are being used very successfully in patients with active Crohn's disease. Metronidazole can be effective in inducing remission in active Crohn's colitis and in treating fistulae, sinus tracts, and abscesses that occur in Crohn's disease involving the perineum. Metronidazole also decreases the endoscopic recurrence of aphthous ulcerations associated with early Crohn's disease at the site of the anastomosis following intestinal resection for Crohn's disease. For patients with perianal Crohn's disease, higher doses of metronidazole for longer periods of time are often required and the relapse rate on withdrawal of therapy is high. Epigastric distress, nausea, anorexia, headaches, yeast infections, and a metallic taste in the mouth are common but reversible side effects of metronidazole. The patient must avoid alcohol while on this agent. Peripheral neuropathy from long-term administration of metronidazole (3 to 6 months at 750 mg/day or greater) is the most severe side effect. Neuropathy is a dose-cumulative side effect and is seen in one-third of patients. An additional one-third of patients may have subclinical neuropathy detected after formal neurologic testing. The neuropathy reverses very slowly (6 to 18 months) and sometimes only incompletely after metronidazole is discontinued. Therefore, every attempt should be made to keep long-term doses of metronidazole at less than 750 mg per day. Ciprofloxacin Ciprofloxacin is a very good alternative for Crohn's disease patients with perineal disease or fistulae, who have either become refractory to metronidazole or who can no longer tolerate its side effects. Ciprofloxacin has been used successfully in the treatment of active Crohn's disease with improvement in symptoms in 50-60% of patients. Combination Metronidazole and Ciprofloxacin Metronidazole plus ciprofloxacin has been examined for the treatment of active, refractory Crohn's disease. In a comparison trial with steroids, ciprofloxacin, 500 mg bid plus metronidazole, 250 mg qid were evaluated. Ten out of 22 Crohn's disease patients treated with antibiotics (45.5%) compared with 12 out of 19 Crohn's disease patients treated with steroids (63%) obtained clinical remission as defined by a CDAI (Crohn's Disease Activity Index) of less than 150. Therefore, ciprofloxacin plus metronidazole may be useful in some patients with active Crohn's disease. Oral Steroids Corticosteroids modify almost every part of the inflammatory response, including cell-mediated immunity and the production of inflammatory mediators such as prostaglandins, leukotrienes, platelet activating factors, and cytokines. They are well established as being efficacious for the treatment of active Crohn's disease, regardless of disease distribution. Most patients who are given oral steroids will have already received one or more 5-ASA medications, and either will not have responded or occasionally will have been intolerant. Oral steroids have been shown to be effective in moderate to severe active Crohn's disease. There is no proven benefit of oral steroids in maintaining remission in this disease setting. Prednisone is the most commonly used oral steroid and is usually initiated at a dose of, at most, 40 mg per day. Dosage varies depending on the severity of the inflammation and the size of the patient. Initial prednisone therapy is usually continued for 2 to 3 weeks, by which time a successful response should be seen. Prednisone can then be slowly tapered by 5 to 10 mg, each 1 to 3 weeks. In Crohn's colitis, adding sulfasalazine to corticosteroids does not result in better efficacy compared with corticosteroids alone. It is well established that there is no role for steroids in remission maintenance in Crohn's disease. However, long-term alternate-day corticosteroid therapy, ie, 20-25 mg of prednisone qod, may be useful in patients with refractory Crohn's disease. Steroids do not prevent relapses of disease. Many patients who respond to the prednisone at higher doses often have a flare of their symptoms as the drug is tapered. These steroid-dependent and/or steroid-refractory Crohn's disease patients are the most at risk for long-term steroid side effects, and every effort must be made to find a way to treat their IBD without steroids. Our current strategy is to use 6-mercaptopurine (6-MP) or azathioprine for steroid dependent patients who can then have their steroids tapered. Patients with severe to fulminant Crohn's disease require hospitalization. In addition to receiving intravenous fluids and electrolytes, being made NPO, being given intravenous nutrition, and usually being placed on antibiotics, severely ill Crohn's disease patients should be treated with high doses of intravenous steroids -- either hydrocortisone at a dose of up to 300 mg per day or methylprednisolone at a dose of up to 60 mg per day. The same steroid dose can be given in divided boluses or as continuous infusions. There has been no trial to date which has compared the efficacy of continuous versus divided dosage infusions. Once improvement is achieved, patients can be switched to an oral steroid, such as prednisone, 40 mg per day, which can then be gradually tapered. The beneficial effects of corticosteroids are counterbalanced by side effects that are frequently seen with their prolonged use. Insomnia, hyperactivity, night sweats, and hyperglycemia are common side effects with high steroid doses. With long-term steroids, even at lower doses (ie, prednisone at a dose of 10 mg), a moon face, acne, development of a fatty (buffalo) hump at the base of the neck, and excessive hair growth are often noted. The use of systemic corticosteroids is severely limited by the more serious side effects, such as avascular necrosis, osteoporosis, cataracts, hypertension, and diabetes mellitus. Because patients receiving high-dose corticosteroids frequently experience emotional lability, jitteriness, and insomnia, treatment with a sedative may be needed. In an occasional patient, corticosteroids can lead to a psychotic reaction and the steroids should be discontinued as quickly as possible. To check for cataracts, regular eye examinations should be performed. To monitor for osteoporosis, regular bone density examinations should be given. Osteoporosis, however, may occur independent of corticosteroid use in individuals with Crohn's disease. Supplementation with calcium and vitamin D should be used for patients on continuous long-term steroid therapy. The use of bisphosphonates has not been critically evaluated in a controlled fashion in inflammatory bowel disease patients on corticosteroids, but hormone replacement has been shown to be beneficial for prevention of bone loss. First-pass rapidly metabolized corticosteroids (ie, budesonide) provide certain advantages over currently available corticosteroids by achieving equivalent efficacy and being associated with fewer systemic side effects and less adrenal suppression. The absence of toxicity in these newer agents relates to their low systemic bioavailability, which is achieved via their extensive first-pass metabolism in the liver and erythrocytes, and by their poor intestinal absorption. Oral budesonide is the best studied of these newer corticosteroids. Recent trials comparing oral budesonide with prednisolone showed comparable efficacy in inducing remission in active Crohn's disease. Because oral budesonide is packaged in a pH-sensitive coating with controlled release in the ileum, it has also been shown to be effective in treating active ileal and ileocecal Crohn's disease. Budesonide has been shown to be superior to a similar (slow-release) formulation of mesalamine in the treatment of patients with active Crohn's disease of the ileum or the ascending colon. Immunomodulators: Azathioprine and 6-MP Immunomodulators that suppress the immune system and down-regulate inflammation, such as 6-MP and azathioprine, are now considered front-line drugs for the long-term therapy of IBD. The rationale for the use of immunomodulators in the treatment of inflammatory bowel disease stems from observations implicating immunological mechanisms in the pathogenesis of this disorder. The most widely used immunosuppressant agents are azathioprine and 6-MP. It is believed that 6-MP and azathioprine have similar efficacy and toxicity. Their exact mechanism of action, however, remains unknown. Azathioprine is metabolized by the liver to 6-MP. Both azathioprine and 6-MP have been shown to be effective in active Crohn's disease patients by improving their overall symptoms, healing fistulae, and allowing the dose of steroids to be reduced. Azathioprine and 6-MP have primarily been used for patients with active Crohn's disease who have disease unresponsive to aminosalicylates, antibiotics, or corticosteroids, or have had long-term use of corticosteroids. In a meta-analysis of randomized, double-blind studies, azathioprine/6-MP has been shown to be more efficacious than placebo in patients with active Crohn's disease. In one of these studies, 73% of patients were able to discontinue or reduce the dosage of corticosteroids. In another study, the combined treatment with azathioprine and prednisolone was shown to be more effective than treatment with prednisolone alone for the induction of remission of Crohn's disease. The duration of therapy correlated with efficacy. Significant efficacy was not seen for azathioprine/6-MP used for less than 17 weeks. Azathioprine and 6-MP are also effective in maintaining remission in Crohn's disease. Indeed, 95% of Crohn's disease patients who successfully respond to initial treatment with the immunomodulatory drugs, azathioprine or 6-MP, will have their induction of remission continued into very successful maintenance of remission for many years. Studies of long-term maintenance with 6-MP and azathioprine have included both unblinded as well as controlled randomized protocols. At least 5 studies have demonstrated that azathioprine is effective for maintenance of remission in patients with Crohn's disease. A recent study of patients with Crohn's disease in remission showed that the 5-year relapse rate of those who stopped azathioprine/6-MP was 75% compared with 32% for those who continued these medications. Controversy exists over whether leukopenia is needed to induce a response to azathioprine or 6-MP. Reduced dosages of azathioprine or 6-MP after 4 years are often successful for long-term maintenance therapy. One of the advantages of using azathioprine or 6-MP to induce remission is that the same medication can be successfully continued for remission maintenance. This is in contrast to steroids, where the initial therapeutic response is high, but steroids cannot be used to maintain remission due to being ineffective as well as the severe side effects. The usefulness of 6-MP or azathioprine is also in contrast to 5-ASA (mesalamine) preparations where the initial response rate in Crohn's disease is modest and the ability to maintain remission in Crohn's disease appears confined to a small number or select subgroups of patients. Reports on the use of azathioprine or 6-MP following surgical resection to prevent recurrence have been limited to one controlled trial to date, but nevertheless suggest efficacy. Most of the experience with azathioprine or 6-MP following surgical resection has come from treating Crohn's disease patients who have had their predominant area of severe disease removed. For many patients, it is preferable not to resect Crohn's disease in other areas of the intestinal tract which are minimally involved and in which complications have not occurred. In treating such patients with azathioprine or 6-MP for the mildly active, nonsurgically resected areas of Crohn's disease, surgical resection revealed that both remission maintenance and recurrence prevention could be achieved. A recently completed study revealed that both 5-ASA and 6-MP were successful in decreasing the endoscopic and clinical recurrence rate, but that 6-MP trended toward a better result. Both 6-MP and azathioprine are used in Crohn's disease patients who have failed to respond to steroids, or patients who are dependent on steroids. These medications, unlike 5-ASA agents and steroids, historically have been shown to take four to six months to demonstrate their full effect, although some patients respond more quickly. In a few individuals, 6-MP or azathioprine may take up to 6 to 9 months to show an effect. Once a desired therapeutic effect is achieved, azathioprine or 6-MP is usually continued for 3 to 4 years, before slightly reducing the dose for long-term maintenance. Azathioprine and 6-MP have less long-term toxicity than do corticosteroids. Intolerance to azathioprine or 6-MP has been noted in up to 10% of patients and includes fever, rash, nausea, and headaches. Pancreatitis occurs in 2-4% of patients on azathioprine or 6-MP, and in such cases, the patient should never be restarted on either medication. Bone marrow depression and mild hepatitis ("transaminitis") are usually able to be reversed by lowering the drug dosage. Long-term side effects occur in less that 2% of patients, but the development of opportunistic infections in patients on immunomodulators plus steroids should be watched for carefully. An increase in lymphoma and leukemia has been reported in patients with renal transplants taking these drugs. Although rare, lymphoma has been reported in Crohn's disease patients on azathioprine or 6-MP; it is unclear if this is related to the medication or the disease itself. Because of the risk of bone marrow depression or even aplastic anemia, monthly complete blood counts (CBCs) must be performed for as long as the patient is taking 6-MP or azathioprine. Commentary After reviewing our current step-up therapeutic approach to new onset Crohn's disease, Dr. Sands proposed that the early use of 6-MP should be considered for several reasons. Dr. Sands pointed out that earlier use of 6-MP would be able to decrease the exposure to steroids by avoiding steroid dependence and thus lessening systemic toxicity. In addition, prolonged maintenance of remission would be a likely result. He also suggested that the natural history of the disease may be able to be altered due to earlier complete mucosal healing achieved by 6-MP. Furthermore, earlier use of 6-MP should allow the Crohn's disease patient to not only avoid steroid dependence, but also avoid the need for surgical resection. 6-MP in the Pediatric Patient With Crohn's Disease Dr. James Markowitz of North Shore-Long Island Health System discussed his data from the multicenter pediatric Crohn's disease 6-MP trial which was presented at the American Gastroenterological Association's annual meeting.[2,3] Dr. Markowitz reported on the final results of an 18-month placebo-controlled multicenter trial evaluating the combination of 6-MP and prednisone as initial therapy for newly diagnosed children with moderate to severe Crohn's disease. In newly diagnosed children treated with 6-MP in addition to prednisone followed by tapering of prednisone, the relapse rate at 18 months was only 9% -- in comparison with a 47% relapse rate in those patients treated with prednisone alone. In addition, the percent of subjects requiring a second course of steroids in one year was 0% in the 6-MP plus prednisone-treated group as opposed to 57% in the patients treated with steroids alone. Most importantly, the cumulative prednisone dose and time remaining off steroids after discontinuation of steroids were both significantly better in the patients begun on 6-MP as initial therapy. Finally, the duration of remission was significantly longer in patients on early 6-MP therapy. Dr. Markowitz's study thus provides pivotal data demonstrating that the initial addition of 6-MP to an initial treatment regimen of steroids in newly diagnosed children with moderate to severe Crohn's disease lessens the cumulative exposure to corticosteroids and improves maintenance of remission. Therefore, immunomodulation with 6-MP is an important first line therapy for children with new-onset moderate to severe Crohn's disease. Concluding Remarks For many years our treatment of Crohn's disease has centered around a step-up therapeutic approach. It is now clear that it is time to rethink our approach to the initial therapy of new onset Crohn's disease. It is likely that the early use of 6-MP will enable us to circumvent side effects of steroids, change the natural course of disease, induce early remission, prevent unnecessary surgery, and markedly improve quality of life. This will also substantially lower the cost of treating our patients. Further clinical trials will be necessary to conclusively substantiate the basis for changing our approach to the therapy of Crohn's disease -- however, the potential implications for our patients are spectacular. References 1.Sands B: The case for 6-MP first line therapy, in, Sachar D (chair): Immunomodulators for new onset Crohn's disease: first line therapy or fall back position [Tuesday, May 18, AGA Clinical Symposium]. Digestive Disease Week, Orlando, Fla, 1999. 2.Markowitz JI: Pediatric perspectives for a life-long disease, in, Sachar D (chair): Immunomodulators for new onset Crohn's disease: first line therapy or fall back position [Tuesday, May 18, AGA Clinical Symposium]. Digestive Disease Week, Orlando, Fla, 1999. 3.Markowitz JI, Grancher K, Kohn N, et al: The multicenter, pediatric Crohn's disease (CD) 6-Mercaptopurine (6MP) trial: final results [Abstract 3342]. Digestive Disease Week, Orlando, Fla, 1999. Sources 1.Sachar D (chair): Immunomodulators for new onset Crohn's disease: first line therapy or fall back position [Tuesday, May 18, AGA Clinical Symposium]. Digestive Disease Week, Orlando, Fla, 1999. 2.Therapeutic Observations in IBD [Tuesday, May 18, AGA Poster Session]. Digestive Disease Week, Orlando, Fla, 1999. 3.Isaacs K, Sandborn W (chairs): Therapeutic monitoring in IBD [Tuesday, May 18, AGA Research Forum]. Digestive Disease Week, Orlando, Fla, 1999.
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