Top-down therapy for IBD: rationale and requisite evidence

86 | FEBRUARY 2010 | volUmE 7 www.nature.com/nrgastro

Imelda GI Clinical Research Center, Imeldalaan 9, 2820 Bonheiden, Belgium. geert.dhaens@ imelda.be

Top-down therapy for IBD: rationale and requisite evidenceGeert R. D’Haens

Abstract | Several trials have shown that early treatment of Crohn’s disease with immunomodulators and anti-TNF agents leads to a superior clinical outcome, including healing of the mucosa, compared with standard therapy alone. Mounting evidence indicates that mucosal healing is associated with a reduced risk of complications, and a reduced need for surgeries and hospitalizations. In the SONIC trial, a combination of the standard azathioprine immunomodulator therapy and infliximab, an anti-TNF agent, had more potent anti-inflammatory effects than either drug alone in patients with Crohn’s disease who had evidence of active inflammation. These findings and those from rheumatoid arthritis trials have prompted the investigation of early initiation of immunomodulator (standard or anti-TNF) therapy for Crohn’s disease, in suitable patients, which has led to substantial improvements in disease management. Careful selection of patients is, however, essential given the potential risk of toxic effects from these therapies and the fact that some patients with IBD will have a favorable disease course without them. Identification of suitable patients, however, remains a challenge, as genetic, phenotypic and environmental factors have not yet been identified that can be used for routine assessment and selection is mainly based on clinical criteria.

D’Haens, G. R. Nat. Rev. Gastroenterol. Hepatol. 7, 86–92 (2010); doi:10.1038/nrgastro.2009.222

IntroductionIBD encompasses a range of chronic, immune-mediated inflammatory disorders of the gastrointestinal tract1,2 that are usually classified under two major condi-tions, Crohn’s disease and ulcerative colitis. In patients with Crohn’s disease the inflammation is typically focal and transmural, and in patients with ulcerative colitis it remains limited to the mucosa. Any part of the gastro-intestinal tract may be affected in patients with Crohn’s disease, although most cases are located in the terminal ileum and/or colon. Ulcerative colitis starts from the rectum and extends proximally, thus affecting different parts of the colon.

In the early phase of Crohn’s disease, the pathology is predominantly inflammatory, which results in inter-mittent symptoms of diarrhea and abdominal pain.3 In the late phase, as a consequence of transmural inflamma-tion, complications, such as stricture, perforation and fistula formation, may be experienced and will often need surgical treatment.4 Following surgical resection, recur-rence of Crohn’s disease is virtually inevitable.5 Thus, the natural history of Crohn’s disease over the longer term can be characterized as progressive and destructive, with structural damage to the bowel becoming irrevers-ible and intestinal function being lost. Manifestations of loss of function include bile-salt diarrhea, steatorrhea, vitamin and mineral deficiencies, anemia, short bowel

syndrome with dehydration and malnutrition, stoma and loss of continence. By contrast, for ulcerative colitis the extent and location of the mucosal inflammation seem to change more in the course of disease. Among patients with ulcerative colitis initially presenting with mere proctitis (inflammation of the rectum only) in one cohort, the risk of progressing to left-sided colitis by 25 years was 53%,6 but inflammatory episodes were intermittent in 90% of patients; 25% of patients had only one acute episode and around 50% were in remission at any given time during the 25 years of follow-up.7 The most aggressive phase of the disease is frequently seen in the first 3 years following diagnosis,7 during which 75% of colectomies for intractable disease are performed.6 Development of dysplasia or adenocarcinoma is associ-ated with longstanding and extensive ulcerative colitis and insufficient suppression of chronic inflammation.8

Little is known about the earliest changes that occur in the intestinal wall of patients with IBD. Chemical agents or genetic manipulations (for example, inter-leukin 10 knockout) have been used to induce colitis in animal models, but the effects of these experiments are hardly compar able to genuine human IBD. In addi-tion, the majority of patients with IBD present to their physician with longstanding symptoms of (bloody) diar-rhea, abdominal pain, iron deficiency, growth retarda-tion, weight loss or a combination of these features. Although the diagnosis can be made rather easily at that point, IBD is already in its chronic stage rather than at the onset of disease. Some postoperative manifestations of IBD, however, provide interesting opportunities to

Competing interestsThe author declares an association with the following companies: Centocor BV, Schering–Plough, Abbott Laboratories and UCB. See the article online for full details of the relationships.

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investigate the features of disease onset. For example, in patients who have recurrent Crohn’s disease in the neo-terminal ileum following ileocolonic resection or who have pouchitis (inflammation of the ileal pouch) follow-ing restorative procto colectomy for ulcerative colitis, the earliest lesions that recur can be observed, biopsied and studied in depth.9 These attractive models of initiation and progression of IBD have, however, not been explored in depth.

This review assesses the outcomes associated with immunosupressive therapies for IBD, used alone or in combination, and their effects on different stages of disease progression. The benefits and adverse effects of top-down therapy (early combined immunosuppression started at diagnosis or soon thereafter), are compared with those of standard treatment (early cortico steroid treatment followed by treatment with immuno-modulators or biologic agents at a later stage if deemed appropriate). I also propose a strategy for management of Crohn’s disease that takes into account clinical evidence, the disease course and the diagnosis and treatment options currently available.

Standard therapy for established IBDMedical therapyThe standard medical treatment for Crohn’s disease is done first with glucocorticosteroids, followed by administra tion of immunosuppressive antimetabolites (azathioprine, mercaptopurine and methotrexate), and biologic agents that also have immunomodulatory prop-erties (infliximab, adalimumab, certolizumab pegol and natalizumab). Steroids are inductive agents that mainly suppress the symptoms of the disease, while immuno-suppressive antimetabolites are maintenance agents that prevent symptom recurrence. Biologic agents are both inductive and maintenance agents and are primarily directed against inflammatory processes. Among the cur-rently available biologic agents, infliximab, adalimumab and certolizumab pegol are antibodies against tumor necrosis factor (TnF), while natalizumab, which will not be discussed in this review, is an antibody against inte grin α4. Agents that modify, reverse or prevent fibro-genesis or that specifically treat per forating complica-tions have not yet reached the market. Therefore, it seems reasonable to try to prevent these complications while only inflammation is present.

Ulcerative colitis is also treated with corticosteroids, immunomodulators and infliximab, the only anti-TnF agent approved for this condition.10 Unlike in Crohn’s disease, aminosalicylates are also highly effective to induce and maintain remission and even to prevent dysplasia and cancer.10,11

SurgerySurgical bowel resection is usually performed in patients with fibrostenotic and/or perforating complications and exceptionally in patients with inflammatory disease that is refractory to medical treatment.12 Up to 75% of patients with Crohn’s disease need one or more surgical inter-ventions during their lifetime.13 with the development

Key points

In patients with active Crohn’s disease who are naive to conventional ■immunomodulators or biologic agents, combination therapy induces better rates of clinical and endoscopic remission than monotherapy

Patients with Crohn’s disease usually have a better response to biologic ■therapy when treatment is initiated earlier in the disease course

Clinical parameters can be used to predict an unfavorable disease course ■in Crohn’s disease and thus to identify patients who should be treated more aggressively early on

As potent and combined immunosupression is possibly associated with more ■toxic effects than standard therapy, the benefit of aggressive treatment needs to be balanced against potentially severe adverse events

and use of increasingly potent medications, the need for surgery may, however, decline.14 resection is generally postponed for as long as possible because of its func-tional consequences, such as vitamin B12 deficiency and bile-acid diarrhea, but also because of the high likelihood of recurrence of Crohn’s disease5 with a similar pattern and behavior at recurrence to those before surgery.15

The need for proctocolectomy in ulcerative colitis is limited to cases in which the disease is refractory to medica tion or in cases of dysplasia or cancer, which account for <10% of all patients.16,17 This intervention is sometimes advocated as a cure for ulcerative colitis, although more than 50% of patients who undergo surgery develop some type of pouchitis and the quality of life achieved with medically induced remission is usually superior to that achieved with surgery.18,19

Lessons on early therapy from rheumatologyClinical trials in patients with rheumatoid arthritis evolved from studies of conventional therapies to studies of earlier interventions in patients at high risk of disease progression. Immunosuppressive therapies (by use of either conventional immunomodulators or biologic agents) have been shown to halt progressive joint damage and prevent erosions and joint-space narrowing in patients who don’t have these lesions yet.20 In this study, a combina tion of methotrexate and adalimumab was shown to be more effective than either treatment alone. evidence even suggests that anti-TnF treatment could rapidly modify the disease course to the point of induc-ing remission, enabling withdrawal of conventional and biologic immunomodulatory therapy in patients treated to early remissions.21 These findings have stimulated efforts in the field of Crohn’s disease towards a ‘hit hard and early’ top-down approach.22,23

Early therapy in Crohn’s diseaseMedical therapyComparison with standard therapySeveral trials have shown that administration of some potent anti-inflammatory medications in the earlier phases of Crohn’s disease yields results that are supe-rior to those achieved with the same therapy given once disease is further established. In a clinical trial in children who had newly diagnosed Crohn’s disease, those treated with a combination of mercaptopurine and induction

foCuS on BIologIC ThERApy foR IBD




therapy with corticosteroids had a remission rate as high as 90%, whereas those who only received corticosteroids (without mercaptopurine) were in remission in approxi-mately 50% of cases, at 15 months of follow-up.24 of note, in a cohort of adults with established Crohn’s disease, corticosteroid induction and therapy with azathioprine, a prodrug of mercaptopurine, led to a remission rate of only 42% at 15 months,25 although these studies cannot be compared.

In the PreCISe 2 program, a clinical response to 26 weeks of certolizumab pegol therapy was seen in 90%, 75%, 62% and 57% of patients refractory to standard therapy if Crohn’s disease had been diagnosed <1 year, 1–2 years, 2–5 years or >5 years, respectively, before initia tion of treatment.26 The response rates to adali-mumab therapy observed in the CHArM trial showed the same trend, with a clinical response in 54%, 49% and 42% of patients with a disease duration of <2 years, 2–5 years and >5 years, respectively.27

The outcome of early immunosuppression was compared with that achieved by standard therapy in a prospec tive randomized controlled trial performed in the Benelux.22 Patients with newly diagnosed Crohn’s disease who had never been exposed to corticosteroids and/or immunomodulators received either early com-bined immunosuppression therapy with three infu-sions of inflix imab (weeks 0, 2 and 6) and 2.5 mg/kg of azathioprine per day, or conventional treatment with cortico steroids. Patients on standard therapy received azathioprine for relapse or if corticosteroid dependency developed; infliximab was added to the standard regimen only if cases proved refractory and infusions were repeated as clinically needed. Azathioprine was replaced by mercaptopurine or methotrexate in case of intoler-ance and corticosteroids were given only if all these measures failed to induce remission. The proportion of patients who reached clinical remission, as measured 6 and 12 months after beginning of therapy, was mark-edly higher among patients treated with early combined immunosuppression than among patients receiving standard therapy (60% versus 36% at 6 months and 62% versus 42% at 12 months). Moreover, the median time to clinical relapse was significantly longer in the combined immunosuppression group than in the standard therapy group (329 versus 174 days). Intriguingly, as drug use was similar in both groups at the end of the trial, mucosal healing (absence of ulcers), assessed endoscopically after 2 years of treatment, was more frequent in patients receiv-ing the combined immunosuppressive treatment than in patients receiving conventional therapy (73% versus 30%). An epidemiologic study of a norwegian popula-tion also reported that treatment without cortico steroids was predictive of mucosal healing.28

Several explanations have been proposed for why early immunomodulatory therapy in patients with Crohn’s disease leads to better clinical results than conventional management. Kugatashan and colleagues demonstrated that mucosal T cells isolated from the gut of children who have early stage Crohn’s disease have a strongly polarized T-helper-1-type response with excessive

production of interferon γ.29 This profile was lost with progression to established Crohn’s disease, which sug-gests that the processes of immunoregulation change as the disease advances. An additional explanation is the presumable absence of fibrosis in the early phases of the disease.22 Furthermore, mucosal healing, which is more frequently achieved by early immuno suppression, seems to be accompanied by a better prognosis. In the Benelux trial, follow-up of the patient cohort for up to 4 years after random ization showed that endoscopic remission, regardless of treatment, was associated with fewer relapses and a reduced need for repeated inflix-imab treatment.30 In the norwegian epidemiological study, mucosal healing after 1 year of medical treatment was also reported to be predictive of reduced subsequent disease activity and need for anti-inflammatory thera-pies.28 In addition, the importance of mucosal healing was demonstrated in the ACCenT 1 maintenance trial with infliximab, in which endoscopically assessed mucosal healing was associated with a significantly lower need for hospitalizations and surgical interven-tions.31 Moreover, in the STorI trial, in which patients with Crohn’s disease who were in remission on combined treatment with infliximab and azathioprine discontinued infliximab infusions, those without mucosal lesions at the time of withdrawal had a significantly lower likelihood of symptomatic relapse.32

The effectiveness of treatment should probably not, however, be based only on healing of mucosal lesions, but rather take into account the entire thickness of the intestinal wall. Several techniques have been used for assessment of bowel wall changes, including MrI, CT enteroclysis and ultrasonography. none of these tools has been validated or used longitudinally in clinical trials, with the exception of an MrI score that was developed for the follow-up of patients with fistulizing Crohn’s disease who were treated with infliximab.33

Early postoperative prevention of recurrenceIn a trial in which 24 patients with Crohn’s disease received infliximab or placebo as preventive treatment after ileocecal resection, the rate of endoscopic recur-rence at 1 year was significantly lower in the infliximab group than in the control group (9.1% versus 84.6%, P <0.01).34 This reduction in the rate of endoscopic recurrence is remarkably substantial. Up to date, the most effective agents for prevention of endoscopic recur-rence have been azathioprine and mercaptopurine, but the results for both of these drugs are more modest than those reported with infliximab.35 As the mechanisms underlying early Crohn’s disease are somewhat similar to those of postoperative recurrence, these data suggest that anti-TnF therapy could be efficacious to treat the disease immediately after diagnosis. of note, cortico-steroids have not been effective for the prevention of postoperative Crohn’s disease recurrence.36

Fistulizing Crohn’s diseaseFistulae are complications of penetrating inflamma-tion and hence define a late phase of Crohn’s disease.

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Conventional immunomodulators and biological agents can be used to treat this phase of the disease, after drain-age of septic collections. Although this approach cannot be considered ‘top-down’ treatment in relation to the overall disease course, comparisons can nevertheless be made between standard and earlier (‘top-down’) approaches to fistula treatment. In a study of 306 patients with draining fistulae responding to a classic induction schedule, 1 year of maintenance inflix imab therapy led to complete fistula closure in 36% of patients, whereas the same result was achieved in only 19% of placebo-treated patients.37 The median duration of fistula closure was 40 weeks in the infliximab group and 23 weeks in the placebo group. In the CHArM study, which assessed adalimumab therapy, drainage of fistulae was studied as a secondary end point.38 Among the 70 patients with draining fistulae who were receiving adalimumab, fis-tulae had closed in 21 patients at week 26, versus 6 of 47 patients who were receiving placebo. The study was not, however, designed to directly assess treatment effects on fistula closure, and rigorous documenta tion of these data was lacking. nevertheless, fistula healing with adali-mumab seems durable, as all fistulae that had healed at week 26 were still healed at week 52. The current european Crohn’s and Colitis organization guide-lines state that for patients who have draining fistulae, anti-TnF therapy should be considered after failure of antibiotics (quinolones and/or metronidazole) and con-ventional immuno modulators, provided that all perianal sepsis and abscesses have been surgically drained.39 MrI scanning has been valuable in guiding therapy in these difficult and often frustrating situations.33

Combined immunosuppressionThe SonIC prospective trial in patients with active Crohn’s disease who had never been exposed to conven-tional immunomodulators or anti-TnF agents demon-strated the superiority of combined treatment with azathioprine and infliximab over monotherapy in terms of both remission without the need for steroids and mucosal healing (assessed endoscopically).23 508 patients were randomly allocated to treatment with infliximab monotherapy (5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter), azathoprine monotherapy (2.5 mg/kg) or the two drugs combined. All patients had normal levels of thiopurine S-methyltransferase (measured to monitor the adverse effects of azathoprine) and were allowed to use concomitant corticosteroids in the first 14 weeks, after which forced dose tapering was initiated. The primary end point, remission without steroids at 6 months, was met in 57% of the patients receiving com-bined treatment, in 45% of those receiving infliximab monotherapy and in 30% of those receiving azathioprine therapy. The absence of ulcers was observed in 44%, 30% and 16% of patients, respectively. The combined therapy was superior to monotherapy in patients who had ele-vated C-reactive protein (CrP) values at baseline or had visible ulcers at colonoscopy, whereas no difference was observed in patients with low CrP values or no ulcers. The incidence of mild and serious adverse events was

comparable in the three treatment groups, although reac-tions to infusions occurred more frequently in patients receiving infliximab monotherapy than in the combined treatment group. Further follow-up of the patients up to 12 months revealed that the combined regimen continued to be superior to monotherapy.

Unlike the results observed in the SonIC study, a prospective Canadian trial (CoMMITT) showed that a combination of methotrexate and infliximab was not superior to infliximab monotherapy for the treatment of Crohn’s disease.40 The CoMMITT study population was different, however, in that azathioprine therapy had already failed for 25% of patients and all patients received induction treatment with corticosteroids. The reasons why the results of this trial were negative for the com-bined therapy remain unclear, but methotrexate most probably has a weaker drug effect on Crohn’s disease than azathioprine and the effect of an immuno suppressive agent in this type of combination treatment is presum-ably not limited to the prevention of immunogenicity alone. In fact, the combined effects of azathioprine and infliximab therapy reported by the SonIC trial were more pronounced than those that would be expected if azathioprine acted only by prevention of antidrug antibody formation.

Early surgeryA european multicenter study compared postoperative Crohn’s disease recurrence in a cohort of 83 patients undergoing resection at the time of diagnosis (early surgery) with a cohort of 124 patients who had surgery a mean of 54 months after diagnosis (late surgery).41 Mean follow-up after surgery was 147 months. Clinical recurrence developed sooner in the cohort undergoing late surgery than in the early surgery group. The need for immunosuppressive therapy after surgery was also higher in the late surgery group, but the reoperation rates were comparable. This study was not, however, a randomized analysis. Patients who had early surgery presumably had more limited and benign disease than patients who underwent late surgery.

A Markov analysis compared ileocecal resection with azathioprine therapy, at any time of disease course, in patients who had corticosteroid-dependent ileal Crohn’s disease and concluded that both strategies were “reason-able options”.42 Therefore, in the absence of convincing pathophysiological evidence that either the medical or the surgical approach is superior, the likeli hood of post-operative recurrence and the functional consequences of resection have to be balanced against the poten-tial toxic effects of medical treatments and the disease burden of chronic active Crohn’s disease, including steroid-dependent or refractory disease.

Early therapy for ulcerative colitisDisease duration in patients with ulcerative colitis is relevant for at least two reasons: longstanding exten-sive colitis carries an enhanced risk of dysplasia;43 acute refractory ulcerative colitis leads to higher col ectomy rates in the first years of the disease.7 The clinical





response and remission and mucosal healing rates after treatment with infliximab among patients with a disease duration of <3 years are similar to those among patients who have been ill for >3 years.44 The impact of treatment with immunomodulators in the early stages of ulcerative colitis has not been studied.

Selection of patients for therapyAlthough there are potent therapeutic regimens avail-able for treatment of inflammatory Crohn’s disease and for the prevention of postoperative recurrence of Crohn’s disease, there are various reasons why these treatments are not offered to all patients early in the disease course. Besides cost, which is an important issue in most coun-tries, issues related to safety, including toxic effects, are still of concern (Box 1).

The most common adverse events of azathioprine and its metabolite mercaptopurine, which have been used extensively to treat IBD for more than 3 decades, are leukopenia and thrombopenia. These effects are usually reversible and genotyping of TPMT, the gene that encodes the thiopurine S-methyltransferase, can prevent the development of agranulocytosis.45 Pancreatitis and impaired liver function problems are also frequent phenomena, but likewise are generally reversible. rare, irreversible effects are venocclusive liver diseases with long-term azathioprine use. A most dreadful complica-tion of antimetabolite treatment is the occurrence of lymphoma, which was reported to be doubled in patients treated with azathioprine compared with that of the

general population.46 A decision analysis model has also suggested that patients receiving infliximab have a raised risk of developing lymphoma compared with patients receiving standard therapy.47 opportunistic infections during conventional immunomodulator treatment are frequent, and more so when patients continue to use corticosteroids.48 The risk seems to be raised further by biologic therapy.49 The most frequent infections associ-ated with conventional immunomodulatory therapy are cytomegalovirus and other viral infections, which can lead to severe morbidity but are rarely lethal. By con-trast, biologic therapy is more frequently associated with mycobacterial infections and other opportunistic infec-tions such as listeriosis, nocardiosis and invasive asper-gillosis.50 Besides infections, anti-TnF treatment can lead to demyelinating disease, to exacerbations of heart failure and also quite frequently to a whole variety of skin manifestations such as eczema, pustulae or drug-induced psoriasis.51 Given the risk of multiple complications, immunomodulatory agents must therefore only be used in patients that really need them. Hence, careful selec-tion of patients for early combined immuno suppression therapy is of paramount importance.

The SonIC trial revealed that the clinical outcome of combined immunoppressive therapy is only superior to that of monotherapies in patients who have ulcers at baseline or in patients with elevated serum CrP levels.23 Furthermore, owing to its adverse effects, combined immunosuppression should be reserved for patients who have a predictably unfavorable disease course and a high likelihood of complications, surgeries, malnutrition and growth retardation. As complications of Crohn’s disease often arise after many years of disease, it has been diffi-cult to examine which genetic, phenotypic and environ-mental factors have an impact on the natural history of the disease. Therefore, selection should mainly be based on clinical parameters at present.

A retrospective study by Beaugerie and colleagues revealed several clinical factors that were associated with a severe disease course in Crohn’s disease.52 These factors included young age (<40 years), the need for cortico-steroid therapy and the presence of perianal disease at diagnosis. on the basis of a scoring system that incor-porated these items, 85% of 1,123 patients with Crohn’s disease registered at the authors’ hospital unit were classi-fied as having “disabling disease within the first 5 years following diagnosis”. These associations have been inde-pendently confirmed by Loly and colleagues, who used a more restrictive definition of severity.53 Severe Crohn’s disease was defined as the development of complex peri-anal disease, any colonic resection, two or more small bowel resections or the construction of a stoma within 5 years of diagnosis. These events occurred in 37% of a cohort of 351 patients referred to the authors’ center. Stricturing behavior or a reported weight loss of >5 kg at diagnosis were independently associated with the time of development of severe disease. Some studies have also suggested a negative impact of smoking on Crohn’s disease course, in particular on the occurrence of post-operative recurrence in female patients,54 while another

Box 1 | Adverse effects of medical therapies for IBD

Corticosteroids

Moon face

Increased appetite

Insomnia, irritability

Disturbed glucose tolerance

Hypertension

Cataract

Osteoporosis and osteonecrosis

Conventional immunomodulators

Leukopenia, thrombopenia

Pancreatitis

Impaired liver function, including venocclusive disease

Lymphoma, including hepatosplenic T-cell lymphoma64

Viral infections

Biologic agents

Lymphoma

Bacterial, mycobacterial and fungal infections

Demyelinating disease

Deterioration of heart failure

Skin damage (e.g. eczema, pustulae and psoriasis)

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study has shown an increased risk of cortico steroid dependency in cigarette smokers who have colonic, nonfibrostenotic disease and a young age at diagnosis.55 A higher incidence of obstruction caused by stenosis was reported in patients who had ileal disease, a severe disease course and treatment with corticosteroids.56 In summary, young age and the presence of perianal disease are associated with a poor prognosis and may be indica-tions for starting combined immunosuppressive therapy. The cutoff for young age of 40 years should, however, be questioned, as the majority of patients with Crohn’s disease are diagnosed before the age of 40 and further stratification by age might, therefore, be necessary.

The presence of a number of genetic factors (such as the HLA-DRB1*0103 allele), serologic and immune response markers or combinations of these (for example, CARD8 polymorphisms associated with antibodies to ompC in a setting of internal perforating disease) may also be relevant in association with worse disease prog-nosis.57 The time to onset of a clinically relevant stricture has been associated with a number of CARD15 variants.58 Patients with mutations in CARD15 are also more likely to require surgical resection.59–61 The frequency of debili-tating disease increases with the increasing number of abnormal serological markers (such as gASCA, AMCA, ALCA, ACCA and antibodies to omp-C).62 In a pedi-atric population, positivity for the serological markers ASCA, anti-ompC, anti-CBir1 and anti-I2 was associ-ated with progressive disease and tissue destruction.63 These efforts are only the beginning of patient stratifi-cation and individualized care. The use of the majority of these markers in clinical practice has not yet been prospectively assessed.

ConclusionsSufficient control of inflammation in the earliest phase of Crohn’s disease should reduce the number of relapses by achieving and maintaining remission and thereby prevent complications and the need for surgical

resection. Corticosteroids can be used as symptomatic anti-inflammatory agents, but the majority of patients will need repeated courses or become steroid-dependent. Moreover, steroids have been associated with reduced mucosal healing rates. Therefore, early addition of an immunomodulator is recommended if steroids are used as induction agents. Biologic therapies are expanding the options available for immunomodulatory therapy.

Structural damage might be self-propagating in some patients despite sufficient control of inflamma-tion; silent disease progression, which manifests sud-denly as a complica tion (stricture, fistula, or abscess) and leads to surgical resection, is indeed seen in some patients. Continued myofibroblast proliferation, initi-ated by inflammation, might explain this phenomenon. Ileocolonoscopy, biopsy and/or CT or MrI entero graphy indicate evidence of active inflammation. Treatment guided by objective signs of inflammation might, therefore, lead to fewer complications than our current standard treatment based on symptoms.

Ideally, phenotypic, serologic and genetic markers could be used to help selection of patients for early therapy. Assessment of such markers, however, is not routine practice yet, and further research is needed in this area. Ultimately, treatment for IBD will be indivi dualized to achieve optimal therapeutic results, minimal disease morbidity and loss of intestinal function and acceptable levels of adverse effects from medication.

1. Baumgart, D. C. & Carding, S. R. Inflammatory bowel disease: cause and immunobiology. Lancet 369, 1627–1640 (2007).

2. Baumgart, D. C. & Sandborn, W. J. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 369, 1641–1657 (2007).

3. Munkholm, P., Langholz, E., Davidsen, M. & Binder, V. Disease activity courses in a regional cohort of Crohn’s disease patients. Scand. J. Gastroenterol. 30, 699–706 (1995).

4. Munkholm, P., Langholz, E., Davidsen, M. & Binder, V. Intestinal cancer risk and mortality in patients with Crohn’s disease. Gastroenterology 105, 1716–1723 (1993).

5. Rutgeerts, P. et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 99, 956–963 (1990).

6. Langholz, E., Munkholm, P., Davidsen, M., Nielsen, O. H. & Binder, V. Changes in extent of ulcerative colitis: a study on the course and prognostic factors. Scand. J. Gastroenterol. 31, 260–266 (1996).

7. Langholz, E., Munkholm, P., Davidsen, M. & Binder, V. Course of ulcerative colitis: analysis of

changes in disease activity over years. Gastroenterology 107, 3–11 (1994).

8. Gupta, R. B. et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 133, 1099–1105 (2007).

9. D’Haens, G. R. et al. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114, 262–267 (1998).

10. Stange, E. F. & Travis, S. P. The European consensus on ulcerative colitis: new horizons? Gut 57, 1029–1031 (2008).

11. Eaden, J., Abrams, K., Ekbom, A., Jackson, E. & Mayberry, J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment. Pharmacol. Ther. 14, 145–153 (2000).

12. Travis, S. P. et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut 55 (Suppl. 1), i16–i35 (2006).

13. Mekhjian, H. S., Switz, D. M., Melnyk, C. S., Rankin, G. B. & Brooks, R. K. Clinical features and natural history of Crohn’s disease. Gastroenterology 77, 898–906 (1979).

14. Ramadas, A. V., Gunesh, S., Thomas, G., Williams, G. T. & Hawthorne, A. B. Reduced Crohn’s resections with increasing immunosuppressant use in a population-based Crohn’s disease cohort in Cardiff [abstract]. Gut 58 (Suppl. 2), A26 (2009).

15. Greenstein, A. J. et al. Perforating and non-perforating indications for repeated operations in Crohn’s disease: evidence for two clinical forms. Gut 29, 588–592 (1988).

16. Edwards, F. C. & Truelove, S. C. The course and prognosis of ulcerative colitis: part 1: short-term prognosis. Gut 4, 300–308 (1963).

17. Järnerot, G., Rolny, P. & Sandberg-Gertzén, H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology 89, 1005–1013 (1985).

18. Yu, E. D., Shao, Z. & Shen, B. Pouchitis. World J. Gastroenterol. 13, 5598–5604 (2007).

19. Cohen, R. D., Brodsky, A. L. & Hannauer, S. B. A comparison of the quality of life in patients with severe ulcerative colitis after total colectomy versus medical treatment with intravenous cyclosporin. Inflamm. Bowel Dis. 5, 1–10 (1999).

Review criteria

The MEDLINE database and the author’s own personal collection of publications were searched for peer-reviewed articles and abstracts on the clinical outcomes of treatments for IBD. The search terms used were “IBD”, “Crohn’s disease”, “ulcerative colitis”, “immunomodulators”, “anti-TNF”, and “biologics”. Only English-language publications were considered. No date restrictions were applied.





20. Breedveld, F. C. et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 54, 26–37 (2006).

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