correspondence
In response to Baang and Fisher: results in G. Ralph Corey, M.D. patients who could be evaluated clinically were Duke University Medical Center consistent with those in the modified inten- Durham, NC [email protected] tion-to-treat population. The population of patients who could be evaluated clinically in our Hai Jiang, Ph.D. study is synonymous with the per-protocol Greg Moeck, Ph.D. population, since it consisted of all patients in The Medicines Company Parsippany, NJ the modified intention-to-treat population who Since publication of their article, the authors report no furmet the criteria for study inclusion, received the ther potential conflict of interest. full-course of study treatment, and underwent 1. European Centre for Disease Prevention and Control (ECDC). an assessment for clinical cure at the post- Antimicrobial resistance surveillance in Europe 2012: annual therapy evaluation by the site investigator, as report of the European Antimicrobial Resistance Surveillance stated in the legend to Figure 1 of our article. Network (EARS-Net). Stockholm: ECDC, 2013. 2. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi In addition, Figure 2 of our article and Tables F. Current management of patients hospitalized with compliS4, S7, and S11 in the Supplementary Appendix, cated skin and soft tissue infections across Europe (2010-2011): available at NEJM.org, are all based on the assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect population of patients who could be evaluated 2013;19(9):E377-E385. clinically. DOI: 10.1056/NEJMc1407925
Tofacitinib versus Methotrexate in Rheumatoid Arthritis To the Editor: In the article by Lee et al. (June 19 issue),1 the reported elevation in levels of serum creatinine and low-density lipoprotein (LDL) cholesterol in a proportion of patients in the tofacitinib group may be a cause for concern, given the prevalence of adverse renal and cardiovascular outcomes among patients with rheumatoid arthritis.2,3 Preliminary data suggest that the half-life of tofacitinib is prolonged in patients with impaired renal function, and if this drug simultaneously reduces renal function, it could create a self-perpetuating cycle prolonging its action.4 Apprehension regarding renal function is counterbalanced by the findings of a phase 2b study of tofacitinib involving patients undergoing renal transplantation. This study reported superior allograft function and efficacy that was similar to cyclosporine in preventing rejection of renal allografts.5 Tofacitinib also may suppress renal tubular secretion of creatinine, thus increasing serum levels without truly affecting renal function. Given the coincident increase in serum LDL cholesterol levels in these patients, one might be concerned about the possibility that tofacitinib induced or exacerbated proteinuria. Are data on urinary protein excretion available to
more fully characterize the renal implications of tofacitinib use? Donal Sexton, M.D. National University of Ireland, Galway Galway, Ireland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus
methotrexate in rheumatoid arthritis. N Engl J Med 2014;370: 2377-86. 2. Karstila K, Korpela M, Sihvonen S, Mustonen J. Prognosis of clinical renal disease and incidence of new renal findings in patients with rheumatoid arthritis: follow-up of a populationbased study. Clin Rheumatol 2007;26:2089-95. 3. del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737-45. 4. Krishnaswami S, Chow V, Boy M, Wang C, Chan G. Pharmacokinetics of tofacitinib, a Janus kinase inhibitor, in patients with impaired renal function and end-stage renal disease. J Clin Pharmacol 2014;54:46-52. 5. Vincenti F, Tedesco Silva H, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant 2012;12:2446-56. DOI: 10.1056/NEJMc1408607
To the Editor: We have major concerns about the safety of tofacitinib, which was developed as
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNL on April 7, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1163
The
n e w e ng l a n d j o u r na l
an inhibitor of the Janus kinase (JAK) pathways JAK1 and JAK3. JAK1 is critical in mediating the development of interferon-γ, which is important in tumor surveillance, and inhibition of JAK1 facilitates tumor formation.1 JAK3 exerts effects on mature lymphocytes, and inhibition of JAK3 may increase the risk of opportunistic infections.2 Serious infections and cancers may occur in patients who receive tofacitinib. Last year, tofacitinib was not approved by the European regulatory agencies because of its overall safety profile. Furthermore, the long-term safety of tofacitinib has not been thoroughly explored. In addition, Piscianz et al.3 found that treated lymphocytes resumed a striking proliferation after the withdrawal of tofacitinib, although they were inhibited during tofacitinib treatment in vitro. Tefferi and Pardanani4 at the Mayo Clinic also found the occurrence of severe withdrawal symptoms during discontinuation of treatment with ruxolitinib (another type of JAK inhibitor). So, we wonder whether the current study showed a withdrawal syndrome associated with tofacitinib. Kai Yuan, M.D. Jianxin Chen, Ph.D. Anlong Xu, Ph.D. Beijing University of Chinese Medicine Beijing, China [email protected] No potential conflict of interest relevant to this letter was reported. 1. Sexl V, Kovacic B, Piekorz R, et al. Jak1 deficiency leads to
enhanced Abelson-induced B-cell tumor formation. Blood 2003; 101:4937-43. 2. Saijo K, Park SY, Ishida Y, Arase H, Saito T. Crucial role of Jak3 in negative selection of self-reactive T cells. J Exp Med 1997; 185:351-6. 3. Piscianz E, Valencic E, Cuzzoni E, et al. Fate of lymphocytes after withdrawal of tofacitinib treatment. PLoS One 2014;9(1): e85463. 4. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011;86:1188-91. DOI: 10.1056/NEJMc1408607
The Authors Reply: In reply to Sexton: in clinical trials of tofacitinib, small, reversible increases in the mean serum creatinine level were noted.1 Parallel, reversible decreases in the measured glomerular filtration rate in patients with rheu-
1164
of
m e dic i n e
matoid arthritis, but not in healthy volunteers, have also been observed.2 Studies indicate that inhibition of tubular secretion of creatinine is unlikely, but they suggest a possible link between increases in the serum creatinine level and a reduction in inflammation.1 In clinical trials, increases in the serum creatinine level plateaued, reversed after discontinuation of treatment, and were not associated with renal failure, proteinuria, or the nephrotic syndrome. The overall elevations of cholesterol levels noted with tofacitinib therapy were not related to proteinuria.1 Since tofacitinib is partially cleared by renal mechanisms, a dose reduction is recommended for patients with impaired renal function. Yuan and colleagues correctly identify infections and cancer as key safety issues with immunomodulators. These issues and the overall safety profile of tofacitinib were studied in a large clinical development program including an ongoing long-term follow-up with more than 7000 patient-years of observation (as of May 9, 2012). The overall safety profile, including the type and frequency of serious infections and cancer, was consistent with that of biologic therapies used for the treatment of rheumatoid arthritis; small, mean decreases in lymphocyte counts have been observed, but severe lymphopenia has remained rare.3 The clinical relevance of the in vitro study by Piscianz et al. is unclear, since the concentrations of tofacitinib evaluated were 100 to 1000 times greater than those observed at therapeutic doses of tofacitinib (
In response to Baang and Fisher: results in G. Ralph Corey, M.D. patients who could be evaluated clinically were Duke University Medical Center consistent with those in the modified inten- Durham, NC [email protected] tion-to-treat population. The population of patients who could be evaluated clinically in our Hai Jiang, Ph.D. study is synonymous with the per-protocol Greg Moeck, Ph.D. population, since it consisted of all patients in The Medicines Company Parsippany, NJ the modified intention-to-treat population who Since publication of their article, the authors report no furmet the criteria for study inclusion, received the ther potential conflict of interest. full-course of study treatment, and underwent 1. European Centre for Disease Prevention and Control (ECDC). an assessment for clinical cure at the post- Antimicrobial resistance surveillance in Europe 2012: annual therapy evaluation by the site investigator, as report of the European Antimicrobial Resistance Surveillance stated in the legend to Figure 1 of our article. Network (EARS-Net). Stockholm: ECDC, 2013. 2. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi In addition, Figure 2 of our article and Tables F. Current management of patients hospitalized with compliS4, S7, and S11 in the Supplementary Appendix, cated skin and soft tissue infections across Europe (2010-2011): available at NEJM.org, are all based on the assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect population of patients who could be evaluated 2013;19(9):E377-E385. clinically. DOI: 10.1056/NEJMc1407925
Tofacitinib versus Methotrexate in Rheumatoid Arthritis To the Editor: In the article by Lee et al. (June 19 issue),1 the reported elevation in levels of serum creatinine and low-density lipoprotein (LDL) cholesterol in a proportion of patients in the tofacitinib group may be a cause for concern, given the prevalence of adverse renal and cardiovascular outcomes among patients with rheumatoid arthritis.2,3 Preliminary data suggest that the half-life of tofacitinib is prolonged in patients with impaired renal function, and if this drug simultaneously reduces renal function, it could create a self-perpetuating cycle prolonging its action.4 Apprehension regarding renal function is counterbalanced by the findings of a phase 2b study of tofacitinib involving patients undergoing renal transplantation. This study reported superior allograft function and efficacy that was similar to cyclosporine in preventing rejection of renal allografts.5 Tofacitinib also may suppress renal tubular secretion of creatinine, thus increasing serum levels without truly affecting renal function. Given the coincident increase in serum LDL cholesterol levels in these patients, one might be concerned about the possibility that tofacitinib induced or exacerbated proteinuria. Are data on urinary protein excretion available to
more fully characterize the renal implications of tofacitinib use? Donal Sexton, M.D. National University of Ireland, Galway Galway, Ireland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus
methotrexate in rheumatoid arthritis. N Engl J Med 2014;370: 2377-86. 2. Karstila K, Korpela M, Sihvonen S, Mustonen J. Prognosis of clinical renal disease and incidence of new renal findings in patients with rheumatoid arthritis: follow-up of a populationbased study. Clin Rheumatol 2007;26:2089-95. 3. del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737-45. 4. Krishnaswami S, Chow V, Boy M, Wang C, Chan G. Pharmacokinetics of tofacitinib, a Janus kinase inhibitor, in patients with impaired renal function and end-stage renal disease. J Clin Pharmacol 2014;54:46-52. 5. Vincenti F, Tedesco Silva H, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant 2012;12:2446-56. DOI: 10.1056/NEJMc1408607
To the Editor: We have major concerns about the safety of tofacitinib, which was developed as
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNL on April 7, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1163
The
n e w e ng l a n d j o u r na l
an inhibitor of the Janus kinase (JAK) pathways JAK1 and JAK3. JAK1 is critical in mediating the development of interferon-γ, which is important in tumor surveillance, and inhibition of JAK1 facilitates tumor formation.1 JAK3 exerts effects on mature lymphocytes, and inhibition of JAK3 may increase the risk of opportunistic infections.2 Serious infections and cancers may occur in patients who receive tofacitinib. Last year, tofacitinib was not approved by the European regulatory agencies because of its overall safety profile. Furthermore, the long-term safety of tofacitinib has not been thoroughly explored. In addition, Piscianz et al.3 found that treated lymphocytes resumed a striking proliferation after the withdrawal of tofacitinib, although they were inhibited during tofacitinib treatment in vitro. Tefferi and Pardanani4 at the Mayo Clinic also found the occurrence of severe withdrawal symptoms during discontinuation of treatment with ruxolitinib (another type of JAK inhibitor). So, we wonder whether the current study showed a withdrawal syndrome associated with tofacitinib. Kai Yuan, M.D. Jianxin Chen, Ph.D. Anlong Xu, Ph.D. Beijing University of Chinese Medicine Beijing, China [email protected] No potential conflict of interest relevant to this letter was reported. 1. Sexl V, Kovacic B, Piekorz R, et al. Jak1 deficiency leads to
enhanced Abelson-induced B-cell tumor formation. Blood 2003; 101:4937-43. 2. Saijo K, Park SY, Ishida Y, Arase H, Saito T. Crucial role of Jak3 in negative selection of self-reactive T cells. J Exp Med 1997; 185:351-6. 3. Piscianz E, Valencic E, Cuzzoni E, et al. Fate of lymphocytes after withdrawal of tofacitinib treatment. PLoS One 2014;9(1): e85463. 4. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011;86:1188-91. DOI: 10.1056/NEJMc1408607
The Authors Reply: In reply to Sexton: in clinical trials of tofacitinib, small, reversible increases in the mean serum creatinine level were noted.1 Parallel, reversible decreases in the measured glomerular filtration rate in patients with rheu-
1164
of
m e dic i n e
matoid arthritis, but not in healthy volunteers, have also been observed.2 Studies indicate that inhibition of tubular secretion of creatinine is unlikely, but they suggest a possible link between increases in the serum creatinine level and a reduction in inflammation.1 In clinical trials, increases in the serum creatinine level plateaued, reversed after discontinuation of treatment, and were not associated with renal failure, proteinuria, or the nephrotic syndrome. The overall elevations of cholesterol levels noted with tofacitinib therapy were not related to proteinuria.1 Since tofacitinib is partially cleared by renal mechanisms, a dose reduction is recommended for patients with impaired renal function. Yuan and colleagues correctly identify infections and cancer as key safety issues with immunomodulators. These issues and the overall safety profile of tofacitinib were studied in a large clinical development program including an ongoing long-term follow-up with more than 7000 patient-years of observation (as of May 9, 2012). The overall safety profile, including the type and frequency of serious infections and cancer, was consistent with that of biologic therapies used for the treatment of rheumatoid arthritis; small, mean decreases in lymphocyte counts have been observed, but severe lymphopenia has remained rare.3 The clinical relevance of the in vitro study by Piscianz et al. is unclear, since the concentrations of tofacitinib evaluated were 100 to 1000 times greater than those observed at therapeutic doses of tofacitinib (
