Annals of Internal Medicine
Editorial
Which Biological Agents Are Most Appropriate for Ulcerative Colitis?
U
lcerative colitis (UC) is the most prevalent inflammatory bowel disease, and its global incidence and prevalence is increasing (1). The classic standard treatment options consisted of 5-aminosalicylic acids, glucocorticoids, and immunomodulators (thiopurines and cyclosporine) for decades. Huge advances have been made recently because detailed insights into the immune system response in this disease have led to the development of artificially synthesized monoclonal antibodies that block key mediators of inflammation (such as tumor necrosis factor-␣), including infliximab, adalimumab, and golimumab (2), as well as integrins, including vedolizumab, which selectively block the ␣47/mucosal addressin cell adhesion molecule–1 (3–5). With the emergence of more and more biological agents, gastroenterologists are faced with the difficult task of deciding if and when biological treatment is needed and, if indicated, choosing the most appropriate biological product for UC. In this issue, Danese and colleagues’ comprehensive systematic review and network meta-analysis of the available biological options for treatment of moderate to severe UC in adults offers help to clinicians faced with this difficult problem because it thoroughly discusses the available randomized, controlled trials (6). Treatment of UC is sequential and should be tailored to the individual patient without any single universally effective medication, although 5-aminosalicylic acid is considered a keystone (7). In the wake of the introduction of biological therapies, many publications have focused on the optimization of conventional treatment (that is, glucocorticoids and thiopurines), but in general, biological agents are perceived by most clinicians as second-line therapeutic options when other therapies have not succeeded, mainly because of their costs and side effects. Biological agents are administered in 2 phases: an induction phase associated with more frequent and generally greater doses intended to induce remission or response and a maintenance phase associated with less frequent dosing intended to sustain any response achieved during induction. The presented meta-analysis of induction studies revealed that all agents were superior to placebo, and for maintenance therapy, synthesis of the available studies demonstrated that all biological agents also had greater efficacy than placebo. Infliximab has been shown to be the best induction therapy to obtain a clinical response, followed by vedolizumab, golimumab, and adalimumab (6). However, for maintenance therapy, the design of studies hampered the analysis because in trials with vedolizumab and golimumab exclusively, persons who responded to induction were eligible for continued (maintenance) therapy and were reassigned when entering the maintenance study. Hence, because persons who responded to induction were more likely to achieve a positive clinical outcome in the long term than those who did not respond, no indirect
effect estimates among the drugs were done. Moreover, the meta-analysis revealed that the occurrence of adverse events did not differ between the biological agents and placebo. Although the meta-analysis provides an excellent overview of the available data on the efficacy and safety of the biological treatment options for UC, including fairly accurate estimates of treatment effect size, clinicians are still left with a difficult task when choosing the best treatment option for each patient. Thus, despite the admirable efforts of the authors and the state-of-the-art method applied, the conclusions about comparative efficacy of the biological agents are hampered, as pointed out by the authors (6), by a lack of studies directly comparing the efficacy and safety of 2 or more of these agents. Despite every possible effort, study populations may not be directly comparable across different studies, leaving the authors as well as clinicians with a fundamental question: Is the observed difference related to the specific drugs or to differences in the study populations? In lieu of these data, clinicians will have to take other considerations into account when deciding which biological agent to choose for individual patients. Because the drugs do not seem to differ in terms of safety, such factors as patient convenience may play a role, favoring agents that can be administered by the patient and thus decreasing the need for regular outpatient contacts. Both the network meta-analysis and primary studies reduce uncertainties or provide answers to questions about choosing the most appropriate biological treatment of UC. However, we are still faced with the fundamental issue of when to initiate or not initiate treatment. Thus, current clinical practice and labeling recommend the use of biological agents only in the face of intolerance or lack of effect of standard treatment. However, this recommendation may change in the future, with a call for earlier introduction of biological treatment, because of what happened for certain subgroups of patients with Crohn disease (8). Introduction of still more medical treatment options hopefully will reduce the need for colectomy, but clinicians must not be tempted to keep trying yet another medical treatment for patients with a severe flare of UC who need surgery because this may increase morbidity and mortality rates. Strategies for handling unsuccessful biological treatment (such as primary nonresponse, secondary loss of response, or secondary–primary nonresponse—that is, unsuccessful reintroduction in a patient previously exposed to the drug) are also needed (9). Although immunogenicity has emerged as an important mechanism driving secondary loss of response in a subset of patients, other mechanisms also may play a role, suggesting that an individualized approach should be adopted in diagnosing and identifying the pathogenesis of loss of response in patients. Prediction, prevention, and interventions may need to be tailored separately to primary nonresponse, secondary loss of response, © 2014 American College of Physicians 733
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a Universite Laval Biblioteque User on 07/28/2017
Editorial
Which Biological Agents Are Most Appropriate for Ulcerative Colitis?
or unsuccessful reinduction (10). In addition, unnecessary continuation of biological therapy may be considered a specific type of treatment shortcoming in a broad sense because it may severely impede patients’ quality of life and impose risk for adverse effects without any clinical justification. Comparative data on the effectiveness and safety of biological agents are extremely useful in clinical decision making for gastroenterologists. This systematic review (6) may assist providers in communicating benefits and risks to patients in addition to offering the appropriate therapy at an early stage. However, even though this comprehensive meta-analysis (6) provides the best available data on treatment of UC with biological agents, direct head-to-head comparisons between biological agents done in real-world settings are still lacking. Ole Haagen Nielsen, MD, DMSc Mark Andrew Ainsworth, MD, PhD, DMSc Herlev Hospital and University of Copenhagen Copenhagen, Denmark Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M14-0605. Requests for Single Reprints: Ole Haagen Nielsen, MD, DMSc,
Department of Gastroenterology, Medical Section D112M, Herlev Hospital, 75 Herlev Ringvej, DK-2730 Herlev, Denmark. Current author addresses are available at www.annals.org. Ann Intern Med. 2014;160:733-734.
References 1. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46-54.e42. [PMID: 22001864] 2. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med. 2013;369:754-62. [PMID: 23964937] 3. D’Haens G, Vermeire S, Cataldi F, Vogelsang H, Allez M, Desreumaux P, et al. Anti-MAdCAM monoclonal antibody PF-005476659 does not affect immune surveillance in the central nervous system of anti-TNF and immunosuppressant experienced Crohn’s disease patients who are anti-TNF inadequate responders: results from the TOSCA study [Abstract]. J Crohns Colitis. 2014; 8(Suppl 1):S4-5. 4. Rutgeerts PJ, Fedorak RN, Hommes DW, Sturm A, Baumgart DC, Bressler B, et al. A randomised phase I study of etrolizumab (rhuMAb 7) in moderate to severe ulcerative colitis. Gut. 2013;62:1122-30. [PMID: 22717454] 5. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864-75. [PMID: 19509315] 6. Danese S, Fiorino G, Peyrin-Biroulet L, Lucenteforte E, Virgili G, Moja L, et al. Biological agents for moderately to severely active ulcerative colitis. A systematic review and network meta-analysis. Ann Intern Med. 2014;160: 704-11. 7. Nielsen OH, Munck LK. Drug insight: aminosalicylates for the treatment of IBD. Nat Clin Pract Gastroenterol Hepatol. 2007;4:160-70. [PMID: 17339853] 8. Peyrin-Biroulet L, Fiorino G, Buisson A, Danese S. First-line therapy in adult Crohn’s disease: who should receive anti-TNF agents? Nat Rev Gastroenterol Hepatol. 2013;10:345-51. [PMID: 23458890] 9. Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014;11:243-55. [PMID: 24393836] 10. Steenholdt C, Brynskov J, Thomsen OO, Munck LK, Fallingborg J, Christensen LA, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2013. [PMID: 23878167]
734 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a Universite Laval Biblioteque User on 07/28/2017
www.annals.org
Annals of Internal Medicine Current Author Addresses: Drs. Nielsen and Ainsworth: Department of
Gastroenterology, Medical Section D112M, Herlev Hospital, 75 Herlev Ringvej, DK-2730 Herlev, Denmark.
www.annals.org
20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a Universite Laval Biblioteque User on 07/28/2017
Editorial
Which Biological Agents Are Most Appropriate for Ulcerative Colitis?
U
lcerative colitis (UC) is the most prevalent inflammatory bowel disease, and its global incidence and prevalence is increasing (1). The classic standard treatment options consisted of 5-aminosalicylic acids, glucocorticoids, and immunomodulators (thiopurines and cyclosporine) for decades. Huge advances have been made recently because detailed insights into the immune system response in this disease have led to the development of artificially synthesized monoclonal antibodies that block key mediators of inflammation (such as tumor necrosis factor-␣), including infliximab, adalimumab, and golimumab (2), as well as integrins, including vedolizumab, which selectively block the ␣47/mucosal addressin cell adhesion molecule–1 (3–5). With the emergence of more and more biological agents, gastroenterologists are faced with the difficult task of deciding if and when biological treatment is needed and, if indicated, choosing the most appropriate biological product for UC. In this issue, Danese and colleagues’ comprehensive systematic review and network meta-analysis of the available biological options for treatment of moderate to severe UC in adults offers help to clinicians faced with this difficult problem because it thoroughly discusses the available randomized, controlled trials (6). Treatment of UC is sequential and should be tailored to the individual patient without any single universally effective medication, although 5-aminosalicylic acid is considered a keystone (7). In the wake of the introduction of biological therapies, many publications have focused on the optimization of conventional treatment (that is, glucocorticoids and thiopurines), but in general, biological agents are perceived by most clinicians as second-line therapeutic options when other therapies have not succeeded, mainly because of their costs and side effects. Biological agents are administered in 2 phases: an induction phase associated with more frequent and generally greater doses intended to induce remission or response and a maintenance phase associated with less frequent dosing intended to sustain any response achieved during induction. The presented meta-analysis of induction studies revealed that all agents were superior to placebo, and for maintenance therapy, synthesis of the available studies demonstrated that all biological agents also had greater efficacy than placebo. Infliximab has been shown to be the best induction therapy to obtain a clinical response, followed by vedolizumab, golimumab, and adalimumab (6). However, for maintenance therapy, the design of studies hampered the analysis because in trials with vedolizumab and golimumab exclusively, persons who responded to induction were eligible for continued (maintenance) therapy and were reassigned when entering the maintenance study. Hence, because persons who responded to induction were more likely to achieve a positive clinical outcome in the long term than those who did not respond, no indirect
effect estimates among the drugs were done. Moreover, the meta-analysis revealed that the occurrence of adverse events did not differ between the biological agents and placebo. Although the meta-analysis provides an excellent overview of the available data on the efficacy and safety of the biological treatment options for UC, including fairly accurate estimates of treatment effect size, clinicians are still left with a difficult task when choosing the best treatment option for each patient. Thus, despite the admirable efforts of the authors and the state-of-the-art method applied, the conclusions about comparative efficacy of the biological agents are hampered, as pointed out by the authors (6), by a lack of studies directly comparing the efficacy and safety of 2 or more of these agents. Despite every possible effort, study populations may not be directly comparable across different studies, leaving the authors as well as clinicians with a fundamental question: Is the observed difference related to the specific drugs or to differences in the study populations? In lieu of these data, clinicians will have to take other considerations into account when deciding which biological agent to choose for individual patients. Because the drugs do not seem to differ in terms of safety, such factors as patient convenience may play a role, favoring agents that can be administered by the patient and thus decreasing the need for regular outpatient contacts. Both the network meta-analysis and primary studies reduce uncertainties or provide answers to questions about choosing the most appropriate biological treatment of UC. However, we are still faced with the fundamental issue of when to initiate or not initiate treatment. Thus, current clinical practice and labeling recommend the use of biological agents only in the face of intolerance or lack of effect of standard treatment. However, this recommendation may change in the future, with a call for earlier introduction of biological treatment, because of what happened for certain subgroups of patients with Crohn disease (8). Introduction of still more medical treatment options hopefully will reduce the need for colectomy, but clinicians must not be tempted to keep trying yet another medical treatment for patients with a severe flare of UC who need surgery because this may increase morbidity and mortality rates. Strategies for handling unsuccessful biological treatment (such as primary nonresponse, secondary loss of response, or secondary–primary nonresponse—that is, unsuccessful reintroduction in a patient previously exposed to the drug) are also needed (9). Although immunogenicity has emerged as an important mechanism driving secondary loss of response in a subset of patients, other mechanisms also may play a role, suggesting that an individualized approach should be adopted in diagnosing and identifying the pathogenesis of loss of response in patients. Prediction, prevention, and interventions may need to be tailored separately to primary nonresponse, secondary loss of response, © 2014 American College of Physicians 733
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a Universite Laval Biblioteque User on 07/28/2017
Editorial
Which Biological Agents Are Most Appropriate for Ulcerative Colitis?
or unsuccessful reinduction (10). In addition, unnecessary continuation of biological therapy may be considered a specific type of treatment shortcoming in a broad sense because it may severely impede patients’ quality of life and impose risk for adverse effects without any clinical justification. Comparative data on the effectiveness and safety of biological agents are extremely useful in clinical decision making for gastroenterologists. This systematic review (6) may assist providers in communicating benefits and risks to patients in addition to offering the appropriate therapy at an early stage. However, even though this comprehensive meta-analysis (6) provides the best available data on treatment of UC with biological agents, direct head-to-head comparisons between biological agents done in real-world settings are still lacking. Ole Haagen Nielsen, MD, DMSc Mark Andrew Ainsworth, MD, PhD, DMSc Herlev Hospital and University of Copenhagen Copenhagen, Denmark Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M14-0605. Requests for Single Reprints: Ole Haagen Nielsen, MD, DMSc,
Department of Gastroenterology, Medical Section D112M, Herlev Hospital, 75 Herlev Ringvej, DK-2730 Herlev, Denmark. Current author addresses are available at www.annals.org. Ann Intern Med. 2014;160:733-734.
References 1. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46-54.e42. [PMID: 22001864] 2. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med. 2013;369:754-62. [PMID: 23964937] 3. D’Haens G, Vermeire S, Cataldi F, Vogelsang H, Allez M, Desreumaux P, et al. Anti-MAdCAM monoclonal antibody PF-005476659 does not affect immune surveillance in the central nervous system of anti-TNF and immunosuppressant experienced Crohn’s disease patients who are anti-TNF inadequate responders: results from the TOSCA study [Abstract]. J Crohns Colitis. 2014; 8(Suppl 1):S4-5. 4. Rutgeerts PJ, Fedorak RN, Hommes DW, Sturm A, Baumgart DC, Bressler B, et al. A randomised phase I study of etrolizumab (rhuMAb 7) in moderate to severe ulcerative colitis. Gut. 2013;62:1122-30. [PMID: 22717454] 5. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864-75. [PMID: 19509315] 6. Danese S, Fiorino G, Peyrin-Biroulet L, Lucenteforte E, Virgili G, Moja L, et al. Biological agents for moderately to severely active ulcerative colitis. A systematic review and network meta-analysis. Ann Intern Med. 2014;160: 704-11. 7. Nielsen OH, Munck LK. Drug insight: aminosalicylates for the treatment of IBD. Nat Clin Pract Gastroenterol Hepatol. 2007;4:160-70. [PMID: 17339853] 8. Peyrin-Biroulet L, Fiorino G, Buisson A, Danese S. First-line therapy in adult Crohn’s disease: who should receive anti-TNF agents? Nat Rev Gastroenterol Hepatol. 2013;10:345-51. [PMID: 23458890] 9. Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014;11:243-55. [PMID: 24393836] 10. Steenholdt C, Brynskov J, Thomsen OO, Munck LK, Fallingborg J, Christensen LA, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2013. [PMID: 23878167]
734 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a Universite Laval Biblioteque User on 07/28/2017
www.annals.org
Annals of Internal Medicine Current Author Addresses: Drs. Nielsen and Ainsworth: Department of
Gastroenterology, Medical Section D112M, Herlev Hospital, 75 Herlev Ringvej, DK-2730 Herlev, Denmark.
www.annals.org
20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a Universite Laval Biblioteque User on 07/28/2017
