Conventional therapy for Crohn’s disease

Abstract

Crohn’s disease (CD) is a multifactorial disorder of unknown cause. Outstanding progress regarding the pathophysiology of CD has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD over the last years. However, many drugs have not been approved by regulatory authorities due to lack of efficacy or severe side effects. Therefore, well-known drugs, including 5-ASA, systemic or topical corticosteroids, and immunosuppressants such as azathioprine, are still the mainstay of CD therapy. Importantly, biologicals such as infliximab have shown to be efficacious in problematic settings such as fistulizing or steroid-dependent CD. This review is intended to give practical guidelines to clinicians for the conventional treatment of CD. We concentrated on the results of randomized, placebo-controlled trials and meta-analyses, when available, that provide the highest degree of evidence. We provide evidence-based treatment algorithms whenever possible. However, many clinical situations have not been answered by controlled clinical trials and it is important to fill these gaps through expert opinions. We hope that this review offers a useful tool for clinicians in the challenging treatment of CD.

Key Words: Crohn's disease; Conventional treatment; Review; Therapy

INTRODUCTION

Crohn’s disease (CD) is a chronic bowel disease charac-terised by a relapsing inflammatory process. It can affect any part of the gastrointestinal tract and is associated with discontinuous, transmural lesions of the gut wall. The current working hypothesis suggests that CD results from an aberrant immune response towards fecal bacteria in a genetically susceptible host[1].

While medical treatment of the acute flare is successful in most patients, one of the most difficult tasks in general medicine is to treat complications such as strictures, abscesses, fistulae and chronic disease activity. In this review, we describe the conventional treatment of CD depending on different clinical situations, such as an acute flare, maintenance of remission, fistulizing or chronically active disease behaviour.

Apart from the below discussed medical and surgical treatment of CD, other factors including changes in lifestyle should be recommended. Herein, probably the most important aspect is smoking cessation. Smoking has shown to be a risk factor for CD relapse after medically or surgically induced remission[2] and is associated with the need for higher doses of corticosteroids and immunosuppressants[3]. Importantly, a prospective trial showed that only one year of smoking cessation leads to a more benign course of disease with a lower rate of relapses[4]. This trial also showed that the ability to quit smoking clearly depended on the physician’s role. So the conventional treatment of CD should start, if neccessary, with convincing the patient to quit smoking.

ACTIVE DISEASE

Definition

The activity of CD can be assessed clinically, endosco-pically or by other indices[5]. The most established way is through the BEST activity index (CDAI), where symptoms and objective criteria such as anemia and body weight are included[6]. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease, and values above 450 are seen with extremely severe disease. In addition other diagnostic values such as blood sedimentation rate, C-reactive protein (CRP) and thrombocytes should also be taken into account. Endoscopic inflammatory evaluation, however, is not necessary in every exacerbation of the disease but might offer important information with respect to disease localisation. This is especially important for the use of topically acting agents such as budesonide in terminal ileal or right colonic CD. Exacerbation of CD through infectious agents should always be considered and excluded if possible.

In addition, the American College of Gastroenterology has defined the different disease activities in clinical practise as follows[7]: mild to moderately active disease is defined as “ambulatory patients able to tolerate oral alimentation without manifestation of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction or > 10% weight loss. In contrast, moderate to severe disease applies to patients that have failed to respond to treatment for mild to moderate disease or those with more prominent symptoms such as fever, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia. Severe disease refers to patients with persisting symptoms despite the introduction of steroids as outpatients, or individuals presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.

5-ASA

No debate has been as longstanding and controversial as whether the use of 5-ASA containing drugs in CD is justified or not. Numerous studies regarding this aspect have been performed over the last 25 years. However, data from current studies do not clearly support either point of view. Different study designs and drug dosages have been used that make comparison of the results rather difficult.

Sulfasalazine is the original compound in this class consisting of 5-ASA linked by an azo-bond to sulfapyridine, which is split off in the colon. Therefore efficacy of sulfasalazine was expected to be limited to colonic disease. Furthermore up to 50% of patients are not able to tolerate sulfasalazine due to nausea, headache, vomiting and epigastric pain. These side effects are suggested to be caused by the sulfapyridine moiety. Therefore, other 5-ASA formulations (mesalamine formulations and the pro-drugs olsalazine and balsalazide) without sulfapyridine have been introduced into the market with different pharmacodynamic and pharmacokinetic profiles (Table 1). These different preparations are therefore suggested to be non-interchangeable.

Table 1 Drugs for the treatment of CD.

Drug	5-ASA (mesalamine or sulfasalazine)
Dosage	3.2-4 g/d
Indications	Mild to moderately active disease, postoperative maintenance
Important side effects	Headache, nausea and abdominal pain, often during treatment with sulfasalazine (in up to 45% of patients); thrombopenia; interstitial nephitis, pancreatitis;
Monitoring	Liver function, full blood count and especially renal function
Pregnancy	Suggested to be safe in conventional doses

Sulfasalazine: Sulfasalzine has been shown to be significantly better than placebo in randomized clinical trials in inducing remission in active CD[8-10]. Subgroup analyses suggested that patients with only colonic disease seem to benefit the most from sulfasalazine therapy[8,9], whereas patients treated previously with prednisone failed to respond[8]. Sulfasalazine has not shown to have steroid-sparing properties[9,11]. Since 5-ASA was identified to be the active moiety in sulfasalazine, other 5-ASA containing formulations (such as mesalamine) have been tested in CD.

Mesalamine: Different pharmacological preparations allow relase of the active drug in different parts of the intestine. Therefore mesalamine, in contrast to sulfasalazine, may also be used in CD including small bowel CD. However, studies on the induction of remission in active CD with mesalamine yielded conflicting results. In total, six placebo-controlled trials with varying dosages of mesalamine have been performed to date. Two earlier studies did not detect a benefit of mesalamine over placebo in inducing remission[12,13]. Tremaine and colleagues observed a significantly greater number of patients that responded (defined as either a decrease of CDAI ≥ 70 or CDAI < 150), but this benefit was rather small (9 patients with mesalamine treatment vs 4 patients in the placebo group). However, no significant differences were found when clinical remission (defined as CDAI < 150) was analyzed[14]. Singleton and colleagues conducted three different trials with mesalamine (Pentasa) that were recently combined in a meta-analysis although two of the three trials were never published in full[15]. This analysis found a statistically significant benefit of mesalamine over placebo. However, this benefit was rather small (CDAI reduction of 18 points for the intention-to-treat-analysis).

In summary the clinical benefit of mesalamine in the treatment of active CD seems to be rather low. However, mesalamine is well tolerated and has a favourable side effect profile compared to sulfasalazine. The latter factor is probably the main reason why mesalamine is significantly used more often compared to sulfasalazine although data from randomized trials are in favor of sulfasalazine. Furthermore, many patients with mild to moderately active disease try a more harmless drug at first before taking corticosteroids.

Budesonide

The introduction of the topically-acting steroid budesonide has become a very potent alternative in the treatment of patients with CD located in the terminal ileum or right colon. Due to rapid metabolism by cytochrome P-450 enzymes in the liver, budesonide has less sytemic bioavailibility than systemic corticosteroids. A recent meta-analysis combined the data from 5 published studies investigating budesonide in comparison to placebo, 5-ASA and systemic corticosteroids[16]. A significant advantage of budesonide in inducing remission was observed in comparison to placebo (odds ratio of 1.85) and mesalamine (odds ratio of 1.73). Accordingly, a patient is 73% more likely to achieve remission with budesonide than mesalamine. Corticosteroids induced remission even more often as compared to budesonide with an odds ratio of 0.87, but in patients with mild and moderate disease (CDAI 200-300), no difference in remission rates was found. Treatment with budesonide was associated with similar side effects compared to mesalamine and placebo. Importantly, fewer side effects, such as acne, moon face and osteoporosis, were observed compared to systemic corticosteroids. The recommended dose of budesonide is 9 mg/d and should be tapered 3 mg every 2-4 wk unless a maintenance therapy with budesonide is suggested (see below).

Systemic corticosteroids

For moderate to severe CD, and especially if therapy with 5-ASA has failed, systemic corticosteroids are the treatment of choice (Table 2). Corticosteroids are fast and effective and induce remission in approximately 70% of patients. In active CD, corticosteroids have been shown to be superior to sulfasalazine, azathioprine and placebo[8,9]. No dose finding studies have yet been performed. Reported doses range from 30 mg/d to 1 mg/kg per day, however most clinicians start with 60 mg/d, although it seems to be favourable to apply a body weight dependent dosage (1 mg/kg). Tapering should be performed according to improvement of clinical symptoms and is usually done in steps of 5-10 mg/wk. At lower dosages, tapering might be reduced to 2.5-5 mg/wk. Whether i.v. application has an advantage over oral in severe acute flares is not clear, although it is frequently used when oral treatment has not been effective.

Table 2 Drugs for the treatment of CD.

Drug	Systemicorticosteroids (prednisone equivalent) or budesonide
Dosage	Corticosteroids: 30-60 mg/d or 1-1.5 mg/kg per day; Budesonide: 9 mg
Indications	Corticosteroids: moderate to severe disease. Budesonide: terminal ileal and right colonic disease in mild to moderate disease, low dose budesonide eventually for maintenace therapy
Important side effects	Weight gain, hypertension, fluid retention, myopathy, mood changes, infections, glaucoma, skin changes including acne, adrenal suppresion. Long term side effects: osteoporosis, cataract, aseptic bone necrosis
Pregnancy	Lower doses seem to be relatively safe
Comments	Avoid long-term use

Azathioprine/6-Mercaptopurine

The most common-ly used immunomodulators are the thiopurines, 6-mercaptopurine and its prodrug azathioprine (Table 3). Numerous clinical trials studied the efficacy of these immunomodulators in active CD. The most convincing data were obtained in the early trial by Present and colleagues where 67% vs 8% of the patients in the 6-mercaptopurine group vs placebo, respectively, achieved remission[17]. However, other trials did not observe a significant difference in the use of azathioprine compared to placebo[8,18]. Despite these conflicting data, a meta-analysis reported an odds ratio of 3.09 favoring azathioprine/6-mercaptopurine therapy over placebo[19] to induce remission. In addition, a recent Cochrane analysis reported an overall response in active CD of 54% vs 33% for azathioprine vs placebo, respectively[20].

Table 3 Drugs for the treatment of CD.

Drug	Azathioprine (6-mercaptopurine)
Dosage	2-2.5 mg/kg (1-1.5 mg/kg)
Indications	Maintenance, chronically active disease, steroid- refractory and steroid-dependency, fistulae, concommittant therapy with infliximab;
Important side effects	Pancreatitis, bone marrow supression, allergic reactions, drug heptatitis, nausea, malaise, bacterial and viral infections; in patients intolerant to azathioprine due to gastrointestinal symptoms, 6-mercaptopurine is suggested (not in side effects such as pancreatitis and bone marrow suppression)
Monitoring	Liver function, lipase and full blood count biweekly for the first three months, if normal then every three months throughout therapy
Pregnancy	Should be avoided, although available studies suggest a potential use especially in patients where maintaining remission is essential
Comments	Entire therapeutic efficacy is observed mostly after 2-4 mo; consider testing for thiopurine methyltransferase (TPMT) genotypes to identify patients with high-risk of bone marrow suppression; consider metabolite monitoring for adaequate dosing; ensure adequate birth control; allow 3 mo time before pregnancy or conceiving

Thiopurines are slow acting drugs and an effect can be observed after 2-3 mo. Thus thiopurines are less frequently used to induce remission in an acute exacerbation but rather to maintain remission. However, they have been shown to have steroid sparing properties[19,20] and furthermore the combination of prednisolone and azathioprine has shown to be superior over prednisolone monotherapy[21]. Therefore it is suggested to add azathioprine to corticosteroids in severe CD.

Methotrexate

In the pivotal trial by Feagan and collea-gues, methotrexate given intramuscularly 25 mg once a week was more likely to induce remission compared to placebo (Table 4). In addition, steroid-sparing properties were noted[22]. However, side effects were more common with methotrexate therapy than with placebo. Other studies using low dose methotrexate did not show a significant benefit[23,24]. In addition, no benefit was obserevd when high intravenous methotrexate was compared to oral azathioprine[25]. Like azathioprine/6-mercaptopurine, intramuscular methotrexate is only rarely used to treat an acute exacerbation of CD but is used more frequently in chronic active CD[26]. Importantly, side effects with methotrexate, specifically liver dysfunction, are common and need to be monitored. In addition, methotrexate is contradicted during pregnancy and should be used very cautiously in women of child-bearing potential.

Table 4 Drugs for the treatment of CD.

Drug	Methotrexate
Dosage	25 mg/wk i.m., if remission is achieved reduce to 15 i.m. (or s.c.)
Indications	Maintenance, chronically active disease, steroid-refractory and steroid-dependency, fistulae
Important side effects	Nausea, abdominal pain, diarrhea, stomatitis; hepatitis, liver fibrosis; hypersensivity pneumonitis
Monitoring	Liver function and full blood count monthly for the first two months, if normal then every two months throughout therapy
Pregnancy	Strictly prohibited
Comments	Entire therapeutic efficacy is observed mostly after 2-4 mo; consider folic acid supplementation with 2.5-5 mg/d; ensure adequate birth control; allow 3 mo time before pregnancy or conceiving

Antibiotics

Although antibiotics are frequently used to treat CD, this practice is not supported by strong evidence from randomized trials. However, increasing knowledge of the impotance of mucosal bacteria for the pathogenesis of CD gives a good rationale for investigating antibiotic approaches[27]. In addition, distinguishing an acute flare from an infectious gastroenteritis/colitis can be difficult. Thus antibiotics provide a therapeutic alternative, which might benefit both an acute flare and a gastrointestinal infection. However, further studies are warranted to establish the role of antibiotics in the treatment of CD and at this time they cannot be recommended as standard therapy.

Metronidazole: Metronidazole (20 mg/kg per day) has been shown to be superior over placebo in reducing the CDAI but not with respect to the induction of remission[28] (Table 5). Furthermore, this benefit was only seen in patients with colonic or ileocolonic disease, whereas no benefit was found with disease location in the ileum. Similar findings were reported from another trial where few patients with colonic involvement showed an improvement[29]. Another study reported no benefit vs placebo[30]. Compared to sulfasalazine, a cross over study reported no difference in the first 4 mo. However, in the cross over design, patients switched to metronidazole showed an improvement of CDAI, whereas in the sulfasalazine group this was not the case[31,32].

Table 5 Drugs for the treatment of CD.

Drug	Metronidazole
Dosage	10-20 mg/kg
Indications	Mild to moderately active disease; fistulae (usually prolonged treatment)
Important side effects	Nausea, metallic taste in the mouth, coating of the tongue, peripheral neuropathy
Monitoring	See side effects
Pregnancy	Long term treatment not yet evaluated, short term treatment appears to be safe

Ciprofloxacin: Ciprofloxacin is often used in a clinical routine, especially in combination with metronidazole (Table 6). Ciprofloxacin was significantly better compared to placebo in inducing remission in a smaller trial[33] and was shown to be similarly effective compared to mesalamine[34]. In contrast, corticosteroids resulted in higher rates of clinical remission compared to ciprofloxacin and metronidazole[35]. In patients with chronically active disease on budesonide, the addition of metronidazole and ciprofloxacin was not superior over budesonide monotherapy, although in patients with colonic CD a trend towards a significant benefit was observed[36].

Table 6 Drugs for the treatment of CD.

Drug	Ciprofloxacin
Dosage	1-2 g/d
Indications	Mild to moderately active disease, fistulae
Important side effects	Taste disturbance, gastrointestinal events, tendopathies
Monitoring	Generelly well tolerated, see side effects
Pregnancy	Probably safe

Infliximab

Infliximab is a chimeric IgG1 monoclonal antibody against TNF-α (Table 7). Apart from inhibiting TNF-α, recent data suggest that the induction of apoptosis in T cells through infliximab might be an important mechnism of action[37]. Infliximab has shown to be superior over placebo in inducing remission in patients with moderate to severe CD resistance to standard therapy[38]. In this trial, after four weeks 33% of patients went into remission after one single infliximab infusion as compared to 4% of the patients given placebo.

Table 7 Drugs for the treatment of CD.

Drug	Infliximab
Dosage	5 mg/kg per infusion; usually started at wk 0, 2, and 6 and then repeated every 8 wk if necessary
Indications	Chronically active disease, steroid-refractory and steroid-dependency, maintenance, fistulae
Important side effects	Nausea, headache, abdominal pain, infections, sepsis; infusions reactions (early or delayed), reactivation of tuberculosis
Monitoring	Vital signs around infusion
Pregnancy	Unknown
Comments	Exclude tuberculosis before infusions, consider concommittant use of imunosuppressants (azathioprine) to reduce antibody formation

Summary: Treatment of active CD

In mild and moderately active CD, 5-ASA or budesonide may be used as first line therapy, despite the limited efficacy of 5-ASA shown in randomized, placebo-controlled trials. The presently available budesonide preparations are only efficacious in disease primarily located within the terminal ileum or right colon. In non-responders, systemic corticosteroids should be used. Severe CD should be treated with systemic corticosteroids. If corticosteroids given orally do not lead to improvement, intravenous application should be considered since enteral absorption might be decreased due to severe intestinal inflammation. Enteral nutrition should also be added particularly in malnourished patients (see below chapter on nutrition for details). If an infectious complication is suspected, the additional therapy with antiobiotics (e.g. ciprofloxacin plus metronidazole) might be beneficial. The combination of systemic corticosteroids and azathioprine is superior to prednisolone monotherapy and this combination might be beneficial in severe cases. In patients refractory to corticosteroids, treatment with infliximab should be considered. Surgery might be neccessary in patients with severe and refractory CD not responding to above mentioned strategies. Intravenous cyclosporin and tacrolimus should only be used in selected severe and refractory cases.

MAINTENANCE OF REMISSION

Maintaining a medically or surgically induced remission of disease is one of the most important but yet most difficult therapeutic goals in the treatment of CD. Maintenance therapy in CD is characterized as treatment with only a few available drugs, moderately high rates of efficacy and frequent side effects. In total, 40%-70% of CD patients will experience a symptomatic relapse in 1 year after a medically or surgically indused remission[8,9]. Silverstein and colleagues reported that a surgically induced remission lasts a mean of 766 d whereas a non-surgically induced remission lasts only 120 d indicating that a surgically induced remission is more stable[39]. It was frequently recommended that the indication for a relapse-preventing therapy should be based on the prospective risk of an individual patient to relapse. Although the estimation of risk for relapse, based on the phenotype or genotype, is still controversial, single well known risk factors like smoking, frequent relapses in the past, a chronic active disease etc. have been described. To stop smoking is a very important therapeutic goal[2,40]. Systemic corticosteroids should not be used for maintaining remission due to lack of efficacy and severe long-term side effects. Since randomized, placebo-controlled trials suggest a different approach in medically or surgically induced remissions, we will handle them separately.

Medically induced remission

5-ASA: Numerous randomized, placebo-controlled studies, including four meta-analyses, have attempted to establish a role for 5-ASA in the maintenance of remission. Different study regimens and durations were performed and a substantial number of trials included only small numbers of patients. The two most recent meta-analyses failed to show a benefit for mesalamine over placebo in the maintenance of medically induced remission[41,42]. However, the preferable side effect profile of 5-ASA, especially mesalamine compared to azathioprine/6-mercaptopurine or methotrexate, is probably the reason why mesalamine is still used frequently to maintain a medically-induced remission. Many clinicians therefore try to maintain remission with mesalamine at least one time, especially in young women of childbearing potential. In addition many patients are in favour of trying a rather harmless drug at first for long-term therapy.

Azathioprine/6-Mercaptopurine: Azathioprine/6-mercaptopurine is the treatment of choice for patients with high risk of relapse. The effectiveness of azathioprine has been described in a recent meta-analysis including five randomized, placebo-controlled trials. In addition, a steroid-sparing effect was observed[43]. No clear direction has been given as to when to start the treatment with azathioprine/6-mercaptopurine. The following indications are most commonly accepted: frequent flares (more than two per year), chronically active disease, and steroid dependence (e.g. if two attempts of tapering steroids have failed). The thiopurines are slow acting drugs and an effect is usually observed after 2-3 mo with approximately 90% of patients responding within the first 4 mo[17].

An earlier open study suggested that azathioprine is no longer effective after 3.5 years[44]. In contrast, the same group reported, in a very recent placebo-controlled trial, that azathioprine is still effective with prolonged use[45]. However, a small increase in the frequency of malignancy, especially lymphoma, cannot be excluded in the long term treatment with azathioprine/6-mercaptopurine[46,47]. This must be weighed against the improved quality of life due to both drugs for patients with CD.

Methotrexate: The potential of methotrexate to induce remission was investigated in a study by Feagan and colleagues. Herein the patients who had achieved remission after weekly 25 mg intramuscularly were randomized to 15 mg methotrexate or placebo. Methotrexate was found to be significantly better than placebo in maintaining remission[26]. However, side effects were more significant than placebo. Methotrexate has not been studied in surgically or medically induced remission by other drugs (e.g. corticosteroids). In summary, methotrexate is suggested to be the alternative to azathioprine/6-mercaptopurine in the maintenance of remission. It has also shown to have steroid-sparing properties with the mean time to respond at about 2 mo.

Budesonide: Lower doses of budesonide (3 or 6 mg) have also been studied for their potential to be effective in the maintenance of remission. Although earlier meta-analyses have not shown that budesonide was superior over placebo[16,48], a recent randomized, placebo-controlled trial found a trend towards a longer quiescent disease in budesonide treated patients compared to placebo[49]. In this trial, no significant difference in total adverse events or corticosteroid-associated events was demonstrated between placebo and budesonide. In addition, a very recent paper by Sandborn and colleagues combined the data of four double-blind, placebo-controlled trials with identical protocols analyzing the efficacy of 6 mg budesonide. Budesonide was shown to be effective for prolonging the time to relapse and for significantly reducing the rates of relapse at 3 and 6 mo but not at 12 mo. Herein no difference in the frequency of adverse events and glucocorticosteroid associated side effects between budesonide and placebo was found[50]. Thus, the current data suggest that budesonide at a dosage of 6 mg seems to have the effect of prolonging remission in CD in terminal ileal or right colonic disease. Budesonide might thus offer a potential alternative in the maintenance of a medically-induced remission, especially in steroid-dependent patients.

Infliximab: Two studies have shown that infliximab is effective in maintaing remission in CD[51,52]. In the Accent I trial, infliximab was shown to be superior over placebo in the maintenance of remission in CD patients that responded to one single infusion of infliximab. Herein, about 20% of patients in remission after the first infusion of infliximab were maintained in remission for one year with repeated infusions every eight weeks[52]. Infliximab was also shown to have steroid-sparing properties. Repeated infusions of infliximab should thus be considered for chronically active or steroid-dependent patients where standard immunosuppressants are not effective or where surgical interventions are not considered. However, repeated infusions of infliximab are costly and data on long-term safety, including the occurrence of malignancies, are limited. Infliximab has been shown to lead to mucosal healing, which was associated with reduced surgical interventions and lower hospitalization rates[53]. However, at this time it is debated whether mucosal healing is an important goal in CD therapy. Further studies are warranted regarding this matter. The development of antibodies against infliximab is frequently found and is associated with reduced efficacy and increased numbers of infusion reactions. The concommitant use of immunosuppressants has been shown to reduce the incidence of antibody formation[54].

Summary: Maintenance after medically induced remission

After a medically-induced remission, maintenance therapy should be initiated based on the individual situation. No medical therapy may be considered in patients with low risk of relapse. However, in patients with high risk for relapse (frequent relapses, colonic involvement and severe disease behaviour), therapy with azathioprine or 6-mercaptopurine should be initiated. In patients with terminal ileal or right colonic disease, low-dose budesonide might offer an alternative especially in steroid-dependent patients. In patients who are not responding or are intolerant to azathioprine/6-mercaptopurine, therapy with methotrexate may be used. If not successful, patients should be considered for maintenance treatment with infliximab.

Postoperative CD (surgically-induced remission)

About 75% of CD patients will require surgery within the first 20 years after the onset of symptoms[55,56]. In addition, recurrence rates after surgical resection are high: after the first resection, up to 80% of patients show an endoscopic recurrence within the first year although most patients are not symptomatic[55-57]. Furthermore, up to 20% have clinical symptoms and 5% require another surgical intervention within the first year. After 5 years, about 50% of patients have a clinical relapse. Systemic corticosteroids and budesonide are not effective in preventing postoperative relapse[58-61], whereas methotrexate, ciprofloxacin and infliximab have not been studied for this indication. Various risk factors for postoperative recurrence have been described but most of these risk factors have not been studied in a prospective manner. Currently smoking is the most consistently described risk factor for postoperative relapse[40,62]. In addition, Rutgeerts and colleagues showed that preoperative disease activity and endoscopic lesions at the neoterminal ileum within the first year after surgery are also associated with higher risk for postoperative recurrence[57]. In addition, a recent study suggested that CD patients with CARD15 mutations have a higher risk of postoperative relapse compared to patients without mutated CARD15. Thus genotyping for CARD15 mutations might offer a potential alternative to identify patients with high risk of postoperative relapse[63]. Further studies are warranted to consider this approach.

5-ASA: As opposed to the controversial discussion about the efficacy of 5-ASA in the treatment of CD, the results on the prevention of postoperative recurrence are quite solid. Camma and colleagues described in a meta-analysis a risk reduction of 13.1% by mesalamine treatment compared to placebo[41]. A more recent placebo-controlled trial reported that mesalamine did not significantly affect the postoperative course of CD, but some relapse-preventing effect was found in patients with isolated small bowel disease[64]. In summary, 5 ASA is the only treatment with an evidence-based relapse preventing effect after a surgically induced remission and is therefore recommended according to recent guidelines[65].

Azathioprine/6-Mercaptopurine: The two largest studies regarding the effect of azathioprine/6-mercaptopurine to prevent postoperative recurrence were recently published. In the first trial, Hanauer and colleagues compared 6-mercaptopurine at the low fixed dose of 50 mg/d to mesalamine 3 g/d and placebo after ileocolic resection[66]. There was a significant benefit of 6-mercaptopurine compared to placebo in preventing clinical and endoscopic recurrence over two years. However, this study has been criticized since it was underpowered and also had a high drop-out rate of patients. Ardizzione and colleagues observed no benefit of azathioprine at standard dosing (2 mg/kg) in preventing clinical relapse after two years in comparison to mesalamine[67]. In summary, although none of these studies offer robust data to support the use of azathioprine/6-mercaptopurine in the prevention of postoperative recurrence, many clinicians use these drugs for this indication.

Antibiotics: In a randomized, placebo-controlled trial a significant decrease was observed in the incidence of severe endoscopic recurrence with metronidazole treatment as compared to placebo after ileal resection[68]. In addition, metronidazole therapy statistically reduced the clinical recurrence rates at 1 year. Metronidazole is still only rarely used on this occasion since long term intake is not tolerated by most patients due to side effects such as metallic taste, nausea and peripheral neuropathy. Ciprofloxazin has not been studied in a randomized, placebo-controlled trial regarding the prevention of postoperative recurrence. Rifaximin, which is a non-absorbable drug with good tolerability covering most Gram-positive and Gram-negative bacteria, might offer a very promising alternative since long term application is tolerated much better[69]. At the moment, although frequently used in clinical practice, none of these antibiotics will be considered standard therapy until more controlled trials provide clear results.

Rutgeerts and colleagues investigated the efficacy of ornidazole, a nitroimidazole antibiotic, for the prevention of clinical recurrence after curative ileocolonic resection in a recent placebo-controlled trial. They found that ornidazole significantly reduced the clinical and endoscopic recurrence rate at 1 year compared to placebo. However, significantly more patients in the ornidazole group dropped out of the study because of side effects. In summary, these data indicate that ornidazole might offer a therapeutic alternative in preventing postoperative recurrence[70].

Summary: Treatment of postoperative CD

No standard treatment algorithm prevents postoperative relapse. Despite the controversial discussion on its efficacy, mesalamine over a period of two years is recommended as the treatment of choice in the prevention of postoperative relapse. However, many patients who undergo surgical resection have already been treated with mesalamine so that alternative regimes should be initiated. Although robust data are lacking, most clinicians use azathioprine/6-mercaptopurine at standard dosing in patients with higher risk of postoperative relapse. To estimate the risk of clinical relapse the diagnosis of endosciopic lesions at the anastomosis 6 mo after resection may be used. Azathioprine/6-mercaptopurine may be started if severe or moderate lesions at the anastomosis are found[71]. Although this regime has never been studied in a randomized trial, it seems to be a reasonable approach. Antibiotics, such as metronidazole or ornidazole, might offer a potential alternative although the long term use is limited due to side effects. In addition, prospective studies investigating infliximab in this setting are warranted.

COMPLICATIONS IN CD

Fistulizing disease behaviour

The treatment of fistulizing CD remains probably the most difficult clinical challenge. Treatment is complicated since very few drugs have proven efficacy whereas most agents used in CD therapy (5-ASA, systemic corticosteroids, budesonide) are ineffective. Fistulae are reported to occur in up to 50% of patients after 20 years of disease[72]. Especially enterocutaneous and enterovaginal fistulae have a severe impact on the quality of live of CD patients. Enterovesical fistulae require surgical intervention due the potential development of an urosepsis. Perianal fistulae are the most common form and are often complicated by an abscess where surgical drainage must be performed. Since complete long term closure of fistulae cannot be achieved in many patients with the available therapies, reduction of fistula drainage and closure of part of the fistulae have been accepted therapeutic goals. Apart from medical treatment approaches as discussed below, surgical interventions such as fistulotomy and insertion of non-cutting setons should be part of the management. A close cooperation between the gastroenterologist and the surgeon is required.

Azathioprine/6-Mercaptopurine: Robust data summarized in the meta-anaylsis by Pearson[19] show a positive effect of azathioprine/6-mercaptopurine on fistula closure with an odds ratio of 4.44 (CI 1.50-13.20). Thus azathioprine/6-mercaptopurine is the basis of long-term treatment of fistulae.

Methotrexate: No randomized trial has been performed using methotrexate to investigate the healing of fistulae. However, retrospective data showed complete or partial response in 56% (9/16) of patients[73]. Methotrexate might thus be considered as the alternative agent to azathioprine/6-mercaptopurine.

Antibiotics: A small uncontrolled study reported a clinical response to metronidazole in 20 out of 21 patients and complete healing after maintenance treatment in 10 out of 18 patients. A follow-up study demonstrated that dosage reduction was associated with exacerbation of fistulae in all patients and healing was again achieved if the drug was reintroduced[74]. Ciprofloxacin alone showed an improvement in 7 out of 10 patients treated with up to 1.5 g over three months[75]. Although controlled clinical trials are lacking, the combination of metronidazole and ciprofloxacin is often initiated.

Infliximab: Infliximab offers robust data from randomized, placebo-controlled trials in the treatment of enterocutaneous fistulae. In the first trial by Present and colleagues, three infusions of infliximab at 0, 2, and 6 wk resulted in complete healing of enterocutaneous fistulae in 55% of patients compared to 13% in the placebo group[76]. Data from the ACCENT 2 trial showed that infliximab maintained healing of enterocutaneous fistulae in 36% patients who responded to the initial three infliximab infusions[77]. However, it was shown that healing of fistulae needed repeated infusions, which is similar to the experiences observed in a clinical routine. In summary, data from controlled clinical trials suggest that infliximab might be the most potent drug in the treatment of CD fistulae. Three infusions with a dose of 5 mg/kg at wk 0, 2, and 6 are recommended as standard for the treatment of fistulizing CD.

Cyclosporin A: Cyclopsorin A offers an effective alternative treatment for CD fistulae. There are numerous uncontrolled trials that describe a mean initial response in 83% of patients with discontinuation of treatment leading to frequent relapses (reviewed in ref. [78]). However, cyclosporin A toxicity can be dramatic, including renal failure, and thus application should be performed only in centers with expertise. Continuous infusions of 4 mg/kg per day is required and concentrations of 300-400 ng/mL should be maintained[78]. Dosing can be switched to oral if patients respond to intravenous cyclosporin.

Tacrolimus: A recent placebo-controlled trial showed that tacrolimus at a dose of 0.2 mg/kg was more effective than placebo in improvement of fistulae (defined as closure of >/= 50% of draining fistulas). However, no difference was observed with respect to fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 wk. In addition, adverse events such as headache, increased serum creatinine levels, and insomnia were found significantly more often in the tacrolimus group[79].

Summary: Treatment of fistulizing CD

No standardized treatment algorithm exists in the medical treatment of fistulizing CD. Importantly, effective management requires good collaboration between the gastroenterologist and the surgeon in both simple and complex fistulae. Azathioprine/6-mercaptopurine are the basis of fistulae treatment. Antibiotic combination therapy, preferable with metronidazole and ciprofloxacin, can be considered over a period of 2-3 mo especially if an abscess might be suspected to occur. In patients with complex fistulae including underlying rectal inflammation not improving from above mentioned strategies, a three dose therapy regimen with infliximab should be applied. If patients respond, therapy with azathioprine and infliximab might be necessary to maintain fistula healing. In refractory cases, therapy with cyclosporine and tacrolimus should be considered.

Chronic active disease

Various definitions of chronic active disease exist and thus results from clinical trials in this complicated group of patients are rather difficult to interpret. The German consensus conference on the treatment of CD describes chronic active disease as the persisting or recurrent occurrence of symptoms over more than 6 mo despite standardized therapy[65]. Patients with chronic active disease should thus be treated first with azathioprine/6-mercaptopurine or alternatively with methotrexate. If patients do not respond or are intolerant to these approaches, infliximab should be given. Due to severe long-term side effects, systemic corticosteroids should be avoided. 5-ASA is not effective in chronically active CD.

Steroid-dependent disease

Steroid-dependency is a frequently observed phenomenon in CD and it is defined as the need for corticosteroids to maintain a patient in stable remission after two unsuccessful attempts to withdraw steroids within the last six months. About 28%-44% of patients will become steroid-dependent after an initial course of corticosteroids[80,81]. Long term use of corticosteroids should be avoided due to severe side effects such as osteoporosis, diabetes and hypertension. Prophylaxis of osteoporosis with calcium and vitamin D should be applied. Similar to patients with chronic active disease, azathioprine/6-mercaptopurine is the treatment of choice and methotrexate is the alternative agent to avoid long term steroid therapy. Two meta-analyses reported a steroid-sparing effect for azathioprine[20,43] and the same properties were observed for methotrexate[26]. In addition, infliximab has also been shown to have steroid-sparing properties and thus should also be considered as an alternative[52].

Steroid-refractory disease

Patients with persisting clinical activity under continuing therapy with corticosteroids at a dose greater than 1 mg/kg per day are described as steroid-refractory. This clinical situation occurs in about 20%-30% of patients treated with corticosteroids[8,9,80]. Only a few drugs have been tested in this situation: azathioprine/6-mercaptopurine and methotrexate have shown to be effective in steroid-refractory patients[20,26,43]. In addition, infliximab offers a therapeutic alternative[52]. However, if medical therapy fails in severe cases, surgical interventions such as colectomy might be necessary.

Gastroduodenal CD

Sympotmatic involvement of stomach and duodenum is a rare phenomenon observed in about 4%-5.5% of patients[82,83]. Endoscopic and histologic involvement might be found in up to 40% of patients[84-86]. Due to the low frequency of patients with symptomatic gastroduodenal involvement, however, randomized, placebo-controlled trials are not available. Combination therapy with high dose acid suppression (proton pump inhibitors) and standard therapy of CD are usually used. Corticosteroids[87], azathioprine[88,89], and infliximab[90] have been reported to be effective in selected patients. However, many patients with obstructive symptoms caused by strictures will have to undergo surgical interventions such as gastroduodenal or gastrojejunal bypass, even performed laparoscopically. Gastroduodenal bypass has been reported to result in a good outcome in up to 87% of patients[91].

Fibrostenotic disease behaviour

CD is often complicated by fibrostenotic strictures that can be located within the whole gastrointestinal tract. Strictures can remain clinically asymptomatic over years until the intraluminal caliber causes obstruction. However, it is often difficult to differentiate between an inflammatory or fibrostenotic stricture. Ultrasound and MRI with the possibility to visualize mucosal blood flow are helpful in differential diagnosis. Before initiating surgical interventions, many clinicians try at least one attempt of medical treatment for strictures suggested to have an inflammatory component. Corticosteroids are most commonly used in this clinical situation. Fibrostenotic strictures will not respond to medical therapy. Endoscopic ballon dilatations, stricturoplasty or resections are required in most cases.

ROLE OF NUTRITION IN CD

Prevention and treatment of malnutrition

During an acute flare of CD, undernutrition with weight loss, protein deficiency and specific deficiencies in vitamins, minerals and trace elements are commonly found. Malnutrition is mainly caused by anorexia, increased intestinal losses and systemic inflammation. In children and adolescents a decrease in growth velocity may occur, secondary to inadequate nutrition and steroid therapy. The relevance and extent of these deficiencies vary according to the site and extent of the diseased intestine as well as disease activity. In active CD, an improvement in nutritional status cannot be achieved by nutritional counselling alone but oral nutritional supplements or tube feeding leads to improvement of the nutritional status[92,93]. Both malnutrition and growth retardation require enteral nutrition (EN).

The use of oral nutritional supplements or tube feeding should also be taken into account in the perioperative setting. An increased frequency of postoperative complications has been shown in undernourished patients with CD[94], with undernutrition being defined as weight loss and/or plasma albumin levels below 35 g/L. Although specific data concerning the effect of perioperative nutrition in CD are lacking, there is a considerable body of evidence on the effect of perioperative nutrition in general gastrointestinal surgery and preoperative nutritional support is therefore recommended in malnourished patients[95]. A prospective study showed that a preoperative oral supplementation with a formula enriched with arginine, omega-3 fatty acids, and RNA was associated with reduced postoperative infections and shorter lengths of hospital stay[96]. Supplementation of specific deficiencies may be crucial. Iron deficiency is most common and should be treated with oral or i.v. iron supplements. Vitamin D and calcium should be supplemented in patients on steroid therapy and patients treated with sulfasalazine are at risk to develop Vitamin B12 deficits.

Treatment of active disease

EN is also effective in the treatment of an acute flare in CD with approximately 60% of all patients reaching remission. In children, active disease frequently leads to growth retardation and enteral nutrition is therefore the treatment of choice. In adults, however, treatment with corticosteroids is more effective as shown by a recent meta-analysis[97]. Enteral nutrition as sole therapy for acute CD is indicated mainly when treatment with corticosteroids is not feasible; e.g. due to intolerance or refusal. Combined therapy (enteral nutrition and drugs) is indicated in undernourished patients as well as in those with inflammatory stenosis of the intestine. If active CD is treated with systemic corticosteroids in combination with EN and supplementary EN is continued after the active phase, it prolongs the relapse free interval[98].

Total parenteral nutrition is no better than enteral nutrition in the therapy of active CD and should therefore be restricted to patients with a contraindication to or intolerance of enteral nutrition[99]. EN in subileus and high grade stenosis does require special caution. A documented stenosis however is not a contraindication to EN per se[100].

EXTRAINTESTINAL MANIFESTATIONS

CD is much more than a bowel disease since it can affect almost every other organ of the body. We will describe only briefly the most common extraintestinal manifestations (EIMs) and the recommended therapeutic approaches. The treatment of most extraintestinal manifestations has not arisen from randomized clinical trials but more from experiences and case reports and thus remains often nonempirical. With respect to all EIMs, a collaboration with rheumatologists, dermatologists and especially ophthalmologists should be part of the therapeutic regimen. The basis of treatment of EIMs is to obtain remission since it will positively affect the course of the particular extraintestinal manifestation, especially if symptoms occur parallel to exacerbation of the disease.

Arthritis

Joint involvement is the most frequently found extraintestinal manifestation in CD, which can be separated into axial and peripheral involvement. Peripheral involvement can be subdivided into a pauciarticular, large joint arthropathy, and a bilateral symmetrical polyarthropathy[101]. Axial involvement can result in sacroiliitis or ankylosing spondylitis. Placebo-controlled trials have shown that sulfasalazine is effective in the treatment of ankylosing spondylitis[102,103]. Furthermore physiotherapy is important. A low dose of corticosteroids (usually no more than 10 mg/d) can be a therapeutic option. Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-II-inhibitors might lead to pain relief but should be avoided since they might exacerbate CD. Many patients need analgetics to control symptoms. The use of tramadol or metamizol is preferable. Due to the experiences with rheumatoid arhritis, methotrexate might be offered as an alternative. In the same respect, infliximab has shown to be very effective[104,105].

Erythema nodosum, pyoderma gangrenosum, ocular involvement, PSC

Erythema nodosum is the most common skin manifestation in conjunction with active CD and usually responds to therapy with corticosteroids. Severe or refractory cases have been shown to respond to infliximab[106]. In pyoderma gangrenosum, corticosteroids are the treatment of choice, even applied by the intravenous route in refractory cases. Topical therapy should be considered as an adjuvant to systemic therapy. However, a recent study reported healing of pyoderma gangrenosum after infliximab treatment in all 13 patients[107]. These results suggest that infliximab might be considered as the treatment of choice for pyoderma gangrenosum, especially in refractory cases. An ocular manifestation such as iridocyclitis or anterior uveitis should be treated with topical steroids and cycloplegics. A case with improvement of uveitis after infliximab treatment was recently reported[108]. Considering primary sclerosing cholangitis (PSC), although more frequently seen in ulcerative colitis, an earlier study showed that ursodeoxycholic acid (UDCA) at a dose of 10-15 mg/d can result in significant liver enzyme improvement[109]. However, a recent 5-year, placebo-controlled trial of high-dose UDCA (17-23 mg/d) failed to show benefit for UDCA on survival or the prevention of cholangiocarcinoma in PSC[110]. Taking all published studies into consideration, Olsson and colleagues conclude that there is, if at all, only a very limited effect of UDCA in PSC. PSC is associated with the occurrence of cholangiocarcinoma where liver transplantation seems to be the only curative approach.

CONCLUSION

Based on the currently available data from randomized, placebo-controlled trials, including meta-analyses, we describe the conventional treatment of Crohn’s disesase. This coventional approach suggests a step-up approach usually in the order of 5-ASA, corticosteroids, immunosuppressants and usually infliximab in refractory or severe cases including fistulizing disease behaviour. In contrast, a more aggressive form of treatment (bottom-down) has been recently proposed. This regimen starts out early at diagnosis of CD with the combination of biologicals (infliximab) in combination with immunosu-ppressants (azathioprine). Studies are warranted to elucidate the role of this new therapeutic approach in comparison to the standard therapy algorithms. Further-more the value of mucosal healing and its effect on the course of CD, including its potential to reduce complications, surgical interventions and hospitalisation rates, should be evaluated in upcoming studies.

The past years have resulted in enormous new insights into the pathophysiology of CD with respect to molecular genetics, mucosal bacteria and immunology. Now it is time to translate these findings into newer therapeutic concepts. Numerous agents, especially biologicals, have been tested but most of them have not been introduced into the market due to low efficacy or severe side effects. Apart from infliximab, other TNFα-antagonists, such as adalimumab or CDP870, might offer a potent alternative in the future. However, apart from evidence-based medicine, CD therapy will always be an individualized therapy. In addition, many patients construct their own therapeutic regimen, especially after long term disease. Such approaches might be effective in individual situations, although they do often not stand the criteria of evidence-based medicine. Moreover, many clinical situations are complex and might never have been studied in randomized, placebo-controlled trials. Therefore, the treatment of CD frequently requires individual decisions and creativity despite a very good basis of evidence-based therapies.