Alimentary Pharmacology and Therapeutics
Invited Editorials Editorial: is thalidomide a good option for patients with refractory Crohn’s disease? G. Rogler Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland. E-mail: [email protected] doi:10.1111/apt.13106
The history of thalidomide is inevitably connected with its serious teratogenicity. In recent years, however, its beneficial biological activities have led to a renaissance of its use.1 Thalidomide has an inhibitory activity against tumour necrosis factor-a (TNF-a), known to play an important pathophysiological role in Crohn’s disease (CD). In 1998, the FDA re-approved thalidomide for erythema nodosum leprosum (ENL) and recently for multiple myeloma.2 As thalidomide targets TNF and there are refractory CD patients in need of additional treatments thalidomide has been introduced in CD treatment and several reports have been published recently.3–6 Gerich and colleagues report on the outcome of 37 patients with refractory CD from a single-centre, retrospective, observational cohort from the Cedars-Sinai Medical Center.7 The patients had moderate-to-severe CD that was refractory to available standard therapies.7 Thalidomide was administrated at a starting dose of 50–100 mg at night and increased to a maximum of 200 mg/day if necessary.7 A clinical response was observed in 54% and a clinical remission in 19% of patients. Given the risk of teratogenicity and the high rates of side effects these numbers are somewhat disappointing. They indicate that in each case a careful risk/benefit analysis will be necessary. In this real life open-label setting remission rates are surprisingly low, as compared with a recent RCT in paediatric patients in whom a remission rate of 46% (12% for placebo) was reported.8 During a median treatment time of 4.4 months adverse events occurred in 68% of patients and 38% experienced
neuropathy.7 The latter is quite a concerning number, given the relatively short treatment time. This leads to an important consideration: long-term treatment, at least in adult patients, is not possible due to side effects.9 So the question arises what long-term benefits the treated patients can expect. Thalidomide cannot be used as maintenance therapy based on recent reports3–6 and the present one.9 So is this a desirable perspective for patients that have chronic active CD and would require a maintenance treatment? Will patients want a treatment with a remission rate of 19% without the possibility of long-term treatment? This remains questionable.
ACKNOWLEDGEMENT Declaration of personal and funding interests: Gerhard Rogler has consulted to Abbot, Abbvie, Augurix, Boehringer, Calypso, FALK, Ferring, Fisher, Genentech, Essex/ MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller; Gerhard Rogler has received speaker's honoraria from Astra Zeneca, Abbott, Abbvie, FALK, MSD, Phadia, Tillots, UCB, and Vifor; Gerhard Rogler has received educational grants and research grants from Abbot, Abbvie, Ardeypharm, Augurix, Calypso, Essex/MSD, FALK, Flamentera, Novartis, Roche, Takeda, Tillots, UCB and Zeller. None of those have been relevant for this editorial. REFERENCES 1. Kumar S, Anderson KC. Drug insight: thalidomide as a treatment for multiple myeloma. Nature clinical practice. Oncology 2005; 2: 262–70. 2. Kumar N, Sharma U, Singh C, Singh B. Thalidomide: chemistry, therapeutic potential and oxidative stress induced teratogenicity. Curr Top Med Chem 2012; 12: 1436–55. 3. Scribano ML, Cantoro L, Marrollo M, Cosintino R, Kohn A. Mucosal healing with thalidomide in refractory Crohn’s disease patients intolerant of anti-TNF-alpha drugs: report of 3 cases and literature review. J Clin Gastroenterol 2014; 48: 530–3. 4. Zheng CF, Xu JH, Huang Y, Leung YK. Treatment of pediatric refractory Crohn’s disease with thalidomide. World J Gastroenterol 2011; 17: 1286–91. 5. Plamondon S, Ng SC, Kamm MA. Thalidomide in luminal and fistulizing Crohn’s disease resistant to standard therapies. Aliment Pharmacol Ther 2007; 25: 557–67.
AP&T invited editorial columns are restricted to discussing papers that have been published in the journal. An editorial must have a maximum of 300 words, may contain one table or figure, and should have no more than 10 references. It should be submitted electronically to the Editors via http://mc.manuscriptcentral.com/apt.
ª 2015 John Wiley & Sons Ltd
785
Invited Editorials 6. Sabate JM, Villarejo J, Lemann M, Bonnet J, Allez M, Modigliani R. An open-label study of thalidomide for maintenance therapy in responders to infliximab in chronically active and fistulizing refractory Crohn’s disease. Aliment Pharmacol Ther 2002; 16: 1117–24. 7. Gerich ME, Yoon JL, Targan SR, Ippoliti AF, Vasiliauskas EA. Long-term outcomes of thalidomide in refractory Crohn’s disease. Aliment Pharmacol Ther 2015; 41: 429–37.
8. Lazzerini M, Martelossi S, Magazzu G, et al. Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial. JAMA 2013; 310: 2164–73. 9. Akobeng AK, Stokkers PC. Thalidomide and thalidomide analogues for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2009; (2): CD007351.
Editorial: is thalidomide a good option for patients with refractory Crohn’s disease? Authors’ reply
although the median duration of response was only 5 months, 30% of responders (15% of all treated patients) maintained response out to at least 1 year. While a partial response is certainly less than ideal, it may be better than the alternatives – such as ongoing steroid use or further bowel resections. Even if benefits are temporary, thalidomide can serve as a bridge to buy needed time until other agents with potential for longterm benefit become available. So, although its long-term use is often limited by toxicity, we tend to agree with Plamondon et al. that thalidomide can serve as an effective short- to medium-term treatment in a select group of Crohn’s patients.6
M. Gerich, J. Yoon & E. Vasiliauskas Cedars Sinai Medical Center, Los Angeles, CA, USA. E-mail: [email protected] doi:10.1111/apt.13136
We would like to thank Professor Rogler for his comments regarding the results of our study and the potential for thalidomide to provide significant benefit to patients with long-standing, refractory Crohn’s disease.1 We agree that the role of thalidomide as a long-term maintenance therapy appears to be fairly limited – in large part due to adverse events, which led over onethird of responders to discontinue thalidomide in our study.2 Yet, while steroid-free clinical remission is certainly desirable for all patients, the unfortunate reality is that it is seldom achievable, even following the introduction of biologic therapies. The results of clinical trials demonstrate that the addition of anti-TNF agents, natalizumab or vedolizumab induces long-term remission in less than a third of Crohn’s patients who are treated.3–5 Despite significant therapeutic advances, this inability to achieve long-term remission remains an issue, particularly among patients with long-standing disease that have already failed one or more biological therapies, which is exactly the type of patients who opted to be treated with thalidomide in our study. Notably, however, approximately two-thirds of these refractory patients were able to reduce or discontinue steroids altogether and,
786
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Rogler G. Editorial: is thalidomide a good option for patients with refractory Crohn’s disease? Aliment Pharmacol Ther 2015; 41: 785–6. 2. Gerich ME, Yoon JL, Targan SR, Ippoliti AF, Vasiliauskas EA. Long-term outcomes of thalidomide in refractory Crohn’s disease. Aliment Pharmacol Ther 2015; 41: 429–37. 3. Peyrin-Biroulet L, Lemann M. Review article: remission rates achievable by current therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2011; 33: 870–9. 4. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005; 353: 1912–25. 5. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369: 711–21. 6. Plamondon S, Ng SC, Kamm MA. Thalidomide in luminal and fistulizing Crohn’s disease resistant to standard therapies. Aliment Pharmacol Ther 2007; 25: 557–67.
Aliment Pharmacol Ther 2015; 41: 785–788 ª 2015 John Wiley & Sons Ltd
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Invited Editorials Editorial: is thalidomide a good option for patients with refractory Crohn’s disease? G. Rogler Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland. E-mail: [email protected] doi:10.1111/apt.13106
The history of thalidomide is inevitably connected with its serious teratogenicity. In recent years, however, its beneficial biological activities have led to a renaissance of its use.1 Thalidomide has an inhibitory activity against tumour necrosis factor-a (TNF-a), known to play an important pathophysiological role in Crohn’s disease (CD). In 1998, the FDA re-approved thalidomide for erythema nodosum leprosum (ENL) and recently for multiple myeloma.2 As thalidomide targets TNF and there are refractory CD patients in need of additional treatments thalidomide has been introduced in CD treatment and several reports have been published recently.3–6 Gerich and colleagues report on the outcome of 37 patients with refractory CD from a single-centre, retrospective, observational cohort from the Cedars-Sinai Medical Center.7 The patients had moderate-to-severe CD that was refractory to available standard therapies.7 Thalidomide was administrated at a starting dose of 50–100 mg at night and increased to a maximum of 200 mg/day if necessary.7 A clinical response was observed in 54% and a clinical remission in 19% of patients. Given the risk of teratogenicity and the high rates of side effects these numbers are somewhat disappointing. They indicate that in each case a careful risk/benefit analysis will be necessary. In this real life open-label setting remission rates are surprisingly low, as compared with a recent RCT in paediatric patients in whom a remission rate of 46% (12% for placebo) was reported.8 During a median treatment time of 4.4 months adverse events occurred in 68% of patients and 38% experienced
neuropathy.7 The latter is quite a concerning number, given the relatively short treatment time. This leads to an important consideration: long-term treatment, at least in adult patients, is not possible due to side effects.9 So the question arises what long-term benefits the treated patients can expect. Thalidomide cannot be used as maintenance therapy based on recent reports3–6 and the present one.9 So is this a desirable perspective for patients that have chronic active CD and would require a maintenance treatment? Will patients want a treatment with a remission rate of 19% without the possibility of long-term treatment? This remains questionable.
ACKNOWLEDGEMENT Declaration of personal and funding interests: Gerhard Rogler has consulted to Abbot, Abbvie, Augurix, Boehringer, Calypso, FALK, Ferring, Fisher, Genentech, Essex/ MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller; Gerhard Rogler has received speaker's honoraria from Astra Zeneca, Abbott, Abbvie, FALK, MSD, Phadia, Tillots, UCB, and Vifor; Gerhard Rogler has received educational grants and research grants from Abbot, Abbvie, Ardeypharm, Augurix, Calypso, Essex/MSD, FALK, Flamentera, Novartis, Roche, Takeda, Tillots, UCB and Zeller. None of those have been relevant for this editorial. REFERENCES 1. Kumar S, Anderson KC. Drug insight: thalidomide as a treatment for multiple myeloma. Nature clinical practice. Oncology 2005; 2: 262–70. 2. Kumar N, Sharma U, Singh C, Singh B. Thalidomide: chemistry, therapeutic potential and oxidative stress induced teratogenicity. Curr Top Med Chem 2012; 12: 1436–55. 3. Scribano ML, Cantoro L, Marrollo M, Cosintino R, Kohn A. Mucosal healing with thalidomide in refractory Crohn’s disease patients intolerant of anti-TNF-alpha drugs: report of 3 cases and literature review. J Clin Gastroenterol 2014; 48: 530–3. 4. Zheng CF, Xu JH, Huang Y, Leung YK. Treatment of pediatric refractory Crohn’s disease with thalidomide. World J Gastroenterol 2011; 17: 1286–91. 5. Plamondon S, Ng SC, Kamm MA. Thalidomide in luminal and fistulizing Crohn’s disease resistant to standard therapies. Aliment Pharmacol Ther 2007; 25: 557–67.
AP&T invited editorial columns are restricted to discussing papers that have been published in the journal. An editorial must have a maximum of 300 words, may contain one table or figure, and should have no more than 10 references. It should be submitted electronically to the Editors via http://mc.manuscriptcentral.com/apt.
ª 2015 John Wiley & Sons Ltd
785
Invited Editorials 6. Sabate JM, Villarejo J, Lemann M, Bonnet J, Allez M, Modigliani R. An open-label study of thalidomide for maintenance therapy in responders to infliximab in chronically active and fistulizing refractory Crohn’s disease. Aliment Pharmacol Ther 2002; 16: 1117–24. 7. Gerich ME, Yoon JL, Targan SR, Ippoliti AF, Vasiliauskas EA. Long-term outcomes of thalidomide in refractory Crohn’s disease. Aliment Pharmacol Ther 2015; 41: 429–37.
8. Lazzerini M, Martelossi S, Magazzu G, et al. Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial. JAMA 2013; 310: 2164–73. 9. Akobeng AK, Stokkers PC. Thalidomide and thalidomide analogues for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2009; (2): CD007351.
Editorial: is thalidomide a good option for patients with refractory Crohn’s disease? Authors’ reply
although the median duration of response was only 5 months, 30% of responders (15% of all treated patients) maintained response out to at least 1 year. While a partial response is certainly less than ideal, it may be better than the alternatives – such as ongoing steroid use or further bowel resections. Even if benefits are temporary, thalidomide can serve as a bridge to buy needed time until other agents with potential for longterm benefit become available. So, although its long-term use is often limited by toxicity, we tend to agree with Plamondon et al. that thalidomide can serve as an effective short- to medium-term treatment in a select group of Crohn’s patients.6
M. Gerich, J. Yoon & E. Vasiliauskas Cedars Sinai Medical Center, Los Angeles, CA, USA. E-mail: [email protected] doi:10.1111/apt.13136
We would like to thank Professor Rogler for his comments regarding the results of our study and the potential for thalidomide to provide significant benefit to patients with long-standing, refractory Crohn’s disease.1 We agree that the role of thalidomide as a long-term maintenance therapy appears to be fairly limited – in large part due to adverse events, which led over onethird of responders to discontinue thalidomide in our study.2 Yet, while steroid-free clinical remission is certainly desirable for all patients, the unfortunate reality is that it is seldom achievable, even following the introduction of biologic therapies. The results of clinical trials demonstrate that the addition of anti-TNF agents, natalizumab or vedolizumab induces long-term remission in less than a third of Crohn’s patients who are treated.3–5 Despite significant therapeutic advances, this inability to achieve long-term remission remains an issue, particularly among patients with long-standing disease that have already failed one or more biological therapies, which is exactly the type of patients who opted to be treated with thalidomide in our study. Notably, however, approximately two-thirds of these refractory patients were able to reduce or discontinue steroids altogether and,
786
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Rogler G. Editorial: is thalidomide a good option for patients with refractory Crohn’s disease? Aliment Pharmacol Ther 2015; 41: 785–6. 2. Gerich ME, Yoon JL, Targan SR, Ippoliti AF, Vasiliauskas EA. Long-term outcomes of thalidomide in refractory Crohn’s disease. Aliment Pharmacol Ther 2015; 41: 429–37. 3. Peyrin-Biroulet L, Lemann M. Review article: remission rates achievable by current therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2011; 33: 870–9. 4. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005; 353: 1912–25. 5. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369: 711–21. 6. Plamondon S, Ng SC, Kamm MA. Thalidomide in luminal and fistulizing Crohn’s disease resistant to standard therapies. Aliment Pharmacol Ther 2007; 25: 557–67.
Aliment Pharmacol Ther 2015; 41: 785–788 ª 2015 John Wiley & Sons Ltd
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
