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Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease
Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient’s disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn’s disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn’s disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease.
Carlos Fernandes1, Mariangela Allocca2, Silvio Danese2 & Gionata Fiorino*,2 1 Department of Gastroenterology, Centro Hospitalar Vila Nova Gaia, Porto, Portugal 2 IBD Center, Humanitas Research Hospital, Rozzano, Milan, Italy *Author for correspondence: Tel.: +39 02 8224 5555 Fax: +39 02 8224 2591 gionataf@ gmail.com
Keywords: anti-TNF therapy • anti-TNF withdrawal • Crohn’s disease • mucosal healing • postoperative recurrence • ulcerative colitis
Inflammatory bowel disease (IBD), such as Crohn’s disease (CD) or ulcerative colitis (UC) is a chronic relapsing and remitting affection that often leads to a progressive damage of the GI tract and to patients’ disability. It is an emergent condition with prevalence around 1% in North America and Europe and with a rapid increase in Asia and Australia. CD incidence in Europe and North America is 12.7/100,000 persons and 20.2/100,000 persons, respectively. Comparing to CD, UC incidence is higher in Europe (24.3/100,000) and similar in North America (19.2/100,000). IBD incidence is higher between the age of 20 and 40 years, mainly affecting in Caucasian and Ashkenazi ethnicity, and people living in developed countries. No significant differences between genders were described [1] . Previously, IBD management only aimed to control symptoms and signs. However, clinical and inflammatory activities are often poor correlated and this approach was not able to modify disease course. Thus, the treat-to-target approach to treat beyond the
10.2217/IMT.14.105 © 2015 Future Medicine Ltd
symptoms has been recently proposed [2] . With a progressive experience with antitumor necrosis factor (TNF) therapy, mucosal healing and deep remission have appeared as tangible targets [3,4] . Prevention of GI tract damage [5] or IBD-related disability [6] are also suggested end points, but we still lack more evidence. The step-up approach was the common strategy in IBD management since decades. Briefly, it consists in a progressive and sequential approach in which the first disease flare is treated with steroids, followed by immunosuppressants (e.g., azathioprine) if frequent flares or steroid-dependence/refractoriness are present. Anti-TNF therapy is only reserved for active disease despite immunosuppressants or immunosuppressants intolerance (Figure 1) . Although this approach may still be valid for some IBD patients, increasingly evidence advocates an early treatment with anti-TNF therapy in selected cases [7] . Currently, five anti-TNF molecules are available for IBD management (Table 1) . Infliximab, adalimumab, certolizumab and
Immunotherapy (2015) 7(2), 175–190
part of
ISSN 1750-743X
175
Review Fernandes, Allocca, Danese & Fiorino forms [12–15] . Nevertheless, some relevant issues on such therapy are still debated. Definition of new indications (e.g., postoperative disease recurrence in CD) and end points (e.g., radiological healing and blockade of intestinal damage) have recently emerged. Moreover, the anti-TNF therapy pharmacokinetics and the possibility of withdraw therapy in selected cases are still debated topics. In this review, we aimed to focus in the recent data concerning the progress of anti-TNF therapy for IBD management.
Anti-TNF therapy
Immunosuppresants
5-ASA
Oral and topical steroids for flares
Figure 1. Conventional step-up approach for inflammatory bowel disease treatment. 5-ASA: 5-aminosalicylic acid; TNF: Tumor necrosis factor.
golimumab are monoclonal antibodies that selectively block TNF-α. Thalidomide, an immunosuppressant agent with anti-TNF properties [8] , has also been evaluated for the management of refractory CD with promising results [9,10] . Nevertheless, considering its potential toxicity [8] and the lack of strong data, it should only be considered in selected cases. Data about the efficacy of thalidomide in UC are still scarce [11] . Anti-TNF therapy is a valid therapeutic option in IBD management, mainly for moderate-to-severe
Mucosal healing Mucosal healing is an important and objective end point in IBD [16] . Nevertheless, an accurate and consensual definition of mucosal healing is still lacking, especially in UC. The absence of mucosal ulceration in CD and the absence of friability, erosions or ulcerations in UC are acceptable definitions [17,18] . Up to current, mucosal healing can be quantified using different scores, most commonly by Crohn’s Disease Endoscopic Index of Severity (CDEIS) [19] and Simple Endoscopic Score for Crohn’s Disease (SES-CD) [20] in CD and Mayo endoscopic subscore [21] and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) [22] for UC. Deep remission consists in mucosal healing without any concomitant clinical symptoms [23] . Histological remission is not always predictable by endoscopy and its significance as a target is still an issue [16] . However, UC patients in deep remission with histological activity have an increased risk of disease flare and colorectal cancer comparing to patients without histological activity [24] . These definitions are still evolving and further studies are needed until a definitive consensus is reached.
Table 1. Anti-tumor necrosis factor molecules currently available for the management of inflammatory bowel disease.
Infliximab
Adalimumab
Certolizumab pegol
Golimumab
Thalidomide
Structure
Chimeric IgG1
Human IgG1
Humanized IgG4
Human IgG1
(RS)-2–2(2,6dioxopiperidin-3yl)-1H-isoindole1,3(2H)-dione
Administration Intravenous route
Subcutaneous
Subcutaneous
Subcutaneous
Oral
Standard dose
Induction: 5 mg/kg at 0, 2 and 6 weeks Maintenance: 5 mg/kg every 8 weeks
Induction: 160 mg at week 0, 80 mg at week 2 Maintenance: 40 mg every 2 weeks
Induction: 400 mg 50–100 mg at 0, 2 and 4 weeks monthly depending Maintenance: 400 on body weight mg every 4 weeks
Not defined
Indications for IBD
CD and UC
CD and UC
CD
CD and UC
UC
CD: Crohn’s disease; UC: Ulcerative colitis.
176
Immunotherapy (2015) 7(2)
future science group
Progress with anti-TNF therapeutics for the treatment of inflammatory bowel disease
Mucosal healing predicts positive outcomes in IBD. It is associated with a lower relapse rate, hospitalization rate and need for surgery in CD and UC. It is also related to less bowel damage and lower relapse rate after anti-TNF therapy withdrawal in CD patients. In UC it predicts a lower risk of colorectal cancer [16] . These data highlight the relevance of mucosal healing in IBD management. Mucosal healing with non anti-TNF agents
Although 5-aminosalicylic acid (5-ASA) appears to have no effect in mucosal healing in CD patients, its effect in UC is well described. UC patients treated with oral 5-ASA and rectal 5-ASA have an overall mucosal healing of 36.9 and 50.3%, respectively [25] . As described for 5-ASA, steroids have different efficacy on mucosal healing in CD and UC patients. Modigliani et al. evaluated steroids ability to achieve mucosal healing in CD patients with active colonic and ileocolonic disease. Prednisolone 1 mg/kg/day was given until clinical remission or at most during 7 weeks. Endoscopic remission was achieved in only 29% of the patients. Steroids seem to be slightly more effective (30–35%) on mucosal healing in UC patients [26,27] . Azathioprine is able to induce mucosal healing in CD. Nevertheless, data are not unequivocal and rates vary from 16 to 70% [28,29] . In UC, azathioprine achieved mucosal healing in 55% of the patients [30] . No strong data about methotrexate on mucosal healing are available. Mucosal healing with anti-TNF agents Crohn’s disease
There is clear evidence that anti-TNFs are able to induce rapid and sustained mucosal healing in CD (Table 2) . Firstly, D’Haens et al. conducted a multicenter, randomized, double-blinded and placebocontrolled trial evaluating endoscopic and histological response after one infusion of IFX with three different doses (5, 10 and 20 mg/kg). Endoscopic evaluation according to CDEIS [19] and histological evaluation according to a specific histological score for CD [31] . Patients receiving IFX improved significantly their CDEIS (13.0 ± 7.1 to 5.3 ± 4.4, p
Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease
Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient’s disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn’s disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn’s disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease.
Carlos Fernandes1, Mariangela Allocca2, Silvio Danese2 & Gionata Fiorino*,2 1 Department of Gastroenterology, Centro Hospitalar Vila Nova Gaia, Porto, Portugal 2 IBD Center, Humanitas Research Hospital, Rozzano, Milan, Italy *Author for correspondence: Tel.: +39 02 8224 5555 Fax: +39 02 8224 2591 gionataf@ gmail.com
Keywords: anti-TNF therapy • anti-TNF withdrawal • Crohn’s disease • mucosal healing • postoperative recurrence • ulcerative colitis
Inflammatory bowel disease (IBD), such as Crohn’s disease (CD) or ulcerative colitis (UC) is a chronic relapsing and remitting affection that often leads to a progressive damage of the GI tract and to patients’ disability. It is an emergent condition with prevalence around 1% in North America and Europe and with a rapid increase in Asia and Australia. CD incidence in Europe and North America is 12.7/100,000 persons and 20.2/100,000 persons, respectively. Comparing to CD, UC incidence is higher in Europe (24.3/100,000) and similar in North America (19.2/100,000). IBD incidence is higher between the age of 20 and 40 years, mainly affecting in Caucasian and Ashkenazi ethnicity, and people living in developed countries. No significant differences between genders were described [1] . Previously, IBD management only aimed to control symptoms and signs. However, clinical and inflammatory activities are often poor correlated and this approach was not able to modify disease course. Thus, the treat-to-target approach to treat beyond the
10.2217/IMT.14.105 © 2015 Future Medicine Ltd
symptoms has been recently proposed [2] . With a progressive experience with antitumor necrosis factor (TNF) therapy, mucosal healing and deep remission have appeared as tangible targets [3,4] . Prevention of GI tract damage [5] or IBD-related disability [6] are also suggested end points, but we still lack more evidence. The step-up approach was the common strategy in IBD management since decades. Briefly, it consists in a progressive and sequential approach in which the first disease flare is treated with steroids, followed by immunosuppressants (e.g., azathioprine) if frequent flares or steroid-dependence/refractoriness are present. Anti-TNF therapy is only reserved for active disease despite immunosuppressants or immunosuppressants intolerance (Figure 1) . Although this approach may still be valid for some IBD patients, increasingly evidence advocates an early treatment with anti-TNF therapy in selected cases [7] . Currently, five anti-TNF molecules are available for IBD management (Table 1) . Infliximab, adalimumab, certolizumab and
Immunotherapy (2015) 7(2), 175–190
part of
ISSN 1750-743X
175
Review Fernandes, Allocca, Danese & Fiorino forms [12–15] . Nevertheless, some relevant issues on such therapy are still debated. Definition of new indications (e.g., postoperative disease recurrence in CD) and end points (e.g., radiological healing and blockade of intestinal damage) have recently emerged. Moreover, the anti-TNF therapy pharmacokinetics and the possibility of withdraw therapy in selected cases are still debated topics. In this review, we aimed to focus in the recent data concerning the progress of anti-TNF therapy for IBD management.
Anti-TNF therapy
Immunosuppresants
5-ASA
Oral and topical steroids for flares
Figure 1. Conventional step-up approach for inflammatory bowel disease treatment. 5-ASA: 5-aminosalicylic acid; TNF: Tumor necrosis factor.
golimumab are monoclonal antibodies that selectively block TNF-α. Thalidomide, an immunosuppressant agent with anti-TNF properties [8] , has also been evaluated for the management of refractory CD with promising results [9,10] . Nevertheless, considering its potential toxicity [8] and the lack of strong data, it should only be considered in selected cases. Data about the efficacy of thalidomide in UC are still scarce [11] . Anti-TNF therapy is a valid therapeutic option in IBD management, mainly for moderate-to-severe
Mucosal healing Mucosal healing is an important and objective end point in IBD [16] . Nevertheless, an accurate and consensual definition of mucosal healing is still lacking, especially in UC. The absence of mucosal ulceration in CD and the absence of friability, erosions or ulcerations in UC are acceptable definitions [17,18] . Up to current, mucosal healing can be quantified using different scores, most commonly by Crohn’s Disease Endoscopic Index of Severity (CDEIS) [19] and Simple Endoscopic Score for Crohn’s Disease (SES-CD) [20] in CD and Mayo endoscopic subscore [21] and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) [22] for UC. Deep remission consists in mucosal healing without any concomitant clinical symptoms [23] . Histological remission is not always predictable by endoscopy and its significance as a target is still an issue [16] . However, UC patients in deep remission with histological activity have an increased risk of disease flare and colorectal cancer comparing to patients without histological activity [24] . These definitions are still evolving and further studies are needed until a definitive consensus is reached.
Table 1. Anti-tumor necrosis factor molecules currently available for the management of inflammatory bowel disease.
Infliximab
Adalimumab
Certolizumab pegol
Golimumab
Thalidomide
Structure
Chimeric IgG1
Human IgG1
Humanized IgG4
Human IgG1
(RS)-2–2(2,6dioxopiperidin-3yl)-1H-isoindole1,3(2H)-dione
Administration Intravenous route
Subcutaneous
Subcutaneous
Subcutaneous
Oral
Standard dose
Induction: 5 mg/kg at 0, 2 and 6 weeks Maintenance: 5 mg/kg every 8 weeks
Induction: 160 mg at week 0, 80 mg at week 2 Maintenance: 40 mg every 2 weeks
Induction: 400 mg 50–100 mg at 0, 2 and 4 weeks monthly depending Maintenance: 400 on body weight mg every 4 weeks
Not defined
Indications for IBD
CD and UC
CD and UC
CD
CD and UC
UC
CD: Crohn’s disease; UC: Ulcerative colitis.
176
Immunotherapy (2015) 7(2)
future science group
Progress with anti-TNF therapeutics for the treatment of inflammatory bowel disease
Mucosal healing predicts positive outcomes in IBD. It is associated with a lower relapse rate, hospitalization rate and need for surgery in CD and UC. It is also related to less bowel damage and lower relapse rate after anti-TNF therapy withdrawal in CD patients. In UC it predicts a lower risk of colorectal cancer [16] . These data highlight the relevance of mucosal healing in IBD management. Mucosal healing with non anti-TNF agents
Although 5-aminosalicylic acid (5-ASA) appears to have no effect in mucosal healing in CD patients, its effect in UC is well described. UC patients treated with oral 5-ASA and rectal 5-ASA have an overall mucosal healing of 36.9 and 50.3%, respectively [25] . As described for 5-ASA, steroids have different efficacy on mucosal healing in CD and UC patients. Modigliani et al. evaluated steroids ability to achieve mucosal healing in CD patients with active colonic and ileocolonic disease. Prednisolone 1 mg/kg/day was given until clinical remission or at most during 7 weeks. Endoscopic remission was achieved in only 29% of the patients. Steroids seem to be slightly more effective (30–35%) on mucosal healing in UC patients [26,27] . Azathioprine is able to induce mucosal healing in CD. Nevertheless, data are not unequivocal and rates vary from 16 to 70% [28,29] . In UC, azathioprine achieved mucosal healing in 55% of the patients [30] . No strong data about methotrexate on mucosal healing are available. Mucosal healing with anti-TNF agents Crohn’s disease
There is clear evidence that anti-TNFs are able to induce rapid and sustained mucosal healing in CD (Table 2) . Firstly, D’Haens et al. conducted a multicenter, randomized, double-blinded and placebocontrolled trial evaluating endoscopic and histological response after one infusion of IFX with three different doses (5, 10 and 20 mg/kg). Endoscopic evaluation according to CDEIS [19] and histological evaluation according to a specific histological score for CD [31] . Patients receiving IFX improved significantly their CDEIS (13.0 ± 7.1 to 5.3 ± 4.4, p
