Medical management of active Crohn's disease
Introduction
The management plan for a patient with Crohn's disease should take into account the activity, site and behaviour of disease, and should always be discussed with the patient.
Determining the activity of disease may be more difficult in
Crohn's disease can present symptoms like pain and diarrhea that may arise from non-disease-related causes, necessitating consideration of alternative explanations such as enteric infections, abscesses, or gallstones It's crucial to identify and treat iron deficiency anemia, as it can contribute to fatigue and lethargy Treatment decisions may need to be made without complete knowledge of disease distribution, particularly in severe cases Clinicians often struggle to accurately assess disease activity, making it essential to gather objective evidence—such as inflammatory markers or colonoscopy results—before initiating or modifying treatment This approach is reinforced by the SONIC study, which demonstrated that patients with endoscopic evidence of active disease experienced significantly greater benefits from therapy.
Choosing the right medication involves balancing drug potency and potential side effects, along with considering previous treatment responses, especially for relapses or steroid-dependent conditions The presence of extraintestinal manifestations also plays a crucial role Different drug formulations have varying local effects, making it essential to tailor the choice to each patient Notably, a systematic review found that 18% of patients with mild disease achieved remission with placebo alone, highlighting the option to forgo active treatment in select cases Therefore, involving patients in therapeutic decisions is vital for optimal care.
In randomized clinical trials, the limited number of patients with various disease locations or behavior patterns often hinders the ability to draw statistically valid conclusions, despite the acknowledged importance of these factors in treatment considerations Sections 5.2 and 5.3 provide consensus statements and supporting information for the medical management of active disease in specific sites and scenarios, while Section 5.4 addresses therapy-specific considerations and the evidence base for individual treatments.
Treatment according to site of disease and disease activity
Mildly active localised ileocaecal Crohn's disease
ECCO Statement 5A Budesonide 9 mg daily is the preferred treatment [EL2a,
RG B] The benefit of mesalazine is limited [EL1a, RG B]. Antibiotics cannot be recommended [EL1b, RG A] No treatment is an option for some patients with mild symptoms [EL5, RG D].
Although the stage at which immunosuppressive and biological therapy is introduced is changing, it is important to remember that an appreciable proportion of patients with
In a study involving 843 patients with Crohn's disease (CD) from the IBSEN cohort, only 25% received immunomodulators and 4% were treated with anti-TNF agents within the first decade post-diagnosis Similarly, a cohort from Olmsted County, Minnesota, revealed that 43% of patients never required steroid treatment Additionally, research from private hospitals in Germany indicated that 27% of patients with mild disease did not need steroids during a median follow-up of 39 months Despite these findings, most patients with active CD experience symptoms that necessitate treatment.
Budesonide 9 mg daily is the favoured therapy to induce remission in mildly active, localised ileocaecal Crohn's disease, because it is superior to both placebo (relative risk
(RR) 1.96, 95% CI 1.19–3.23) and mesalazine (RR 1.63; 95%
CI 1.23–2.16) 6 Budesonide is preferred to prednisolone for mild disease because it is associated with fewer side- effects (RR 0.64, 95% CI 0.54–0.76) However, budesonide is significantly less effective than conventional steroids for induction of remission (RR 0.86, 95% CI 0.76–0.98), particularly among patients with severe disease
(CDAIN300) (RR 0.52, 95% CI 0.28–0.95) In individual studies, budesonide achieves remission in 51–60% over 8–
A recent study comparing budesonide (Budeno-falk®) and mesalazine for active Crohn's disease revealed no significant differences in treatment outcomes, with remission rates of 69.5% for budesonide and 62.1% for mesalazine in the intention-to-treat population Notably, 89% of patients treated with budesonide and 79% of those on mesalazine experienced a clinically relevant but statistically insignificant CDAI drop of 100 points Both treatments demonstrated comparable effectiveness in patients with mild disease (CDAI < 300 points) These findings, presented in abstract form after the 2008 Consensus meeting in Vienna, contrast with a previous meta-analysis that indicated no significant benefit of mesalazine over placebo for managing mild to moderately active ileocaecal Crohn's disease, although a notable reduction in CDAI was observed in patients receiving ethylcellulose-coated mesalazine at a dosage of 4 g/day.
A study involving 615 patients indicated that while mesalazine shows a marginal clinical benefit (p=0.04) for active Crohn's disease (CD), lower doses cannot be recommended Nonetheless, recent conflicting data suggest that mesalazine warrants further investigation for treating mildly active CD.
A further study of high-dose (6 g daily) mesalazine for active CD is currently under way Future meta-analyses should incorporate more recent studies with high-dose formulations.
Antibiotics such as metronidazole and ciprofloxacin, whether used alone or with mesalazine, are generally not recommended due to their frequent side effects Similarly, nutritional therapy tends to be poorly tolerated by adults, despite some case series and small trials indicating modest effectiveness for these treatments.
Moderately active localised ileocaecal Crohn's disease
ECCO Statement 5B Moderately active, localised ileocaecal Crohn's disease should preferably be treated with budesonide 9 mg/day [EL1a, RG A], or with systemic corticosteroids [EL1a,
In cases where septic complications are suspected, the addition of antibiotics is recommended For treatment, a combination of azathioprine/6-mercaptopurine or methotrexate with steroids is a viable option Additionally, anti-TNF therapy may be considered for patients showing objective evidence of active disease who have previously been refractory, dependent, or intolerant to steroids It is crucial to thoroughly discuss and assess the associated risks with patients.
For moderately active Crohn's disease (CD), budesonide or prednisolone are effective initial induction therapies, with prednisolone being highly effective but associated with more side effects A systematic review showed corticosteroids significantly outperformed placebo in inducing remission (RR 1.99; 95% CI 1.51–2.64; p < 0.00001) Notably, adverse events were similar between steroids and high-dose 5-ASA, with no increased study withdrawals due to side effects Prednisolone is also more cost-effective than budesonide, and its dosage is adjusted based on therapeutic response, although rapid dose reduction may lead to early relapse The consensus advises against using sole nutritional therapy, antibiotics (unless septic complications are suspected), or surgery as first-line treatments for moderately active ileal CD While corticosteroids remain essential for treating active disease, efforts should be made to minimize their use, as only about 25% of patients remain in remission after one year of corticosteroid treatment, even with immunomodulators.
Early introduction of anti-TNF agents can effectively minimize steroid therapy in patients with Crohn's disease The selection of candidates for biological therapy should consider clinical characteristics, previous treatment responses, phenotype, and co-morbidities Certain groups, particularly steroid-refractory or steroid-dependent patients, may experience significant benefits from early biological intervention A study involving 133 treatment-naive patients with active Crohn's disease demonstrated that early combined immunosuppression led to a higher remission rate at week 26—60% of patients in this group achieved remission without corticosteroids or surgical intervention, compared to only 35.9% in the conventional treatment group.
64 controls, giving an absolute difference of 24.1% (95% CI 7.3–
40.8, p= 0.006) It has now been established (through the
The SONIC study demonstrates that the combination of infliximab and azathioprine is more effective than infliximab alone in achieving and maintaining steroid-free remission in early-stage disease patients This topic is further explored in the section on maintaining remission, highlighting that the difference between induction and maintenance therapy is primarily a matter of convenience, as a smooth transition should occur for individual patients Additionally, Section 5.4.4 provides evidence on the efficacy of individual anti-TNF agents.
Severely active localised ileocaecal Crohn's disease
Severely active localised ileocaecal Crohn's disease should initially be treated with systemic corticosteroids
For patients experiencing a relapse of their condition, anti-TNF therapy, with or without an immunomodulator, is recommended if there is clear evidence of active disease In cases of infrequent relapses, restarting steroids alongside an immunomodulator may be suitable Additionally, surgical options should be considered and discussed as a viable alternative for certain patients.
The initial treatment for severe ileal Crohn's disease (CD) typically involves prednisolone or intravenous hydrocortisone Recent advancements in the last five years have highlighted the potential to use clinical criteria at diagnosis to forecast the disease's progression This development has influenced the decision to initiate anti-TNF and immunomodulator therapies in patients identified with poor prognostic markers Notably, ongoing treatment with infliximab or adalimumab has been linked to a significant reduction in disease activity, approximately 30%.
12 months) in surgery and hospitalization for CD, 19,20 the threshold is likely to decrease further Nevertheless, there are no data that specifically apply to localised ileocaecal disease.
Anti-TNF therapy is primarily recommended for patients who do not respond to initial treatments and are not candidates for surgery However, surgical options should not be dismissed in favor of medications like adalimumab, infliximab, or certolizumab pegol, especially since the latter is not licensed for Crohn's disease in Europe The decision regarding treatment should involve collaboration between the patient, physician, and surgeon While anti-TNF therapy can decrease the need for surgical resection, the criteria for surgery in localized ileocaecal disease are more lenient compared to other areas Some experts prefer laparoscopic-assisted resection over anti-TNF therapy for this specific condition, and others recommend surgical intervention if medical treatments fail within 2-6 weeks Research indicates that combining infliximab with azathioprine is more effective than using either drug alone for inducing and maintaining remission, particularly in patients with elevated serum CRP or mucosal lesions However, this combination does not show superior benefits for patients with active inflammation The effectiveness of combining other anti-TNF agents with immunosuppressives in treatment-naive patients remains uncertain.
It may sometimes be difficult to distinguish between active disease and a septic complication, but antibiotics should be reserved for patients with a temperature or focal tenderness,
Colonic disease
Active colonic Crohn's disease (CD) can be managed with sulfasalazine for mild cases or systemic corticosteroids for more severe symptoms For patients experiencing a relapse with moderate to severe disease, anti-TNF therapy, potentially combined with an immunomodulator, is recommended In cases of infrequent relapses, it may be suitable to restart steroids alongside an immunomodulator Prior to starting immunomodulator or anti-TNF treatments, it is essential to evaluate and discuss surgical options.
It is easier to confirm the activity and severity of colonic
Colonic disease in Crohn's disease (CD) tends to respond better to anti-TNF therapy compared to isolated small bowel disease, likely due to the accessibility of ileocolonoscopy for active ileal disease Systemic corticosteroids like prednisolone are effective treatments, while budesonide is not suitable for colonic disease unless it primarily affects the proximal colon Consequently, steroids are considered the first-line therapy, with immunomodulators serving as steroid-sparing options for patients who experience relapses Treatment decisions should consider the patient's previous response to therapy and disease patterns, allowing for a conventional approach if there is infrequent relapse and a history of rapid steroid response.
It is crucial for gastroenterologists and their patients to have realistic expectations regarding treatment options Patients should not endure repeated steroid cycles when effective anti-TNF therapies are available for achieving and maintaining steroid-free remission If symptoms persist despite steroid treatment (with or without immunomodulators), an endoscopic assessment of disease activity is necessary, and anti-TNF therapy should be initiated if activity is confirmed In cases where patients do not respond or lose their response to anti-TNF therapy, surgical intervention is typically warranted In severe cases of colonic disease, particularly when accompanied by perianal sepsis, surgery to defunction the colon may be essential for symptom management prior to safely administering anti-TNF therapy.
The use of sulfasalazine and metronidazole for adults with colonic Crohn's disease (CD) has largely fallen out of favor, as sulfasalazine at a daily dose of 4 g is only modestly effective and associated with significant side effects While there is no conclusive evidence supporting the efficacy of mesalazine for active colonic CD, opinions differ regarding the use of topical mesalazine as an adjunctive treatment for left-sided colonic CD; it may be considered for distal colonic CD, although recommendations are mixed.
Extensive small bowel disease
Extensive small bowel Crohn's disease should be treated with systemic corticosteroids and thiopurines or metho- trexate [EL5, RG D] For patients who have relapsed, anti-
TNF therapy, with or without azathioprine, is a suitable choice for patients exhibiting moderate to severe active disease, as supported by evidence Additionally, providing nutritional support is recommended It is also important to consider and discuss surgical options early in the treatment process.
Patients exhibiting clinical features indicative of a poor prognosis are currently considered the most appropriate candidates for the early initiation of thiopurines, methotrexate, and/or anti-TNF therapy.
Extensive small bowel disease (N100 cm) presents a greater inflammatory burden compared to localized cases, often leading to nutritional deficiencies The use of steroids, alongside the early introduction of immunomodulators for their steroid-sparing benefits, is recommended Nutritional support should complement other treatments and may serve as primary therapy in mild disease cases Additionally, early initiation of anti-TNF therapy is advisable for patients exhibiting clinical indicators of poor prognosis, as research indicates that early treatment enhances the effectiveness of anti-TNF therapy.
In the CHARM trial, adalimumab demonstrated clinical remission rates of nearly 60% in patients with Crohn's disease for two years, significantly higher than the 40% observed in those with a longer disease duration (p