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Use of corticosteroids and immunosuppressive drugs in inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease

Digestive and Liver Disease, June 2017, Volume 49, Issue 6, Pages 604-617

Abstract

The two main forms of intestinal bowel disease, namely ulcerative colitis and Crohn’s disease, are not curable but can be controlled by various medical therapies. The Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) has prepared clinical practice guidelines to help physicians prescribe corticosteroids and immunosuppressive drugs for these patients. The guidelines consider therapies that induce remission in patients with active disease as well as treatment regimens that maintain remission. These guidelines complement already existing guidelines from IG-IBD on the use of biological drugs in patients with inflammatory bowel diseases.

Keywords: Corticosteroids, Crohn's disease, Guidelines, IBD, Immunosuppressors, Ulcerative colitis.

1 Introduction

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions affecting the digestive system. The two most common forms of IBDs are ulcerative colitis (UC), which affects only the colonic mucosa, and Crohn’s disease (CD), which can segmentally affects the entire digestive tract. UC and CD are autoimmune disorders that are not medically curable, although various medical therapies can control them [1] .

The European Crohn’s and Colitis Organisation (ECCO) has prepared clinical practice guidelines on the diagnosis and management of CD [2] and UC [3] . Nonetheless, because cultural values and economic and legal issues differ between countries, national guidelines are also needed. In Italy, guidelines are available on the use of biologics in treating adults with IBD [4] , but the use of corticosteroids and immunosuppressive drugs in IBD has not been addressed. For this reason, the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) decided to develop Italian guidelines on the use of corticosteroids and immunosuppressive drugs in IBD.

In January 2011, the IG-IBD invited 17 of its members, all associated with Italian IBD referral centers, to a planning meeting during which participants agreed on the main topics of the guidelines, namely definitions, treatment efficacy in UC and CD, and side effects. Groups of participants were assigned different topics to investigate via bibliographic research in Medline/PubMed and the Cochrane databases, selecting only papers in the English language, and they drafted provisional guidelines statements accompanied with notes on the level of evidence (LE) and grade of recommendation (GR). For this purpose, we used the 2011 version of the “Levels of evidence” of the Oxford Centre for Evidence-Based Medicine ( Table 1 ) [5] . After the statements had been prepared, they were discussed among the 17 authors, an additional 29 Italian experts belonging to IG-IBD (from referral and non-referral gastroenterological centers), and two representatives of a national patients’ association (Associazione Malattie Infiammatorie Croniche Intestinali) during two consensus conferences. Each statement was voted during a meeting in Bologna in November 2013 upon by the 48 participants and accepted when it received at least 80% approval.

Question Step 1 (Level 1 a ) Step 2 (Level 2 a ) Step 3 (Level 3 a ) Step 4 (Level 4 a ) Step 5 (Level 5)
How common is the problem? Local and current random sample surveys (or censuses) Systematic review of surveys that allow matching to local circumstances b Local non-random sample b Case-series b n/a
Is this diagnostic or monitoring test accurate? (Diagnosis) Systematic review of cross sectional studies with consistently applied reference standard and blinding Individual cross sectional studies with consistently applied reference standard and blinding Non-consecutive studies, or studies without consistently applied reference standards b Case-control studies, or “poor or non-independent reference standard b Mechanism-based reasoning
What will happen if we do not add a therapy? (Prognosis) Systematic review of inception cohort studies Inception cohort studies Cohort study or control arm of randomized trial a Case-series or case- control studies, or poor quality prognostic cohort study b n/a
Does this intervention help? (Treatment Benefits) Systematic review of randomized trials or n -of-1 trials Randomized trial or observational study with dramatic effect Non-randomized controlled cohort/follow-up study b Case-series, case-control studies, or historically controlled studies b Mechanism-based reasoning
What are the COMMON harms? (Treatment Harms) Systematic review of randomized trials, systematic review of nested case-control studies, n -of-1 trial with the patient you are raising the question about, or observational study with dramatic effect Individual randomized trial or (exceptionally) observational study with dramatic effect Non-randomized controlled cohort/follow-up study (post-marketing surveillance) provided there are sufficient numbers to rule out a common harm. (For long-term harms the duration of follow-up must be sufficient.) b Case-series, case-control, or historically controlled studies b Mechanism-based reasoning
What are the RARE harms? (Treatment Harms) Systematic review of randomized trials or n -of-1 trial Randomized trial or (exceptionally) observational study with dramatic effect
Is this (early detection) test worthwhile? (Screening) Systematic review of randomized trials Randomized trial Non-randomized controlled cohort/follow-up study b Case-series, case-control, or historically controlled studies b Mechanism-based reasoning

a Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO), because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.

b As always, a systematic review is generally better than an individual study.

Table 1Levels of evidence and grades of recommendation according to the Oxford Centre for Evidence-Based Medicine, 2011 version.For details, see http://cebm.net/index.asp?o=565 3 [5] .

 

After the voting, each expert finalized the text relative to his or her topic. The final document was compiled and edited by three authors (PG, FR and SA). It was then circulated and approved by all 17 experts in September 2016. Minor changes based on literature search were proposed by the experts and, subsequently, voted online. Literature search was performed by each expert before the meeting held in Bologna e by Authors between 2013 and 2016 in order to include articles published until September 2016. For literature search, PubMed, Embase and the Cochrane database were used.

2 Definitions

Participants at the consensus conference felt the need to establish definitions regarding disease activity and response to therapy. The definitions they adopted reflect common practice and usage in controlled clinical trials and are mostly in agreement with the definitions reported in earlier Italian guidelines for therapy with tumor necrosis factor (TNF) antagonists [4] .

2.1 Disease activity

In clinical practice, for both CD and UC, disease activity is evaluated considering signs and symptoms and the results of endoscopy, laboratory testing, and imaging.

The clinical activity of IBD is usually classified as mild, moderate or severe. The evaluation of CD clinical activity in clinical trials is usually done with the CD activity index (CDAI) [6] or the Harvey–Bradshaw index (HBI) [7] ( Table 2 ), but the limitations of these indices are largely recognized. In particular, they do not precisely define the clinical entity, but are largely based on the subjective evaluation of a patient’s wellbeing.

  Crohn’s disease activity index [6] Harvey–Bradshaw index [7]
Remission 0–150 0–5
Mild 150–225 5–7
Moderate 221–450 8–16
Severe >450 >16

Table 2Disease activity indices for Crohn’s disease.

 

For UC, the Truelove–Witts criteria ( Table 3 ) [8] and the Disease Activity Index (DAI), also called the Mayo score ( Table 4 ) [9] , are used. The Mayo score is a 12-point scale that includes a clinical portion (number of bowel movements, the severity of rectal bleeding, and overall clinical evaluation) and an endoscopic portion.

  Mild Moderate Severe
Bloody diarrhea, bowel movements per day <4 ≥4 ≥6
Temperature, °C <37.5 >37.5 >37.5
Pulse, bpm <90 90 >90
Hemoglobin, g/dl >11.5 ≥10.5 ≤10.5 (or ≤75% of baseline)
Erythrocyte sedimentation rate, mm/h <20 >20 or <30 >30

Table 3Truelove and Witts’ criteria [8] for ulcerative colitis.

Category Points
Stool frequency (per day)
Normal number of stools for the patient 0
1–2 stools more than normal 1
3–4 stools more than normal 2
5 or more stools more than normal 3
 
Rectal bleeding
No blood seen 0
Streaks of blood with stool less than half of the time 1
Obvious blood with stool most of the time 2
Blood alone passed 3
 
Endoscopic findings
Normal or inactive disease 0
Mild disease (erythema, decreased vascular pattern, mild friability) 1
Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 2
Severe disease (spontaneous bleeding, ulceration) 3
 
Physician’s overall assessment
Normal 0
Moderate disease 2
Mild disease 1
Severe disease 3
 
Total score (range) 0–12

Table 4Disease activity index for ulcerative colitis, also called Mayo score [9] .

 

2.2 Response to therapy

 

Statement 1
Crohn’s disease
Response : Reduction of CDAI by ≥100 points or HBI by ≥3 points. Remission : CDAI <150 or HBI <4, off steroids. Relapse : Flare of symptoms with CDAI >150 or HBI >4 in a patient who was in clinical remission. Recurrence : Appearance of new CD lesions after curative resection of macroscopic disease, usually in the neoterminal ileum or at the anastomotic level, detected by endoscopy, radiography or clinical examination.
Ulcerative colitis
Response : Clinical and endoscopic improvement according to the activity index used.
Remission : Stool frequency ≤3/day without bleeding or urgency. Relapse : Flare of symptoms in a patient who was in clinical remission.

 

 

In CD clinical trials, treatment response is usually defined as a decrease in CDAI or HBI of at least 100 or 3 points, respectively 2 10 11 12 13 14 . A less robust evaluation is a reduction of 70 CDAI points or more, or alternatively a 25% reduction in total score 10 11 12 13 14 . Remission is indicated by a CDAI <150 or HBI <4 10 11 12 13 14 .

In UC, response is usually defined by a combined improvement in clinical and endoscopic findings. Using the Mayo score, response is defined as a reduction of at least 3 points or 30% of the score, with an absolute sub-score for rectal bleeding of 0 or 1 9 15 16 . Remission is generally defined as a stool frequency of ≤3, without urgency or bleeding 15 16 , but with the Mayo score it is defined as a total score of ≤2, with no individual score >1 15 16 . In both clinical trials and daily practice, a combined clinical-endoscopic evaluation is useful.

In both CD and UC, relapse is defined as a flare-up of symptoms combined with an increase of disease laboratory biomarkers or pathological imaging findings. An early relapse is generally considered to occur within three months after achieving remission. The frequency of relapse is generally defined as infrequent (≤1/year), frequent (≥2/year), or continuous (symptoms persist despite therapy).

Finally, in CD, recurrence indicates the reappearance of disease after curative surgery, and is defined on the basis of clinical, endoscopic or radiological findings. Endoscopic recurrence is graded using the score of Rutgeerts et al. [17] . There are currently no agreed standards for the ultrasonographic or radiologic assessment of recurrence.

2.3 Response to steroid therapy

 

Statement 2
Steroid-induced response : Substantial symptoms improvement within 1–2 weeks of an adequate dose of systemic steroids or within 2–4 weeks when using low-bioavailability steroids. In severe UC, response should be evaluated within 3–5 days.
Steroid-induced remission : Complete symptoms disappearance off steroids within 3 (systemic) or 3–6 (low-bioavailability) months.
Steroid refractoriness : Active disease despite an adequate dose and duration of steroid treatment (prednisone, 0.75–1 mg/kg day orally for at least 2 weeks; methylprednisolone, 1 mg/kg day intravenously for 1 week).
Steroid dependency : Impossibility of discontinuing systemic steroids within 3 months (6–9 months for budesonide in CD) without clinical relapse, or relapse within 3 months of steroid weaning.

 

 

Systemic and low-bioavailability steroids are commonly used in CD and UC, but steroid-induced clinical response and remission have not been adequately defined in clinical trials. Nonetheless, on the basis of common practice, the consensus participants defined steroid-induced clinical response as a substantial symptoms improvement within 1–2 weeks of an adequate dose of systemic steroids, or within 2–4 weeks when using low-bioavailability steroids (e.g. budesonide). In severe UC, the response to systemic steroids must be evaluated within 3–5 days. Consensus participants defined a steroid-induced clinical remission as complete symptoms disappearance within 3 (systemic) or 3–6 (low-bioavailability) months off steroids. These definitions largely reflect common daily practice and are in accordance with previous agreed definitions of steroid refractoriness and dependency [4] .

2.4 Response to thiopurines and methotrexate

 

Statement 3
Clinical response to thiopurines or methotrexate at the adequate dose should be assessed between 3 and 6 months.
Clinical remission is the establishment and maintenance of steroid-free remission.
Intolerance is the inability to take thiopurines or methotrexate at an adequate dose and duration.

 

 

Azathioprine and mercaptopurine are members of the thiopurine class of medication, which is widely used in the treatment of IBD, mainly in steroid-dependent patients. Although the drugs’ mechanisms of action are incompletely understood, they are effective in approximately two thirds of patients, while up to one fifth of patients discontinue the therapy because of adverse events [18] . For these drugs, a dose-finding study or head-to-head comparison has not yet been reported, although the most effective doses are thought to be 2–3 mg/kg for azathioprine and 1–1.5 mg/kg for mercaptopurine. The drugs significantly delay the onset of disease activity, with clinical benefits occurring after 2–3 months of treatment [19] . A 2009 Cochrane review found that the response rate was higher (NNT = 4) in studies lasting more than 16 weeks than in trials with shorter treatment durations [20] , but an update of this review in 2013 did not confirm this finding [21] .

Methotrexate, a drug initially developed to treat leukemia, has subsequently been used in low doses in a number of immune disorders, including IBD. Randomized controlled trials (RCTs) are scarce, although three have been performed in CD (reviewed in Ref. [22] ). With methotrexate there is a slow onset of clinical efficacy, and the occurrence of intolerance due to adverse events is an issue. The suggested weekly dose is 25 mg for 12–24 weeks and then 15 mg intramuscularly for maintenance of remission [22] .

2.5 Response to cyclosporine

Cyclosporine as rescue therapy for steroid-refractory, severe UC was first tested in the 1980s and subsequently used in only two RCTs and several case series (reviewed in Ref. [23] ). A single-center RCT demonstrated that a low intravenous dose (2 mg/kg) was as effective as a previously used higher dose (4 mg/kg) for inducing remission, adjusting the dose during the treatment; the median response time was 4 days in both groups [24] .

3 Ulcerative colitis

3.1 Active disease: induction of remission

3.1.1 Severe ulcerative colitis

 

Statement 4
Patients with severe active UC of any extent should be admitted to hospital for intensive treatment [LE: 5; GR: D]. Patients are best cared for jointly by a gastroenterologist and a surgeon, who should assess the possibility of surgery at admission and daily thereafter [LE: 5; GR: D].

 

 

Approximately 15–19% of patients with UC have a severe attack some time during their illness 25 26 . Acute severe UC, defined by the Truelove–Witts criteria ( Table 3 ), is a potentially life-threatening condition that requires hospitalization and intensive medical therapy [27] .

Before the introduction of efficacious treatments, the risk of dying from severe attacks was about 30% [28] . Since 1952, steroid therapy has been increasingly used, resulting in a drop of mortality from 27.3% [28] to lower than 1% [29] when colectomy is performed in a specialist center. The short-term colectomy rate in severe UC has remained stable over the past 30 years at about 29.4% (95% CI, 27–32%) [29] . Currently, the availability of different therapeutic options (e.g. cyclosporine, infliximab) complicates the decision to treat surgically, because an experienced clinician must determine when to start a rescue therapy and when a medical treatment has failed; these assessments are best done jointly by the patient’s gastroenterologist and surgeon, both at admission and daily thereafter.

Statement 5
Intravenous corticosteroids are the mainstay of therapy for severe acute UC [LE: 1b; GR: B]. Type of steroid and optimal daily dose have not been formally investigated. Treatment with methylprednisolone (0.75–1 mg/kg daily) or hydrocortisone (100 mg q.i.d.) seems to be equally effective [LE: 5; GR: D]. Different modalities of intravenous administration (continuous infusion or bolus) are equally effective [LE: 1b; GR: A].

 

 

3.1.1.1 Intravenous corticosteroids

After Truelove and Jewell published their study in 1974 [30] , intravenous corticosteroids (IVCS) became the mainstay of treatment for severe UC exacerbations in a daily dose equivalent to 400 mg hydrocortisone or 0.75–1 mg/kg methylprednisolone. Optimization of IVCS treatment in severe UC is hindered by the lack of dose-ranging or comparative studies testing different corticosteroids. A meta-analysis of the response to corticosteroids in severe UC failed to demonstrate a correlation between dose and colectomy rate [29] . The modalities of steroid administration have never been formally investigated, although most clinicians use an intravenous bolus; continuous infusion of methylprednisolone does not enhance the rate of clinical response nor affect the frequency of steroid-related adverse events [31] .

Statement 6
Improvement in severe UC should be assessed by a combination of clinical, biochemical and radiological tests [LE: 2b; GR: B]. Patients with severe acute UC who do not improve within 3–5 days of intensive medical therapy should be either referred for surgery or offered second-line therapies [LE: 2b; GR: B]. Second-line therapy with either cyclosporine [LE: 1b; GR: B] or infliximab [LE: 1b; GR: B] is appropriate. Failure to improve within 4–7 days from starting second-line treatment is an indication for surgery [LE: 5; GR: D].

 

 

3.1.1.2 Colectomy

Patients with acute severe UC who do not improve after 3–5 days of IVCS are unlikely to further benefit from this treatment and should be considered for either colectomy or rescue therapy. This situation requires simple, objective predictors of response to help clinical decision-making that could avoid an ineffective continuation of IVCS treatment and facilitate a timelier decision. Clinical improvement is usually assessed by a combination of various clinical, laboratory and radiological tests 32 33 34 35 .

Clinical evaluation commonly considers pulse rate, temperature and stool frequency [34] . Stool frequency has been shown to predict colectomy: a frequency >12/day on day 2 was associated with a 55% colectomy rate in a retrospective study [34] , whereas a frequency >8/day on day 3 of intensive treatment predicted colectomy in 85% of patients in a prospective study [35] . The objective measure of daily stools on day 3 of admission has been recently validated in the pediatric population [36] .

Laboratory markers that can predict the need for colectomy in acute severe UC include serum levels of C-reactive protein (CRP) and albumin, and serum pH. CRP is the most important biochemical predictive marker, as demonstrated by Travis et al. [35] . In their prospective study, CRP >45 mg/l and a daily stool frequency of 3–8 on day 3 of treatment predicted colectomy in 85% of patients. Additionally, prospective data from a pediatric population with severe UC identified CRP (odds ratio (OR) = 1.3; 95% CI, 1.1–1.6), nocturnal diarrhea (OR = 3.4; 95% CI, 1.9–6.1), number of daily stools (OR = 2.7; 95% CI, 1.7–4.3) and blood in stools (OR = 4.2; 95% CI, 2.0–8.9) as significant predictors of IVCS failure at day 3 [36] . Other negative predictors are an elevated stool frequency, the presence of colonic dilatation and hypoalbuminemia [37] ; metabolic alkalosis [38] ; radiological findings such as ileus, colonic dilatation, mucosal islands, or persistent small bowel distension [39] ; and toxic megacolon [40] . Sigmoidoscopic findings such as extensive deep colonic ulcerations and cytomegalovirus infection have also been associated with a high risk of colectomy 41 42 .

Although these clinical and laboratory variables help decision-making, the optimal treatment sequence of colectomy and rescue therapies (e.g. cyclosporine and infliximab) is yet to be determined and the clinical decision today is still empirical.

3.1.1.3 Rescue therapies

The effectiveness of intravenous cyclosporine in treating severe UC has been evaluated in two RCTs that compared a 4 mg/kg daily dose to placebo or corticosteroids. The first trial by Lichtiger and Present [27] enrolled 20 patients and found that 9 of 11 patients (82%) on cyclosporine responded within one week, compared with none of 9 patients on placebo (p < 0.001). The second trial, published by D’Haens et al. in 2001, compared intravenous cyclosporine as first-line therapy to methylprednisolone, and found similar colectomy rates at 1 year: 36% in the cyclosporine group vs. 40% in the methylprednisolone group [43] . Later, a single-center RCT showed that a lower dose of intravenous cyclosporine (2 mg/kg daily) had the same efficacy as 4 mg/kg daily [24] . According to a Cochrane review [44] , short-term cyclosporine therapy induces a rapid response, has only mild adverse effects, and therefore is recommended as a possible second-line therapy; however, this conclusion is based on small studies with short-term follow-up. Regarding safety, a retrospective review from a major specialist center found a high risk of opportunistic and life-threatening infections [45] , suggesting the use of antibiotic prophylaxis in patients receiving two or more immunosuppressive drugs.

Two placebo-controlled trials evaluated the efficacy of infliximab in patients with severe, IVCS-refractory UC. The first trial enrolled 11 patients, assigning 8 to the infliximab arm and 3 to placebo (this trial was discontinued prematurely because of slow recruitment); 4 of 8 patients who received a single dose of infliximab at 5, 10 or 20 mg/kg responded by week 2, while none of the placebo-treated patients responded [46] . The second RCT, by Jarnerot et al. [47] , enrolled patients with severe or moderately severe UC according to the Seo index (>150) [48] who did not respond to IVCS within 3–7 days. Patients were randomized to placebo or a single infusion of infliximab (4–5 mg/kg). Significantly more patients in the placebo group (14/21) than in the infliximab group (7/24) had colectomy (OR = 4.9; 95% CI, 1.4–17) within 3 months; no patient died, and none had serious side effects. Despite these encouraging results, the ideal infliximab dosing schedule remains unknown although one non-controlled trial [49] suggested that two or three infusions are more effective in preventing early colectomy than a single treatment.

The efficacies of cyclosporine and infliximab were compared in one open-label RCT [50] . Patients with steroid-resistant, acute severe UC were randomized to either cyclosporine (2 mg/kg day intravenously for one week; then orally for 98 days) or infliximab (5 mg/kg on days 0, 14, and 42). Patients with a clinical response (Lichtiger score <10) on day 7 were started on azathioprine (2.5 mg/kg day). The primary end point was the rate of treatment failure defined by any one of the following: no clinical response at day 7, no steroid-free remission at day 98, relapse between days 7 and 98, a severe adverse event, colectomy, or death. One hundred fifteen patients were included in the intention to treat analysis (58 received cyclosporine and 57 infliximab). Rates of treatment failure were 60% with cyclosporine and 54% with infliximab ( p = 0.52). Response rates at day 7 were similar (86% vs. 84%, p = 0.76) as was the day-98 colectomy rate (18% vs. 21%; p = 0.66); no death occurred. Therefore, cyclosporine and infliximab were found to be equivalent regarding short-term remission and need for urgent colectomy. Similar results were found in a recently published open-label, pragmatic randomized trial [51] .

3.1.2 Mild and moderate ulcerative colitis

Mild and moderate disease activities are the most common clinical presentations of UC patients seen in daily practice. Mild disease is defined as a total Mayo score <6 while moderate disease is defined as a total Mayo score <9 [9] . Management of these forms of active UC requires the evaluation of disease activity (by clinical and endoscopic means), disease extent, and levels of inflammatory markers. Disease activity is defined clinically by the Truelove–Witts criteria ( Table 3 ). Disease extent is distinguished by the Montreal classification in three subgroups: ulcerative proctitis (inflammation limited to the rectum), left-sided UC (up to the splenic flexure; also called distal UC) and extensive UC (pancolitis) [52] . Assessment of disease extent also has therapeutic implications by facilitating the identification of the most appropriate drug formulation.

3.1.2.1 Ulcerative proctitis and left-sided ulcerative colitis

 

Statement 7
In the treatment of active, left-sided UC, traditional topical corticosteroids are effective but less so than topical mesalazine [LE: 1a; GR: A].
Topical formulations of traditional corticosteroids or of beclomethasone dipropionate, alone [LE: 5; GR: D] or combined with oral plus topical mesalazine [LE: 1b; GR: B], are an effective second-line treatment in active mild-moderate ulcerative proctitis or distal UC.
Traditional oral corticosteroids should be considered in cases of failure or intolerance to first-level treatments, or to provide a prompt relief of symptoms [LE: 1b; GR: A].

 

 

Corticosteroids represent a major line of treatment for active UC, and their efficacy is also confirmed for topical formulations in active distal UC [30] .

Truelove in 1958 [53] demonstrated that topical hydrocortisone hemisuccinate was more effective than placebo: 40 patients with mild or moderate active UC were randomized to treatment with hydrocortisone hemisuccinate sodium (100 mg for 1 week) or placebo. At the end of the study, 55% (11/20) of hydrocortisone-treated patients were symptom-free versus 5% (1/20) of the placebo-treated group. Moreover, endoscopic improvement was seen in 60% (12/20) of hydrocortisone-treated patients versus 10% (2/20) of placebo-treated patients. However, no difference between groups was noted after six months of maintenance treatment. In a subsequent study [54] , Truelove found that a two-week treatment with rectal hydrocortisone (100 mg/daily) plus oral prednisolone (20 mg/daily) was more effective (100%, 20/20) than hydrocortisone alone (70%, 14/20) or oral prednisolone alone (35%, 14/40). However, steroid-related side effects were observed in the long-term, limiting their use.

Mesalazine (5-aminosalicylic acid), another effective compound for the topical treatment of active ulcerative proctitis and left-sided UC, has been compared to topical conventional corticosteroids in several trials. A meta-analysis by Marshall and Irvine [55] found that topical mesalazine was superior to topical conventional corticosteroids for inducing remission of symptoms, endoscopic improvement, and histologic improvement, with pooled ORs of 2.42 (95% CI, 1.72–3.41), 1.89 (95% CI, 1.29–2.76), and 2.03 (95% CI, 1.28–3.20), respectively.

In order to reduce the systemic absorption of conventional corticosteroids and the related side effects, a second generation of corticosteroids was created 56 57 58 59 60 . These low-bioavailability steroids have limited absorption, high glucocorticoid receptor binding affinity and an efficient first-pass hepatic metabolism. One of these drugs is beclomethasone dipropionate (BDP). BDP has been used for several years in the topical treatment of asthma and allergic rhinitis, providing high local anti-inflammatory action and low or no systemic activity [60] .

Mulder et al. [61] compared topical BDP (2 or 3 mg) with prednisolone phosphate (30 mg daily) in the treatment of ulcerative proctitis. No difference was registered between the three groups in terms of efficacy, while a reduction in fasting cortisol level was recorded in the prednisolone group. Subsequently, Campieri et al. [62] compared topical BDP (3 mg/day) with topical prednisolone phosphate (30 mg/day) in a 4-week RCT. At the end of the study, no difference was registered between the two groups in terms of clinical or endoscopic efficacy, but the hypothalamic–adrenocortical axis was significantly inhibited in the prednisolone group only. Therefore, these studies suggest that topical BDP has similar efficacy without the steroid-related side effects of prednisolone.

Several studies compared topical BDP with topical mesalazine. Mulder et al. [63] compared BDP (3 mg), mesalazine (2 g), and combination therapy (BDP + mesalazine) for 4 weeks in patients with active distal colitis. BDP and mesalazine were similarly effective in inducing clinical (70% vs. 76%, respectively) and endoscopic (75% vs. 71%, respectively) improvement, but the combination treatment had better efficacy (100% for both parameters) than each drug alone.

Gionchetti et al. [64] compared topical BDP (3 mg/day) with topical mesalazine (1 g/day) for 6 weeks in 217 patients with active, mild or moderate distal UC. A significant decrease in the clinical portion of the Mayo score was registered in both groups, with a clinical remission rate of 36.7% in the BDP group and 29.2% in the mesalazine group. No changes from baseline in morning cortisol levels were observed in the BDP group.

Similar results were obtained by Biancone et al. [65] , who compared different formulations (enema and foam) of topical BDP and mesalazine. After 4 and 8 weeks of treatment, no difference was seen between BDP and mesalazine in terms of improvement (week 4, 78% vs. 79%; week 8, 84% vs. 90%, respectively) or remission (week 4, 24% vs. 28%; week 8, 36% vs. 52%, respectively).

A meta-analysis by Manguso and Balzano [66] found that topical BDP was as effective as topical mesalazine in inducing clinical improvement or remission in patients with active ulcerative proctitis or left-sided UC. However, for patients who are refractory to these treatments, traditional oral corticosteroids represent a further treatment option [67] .

3.1.2.2 Extensive ulcerative colitis

 

Statement 8
Traditional oral corticosteroids are highly effective in the treatment of extensive mild to moderate active UC, but given the high risk of side effects, should be used as second-line therapy (after failure of oral plus topical mesalazine) or for prompt relief of symptoms [LE: 1b; GR: A].
Oral BDP, alone or combined with oral mesalazine, is more effective than mesalazine alone [LE: 1b; GR: A].

 

 

Traditional oral corticosteroids are the first-line therapy in patients with extensive mild to moderate active UC who fail to respond to oral plus topical mesalazine. Traditional oral corticosteroids are superior to sulfasalazine in this setting, as shown in the 1960s. Truelove et al. [68] compared the efficacies of oral prednisolone (20 mg/day) plus topical hydrocortisone (100 mg/day) and oral sulfasalazine (8 g/day) in 118 patients with active UC; after 2 weeks, 76% (44/58) of patients treated with prednisolone were in clinical remission vs. 52% (31/60) of patients treated with sulfasalazine. Similarly, Lennard-Jones et al. [69] demonstrated that oral prednisone (60 mg/day) was more effective and faster than sulfasalazine (4 g/day) and topical hydrocortisone (100 mg/day) in inducing clinical remission, with 11/20 (55%), 8/20 (40%) and 3/20 (15%) patients, respectively, entering remission. Baron et al. [66] found that a 40 mg/day dosage of oral prednisone had the same efficacy as 60 mg/day but fewer side effects.

More recently, some of us investigated the efficacy of an enteric-coated oral formulation of BDP, a low-bioavailability steroid. In a first RCT [70] , we found that BDP was equally effective at dosages of 5 and 10 mg/day, but morning plasma cortisol levels were more affected by the higher than lower dose. In a subsequent RCT [71] , 119 patients with active, mild to moderate, left-sided or extensive UC were treated with mesalazine (3.2 g/day) plus oral BDP (5 mg/day) or mesalazine plus placebo. After 4 weeks, the BDP group had a significantly greater reduction in the DAI (Δ 3.7 vs. Δ 3.0; p = 0.014) and more patients in clinical remission (58.6% vs. 34.4%, p = 0.008) than did the placebo group. During the study, serum cortisol levels fell in the BDP group (vs. baseline, p = 0.002), but pituitary-adrenal function was not suppressed.

Campieri et al. compared oral BDP (5 mg/day) to oral mesalazine (2.4 g/day) in 177 patients with active, mild to moderate, left-sided or extensive UC, and found the same efficacy (clinical remission, 63% BDP vs. 62.5% mesalazine) [72] . In patients with extensive disease, improvement on the DAI was greater in BDP-treated than mesalazine-treated patients ( p < 0.05). Papi et al. [73] administered oral BDP (10 mg/day for 4 weeks; then 5 mg/day for 4 weeks) to 64 consecutive patients with active UC unresponsive to a standard course of mesalazine; the treatment induced 48 patients (75%) to enter remission.

Finally, a recent double-blind RCT compared the therapeutic efficacy and safety of BDP (5 mg once daily for 4 weeks and then every other day for an additional 4 weeks) and prednisone (40 mg once daily for the initial 2 weeks tapered by 10 mg every 2 weeks) [74] . A total of 282 patients with active, mild-to-moderate UC were studied for 8 weeks. Efficacy was defined as DAI <3 or a reduction in DAI by ≥3 points in patients with a baseline value ≥7, while the assessment of safety considered steroid-related adverse events and low morning serum cortisol. BDP was found to be non-inferior to prednisone in terms of efficacy, with response rates of 64.6% and 66.2%, respectively ( p = 0.78) and to have a similar safety profile.

Another low-bioavailability steroid tested for use in extensive UC is budesonide MMX, a once-daily oral formulation that uses proprietary Multi-Matrix technology to ensure colonic delivery of the drug. The CORE I trial compared budesonide MMX (9 or 6 mg), mesalazine (2.4 g) and placebo in patients with active mild-moderate UC, and found that only budesonide MMX (9 mg) was significantly more effective than placebo in inducing remission at 8 weeks (17.9% vs. 7.4%; p < 0.0143) [75] . Subsequently, the CORE II trial administered budesonide MMX (9 or 6 mg), enteric-coated budesonide (9 mg) or placebo once daily for 8 weeks [76] . Budesonide MMX 9 mg was significantly more effective than placebo (17.4% vs. 4.5%, p = 0.0047); similar results were obtained for budesonide enteric coated (12.6% vs. 4.5%, p = 0.0481).

3.2 Remission: maintenance with immunosuppressive therapies

3.2.1 Azathioprine and mercaptopurine

 

Statement 9
Thiopurines are recommended for patients with steroid-dependent UC [LE: 1a; GR: A] and for patients in whom cyclosporine was used to induce remission [LE: 3; GR: C].
Thiopurines can also be considered as a treatment for a severe attack of UC in patients responding to intensive intravenous steroids for the induction of remission [LE: 5; GR: D].
In thiopurine-naïve patients responding to infliximab for the induction of remission, azathioprine or mercaptopurine can be considered an alternative to infliximab for maintenance of remission [LE: 5; GR: D].
Thiopurines are an option in patients who have experienced early or frequent relapses while taking mesalazine at optimal dose or who are intolerant to mesalazine [LE: 5; GR: D]. Addition or continuation of oral mesalazine is recommended but special attention must be given to the possible occurrence of myelotoxicity [LE: 5; GR: D].
The switch to mercaptopurine may be considered in UC patients with azathioprine intolerance [LE: 3; GR: C].
Thiopurines can be given for at least 5 years [LE: 5; GR: D].

 

 

About 22% of UC patients become steroid-dependent one year after the first course of corticosteroid therapy [28] . Steroid-dependent UC can be managed with thiopurines.

An investigator-blind RCT compared azathioprine (2 mg/kg daily) to oral mesalazine (5-aminosalicylic acid; 3.2 g/day) in 72 patients with steroid-dependent UC [77] . After 6 months, treatment success (i.e. clinical and endoscopic remission and steroid discontinuation) was recorded in significantly more patients in the azathioprine group (19/36 patients, 53%) than in the mesalazine group (7/36, 21%); OR = 4.78 (95% CI, 1.57–14.5). Similar results were obtained in the per-protocol analysis: 58% vs. 21%; OR = 5.26 (95% CI, 1.59–18.1). Therefore, azathioprine is more effective than mesalazine. Additional data on the effectiveness of azathioprine come from an open-label, observational study of 42 steroid-dependent UC patients; with azathioprine, the steroid-free remission rates at 12, 24 and 36 months were 55%, 52%, and 45%, respectively [78] .

Five meta-analyses assessed the efficacy of azathioprine or mercaptopurine, compared to placebo or standard care (5-aminosalicylic acid), in preventing clinical relapses in patients with UC in remission 79 80 81 82 83 . These meta-analyses calculated a number needed to treat (NNT), for maintaining clinical remission, between 4 and 5. The most recent meta-analysis considered four studies involving 232 UC patients, and found a statistically significant benefit of azathioprine in preventing relapse (RR = 0.68; 95% CI, 0.54–0.86) [82] . According to five retrospective studies 84 85 86 87 88 , after the induction of remission with cyclosporine, thiopurine treatment reduced the risk of colectomy by about 50% at 5 years.

There is limited information about the best duration of immunosuppressive therapy in UC. The timing of azathioprine withdrawal was examined in a placebo-controlled double-blind RCT that enrolled 79 UC patients who had been taking azathioprine for six or more months [89] . These 79 patients included 67 in full remission for two months or more and 12 with chronic, low-grade or corticosteroid-dependent disease. The one-year relapse rate was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those who had been switched to placebo (hazard rate ratio, 0.5). A subgroup of patients in remission for more than six months, who continued azathioprine, had more cases of relapse than the placebo group did at 1 year (31% vs. 61%, p = 0.01). This result suggests that azathioprine use should be continued for at least 2 years. However, in two retrospective series 90 91 , the duration of azathioprine treatment was not associated with the relapse rate after stopping treatment.

Based on experiences with CD, thiopurines should be given for at least 4 years 92 93 , with longer treatment periods evaluated on a case-by-case basis.

3.2.2 Methotrexate

 

Statement 10
Methotrexate is not indicated in the maintenance of remission in patients with steroid-dependent chronic active UC [LE: 1b; GR: B].

 

 

Data about the use of methotrexate in maintaining remission in UC patients are substantially negative. In particular, a placebo-controlled trial of 67 patients with UC found no statistically significant benefit of oral methotrexate (12.5 mg once weekly) over placebo in maintaining (or inducing) remission [94] . In a recent European multicenter, double-blind placebo-controlled trial [95] that enrolled 111 steroid-dependent UC patients, parenteral methotrexate (intramuscularly or subcutaneously, 25 mg/week) was not superior to placebo in reaching the primary end point (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. However, methotrexate was superior to placebo for inducing clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) without steroids at week 16 (41.7% vs 23.5%; 95% CI, 1.1%–35.2%; p = 0.04).

4 Crohn’s disease

4.1 Active disease: management and induction of remission

4.1.1 Severe Crohn’s disease

In clinical practice, severe CD may be defined by the presence of severe malnourishment (e.g. BMI < 18), complicated disease (e.g. stenosis or abscess), severe symptoms despite medical treatment, persistently elevated CRP, anatomical extent of disease, or severe extraintestinal manifestations [14] . Management of severe CD requires hospitalization, intensive medical treatment and close monitoring for the need for surgery.

Statement 11
Intravenous steroids are the first-line treatment for severe luminal CD [LE: 1b; GR: A]. Septic complications should be ruled out [LE: 5; GR: D].

 

Statement 12
The optimal dose of methylprednisolone (or equivalent) is 0.75–1 mg/kg day [LE: 1b; GR: A]. The maximum daily dose is 60–80 mg [LE: 5; GR: D].

 

 

Because the pharmacological treatment of severe CD has not been specifically studied, we must extrapolate results from trials on moderate-to-severe CD. However, these studies have seldom included large numbers of patients with severe disease and only rarely report response rates stratified by disease severity. Nonetheless, there is enough evidence 96 97 98 99 to show that systemic IVCS (e.g. methylprednisolone, 1 mg/kg day up to 60 mg/day) induce remission more frequently than placebo (60% vs. 30–45%), whereas budesonide, in its current formulations, is not effective unless the disease primarily affects the proximal colon. Therefore, steroids remain first-line therapy, with immunomodulators as steroid-sparing agents for patients who relapse 2 3 .

Statement 13
The maximum duration of steroid therapy at full dosage is 2 weeks [LE: 1B; GR: A].

 

Statement 14
When response is achieved, the patient should be switched to oral steroids, e.g. 48 mg/day methylprednisolone or equivalent [LE: 5; GR: D].

 

 

So far, the optimal steroid dosage regime for active severe CD has not been defined in a dose-ranging study. There is some evidence that 0.5–0.75 mg/kg day or 40 mg/day doses of prednisone (or equivalent) induce remission in 50–70% of cases 100 101 , while higher doses of prednisone or methylprednisolone (1 mg/kg day) reach 80–90% remission rates [100] .

Statement 15
Tapering by 4–8 mg/week until complete weaning within 8–12 weeks is recommended [LE: 4; GR: C].

 

 

The reported time to peak response ranges from 9 weeks [96] to more than 26 weeks [99] . A Cochrane review found that the peak response OR reached 2.61 (95% CI, 1.69–4.03) at >17 weeks of therapy [101] . However, a two-week duration of full steroid dosage seems reasonable in order to maximize the response. After the period of full dosage, the dosage should be tapered to avoid sudden relapses; this recommendation of the ECCO guidelines [2] is based on pivotal trials (National Cooperative Crohn’s Disease Study [96] and European Cooperative Crohn’s Disease Study [97] ) but has not been specifically investigated. Tapering schedules that lead to steroid weaning in 8 weeks, and that are therefore acceptable, include:

  • 8 mg/day weekly reduction in methylprednisolone dose from 48 to 16 mg/day, then 4 mg/day weekly reduction until complete weaning, or

  • 10 mg/day weekly reduction in prednisone from 60 to 20 mg/day, then 5 mg/day reduction until complete weaning.

Statement 16
Low-bioavailability steroids (budesonide and BDP) are not indicated in the treatment of severe CD [LE: 1b; GR: A].

 

 

According to two meta-analyses, budesonide (and possibly other topically active steroids like BDP) is significantly less effective than conventional steroids in the induction of remission. Papi et al. [102] in 2000 reported that budesonide was less effective than conventional corticosteroids for inducing remission of active CD, with a pooled rate difference of −8.5% (95% CI, −16.4 to −0.7%; p = 0.02). Subsequently, a Cochrane review in 2008 [102] found that budesonide was significantly less effective than conventional steroids for inducing remission (RR = 0.86; 95% CI, 0.76–0.98), particularly in patients with severe disease (CDAI >300) (RR = 0.52; 95% CI, 0.28–0.95).

Statement 17
Thiopurines and methotrexate do not induce remission in severe CD, but can be considered for long-term maintenance [LE: 2; GR: B].

 

 

Patients who experience severe episodes of disease activity should be promptly put on more aggressive maintenance regimens. Additionally, to prevent subsequent relapses, these patients should be prescribed immunomodulators early, i.e. at discharge.

Statement 18
In steroid-refractory patients, rescue treatment with anti-TNF antibodies may be considered [LE: 2; GR: B], although surgery is a valuable option in cases of limited disease extent [LE: 5; GR: D].

 

 

Over the past 15 years, the use of TNF antagonists has expanded in clinical practice. Infliximab 104 105 and adalimumab [106] have been demonstrated to be effective in treating steroid-resistant severe CD. Their earlier use in selected patients, i.e. those with aggressive disease and with disease markers suggesting poorer long-term outcome, has also been proposed 2 3 4 . This proposal is based on the observation that continued treatment with infliximab or adalimumab is associated with a substantial reduction (about 30% at 1 year) in surgery and disease-related hospitalizations 107 108 . Therefore the use of anti-TNF agents may be advocated as first-line treatment in selected cases, as recommended by the Italian Society of Gastroenterology and IG-IBD [4] .

Alternative medical rescue regimens are cyclosporine and tacrolimus (RR = 4.61; 95% CI, 2.09–10.17) [109] , although neither is approved for IBD treatment in Italy. Oral cyclosporine (5–7.5 mg/kg day) was found to be superior to placebo in one RCT [110] , but subsequent trials did not confirm this result 111 112 113 .

Statement 19
In complicated disease, surgery should be offered if adverse outcomes occur or if second-line treatments are contraindicated [LE: 5; GR: D].

 

 

Surgery is a safe and effective rescue treatment at any time after first-line treatment with steroids is found to be ineffective. Disease location, however, is important: the threshold for operation is low when disease is localized and the rectum is not involved, while it is high when there is extensive disease or if the rectal involvement is severe (in these patients, surgery could be mutilating or less effective in controlling disease). Surgery is a first-line option in elderly patients, because in these patients second-line treatments are more hazardous than in younger patients [114] .

4.1.2 Mild and moderate Crohn’s disease

Management of mild and moderate CD usually does not require hospitalization or intensive medical treatment, but always requires a surgical evaluation and the offer of prompt surgery when needed.

Statement 20
Budesonide is the first-line treatment for mildly active ileal or ileal and right-sided colonic CD [LE: 1a; GR: A]. Budesonide is slightly less effective than conventional systemic steroids but has a better safety profile [LE: 1a; GR: A].
Budesonide should be used at 9 mg/day up to 8 weeks [LE: 1b; GR: A]. The dose may be tapered to 6 mg/day and subsequently to 3 mg/day for a further 4 weeks [LE: 1b; GR: A]. Prolonged low-dose budesonide treatment is not recommended [LE: 5; GR: D].
Patients who fail to enter remission with a standard dose of oral budesonide should receive a systemic steroid course [LE: 5; GR: D].

 

 

Budesonide is a 17-alpha-acetal-substituted glucocorticoid with high affinity for the glucocorticoid receptor and potent anti-inflammatory activity, despite a systemic bioavailability of only 10–15% due to rapid first-pass metabolism in the liver [115] . Oral budesonide has been extensively studied in CD. In active disease, several RCTs have compared budesonide to placebo 116 117 , 5-aminosalicylic acid 118 119 and conventional corticosteroids in both adults 120 121 122 123 and children 124 125 . Additionally, RCTs have compared budesonide to placebo for maintaining clinical remission in quiescent CD induced either medically 126 127 128 129 130 131 132 or surgically 133 134 . Moreover, several systematic reviews and meta-analyses on the topic have been published 101 102 135 136 137 138 .

Oral budesonide should be used as first-line treatment for mild to moderately active ileocecal CD. Compared to placebo, budesonide is significantly better in inducing remission after 2, 4 and 8 weeks, with RR = 2.97 (95% CI, 1.67–5.29), RR = 1.67 (95% CI, 1.12–2.47), and RR = 1.96 (95% CI, 1.19–3.23), respectively [102] . The dosage of 9 mg/day for 8 weeks is optimal [116] . Compared to mesalazine, the efficacy of oral budesonide is controversial. A first multicenter, double-blind RCT compared 9 mg/day budesonide controlled ileal release to 4 g/day mesalazine for inducing remission in mild–moderately active CD [118] ; after 8 weeks of treatment remission rates were 69% and 45%, respectively ( p = 0.001), while after 16 weeks they were 62% and 36% ( p < 0.001). More recently, however, a multicenter, double-blind RCT that compared 9 mg/day, pH-modified-release budesonide to 4.5 g/day Eudragit-L–coated mesalazine found similar efficacies in inducing remission at 8 weeks: 69.5% in the budesonide group and 62.1% in the mesalazine group ( p = 0.001 for noninferiority) [119] .

Several RCTs compared oral budesonide (9 mg/day) with a standard dose of conventional corticosteroids (40 mg/day prednisolone or prednisone, or 48 mg/day methylprednisolone) for inducing remission in mild to moderately active CD 120 121 122 123 : in all four trials, remission rates were similar between groups, but corticosteroid-related adverse effects were significantly less common in the budesonide-treated patients. Similar results were reported in two small RCTs in children 124 125 . However when the results of the individual trials were pooled in meta-analyses 102 103 135 136 , budesonide was found to be less effective than conventional corticosteroids in inducing remission: the risk difference was small, approximately 9%, but statistically significant. A subgroup analysis of patients with severe CD (CDAI >300) showed that budesonide was consistently less effective than conventional corticosteroids for inducing short-term remission (RR = 0.52; 95% CI, 0.28–0.95) [103] . Conversely, in patients with mild disease (CDAI <300), no difference was observed between budesonide and systemic steroids (RR = 0.91; 95% CI, 0.77–1.07) [136] .

The two formulations of oral budesonide (controlled ileal release and pH-dependent release) have similar efficacy [103] . Meta-analyses have shown that the likelihood of corticosteroid-related adverse events and adrenal suppression is significantly lower in budesonide-treated patients, with an absolute risk reduction of approximately 22% and a number needed to harm (NNH) of 5 102 103 .

Maintenance treatment with low-dose budesonide (3–6 mg/day) for up to 12 months was no better than placebo in preventing relapse after medically or surgically induced remission 102 103 , although 6 mg/day budesonide may be effective for prolonging the time to relapse [138] . In steroid-dependent patients, the switch from systemic steroids to 6 mg/day budesonide for 12 weeks was better than a switch to placebo for maintaining remission with a similar safety profile [139] . Long-term budesonide treatment is not effective in preventing relapse and, therefore, is not recommended for maintenance of remission in CD.

Statement 21
Conventional oral systemic steroids should be considered as the first-line treatment for moderately active CD [LE: 1a; GR: A]. Budesonide is an option in ileocecal CD, but its efficacy is lower than that of systemic steroids [LE: 1b; GR: B].
The recommended dose of oral systemic steroids in moderately active CD is 0.75–1 mg/kg day [LE: 1b; GR: B]. Steroids should be tapered and discontinued within 12 weeks [LE: 5; GR: D]. Prolonging steroid course after clinical remission does not improve outcomes [LE: 1b; GR: B].
In mild–moderate colonic, jejunoileal or predominantly upper gastrointestinal CD, oral systemic steroids should be considered as a first-line treatment [LE: 1a; GR: A]. In mild colonic CD, sulfasalazine is an option [LE: 1b; GR: B]. In patients with mild activity and predominantly upper gastrointestinal location, proton pump inhibitors are another possible first-line treatment [LE: 4; GR: C].

 

 

The use of conventional corticosteroids, such as prednisone, is generally reserved for patients with moderate to severe disease. A Cochrane review examined the use of systemic corticosteroids for inducing remission in active CD; the meta-analysis of two RCTs found corticosteroids significantly more effective than placebo (RR = 1.99; 95% CI, 1.51–2.64; p < 0.00001) [101] . No dose-response studies in patients with CD have been reported, and the initial dose and tapering schedule are largely empirical. In two population-based studies, approximately 80% of patients responded to systemic prednisone regardless of the initial dose, either 1 mg/kg day [140] or 40–60 mg/day [26] . In a prospective French study of 142 patients with moderately active ileocolonic CD, an initial oral dose of 1 mg/kg day prednisolone gave a short-term remission rate of 92% at 7 weeks [100] . However, there is no additional benefit from prolonging steroid-treatment after remission is achieved or extending the duration of the tapering period 100 141 143 .

Although systemic steroids are highly effective in inducing clinical remission in the short term, observational studies have shown that less than 50% of patients remain in remission one year after the first steroid course 26 139 141 142 . This finding suggests that steroid refractoriness and dependency are the rule rather than the exception. Prolonged steroid treatment is not effective in maintaining remission 144 145 and is therefore not recommended.

4.1.3 Steroid-dependent Crohn’s disease

 

Statement 22
Steroid-dependent patients should be treated with thiopurines [LE: 1a; GR: A]. The dose should be optimized (azathioprine, 2–2.5 mg/kg day; mercaptopurine, 1–1.5 mg/kg day) and the efficacy should be evaluated between 3 and 6 months [LE: 1a; GR: A].
Methotrexate is an option in patients unresponsive or intolerant to thiopurines [LE: 1b; GR: A]. The recommended dosage regime is 25 mg/weekly intramuscularly for up to 16 weeks [LE: 1b; GR: A].

 

 

The goal of treatment in CD patients is remission without steroids, to avoid the significant adverse events that this class of drugs commonly induces. For this reason, steroid-dependent CD patients should be treated with immunosuppressive drugs (e.g. azathioprine, mercaptopurine, methotrexate) in order to suspend steroids in the shortest possible time.

4.2 Remission: maintenance with immunosuppressive therapies

4.2.1 Thiopurines

 

Statement 23
Thiopurines are recommended for treating steroid-dependent and steroid-refractory patients [LE: 1a; GR: B] as well as patients requiring a second course of steroids within one year [LE: 5; GR: D]. Thiopurines can be used alone or combined with biologics [LE: 1b; GR: A].
Thiopurines should also be considered in patients with extensive disease and in those experiencing a severe flare-up [LE: 5; GR: D].
Thiopurine treatment is best continued over a long time, given the high risk of relapse after discontinuation [LE: 1a; GR: A].
Thiopurines are recommended in patients at high risk of early post-operative recurrence [LE: 1b; GR: B].
Azathioprine and mercaptopurine are equally effective; for patients experiencing side effects from one of the drugs, a switch to the other may be useful [LE: 4; GR: D].
Thioguanine is not recommended because of liver toxicity [LE: 1b; GR: B].

 

 

Numerous clinical trials have proven the effectiveness of thiopurines in patients with CD. An RCT conducted in 1979 [96] found a better response to azathioprine than to placebo but without statistical significance, possibly because of the low dosage tested (1 mg/kg). Subsequently, a two-year, double-blind RCT conducted by Present et al. [146] in 83 chronically ill patients achieved remission in 67% of those treated with mercaptopurine vs. 8% those administered placebo ( p < 0.0001). Mercaptopurine was also more effective than placebo at closing fistulas (31% vs. 6%) and permitting discontinuation or reduction of steroid dosage (75% vs. 36%; p < 0.001 Candy et al. [147] ran a single-center, placebo-controlled trial to determine whether the addition of azathioprine to a diminishing-dose 12-week course of prednisolone affected the remission rate; although there was no short-term benefit of azathioprine (12 weeks), at 15 months significantly more patients who received azathioprine were in remission (14/33, 42%) than patients who received placebo (2/30, 7%; p = 0.001).

Although these studies demonstrate the efficacy of thiopurines, the issue remains of how long treatment should be continued. One trial withdrew azathioprine from patients who had been on the drug for at least six months, and found that the rate of relapse one year after discontinuation was significantly higher than in a control group that continued treatment [148] ; the time that patients had been on azathioprine prior to the trial did not affect the risk of relapse, but only a small number of patients had received the drug for more than two years (24 patients). Similar results were obtained in an RCT in which patients who had been on azathioprine for more than 42 months were randomized to continue the drug or receive placebo for 18 months [93] . Patients who received placebo relapsed more often than those who maintained treatment (21.3% vs. 7.9%, respectively), leading the authors to conclude that maintenance therapy with azathioprine is possible beyond 3.5 years despite the risk of relapse and toxicity due to prolonged treatment. The study also found that two biological markers, CRP (>20 mg/l) and hemoglobin (<12 g/dl), were associated with a higher rate of relapse in the 18 months following treatment cessation [93] .

The risk of relapse after azathioprine discontinuation has also been investigated in three retrospective studies. Bouhnik et al. [92] observed that azathioprine was beneficial for maintaining remission up to, but not beyond, four years and that male and younger patients had a higher relapse risk. Unfortunately, very few patients completed the 4 years of observation. Conversely, Kim et al. [149] found a higher relapse rate among patients who ceased treatment with mercaptopurine than among those who continued treatment, leading the authors to suggest indefinite use of the drug once remission has been achieved. Finally, Fraser et al. [87] analyzed the medical records of 622 IBD patients (including 272 with CD) who had received azathioprine for a mean duration of 634 days; 79 patients with CD stopped treatment following prolonged remission, leading to relapse in 49 cases. The duration of azathioprine treatment was unrelated to the relapse rate.

The efficacy of azathioprine in preventing relapses was examined by Khan et al. within a broader systematic review of immunosuppressive therapies for IBD [81] . In patients with quiescent CD, azathioprine did not show a significant benefit over placebo in preventing relapse. However, azathioprine was of benefit in patients who continued treatment after achieving remission, with NNT = 6 [81] .

In a Cochrane review, Chande et al. [21] investigated the ability of thiopurines to maintain remission in CD, and found that azathioprine was significantly more effective than placebo over a 6- to 18-month period (azathioprine vs. placebo: 73% vs. 62%; RR = 1.19; 95% CI, 1.05–1.34; NNT = 9). No statistically significant difference was found between thiopurines (azathioprine or mercaptopurine) and either mesalazine or sulphasalazine treatment (69% vs. 67%, respectively). No significant difference was found between combination therapy with azathioprine (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) and monotherapy with infliximab (80% vs. 80%) at one year, nor between mercaptopurine (50%) and methotrexate (53%).

The use of immunosuppressive drugs in the maintenance of remission is now being complicated by the availability of biological therapies, which have changed our approach to the management of patients with steroid-dependent refractory disease. An open-label RCT evaluated the effects of continuing or interrupting immunosuppressive drugs during the two years that patients were receiving infliximab as maintenance therapy [150] . No significant difference was observed between patients who continued immunosuppressive drugs and those who stopped them, in terms of alterations in infliximab dosage, dosing intervals, and mucosal healing. However, the concomitant use of immunosuppressive drugs resulted in higher infliximab trough levels and lower CRP levels than in patients who discontinued immunosuppressive therapy [21] . A subsequent RCT provided contrasting data indicating that the early use of infliximab, combined with azathioprine in patients naïve to both drugs, improves clinical and mucosal healing outcomes at 6 months and up to one year [151] . Further evidence for the efficacy of combined treatment early in the course of the disease, not only in the short term but also at one year, is provided by D’Haens et al. [152] who studied 133 recently diagnosed patients who were naïve to steroids, immunosuppressive drugs and biologics; patients were randomized to either a combination of azathioprine and infliximab or conventional treatment with steroids and azathioprine in sequence. Rates of steroid-free remission were 61% in the combined treatment group and 42% in the conventionally treated group ( p = 0.0278) [152] .

Thioguanine, a metabolite of mercaptopurine, was found to have similar efficacy to the parent drug and was also useful in patients intolerant to azathioprine and mercaptopurine 153 154 . However, hepatic side effects preclude its use.

The efficacy of thiopurines in reducing recurrence after surgical resection has also been evaluated. One study found that mercaptopurine, but not mesalazine, was more effective than placebo in preventing clinical and endoscopic post-operative relapse [155] , while another found no difference between azathioprine and 5-aminosalicylate after surgery [156] . A meta-analysis [157] considered four RCTs (433 patients) that compared azathioprine or mercaptopurine to control treatments (placebo with or without antibiotic induction therapy or mesalamine), and found a significant advantage of thiopurines in the prevention of relapse (NNT = 13 at one year; NNT = 8 at two years). Severe endoscopic recurrence was significantly less frequent in thiopurine-treated patients (mean difference, 15%; 95% CI, 1.8–29%; p = 0.026, NNT = 7), but very severe recurrence was not prevented. Although thiopurines were associated with a higher rate of adverse events, their use remains an option in uncomplicated disease and in patients at high risk of relapse [156] .

A recent retrospective study of 326 patients came to the same conclusions [158] . Treatment with either azathioprine or mercaptopurine was recorded in 161 of 326 patients (49%). Long-term treatment with thiopurines was associated with a significant reduction in re-operation rates compared with patients treated for less than three months or untreated. Evidence for the efficacy of immunosuppressive therapy (mercaptopurine) in reducing the need for steroids and improving the remission rates was also demonstrated in 55 children with active CD [159] .

4.2.2 Methotrexate

 

Statement 24
Methotrexate can be used to maintain remission in patients in whom this drug was used for induction [LE: 1b; GR: A] and in patients who are intolerant or refractory to thiopurines [LE: 5; GR: D].

 

 

Methotrexate is another immunosuppressive therapy commonly used in CD, mainly in patients who have failed to respond or are intolerant to thiopurines. There is good evidence for the use of methotrexate in inducing and maintaining remission in patients with steroid-dependent or steroid-refractory CD [160] . Patel et al. conducted a Cochrane review of five RCTs (333 patients) [22] , and found that intramuscular methotrexate was significantly more effective than placebo for maintaining remission after 40 weeks of therapy (65% vs. 39%; RR = 1.67; 95% CI, 1.05–2.67; NNT = 4). The pooled analysis of two studies evaluating 145 patients and including one high-quality trial (126 patients) failed to find a statistically significant difference in the remission rates between combination therapy (methotrexate and infliximab) and infliximab monotherapy after 36–48 weeks (54% vs. 53%).

4.2.3 Other immunosuppressive drugs

There is limited experience in the use of other immunosuppressive drugs for maintaining remission in CD. Cyclosporine was not found to be beneficial in two RCTs 161 162 . Tacrolimus was found to be efficacious in patients with steroid-resistant disease but the evidence is limited to small uncontrolled studies 163 164 , while no statically significant difference was found between tacrolimus and placebo in inducing remission of perianal fistula in CD patients [165] . The use of mycophenolate mofetil was explored in an RCT with azathioprine as a comparator [166] and in other small studies 167 168 169 , with little evidence of efficacy. Everolimus, a rapamycin derivative, was tested in comparison to azathioprine, but the trial was stopped before enrollment was complete due to lack of efficacy [170] .

Conflict of interest

PG has served as consultant for and received research grant from Abbvie, Ferring, Hospira, Janssen, MSD, Mundipharma, Takeda.

Appendix A Supplementary data

The following is Supplementary data to this article: Attached file

References

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