Scandinavian Journal of Gastroenterology. 2015; 50: 90–112
REVIEW
Conventional drug therapy for inflammatory bowel disease
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ROBERT V BRYANT, OLIVER BRAIN & SIMON P.L. TRAVIS Translational Gastroenterology Unit, Oxford University Hospitals Trust, Oxford, UK
Abstract Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice.
Key Words: Crohn’s disease, inflammatory bowel disease, ulcerative colitis
Introduction
Approach to medical therapy for IBD (Table I)
Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are lifelong inflammatory conditions of rising prevalence worldwide [1]. The aetiology of IBD is complex, multifactorial and incompletely understood, involving susceptible host genetics, microbiota and environmental factors [2,3]. Despite major therapeutic advances over the past decade, a medical cure for IBD does not yet exist, and many patients live with a considerable symptom burden despite treatment [4,5]. Most patients with IBD are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate (MTX), calcineurin inhibitors, infliximab (IFX) and adalimumab (ADA). It relates to societal practice guidelines (such as European Crohn’s and Colitis Organisation [ECCO]) [6–10], illustrating drug efficacy, safety and salient practice points for optimal and appropriate practice.
Patient, disease- and medication-related factors, as well as managing the manageable and targets for treatment, need to be considered (Table I). Patient factors Most patients with IBD require lifelong medical therapy. Given that IBD affects a young patient demographic with normal life expectancy [11], treatment decisions must be strategic, balancing drug potency, side effects and the likely duration of therapy [7]. The choice of therapy is best personalised, tailored to patient goals and treatment acceptability [12]. Shared decision-making between patients and clinicians allows for better patient understanding of any risk– benefit profile, facilitating greater confidence in the chosen strategy, which may ultimately lead to improved treatment adherence [13,14]. Disease-related factors Clinical classification of IBD is the starting point for therapeutic decisions. The Montreal classification
Correspondence: Simon Travis, Translational Gastroenterology Unit, Oxford University Hospitals Trust, Headley Way, Headington, Oxford, OX3 9DU, UK. E-mail: [email protected]
(Received 3 September 2014; revised 15 September 2014; accepted 19 September 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.968864
Conventional drug therapy for IBD
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Table I. Approach to management of IBD. Consideration
Management approach
Patient factors
Patient preference Lifestyle and behavioural factors Family history and genetic susceptibility
Disease-related factors
Disease classification and extent Prior surgery Prognostic factors
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Disease activity
Medication-related factors
Managing the manageable
Risk versus benefit profile Prior therapy Disease remission Venous thromboembolic disease Bone health Body composition Opportunistic infection Vitamin D Fatigue
Treat to target
Define remission Treatment targets
Shared decision-making model, tailoring therapy Smoking, physical activity, diet Explore heritability of IBD. Future therapeutic decision-making may involve genetic profiling. Use of Montreal classification criteria advocated Classify as remission induction or remission maintenance Influences choice of therapy, indicates biologic severity of disease Younger age of diagnosis, stricturing and perianal disease, requirement for steroids at diagnosis Beyond symptoms incorporating composite of objective assessments (endoscopy, histology, radiology and biomarkers). Use validated indices of severity Patient education, appropriate follow-up and monitoring To every drug, a patient may be responsive, refractory, intolerant or dependent Defining remission beyond symptoms as a goal for therapy Thromboprophylaxis in hospitalised patients with IBD Osteopenia/porosis is common and bone protection measures are a measure of quality care in IBD Low lean mass is common in patients with IBD and contributes to morbidity Adherence to pre-screening and vaccination guidelines for immunosuppressive and biologic therapy Optimisation of vitamin D levels benefits bone health, disease activity, and quality of life in IBD Fatigue is common and warrants screening for contributory factors (cortisol, thyroid function and testosterone levels) Resolution of clinical symptoms as well as mucosal healing Regular assessment of disease activity using objective measures used to guide subsequent treatment and retard disease progression
Practice points: Use a ‘treat to target’ approach where clinical and biological disease activity measures are used to guide therapy. Aim of therapy is to modify the course of disease, to improve quality of life and avoid disability.
system and its later Paris modification with regard to children provide a common language, including age at diagnosis, disease location, extent and behaviour [4,5,15,16]. Previous surgery, such as ileocaecal resection, should also be taken into account, along with the context of the decision (educational, family or occupational hurdles) and environmental factors, particularly smoking [17,18]. Prognostic factors at diagnosis are also best taken into account such as a young age (5 kg), requirement for steroids, stricturing phenotype or perianal disease, which may be associated with the later development of ‘disabling’ CD [19,20]. In particular, stricturing disease and weight loss have a 78% predictive value for a poor prognosis in CD [20], which may prompt consideration for early biological or immunomodulator therapy even if disease activity is mild or moderate [12]. Suppression of inflammation early in the course of disease may avoid diseaserelated complications and progressive disability, akin to other inflammatory conditions such as rheumatoid arthritis [21–24]. Disease activity is an important determinant of therapy for IBD. Determining disease activity using
symptoms alone is inaccurate, given that gastrointestinal symptoms are not solely inflammatory in origin. Inflammation, after all, may stir up the enteric nerves to incite dysmotility. Everyone is aware of postinfective irritable bowel syndrome (IBS); why not post-inflammatory IBS? [25] Conversely, insidious progression of disease can occur in the absence of symptoms. A composite and objective assessment of disease activity and classification beyond symptoms should be pursued; incorporating endoscopy, histology, radiology and serologic markers as appropriate [4,5,26–28]. Validated indices of disease assessment, such as the UC endoscopic index of severity, represent a common language, to reduce inter-observer variability [29,30]. Medication-related factors Selection of medical therapy depends on the balance between drug potency and safety. First consider the response to, and optimisation of, previous therapy. To every drug a patient may be responsive, refractory, intolerant or dependent. It helps to define individual responses in these terms, checking that therapy has
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been optimised, since this influences therapeutic decisions [4,5].
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Managing the manageable Often overlooked, but central to patient quality of life are the ancillary factors of therapy. Considerable reduction in morbidity can be achieved with a conscientious approach to eminently ‘manageable’ disease-related factors. For instance, IBD is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE) [31,32]. Societal guidelines recommend thromboprophylaxis in hospitalised patients with IBD, yet a remarkable 65% of gastroenterologists do not use pharmacological VTE prophylaxis in the setting of acute severe colitis (ASC) [32]. Osteopenia affects 30–48% of patients with IBD and those with CD, a high cumulative steroid dose, or male patients are disproportionately affected [33,34]. Bone protection should be a quality measure of care in IBD [35]. Altered body composition, particularly low lean mass, affects up to 30% of patients with CD [36], so bone mineral densitometry is recommended and supplementation with calcium and vitamin D has been shown to increase bone density [37]. Optimising serum vitamin D levels has benefits beyond bone health, (including disease activity, quality of life, muscle function and even colorectal cancer in IBD [38,39]), so vitamin D levels are best checked and optimised. Physical fatigue is common in patients with IBD and may relate to attenuated muscle protein synthesis pathways in this patient group, though remediable factors, including alterations in thyroid function, testosterone, vitamin D, and cortisol levels, need to be excluded [39,40]. The risk of opportunistic infection in patients with IBD may be reduced by adherence to screening or vaccination guidelines [41,42], so centres looking after patients with IBD had best address these factors. Treat to target The goal of therapy for IBD is to modify the course of disease, to improve quality of life and avoid disability, while balancing the risks associated with therapy [43]. The concept of ‘treat to target’, where regular assessment of disease activity using objective clinical and biological outcome measures is used to guide subsequent treatment, aims to retard to disease progression [44]. As yet (2014), the benefit of aspiring to those targets has yet to be proven, but the concept (considering rheumatoid arthritis) is credible and almost always understood by patients. With targets come measurements, introducing
metrics into clinical care, objectively to measure progress. Treatment targets that affect the future quality of life have yet to be agreed, although clinical, endoscopic, radiological and histological end points are being explored in addition to patient-reported outcomes. One again, language matters. Consensus recommendations define remission in UC as both resolution of clinical symptoms (diarrhoea and rectal bleeding) together with endoscopic mucosal healing (resolution of visible inflammation and ulceration at endoscopy) [4]. This has been associated with extended clinical remission, lower rates of hospitalisation and lower rates of colectomy [45]. Histological healing may be an aspirational target for UC, conferring prognostic benefit beyond that of endoscopic remission [46–49]. Nevertheless, most clinical trials in CD define disease remission as a CD activity index (CDAI) score 10–14 days of 5-ASA therapy for patients with active UC. Mesalazine has a limited role in CD.
Corticosteroids Corticosteroids have long been used in the management of IBD. The first ever randomised controlled trial in Gastroenterology evaluated corticosteroids in UC, conducted in Oxford in 1955 [57]. Corticosteroids reduce NF-kB activation and downregulate proinflammatory cytokines [95]. Budesonide is a synthetic steroid with potent antiinflammatory effects and low systemic bioavailability due to inactivation by first-pass hepatic metabolism [96]. Budesonide has been extensively used in IBD; as rectal therapy since 1987 [97] and oral therapy since 1993 [98]. Oral budesonide in standard form is ineffective for colonic disease [99], leading to a novel oral formulation of budesonide that uses the multi-matrix system (MMX) to extend release to the colon for mild-to-moderately active UC [100,101]. Efficacy (Table III) Conventional corticosteroids Ulcerative colitis. Two placebo-controlled trials assessing prednis(ol)one in outpatients with mild-to-moderate UC achieved remission induction in 68% of patients (NNT = 2; 95% CI 1.4–5.0) [57,102,103]. Meta-analysis confirms that conventional corticosteroids are significantly more effective than placebo for remission induction in UC (RR of no remission 0.65, 95% CI 0.45–0.93) [104]. Oral prednisolone combined with rectal hydrocortisone induced remission in 76% of patients with mild-to-moderate disease within 2 weeks [105]. However, rates of sustained remission after corticosteroid therapy are disappointing. Out of 84% patients who initially respond to steroids, only 49% remain steroid- and surgery-free after 1 year [106], although none received thiopurines. The optimal starting dose of prednisolone is 40 mg/day; higher doses are associated with increased side effects and little therapeutic gain [12]. Tapering of oral prednisolone best occurs over about 8 weeks, with many physicians choosing to taper by 5 mg/week. Shorter courses (30%) Headache (17%) Fatigue (2%) Hepatotoxicity
Non-Hodgkin lymphoma (4–9/10,000 patient years) Pancreatitis (4%) Serious infection (5%) HSTCL (rare) Cessation (17%) Nausea (8%) Hepatotoxicity (4%) Allergy (2%) Myelotoxicity (4%)
Achieved in 53% of patients [120] Achieved in 44–58% of patients [123,124] Reduced risk of recurrence (RR 0.59, 95% CI 0.38– 0.92, NNT = 7) [90] Clinical remission in 39% patients (p = 0.025 vs. placebo) [119] Clinical remission 65% (p = 0.04 vs. placebo) [135] UC (steroid-dependent) remission induction UC remission maintenance
Serious Common Efficacy Indication Preparation First use in IBD Drug
Table IV. Thiopurines and methotrexate.
Therapeutic use in IBD
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Adverse events
R. V. Bryant et al. pooled data for rectal hydrocortisone, prednisolone or b-methasone revealed symptomatic, endoscopic and histologic remission rates of 45%, 34% and 30%, respectively [81]. However, rectal corticosteroids are less effective than rectal 5-ASA therapy so their use is best reserved for combination therapy in those patients with distal colitis not responding to rectal 5-ASA alone [78,82]. Crohn’s disease. Cochrane systematic review found conventional corticosteroids to be more effective than placebo for inducing remission in CD (RR 1.99; 95% CI 1.51–2.64, p < 0.00001) [95]. Remission rates of 60% have been demonstrated using 0.5– 0.75 mg/kg/day of prednisolone tapered over 17 weeks [108]. Cochrane review of nine trials comparing conventional corticosteroids with oral budesonide revealed budesonide to be less effective for induction of remission (RR 0.86, 95% CI 0.76–0.98), particularly among patients with severe disease (CDAI >300) (RR 0.52, 95% CI 0.28–0.95) [109]. Conventional corticosteroids are neither an effective nor appropriate maintenance therapy for CD remission; Cochrane review did not find any significant difference between steroids and placebo after 6, 12 or 24 months [110].
Budesonide and budesonide MMX Ulcerative colitis. The safety and efficacy of budesonide MMX was assessed in patients with mild- or moderately active UC in the randomised, placebocontrolled CORE I and II trials [100,101]. Budesonide MMX 9 mg/day over 8 weeks was significantly more effective for induction of clinical and endoscopic remission than placebo (17.9–17.4% vs. 7.4– 4.5%, p < 0.05, CORE I–II, respectively). Although these rates may appear modest, the stringency of the remission end point means that the OR for benefit over placebo is higher than most other agents. Budesonide MMX was significantly more effective than placebo in achieving histological healing as a secondary end point (16.5% vs. 6.7%, p < 0.05). Prior failure of 5-ASA therapy was not shown to influence the efficacy of budesonide MMX in these trials. Evolving treatment algorithms propose the use of budesonide MMX, instead of conventional steroids, when optimised 5-ASA therapy fails for mild-to-moderate UC [111]. Crohn’s disease. Cochrane systematic review reported budesonide controlled ileal release (CIR) to be significantly more effective than both placebo and oral mesalazine for remission induction in CD (RR 1.96,
Conventional drug therapy for IBD
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95% CI 1.19–3.23; RR 1.63, 95% CI 1.23–2.16; respectively) [109]. Remission induction has been shown to be achieved in 51–63% of patients with active ileal or ileocaecal CD receiving 9 mg budesonide CIR over 8–10 weeks [7,112]. Budesonide 9 mg daily is recommended first-line therapy for mildly active, localised ileocaecal CD [7]. Budesonide therapy may delay time to relapse after medically induced remission in CD, but has not been shown to be effective in maintaining remission at 12 months [113].
Safety Conventional corticosteroids are associated with a high rate of adverse events, which introduced the concept of corticosteroid-free remission as an important end point for IBD therapy [12]. Steroid-related adverse effects fall into three broad groups [7]. Early effects are due to supraphysiologic doses to induce remission, including cosmetic (acne, moon face, oedema, skin striae), sleep and mood disturbance, dyspepsia, or glucose intolerance [7]. Effects associated with prolonged use (>12 weeks) include cataracts, osteoporosis, osteonecrosis and myopathy [7]. Osteoprotective therapy with supplementation of calcium and vitamin D is advised for all patients, steroid therapy for ‡8 weeks [7]. Susceptibility to infection is a concern; a registry of 6290 patients treated with IFX, found prednisolone to be associated with an increased risk of serious infections (OR 2.10, 95% CI 1.46–3.34, p < 0.001) [114]. An increased risk of post-operative sepsis with steroids has been reported in 159 patients with IBD, but not thiopurines (OR 3.7 vs. 1.7, respectively) [115]. Furthermore, conventional corticosteroids are associated with higher mortality; in patients with CD followed over a mean of 5.2 years, prednisolone was associated with increased mortality (hazard ratio (HR) 2.14, 95% CI 1.55–2.95, p < 0.001) [116]. Lastly, steroids are associated with adverse events during withdrawal, including adrenal insufficiency, syndrome of pseudorheumatism or raised intracranial pressure [7]. Budesonide is associated with fewer adverse events than conventional steroids (RR 0.64, 95% CI 0.54– 0.76) and better preservation of adrenal function [109]. Budesonide MMX has an overall safety profile comparable to placebo. Mean morning plasma cortisol levels are reduced at weeks 2 and 4 of therapy, but remain within normal limits (5–25 mg/dl) and increase toward baseline by 8 weeks of budesonide MMX therapy [100]. Rectal budesonide therapy shows similar efficacy to conventional rectal corticosteroids, with less associated hypothalamic–pituitary–adrenal axis suppression [81].
97
Practice points and ECCO guidelines [4–7,65,94] .
. .
.
Oral prednisolone (40 mg/day, tapering over 8 weeks) is currently recommended for outpatients with UC who fail to achieve resolution of rectal bleeding with optimised 5-ASA therapy. Newer treatment algorithms may include budesonide MMX. Oral or intravenous conventional corticosteroids are recommended for remission induction of severe, extensive small bowel or active colonic CD. Budesonide CIR is effective for remission induction of mild–moderate ileal CD.
Immunomodulators Thiopurine antimetabolites, first trialled in IBD in 1970 [117], inhibit cell growth and exert antiinflammatory effects by interfering with nucleic acid synthesis [118]. Azathioprine (AZA) is metabolised to mercaptopurine (MP) and subsequently to 6-thioguanine nucleotides. MTX, first trialled in IBD in 1995 [119], is a dihydrofolate reductase inhibitor, which may be administered via oral, subcutaneous or intramuscular routes. Calcineurin inhibitors (CNI), ciclosporin A (CsA) and tacrolimus, inhibit T-cell signalling pathways. Efficacy (Table IV) Azathioprine and mercaptopurine UC remission induction. There are few data on thiopurines for active UC [6,12]. A randomised controlled trial reported that AZA (2 mg/kg/day) is more effective for inducing both clinical and endoscopic remission and discontinuing oral steroids than 5-ASA in patients with steroid-dependent UC (ITT analysis, 53% vs. 21%, respectively; OR 4.78 95% CI 1.57–14.5) [120]. Retrospective case series have reported that thiopurine therapy in patients who have responded to CsA as rescue therapy for intravenous steroid-refractory UC, reduces subsequent colectomy rate at 1 year (26% vs. 81% colectomy rate, AZA vs. no AZA, respectively) [6,121]. UC remission maintenance. Meta-analysis of seven controlled studies found thiopurines to be more effective than placebo for prevention of relapse of UC (OR 2.59, 95% CI 1.51–4.34), with an absolute risk reduction of 23% and NNT of 5 [122]. Subsequent Cochrane review of four studies, including 232 patients and generally poor quality data, found
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AZA superior to placebo for maintaining remission in UC compared to placebo (54% vs. 65% failed to maintain remission, respectively; RR 0.68, 95% CI 0.54–0.86) [123]. Observational cohort data from Oxford over a 30-year period showed an overall remission rate of 58% among 346 patients with UC treated with AZA, increasing to 87% after 6 months of therapy [124]. The proportion of patients in remission at 5 years was 62% [124], but this seems likely to overestimate efficacy among those who can tolerate treatment. CD remission induction. Cochrane meta-analysis including 11 randomised trials reported that AZA or MP offered no significant advantage over placebo for induction of clinical remission in active CD (48% vs. 37%, respectively, RR 1.23, 95% CI 0.97–1.55) [125]. CD remission maintenance. Administration of AZA (2– 2.5 mg/kg/day) early in the disease course of CD has not been shown to induce sustained clinical remission compared with placebo or conventional management over 76–156 weeks in two randomised trials [126,127]. No benefit was seen in terms of reduction of rates of surgery or anti-tumour necrosis factor (anti-TNF) use. Secondary analysis however showed that a higher proportion of patients receiving AZA were free of perianal surgery when compared to those conventionally treated (96% vs. 82% at 36 months, respectively, p = 0.036) [126]. Post-hoc analysis reported lower clinical relapse rates (defined as CDAI >220 points) among those treated with AZA compared to placebo (11.8% vs. 30.2%, respectively, p = 0.01) [127]. Meta-analysis has also shown that thiopurines lead to significant reductions in steroid dosage compared to placebo; 64% of treated patients were able to reduce their prednisolone dose to 8 mg/l) [150]. Cochrane analysis including three randomised trials reported that IFX maintains clinical remission (RR 2.5, 95% CI 1.64–3.80) and has corticosteroid sparing effects (RR 3.13, 95% CI 1.25–7.81) [151]. Adalimumab UC remission induction. In ULTRA 1 and 2 trials, 884 patients with moderate-to-severely active UC (anti-TNF naïve in ULTRA 1 and anti-TNF exposed in ULTRA 2) were randomised to ADA or placebo [152,153]. The primary end point of clinical remission at 8 weeks was achieved in 18.5% and 16.5% of patients receiving ADA induction dosing of 160/80/
1997
2006
Infliximab
Adalimumab
CD (moderate-to-severe luminal despite conventional therapy) remission induction (4–12 weeks) CD (severe luminal despite conventional therapy) remission maintenance (Week 30)
Infliximab 5 mg/kg at 0/2/ 6 weeks induction
Adalimumab 40 mg every other week (CHARM, EXTEND trials)
Adalimumab 40 mg every other week (ULTRA 2 trial) Adalimumab 160 mg/80 mg induction then 40 mg every other week (EXTEND trial)
Adalimumab 160/ 80 induction then 40 mg every other week (ULTRA 1/2 trials) UC (moderate-to-severe despite conventional therapy) remission induction (Week 8) UC (moderate-to-severe) remission maintenance (Week 52) CD (moderate-to-severe luminal despite conventional therapy) remission induction (week 12) CD (moderate-to-severe luminal despite conventional therapy) remission maintenance (Week 56)
UC (moderate-to-severe) remission maintenance (Week 54)
Infliximab 5 mg/kg 8 weekly (ACT 1/2 trial)
Infliximab 5 mg/kg 8 weekly (ACCENT1 trial)
UC (moderate-to-severe) remission induction (week 8)
Indication
Infliximab 5 mg/kg at 0/2/ 6 weeks induction (ACT 1/2 trial)
Preparation
Therapeutic use in IBD
Cessation due to adverse event (10%) Injection or infusion site reaction
Clinical remission in »66% patients overall [143] (RR 3.2, 95% CI 2.18– 4.76) [145] Endoscopic remission RR 1.88 (95% CI 1.54–2.28) [145] Clinical remission in 34.7% patients overall Endoscopic remission in 45.5% patients [143] Clinical response in 81–89% of patients overall [141,148]
Clinical remission in 28–38% patients Endoscopic remission in 24% patients [156,158]
Clinical remission in 52% patients Mucosal healing in 27% patients [156]
Clinical remission in 17.3% of patients [153]
Clinical remission in 39% patients at 30 weeks (among responders to induction) [149] (RR 2.5, 95% CI 1.64–3.80) [151] Clinical remission in 16.5– 18.5% patients Mucosal healing in 41.1%46.9% patients [152,153]
Common
Infection (3%) Death Anaphylaxis Lupus-like reaction Tuberculosis Lymphoma (HSTCL) Non-haematological malignancy
Serious
Adverse events Efficacy
Abbreviations: UC = Ulcerative colitis; CD = Crohn’s disease; RR = Relative risk; CI = Confidence interval
First use in IBD
Drug
Table V. Infliximab and adalimumab.
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100 R. V. Bryant et al.
Conventional drug therapy for IBD 40 mg compared with 9.2% and 9.3% (p = 0.031 and p < 0.05) for placebo in ULTRA 1 and 2 trials, respectively. Mucosal healing at 8 weeks was achieved in 46.9% and 41.1% of patients, respectively.
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induction therapy from both the EXTEND and CHARM trials found that 30% maintained remission at 4 years [159].
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Combination therapy UC remission maintenance. In the ULTRA 2 trial, clinical remission was achieved in 17.3% of patients receiving ADA (160/80 mg induction then 40 mg every other week) at week 52, compared to 8.5% on placebo (p = 0.004) [153]. Lower rates of clinical remission were achieved in those previously treated with anti-TNF therapy. For those who responded to ADA at 8 weeks (248 patients, 49.6%), 30.9% and 43.1% achieve clinical remission and mucosal healing at week 52, respectively [154]. The risk of hospitalisation was reduced in patients receiving ADA compared to placebo during 52 weeks of therapy (OR 0.18 vs. 0.26, p = 0.03 at week 52), though colectomy rates were not reduced [155]. CD remission induction. The seminal CLASSIC-1 trial randomised 299 patients with moderate–to-severe CD naïve to anti-TNF therapy to receive either subcutaneous injections of ADA at weeks 0 and 2 of varying doses (40/20, 80/40 and 160/80 mg) or placebo. 36% of patients who received the 160/80-mg dose regimen, as compared to 12% of patients who received placebo (p = 0.001) achieved remission at 4 weeks as per a CDAI
REVIEW
Conventional drug therapy for inflammatory bowel disease
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ROBERT V BRYANT, OLIVER BRAIN & SIMON P.L. TRAVIS Translational Gastroenterology Unit, Oxford University Hospitals Trust, Oxford, UK
Abstract Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice.
Key Words: Crohn’s disease, inflammatory bowel disease, ulcerative colitis
Introduction
Approach to medical therapy for IBD (Table I)
Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are lifelong inflammatory conditions of rising prevalence worldwide [1]. The aetiology of IBD is complex, multifactorial and incompletely understood, involving susceptible host genetics, microbiota and environmental factors [2,3]. Despite major therapeutic advances over the past decade, a medical cure for IBD does not yet exist, and many patients live with a considerable symptom burden despite treatment [4,5]. Most patients with IBD are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate (MTX), calcineurin inhibitors, infliximab (IFX) and adalimumab (ADA). It relates to societal practice guidelines (such as European Crohn’s and Colitis Organisation [ECCO]) [6–10], illustrating drug efficacy, safety and salient practice points for optimal and appropriate practice.
Patient, disease- and medication-related factors, as well as managing the manageable and targets for treatment, need to be considered (Table I). Patient factors Most patients with IBD require lifelong medical therapy. Given that IBD affects a young patient demographic with normal life expectancy [11], treatment decisions must be strategic, balancing drug potency, side effects and the likely duration of therapy [7]. The choice of therapy is best personalised, tailored to patient goals and treatment acceptability [12]. Shared decision-making between patients and clinicians allows for better patient understanding of any risk– benefit profile, facilitating greater confidence in the chosen strategy, which may ultimately lead to improved treatment adherence [13,14]. Disease-related factors Clinical classification of IBD is the starting point for therapeutic decisions. The Montreal classification
Correspondence: Simon Travis, Translational Gastroenterology Unit, Oxford University Hospitals Trust, Headley Way, Headington, Oxford, OX3 9DU, UK. E-mail: [email protected]
(Received 3 September 2014; revised 15 September 2014; accepted 19 September 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.968864
Conventional drug therapy for IBD
91
Table I. Approach to management of IBD. Consideration
Management approach
Patient factors
Patient preference Lifestyle and behavioural factors Family history and genetic susceptibility
Disease-related factors
Disease classification and extent Prior surgery Prognostic factors
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Disease activity
Medication-related factors
Managing the manageable
Risk versus benefit profile Prior therapy Disease remission Venous thromboembolic disease Bone health Body composition Opportunistic infection Vitamin D Fatigue
Treat to target
Define remission Treatment targets
Shared decision-making model, tailoring therapy Smoking, physical activity, diet Explore heritability of IBD. Future therapeutic decision-making may involve genetic profiling. Use of Montreal classification criteria advocated Classify as remission induction or remission maintenance Influences choice of therapy, indicates biologic severity of disease Younger age of diagnosis, stricturing and perianal disease, requirement for steroids at diagnosis Beyond symptoms incorporating composite of objective assessments (endoscopy, histology, radiology and biomarkers). Use validated indices of severity Patient education, appropriate follow-up and monitoring To every drug, a patient may be responsive, refractory, intolerant or dependent Defining remission beyond symptoms as a goal for therapy Thromboprophylaxis in hospitalised patients with IBD Osteopenia/porosis is common and bone protection measures are a measure of quality care in IBD Low lean mass is common in patients with IBD and contributes to morbidity Adherence to pre-screening and vaccination guidelines for immunosuppressive and biologic therapy Optimisation of vitamin D levels benefits bone health, disease activity, and quality of life in IBD Fatigue is common and warrants screening for contributory factors (cortisol, thyroid function and testosterone levels) Resolution of clinical symptoms as well as mucosal healing Regular assessment of disease activity using objective measures used to guide subsequent treatment and retard disease progression
Practice points: Use a ‘treat to target’ approach where clinical and biological disease activity measures are used to guide therapy. Aim of therapy is to modify the course of disease, to improve quality of life and avoid disability.
system and its later Paris modification with regard to children provide a common language, including age at diagnosis, disease location, extent and behaviour [4,5,15,16]. Previous surgery, such as ileocaecal resection, should also be taken into account, along with the context of the decision (educational, family or occupational hurdles) and environmental factors, particularly smoking [17,18]. Prognostic factors at diagnosis are also best taken into account such as a young age (5 kg), requirement for steroids, stricturing phenotype or perianal disease, which may be associated with the later development of ‘disabling’ CD [19,20]. In particular, stricturing disease and weight loss have a 78% predictive value for a poor prognosis in CD [20], which may prompt consideration for early biological or immunomodulator therapy even if disease activity is mild or moderate [12]. Suppression of inflammation early in the course of disease may avoid diseaserelated complications and progressive disability, akin to other inflammatory conditions such as rheumatoid arthritis [21–24]. Disease activity is an important determinant of therapy for IBD. Determining disease activity using
symptoms alone is inaccurate, given that gastrointestinal symptoms are not solely inflammatory in origin. Inflammation, after all, may stir up the enteric nerves to incite dysmotility. Everyone is aware of postinfective irritable bowel syndrome (IBS); why not post-inflammatory IBS? [25] Conversely, insidious progression of disease can occur in the absence of symptoms. A composite and objective assessment of disease activity and classification beyond symptoms should be pursued; incorporating endoscopy, histology, radiology and serologic markers as appropriate [4,5,26–28]. Validated indices of disease assessment, such as the UC endoscopic index of severity, represent a common language, to reduce inter-observer variability [29,30]. Medication-related factors Selection of medical therapy depends on the balance between drug potency and safety. First consider the response to, and optimisation of, previous therapy. To every drug a patient may be responsive, refractory, intolerant or dependent. It helps to define individual responses in these terms, checking that therapy has
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been optimised, since this influences therapeutic decisions [4,5].
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Managing the manageable Often overlooked, but central to patient quality of life are the ancillary factors of therapy. Considerable reduction in morbidity can be achieved with a conscientious approach to eminently ‘manageable’ disease-related factors. For instance, IBD is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE) [31,32]. Societal guidelines recommend thromboprophylaxis in hospitalised patients with IBD, yet a remarkable 65% of gastroenterologists do not use pharmacological VTE prophylaxis in the setting of acute severe colitis (ASC) [32]. Osteopenia affects 30–48% of patients with IBD and those with CD, a high cumulative steroid dose, or male patients are disproportionately affected [33,34]. Bone protection should be a quality measure of care in IBD [35]. Altered body composition, particularly low lean mass, affects up to 30% of patients with CD [36], so bone mineral densitometry is recommended and supplementation with calcium and vitamin D has been shown to increase bone density [37]. Optimising serum vitamin D levels has benefits beyond bone health, (including disease activity, quality of life, muscle function and even colorectal cancer in IBD [38,39]), so vitamin D levels are best checked and optimised. Physical fatigue is common in patients with IBD and may relate to attenuated muscle protein synthesis pathways in this patient group, though remediable factors, including alterations in thyroid function, testosterone, vitamin D, and cortisol levels, need to be excluded [39,40]. The risk of opportunistic infection in patients with IBD may be reduced by adherence to screening or vaccination guidelines [41,42], so centres looking after patients with IBD had best address these factors. Treat to target The goal of therapy for IBD is to modify the course of disease, to improve quality of life and avoid disability, while balancing the risks associated with therapy [43]. The concept of ‘treat to target’, where regular assessment of disease activity using objective clinical and biological outcome measures is used to guide subsequent treatment, aims to retard to disease progression [44]. As yet (2014), the benefit of aspiring to those targets has yet to be proven, but the concept (considering rheumatoid arthritis) is credible and almost always understood by patients. With targets come measurements, introducing
metrics into clinical care, objectively to measure progress. Treatment targets that affect the future quality of life have yet to be agreed, although clinical, endoscopic, radiological and histological end points are being explored in addition to patient-reported outcomes. One again, language matters. Consensus recommendations define remission in UC as both resolution of clinical symptoms (diarrhoea and rectal bleeding) together with endoscopic mucosal healing (resolution of visible inflammation and ulceration at endoscopy) [4]. This has been associated with extended clinical remission, lower rates of hospitalisation and lower rates of colectomy [45]. Histological healing may be an aspirational target for UC, conferring prognostic benefit beyond that of endoscopic remission [46–49]. Nevertheless, most clinical trials in CD define disease remission as a CD activity index (CDAI) score 10–14 days of 5-ASA therapy for patients with active UC. Mesalazine has a limited role in CD.
Corticosteroids Corticosteroids have long been used in the management of IBD. The first ever randomised controlled trial in Gastroenterology evaluated corticosteroids in UC, conducted in Oxford in 1955 [57]. Corticosteroids reduce NF-kB activation and downregulate proinflammatory cytokines [95]. Budesonide is a synthetic steroid with potent antiinflammatory effects and low systemic bioavailability due to inactivation by first-pass hepatic metabolism [96]. Budesonide has been extensively used in IBD; as rectal therapy since 1987 [97] and oral therapy since 1993 [98]. Oral budesonide in standard form is ineffective for colonic disease [99], leading to a novel oral formulation of budesonide that uses the multi-matrix system (MMX) to extend release to the colon for mild-to-moderately active UC [100,101]. Efficacy (Table III) Conventional corticosteroids Ulcerative colitis. Two placebo-controlled trials assessing prednis(ol)one in outpatients with mild-to-moderate UC achieved remission induction in 68% of patients (NNT = 2; 95% CI 1.4–5.0) [57,102,103]. Meta-analysis confirms that conventional corticosteroids are significantly more effective than placebo for remission induction in UC (RR of no remission 0.65, 95% CI 0.45–0.93) [104]. Oral prednisolone combined with rectal hydrocortisone induced remission in 76% of patients with mild-to-moderate disease within 2 weeks [105]. However, rates of sustained remission after corticosteroid therapy are disappointing. Out of 84% patients who initially respond to steroids, only 49% remain steroid- and surgery-free after 1 year [106], although none received thiopurines. The optimal starting dose of prednisolone is 40 mg/day; higher doses are associated with increased side effects and little therapeutic gain [12]. Tapering of oral prednisolone best occurs over about 8 weeks, with many physicians choosing to taper by 5 mg/week. Shorter courses (30%) Headache (17%) Fatigue (2%) Hepatotoxicity
Non-Hodgkin lymphoma (4–9/10,000 patient years) Pancreatitis (4%) Serious infection (5%) HSTCL (rare) Cessation (17%) Nausea (8%) Hepatotoxicity (4%) Allergy (2%) Myelotoxicity (4%)
Achieved in 53% of patients [120] Achieved in 44–58% of patients [123,124] Reduced risk of recurrence (RR 0.59, 95% CI 0.38– 0.92, NNT = 7) [90] Clinical remission in 39% patients (p = 0.025 vs. placebo) [119] Clinical remission 65% (p = 0.04 vs. placebo) [135] UC (steroid-dependent) remission induction UC remission maintenance
Serious Common Efficacy Indication Preparation First use in IBD Drug
Table IV. Thiopurines and methotrexate.
Therapeutic use in IBD
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Adverse events
R. V. Bryant et al. pooled data for rectal hydrocortisone, prednisolone or b-methasone revealed symptomatic, endoscopic and histologic remission rates of 45%, 34% and 30%, respectively [81]. However, rectal corticosteroids are less effective than rectal 5-ASA therapy so their use is best reserved for combination therapy in those patients with distal colitis not responding to rectal 5-ASA alone [78,82]. Crohn’s disease. Cochrane systematic review found conventional corticosteroids to be more effective than placebo for inducing remission in CD (RR 1.99; 95% CI 1.51–2.64, p < 0.00001) [95]. Remission rates of 60% have been demonstrated using 0.5– 0.75 mg/kg/day of prednisolone tapered over 17 weeks [108]. Cochrane review of nine trials comparing conventional corticosteroids with oral budesonide revealed budesonide to be less effective for induction of remission (RR 0.86, 95% CI 0.76–0.98), particularly among patients with severe disease (CDAI >300) (RR 0.52, 95% CI 0.28–0.95) [109]. Conventional corticosteroids are neither an effective nor appropriate maintenance therapy for CD remission; Cochrane review did not find any significant difference between steroids and placebo after 6, 12 or 24 months [110].
Budesonide and budesonide MMX Ulcerative colitis. The safety and efficacy of budesonide MMX was assessed in patients with mild- or moderately active UC in the randomised, placebocontrolled CORE I and II trials [100,101]. Budesonide MMX 9 mg/day over 8 weeks was significantly more effective for induction of clinical and endoscopic remission than placebo (17.9–17.4% vs. 7.4– 4.5%, p < 0.05, CORE I–II, respectively). Although these rates may appear modest, the stringency of the remission end point means that the OR for benefit over placebo is higher than most other agents. Budesonide MMX was significantly more effective than placebo in achieving histological healing as a secondary end point (16.5% vs. 6.7%, p < 0.05). Prior failure of 5-ASA therapy was not shown to influence the efficacy of budesonide MMX in these trials. Evolving treatment algorithms propose the use of budesonide MMX, instead of conventional steroids, when optimised 5-ASA therapy fails for mild-to-moderate UC [111]. Crohn’s disease. Cochrane systematic review reported budesonide controlled ileal release (CIR) to be significantly more effective than both placebo and oral mesalazine for remission induction in CD (RR 1.96,
Conventional drug therapy for IBD
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95% CI 1.19–3.23; RR 1.63, 95% CI 1.23–2.16; respectively) [109]. Remission induction has been shown to be achieved in 51–63% of patients with active ileal or ileocaecal CD receiving 9 mg budesonide CIR over 8–10 weeks [7,112]. Budesonide 9 mg daily is recommended first-line therapy for mildly active, localised ileocaecal CD [7]. Budesonide therapy may delay time to relapse after medically induced remission in CD, but has not been shown to be effective in maintaining remission at 12 months [113].
Safety Conventional corticosteroids are associated with a high rate of adverse events, which introduced the concept of corticosteroid-free remission as an important end point for IBD therapy [12]. Steroid-related adverse effects fall into three broad groups [7]. Early effects are due to supraphysiologic doses to induce remission, including cosmetic (acne, moon face, oedema, skin striae), sleep and mood disturbance, dyspepsia, or glucose intolerance [7]. Effects associated with prolonged use (>12 weeks) include cataracts, osteoporosis, osteonecrosis and myopathy [7]. Osteoprotective therapy with supplementation of calcium and vitamin D is advised for all patients, steroid therapy for ‡8 weeks [7]. Susceptibility to infection is a concern; a registry of 6290 patients treated with IFX, found prednisolone to be associated with an increased risk of serious infections (OR 2.10, 95% CI 1.46–3.34, p < 0.001) [114]. An increased risk of post-operative sepsis with steroids has been reported in 159 patients with IBD, but not thiopurines (OR 3.7 vs. 1.7, respectively) [115]. Furthermore, conventional corticosteroids are associated with higher mortality; in patients with CD followed over a mean of 5.2 years, prednisolone was associated with increased mortality (hazard ratio (HR) 2.14, 95% CI 1.55–2.95, p < 0.001) [116]. Lastly, steroids are associated with adverse events during withdrawal, including adrenal insufficiency, syndrome of pseudorheumatism or raised intracranial pressure [7]. Budesonide is associated with fewer adverse events than conventional steroids (RR 0.64, 95% CI 0.54– 0.76) and better preservation of adrenal function [109]. Budesonide MMX has an overall safety profile comparable to placebo. Mean morning plasma cortisol levels are reduced at weeks 2 and 4 of therapy, but remain within normal limits (5–25 mg/dl) and increase toward baseline by 8 weeks of budesonide MMX therapy [100]. Rectal budesonide therapy shows similar efficacy to conventional rectal corticosteroids, with less associated hypothalamic–pituitary–adrenal axis suppression [81].
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Practice points and ECCO guidelines [4–7,65,94] .
. .
.
Oral prednisolone (40 mg/day, tapering over 8 weeks) is currently recommended for outpatients with UC who fail to achieve resolution of rectal bleeding with optimised 5-ASA therapy. Newer treatment algorithms may include budesonide MMX. Oral or intravenous conventional corticosteroids are recommended for remission induction of severe, extensive small bowel or active colonic CD. Budesonide CIR is effective for remission induction of mild–moderate ileal CD.
Immunomodulators Thiopurine antimetabolites, first trialled in IBD in 1970 [117], inhibit cell growth and exert antiinflammatory effects by interfering with nucleic acid synthesis [118]. Azathioprine (AZA) is metabolised to mercaptopurine (MP) and subsequently to 6-thioguanine nucleotides. MTX, first trialled in IBD in 1995 [119], is a dihydrofolate reductase inhibitor, which may be administered via oral, subcutaneous or intramuscular routes. Calcineurin inhibitors (CNI), ciclosporin A (CsA) and tacrolimus, inhibit T-cell signalling pathways. Efficacy (Table IV) Azathioprine and mercaptopurine UC remission induction. There are few data on thiopurines for active UC [6,12]. A randomised controlled trial reported that AZA (2 mg/kg/day) is more effective for inducing both clinical and endoscopic remission and discontinuing oral steroids than 5-ASA in patients with steroid-dependent UC (ITT analysis, 53% vs. 21%, respectively; OR 4.78 95% CI 1.57–14.5) [120]. Retrospective case series have reported that thiopurine therapy in patients who have responded to CsA as rescue therapy for intravenous steroid-refractory UC, reduces subsequent colectomy rate at 1 year (26% vs. 81% colectomy rate, AZA vs. no AZA, respectively) [6,121]. UC remission maintenance. Meta-analysis of seven controlled studies found thiopurines to be more effective than placebo for prevention of relapse of UC (OR 2.59, 95% CI 1.51–4.34), with an absolute risk reduction of 23% and NNT of 5 [122]. Subsequent Cochrane review of four studies, including 232 patients and generally poor quality data, found
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AZA superior to placebo for maintaining remission in UC compared to placebo (54% vs. 65% failed to maintain remission, respectively; RR 0.68, 95% CI 0.54–0.86) [123]. Observational cohort data from Oxford over a 30-year period showed an overall remission rate of 58% among 346 patients with UC treated with AZA, increasing to 87% after 6 months of therapy [124]. The proportion of patients in remission at 5 years was 62% [124], but this seems likely to overestimate efficacy among those who can tolerate treatment. CD remission induction. Cochrane meta-analysis including 11 randomised trials reported that AZA or MP offered no significant advantage over placebo for induction of clinical remission in active CD (48% vs. 37%, respectively, RR 1.23, 95% CI 0.97–1.55) [125]. CD remission maintenance. Administration of AZA (2– 2.5 mg/kg/day) early in the disease course of CD has not been shown to induce sustained clinical remission compared with placebo or conventional management over 76–156 weeks in two randomised trials [126,127]. No benefit was seen in terms of reduction of rates of surgery or anti-tumour necrosis factor (anti-TNF) use. Secondary analysis however showed that a higher proportion of patients receiving AZA were free of perianal surgery when compared to those conventionally treated (96% vs. 82% at 36 months, respectively, p = 0.036) [126]. Post-hoc analysis reported lower clinical relapse rates (defined as CDAI >220 points) among those treated with AZA compared to placebo (11.8% vs. 30.2%, respectively, p = 0.01) [127]. Meta-analysis has also shown that thiopurines lead to significant reductions in steroid dosage compared to placebo; 64% of treated patients were able to reduce their prednisolone dose to 8 mg/l) [150]. Cochrane analysis including three randomised trials reported that IFX maintains clinical remission (RR 2.5, 95% CI 1.64–3.80) and has corticosteroid sparing effects (RR 3.13, 95% CI 1.25–7.81) [151]. Adalimumab UC remission induction. In ULTRA 1 and 2 trials, 884 patients with moderate-to-severely active UC (anti-TNF naïve in ULTRA 1 and anti-TNF exposed in ULTRA 2) were randomised to ADA or placebo [152,153]. The primary end point of clinical remission at 8 weeks was achieved in 18.5% and 16.5% of patients receiving ADA induction dosing of 160/80/
1997
2006
Infliximab
Adalimumab
CD (moderate-to-severe luminal despite conventional therapy) remission induction (4–12 weeks) CD (severe luminal despite conventional therapy) remission maintenance (Week 30)
Infliximab 5 mg/kg at 0/2/ 6 weeks induction
Adalimumab 40 mg every other week (CHARM, EXTEND trials)
Adalimumab 40 mg every other week (ULTRA 2 trial) Adalimumab 160 mg/80 mg induction then 40 mg every other week (EXTEND trial)
Adalimumab 160/ 80 induction then 40 mg every other week (ULTRA 1/2 trials) UC (moderate-to-severe despite conventional therapy) remission induction (Week 8) UC (moderate-to-severe) remission maintenance (Week 52) CD (moderate-to-severe luminal despite conventional therapy) remission induction (week 12) CD (moderate-to-severe luminal despite conventional therapy) remission maintenance (Week 56)
UC (moderate-to-severe) remission maintenance (Week 54)
Infliximab 5 mg/kg 8 weekly (ACT 1/2 trial)
Infliximab 5 mg/kg 8 weekly (ACCENT1 trial)
UC (moderate-to-severe) remission induction (week 8)
Indication
Infliximab 5 mg/kg at 0/2/ 6 weeks induction (ACT 1/2 trial)
Preparation
Therapeutic use in IBD
Cessation due to adverse event (10%) Injection or infusion site reaction
Clinical remission in »66% patients overall [143] (RR 3.2, 95% CI 2.18– 4.76) [145] Endoscopic remission RR 1.88 (95% CI 1.54–2.28) [145] Clinical remission in 34.7% patients overall Endoscopic remission in 45.5% patients [143] Clinical response in 81–89% of patients overall [141,148]
Clinical remission in 28–38% patients Endoscopic remission in 24% patients [156,158]
Clinical remission in 52% patients Mucosal healing in 27% patients [156]
Clinical remission in 17.3% of patients [153]
Clinical remission in 39% patients at 30 weeks (among responders to induction) [149] (RR 2.5, 95% CI 1.64–3.80) [151] Clinical remission in 16.5– 18.5% patients Mucosal healing in 41.1%46.9% patients [152,153]
Common
Infection (3%) Death Anaphylaxis Lupus-like reaction Tuberculosis Lymphoma (HSTCL) Non-haematological malignancy
Serious
Adverse events Efficacy
Abbreviations: UC = Ulcerative colitis; CD = Crohn’s disease; RR = Relative risk; CI = Confidence interval
First use in IBD
Drug
Table V. Infliximab and adalimumab.
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Conventional drug therapy for IBD 40 mg compared with 9.2% and 9.3% (p = 0.031 and p < 0.05) for placebo in ULTRA 1 and 2 trials, respectively. Mucosal healing at 8 weeks was achieved in 46.9% and 41.1% of patients, respectively.
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induction therapy from both the EXTEND and CHARM trials found that 30% maintained remission at 4 years [159].
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Combination therapy UC remission maintenance. In the ULTRA 2 trial, clinical remission was achieved in 17.3% of patients receiving ADA (160/80 mg induction then 40 mg every other week) at week 52, compared to 8.5% on placebo (p = 0.004) [153]. Lower rates of clinical remission were achieved in those previously treated with anti-TNF therapy. For those who responded to ADA at 8 weeks (248 patients, 49.6%), 30.9% and 43.1% achieve clinical remission and mucosal healing at week 52, respectively [154]. The risk of hospitalisation was reduced in patients receiving ADA compared to placebo during 52 weeks of therapy (OR 0.18 vs. 0.26, p = 0.03 at week 52), though colectomy rates were not reduced [155]. CD remission induction. The seminal CLASSIC-1 trial randomised 299 patients with moderate–to-severe CD naïve to anti-TNF therapy to receive either subcutaneous injections of ADA at weeks 0 and 2 of varying doses (40/20, 80/40 and 160/80 mg) or placebo. 36% of patients who received the 160/80-mg dose regimen, as compared to 12% of patients who received placebo (p = 0.001) achieved remission at 4 weeks as per a CDAI
