The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Tumor Necrosis Factor Inhibitors for Inflammatory Bowel Disease To the Editor: Nielsen and Ainsworth (Aug. 22 issue)1 state that etanercept is not effective in the treatment of inflammatory bowel disease because it may lack the capacity to induce mucosal T-cell apoptosis in the way that antibodybased tumor necrosis factor (TNF) inhibitors do. Infliximab and adalimumab induce apoptosis of activated monocytes.2 Certolizumab pegol does not induce apoptosis of T cells or monocytes3 but is effective in Crohn’s disease. Furthermore, several studies have shown that etanercept, like adalimumab and infliximab, can induce apoptosis.4 These observations indicate that additional modes of action are involved in the efficacy of TNF inhibitors in inflammatory bowel disease. Despite widespread use of these therapies in patients with this disease, their precise mechanism of action remains unclear, although several different mechanisms have been proposed. Recently, a new mechanism of action of infliximab and certolizumab pegol was identified; it involved the modulation of nonapoptotic pathways through down-regulation of proinflammatory growth differentiation factor 1 (GDF-1).5 These effects require further investigation in vivo. Laurent Peyrin-Biroulet, M.D., Ph.D. INSERM Unité 954 Vandoeuvre-lès-Nancy, France [email protected] Dr. Peyrin-Biroulet reports receiving consulting and lecture fees from Merck and AbbVie and consulting fees from UCB Pharma. No other potential conflict of interest relevant to this letter was reported. 1. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibi-
tors for inflammatory bowel disease. N Engl J Med 2013;369:75462. 2. Shen C, Assche GV, Colpaert S, et al. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 2005;21:251-8. 3. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis 2007;13:1323-32.
4. Coury F, Ferraro-Peyret C, Le Cam S, et al. Peripheral blood
lymphocytes from patients with rheumatoid arthritis are differentially sensitive to apoptosis induced by anti-tumour necrosis factor-alpha therapy. Clin Exp Rheumatol 2008;26:234-9. 5. Derer S, Till A, Haesler R, et al. mTNF reverse signalling induced by TNFα antagonists involves a GDF-1 dependent pathway: implications for Crohn’s disease. Gut 2013;62:376-86. DOI: 10.1056/NEJMc1312800
The Author and a Colleague Reply: The mechanism of clinical efficacy of TNF-α inhibitors is unknown. One proposed mechanism is apoptosis. However, etanercept triggers apoptosis in a fashion similar to that of infliximab and adalimumab1; moreover, certolizumab pegol is beneficial in Crohn’s disease without inducing apoptosis. Thus, the efficacy of TNF inhibitors might be mediated by apoptosis-independent mechanisms. A rationale for modulation of a nonapoptotic pathway through GDF-1 has been suggested.2 The inefficacy of etanercept in inflammatory bowel disease might also be a consequence of the fact that neutralization of soluble TNF is not crucial in controlling inflammation in patients with this disease, whereas in rheumatoid arthritis, neutralization of soluble TNF is efficient in reducing joint inflammation.3 Apart from differences in the pathogenesis of these diseases, there are also differences in the functional properties of TNF inhibitors, since etanercept binds with less avidity to transmembrane TNF than other TNF inhibitors.4 Other modes of action of TNF this week’s letters 2561 Tumor Necrosis Factor Inhibitors for Inflammatory Bowel Disease 2562 Noncommunicable Diseases 2563 Cochlear Implants 2564 A Recombinant Viruslike Particle Influenza A (H7N9) Vaccine
n engl j med 369;26 nejm.org december 26, 2013
The New England Journal of Medicine Downloaded from nejm.org at PRINCETON UNIVERSITY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2561
The
n e w e ng l a n d j o u r na l
inhibitors have been proposed, including transmembrane-mediated reverse signaling, down-regulation of proinflammatory cytokines, complement-mediated cytotoxicity, and activation of regulatory immune cells.5 Altogether, the underlying modes of action of TNF inhibitors are more complex than initially hypothesized. Mehmet Coskun, Ph.D. Ole Haagen Nielsen, M.D., D.M.Sc. Herlev Hospital Copenhagen, Denmark [email protected] Dr. Coskun reports no potential conflict of interest relevant to this letter. Since publication of his article, Dr. Nielsen reports no further potential conflict of interest.
of
m e dic i n e
1. Coury F, Ferraro-Peyret C, Le Cam S, et al. Peripheral blood
lymphocytes from patients with rheumatoid arthritis are differentially sensitive to apoptosis induced by anti-tumour necrosis factor-alpha therapy. Clin Exp Rheumatol 2008;26:234-9. 2. Derer S, Till A, Haesler R, et al. mTNF reverse signalling induced by TNFα antagonists involves a GDF-1 dependent pathway: implications for Crohn’s disease. Gut 2013;62:376-86. 3. Perrier C, de Hertogh G, Cremer J, et al. Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis. Inflamm Bowel Dis 2013;19:246-53. 4. Vos AC, Wildenberg ME, Duijvestein M, Verhaar AP, van den Brink GR, Hommes DW. Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 2011;140:221-30. 5. Peake ST, Bernardo D, Mann ER, Al-Hassi HO, Knight SC, Hart AL. Mechanisms of action of anti-tumor necrosis factor α agents in Crohn’s disease. Inflamm Bowel Dis 2013;19:1546-55. DOI: 10.1056/NEJMc1312800
Noncommunicable Diseases To the Editor: Hunter and Reddy (Oct. 3 issue)1 outline issues associated with the changing global burden of noncommunicable diseases. The strategies for prevention and control touch on multiple sectors. However, the article does not give a clear sense of what might be most urgent in addressing the problem. This question would be especially relevant for low-income countries that are best served by prioritized utilization of their scarce resources. I would argue that the development of health care facilities that are capable of dealing with noncommunicable diseases should be central to the efforts aimed at addressing these diseases in the developing world. Although evidence of the effectiveness of preventive strategies directed at selected risk factors is quite promising,2 low-income countries will very likely face challenges in their implementation.3 This means that clinical diseases will require care. I am a clinician working in a low-income country with a health care setup that is utterly incapable of caring for patients with chronic illnesses who require screenings, long-term followup, laboratory support, and affordable medications. Effective communication between patients and health care workers is also limited in this clinical setting. I consider the development of health care facilities to be an urgent matter even in my current everyday clinical practice. Subarna M. Dhital, M.D. Biomed Diabetes and Endocrinology Center Kathmandu, Nepal [email protected] No potential conflict of interest relevant to this letter was reported.
2562
1. Hunter DJ, Reddy KS. Noncommunicable diseases. N Engl J
Med 2013;369:1336-43.
2. Capewell S, O’Flaherty M. Rapid mortality falls after risk-
factor changes in populations. Lancet 2011;378:752-3.
3. Justice J. Policies, plans and people: culture and health de-
velopment in Nepal. Berkeley: University of California Press, 1986. DOI: 10.1056/NEJMc1313604
To the Editor: Hunter and Reddy discuss succinctly the importance of noncommunicable diseases in developing countries. International initiatives such as those related to maternal and child deaths, infectious diseases, and the distribution of antiretroviral drugs have turned Africans who once would have died in the villages into patients who are now considered to have potentially curable diseases. Nowadays, mothers do not have “pure” peripartum sepsis, but rather sepsis with human immunodeficiency virus infection and concomitant tuberculosis. Because of well-funded public health programs, more patients require intensive care unit (ICU) services for such conditions, but providers of anesthesia and intensive care do not receive funding from these international programs. The “25 by 25” initiative and the incorporation of noncommunicable diseases into the post2015 Sustainable Development Goals will increase pressure on these ICUs because many cardiovascular and respiratory diseases are not really treatable in a typical African ward. The ongoing fight against communicable diseases and the future one against noncommunicable diseases are jeopardized if there is no
n engl j med 369;26 nejm.org december 26, 2013
The New England Journal of Medicine Downloaded from nejm.org at PRINCETON UNIVERSITY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Tumor Necrosis Factor Inhibitors for Inflammatory Bowel Disease To the Editor: Nielsen and Ainsworth (Aug. 22 issue)1 state that etanercept is not effective in the treatment of inflammatory bowel disease because it may lack the capacity to induce mucosal T-cell apoptosis in the way that antibodybased tumor necrosis factor (TNF) inhibitors do. Infliximab and adalimumab induce apoptosis of activated monocytes.2 Certolizumab pegol does not induce apoptosis of T cells or monocytes3 but is effective in Crohn’s disease. Furthermore, several studies have shown that etanercept, like adalimumab and infliximab, can induce apoptosis.4 These observations indicate that additional modes of action are involved in the efficacy of TNF inhibitors in inflammatory bowel disease. Despite widespread use of these therapies in patients with this disease, their precise mechanism of action remains unclear, although several different mechanisms have been proposed. Recently, a new mechanism of action of infliximab and certolizumab pegol was identified; it involved the modulation of nonapoptotic pathways through down-regulation of proinflammatory growth differentiation factor 1 (GDF-1).5 These effects require further investigation in vivo. Laurent Peyrin-Biroulet, M.D., Ph.D. INSERM Unité 954 Vandoeuvre-lès-Nancy, France [email protected] Dr. Peyrin-Biroulet reports receiving consulting and lecture fees from Merck and AbbVie and consulting fees from UCB Pharma. No other potential conflict of interest relevant to this letter was reported. 1. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibi-
tors for inflammatory bowel disease. N Engl J Med 2013;369:75462. 2. Shen C, Assche GV, Colpaert S, et al. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 2005;21:251-8. 3. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis 2007;13:1323-32.
4. Coury F, Ferraro-Peyret C, Le Cam S, et al. Peripheral blood
lymphocytes from patients with rheumatoid arthritis are differentially sensitive to apoptosis induced by anti-tumour necrosis factor-alpha therapy. Clin Exp Rheumatol 2008;26:234-9. 5. Derer S, Till A, Haesler R, et al. mTNF reverse signalling induced by TNFα antagonists involves a GDF-1 dependent pathway: implications for Crohn’s disease. Gut 2013;62:376-86. DOI: 10.1056/NEJMc1312800
The Author and a Colleague Reply: The mechanism of clinical efficacy of TNF-α inhibitors is unknown. One proposed mechanism is apoptosis. However, etanercept triggers apoptosis in a fashion similar to that of infliximab and adalimumab1; moreover, certolizumab pegol is beneficial in Crohn’s disease without inducing apoptosis. Thus, the efficacy of TNF inhibitors might be mediated by apoptosis-independent mechanisms. A rationale for modulation of a nonapoptotic pathway through GDF-1 has been suggested.2 The inefficacy of etanercept in inflammatory bowel disease might also be a consequence of the fact that neutralization of soluble TNF is not crucial in controlling inflammation in patients with this disease, whereas in rheumatoid arthritis, neutralization of soluble TNF is efficient in reducing joint inflammation.3 Apart from differences in the pathogenesis of these diseases, there are also differences in the functional properties of TNF inhibitors, since etanercept binds with less avidity to transmembrane TNF than other TNF inhibitors.4 Other modes of action of TNF this week’s letters 2561 Tumor Necrosis Factor Inhibitors for Inflammatory Bowel Disease 2562 Noncommunicable Diseases 2563 Cochlear Implants 2564 A Recombinant Viruslike Particle Influenza A (H7N9) Vaccine
n engl j med 369;26 nejm.org december 26, 2013
The New England Journal of Medicine Downloaded from nejm.org at PRINCETON UNIVERSITY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2561
The
n e w e ng l a n d j o u r na l
inhibitors have been proposed, including transmembrane-mediated reverse signaling, down-regulation of proinflammatory cytokines, complement-mediated cytotoxicity, and activation of regulatory immune cells.5 Altogether, the underlying modes of action of TNF inhibitors are more complex than initially hypothesized. Mehmet Coskun, Ph.D. Ole Haagen Nielsen, M.D., D.M.Sc. Herlev Hospital Copenhagen, Denmark [email protected] Dr. Coskun reports no potential conflict of interest relevant to this letter. Since publication of his article, Dr. Nielsen reports no further potential conflict of interest.
of
m e dic i n e
1. Coury F, Ferraro-Peyret C, Le Cam S, et al. Peripheral blood
lymphocytes from patients with rheumatoid arthritis are differentially sensitive to apoptosis induced by anti-tumour necrosis factor-alpha therapy. Clin Exp Rheumatol 2008;26:234-9. 2. Derer S, Till A, Haesler R, et al. mTNF reverse signalling induced by TNFα antagonists involves a GDF-1 dependent pathway: implications for Crohn’s disease. Gut 2013;62:376-86. 3. Perrier C, de Hertogh G, Cremer J, et al. Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis. Inflamm Bowel Dis 2013;19:246-53. 4. Vos AC, Wildenberg ME, Duijvestein M, Verhaar AP, van den Brink GR, Hommes DW. Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 2011;140:221-30. 5. Peake ST, Bernardo D, Mann ER, Al-Hassi HO, Knight SC, Hart AL. Mechanisms of action of anti-tumor necrosis factor α agents in Crohn’s disease. Inflamm Bowel Dis 2013;19:1546-55. DOI: 10.1056/NEJMc1312800
Noncommunicable Diseases To the Editor: Hunter and Reddy (Oct. 3 issue)1 outline issues associated with the changing global burden of noncommunicable diseases. The strategies for prevention and control touch on multiple sectors. However, the article does not give a clear sense of what might be most urgent in addressing the problem. This question would be especially relevant for low-income countries that are best served by prioritized utilization of their scarce resources. I would argue that the development of health care facilities that are capable of dealing with noncommunicable diseases should be central to the efforts aimed at addressing these diseases in the developing world. Although evidence of the effectiveness of preventive strategies directed at selected risk factors is quite promising,2 low-income countries will very likely face challenges in their implementation.3 This means that clinical diseases will require care. I am a clinician working in a low-income country with a health care setup that is utterly incapable of caring for patients with chronic illnesses who require screenings, long-term followup, laboratory support, and affordable medications. Effective communication between patients and health care workers is also limited in this clinical setting. I consider the development of health care facilities to be an urgent matter even in my current everyday clinical practice. Subarna M. Dhital, M.D. Biomed Diabetes and Endocrinology Center Kathmandu, Nepal [email protected] No potential conflict of interest relevant to this letter was reported.
2562
1. Hunter DJ, Reddy KS. Noncommunicable diseases. N Engl J
Med 2013;369:1336-43.
2. Capewell S, O’Flaherty M. Rapid mortality falls after risk-
factor changes in populations. Lancet 2011;378:752-3.
3. Justice J. Policies, plans and people: culture and health de-
velopment in Nepal. Berkeley: University of California Press, 1986. DOI: 10.1056/NEJMc1313604
To the Editor: Hunter and Reddy discuss succinctly the importance of noncommunicable diseases in developing countries. International initiatives such as those related to maternal and child deaths, infectious diseases, and the distribution of antiretroviral drugs have turned Africans who once would have died in the villages into patients who are now considered to have potentially curable diseases. Nowadays, mothers do not have “pure” peripartum sepsis, but rather sepsis with human immunodeficiency virus infection and concomitant tuberculosis. Because of well-funded public health programs, more patients require intensive care unit (ICU) services for such conditions, but providers of anesthesia and intensive care do not receive funding from these international programs. The “25 by 25” initiative and the incorporation of noncommunicable diseases into the post2015 Sustainable Development Goals will increase pressure on these ICUs because many cardiovascular and respiratory diseases are not really treatable in a typical African ward. The ongoing fight against communicable diseases and the future one against noncommunicable diseases are jeopardized if there is no
n engl j med 369;26 nejm.org december 26, 2013
The New England Journal of Medicine Downloaded from nejm.org at PRINCETON UNIVERSITY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
