correspondence 3. Miri-Moghaddam E, Sargolzaie N. Cut off determination of
discrimination indices in differential diagnosis between iron deficiency anemia and β-thalassemia minor. Int J Hematol Oncol Stem Cell Res 2014;8:27-32. 4. Aslan D, Gumruk F, Gurgey A, Altay C. Importance of RDW value in differential diagnosis of hypochrome anemias. Am J Hematol 2002;69:31-3. DOI: 10.1056/NEJMc1413161
The Author Replies: I agree with Brodzik et al. about the role of H. pylori infection in inducing refractory iron deficiency. When there is no response to oral iron supplementation, patients should be screened for infection.1 Although there are no prospective data to prove that PPI use leads to iron deficiency, the need for this therapy should be reevaluated in patients with iron deficiency. I also strongly agree with the comments of Aviner et al. regarding the detrimental effect of iron deficiency in infants and toddlers. Their letter reinforces the concept that replete iron stores are beneficial across all age groups. Differentiating between iron deficiency and thalassemia as causes of anemia is important,
but most of the data show that neither the redcell distribution width nor combinations of redcell indexes can make this distinction reliably.2,3 For some patients, a trial of oral iron may be cost-effective, but the results can be confounded by a lack of adherence to treatment and concurrent illness.4 Thomas G. DeLoughery, M.D. Oregon Health and Science University Portland, OR [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Hershko C, Camaschella C. How I treat unexplained refrac-
tory iron deficiency anemia. Blood 2014;123:326-33. 2. Beyan C, Kaptan K, Ifran A. Predictive value of discrimination indices in differential diagnosis of iron deficiency anemia and beta-thalassemia trait. Eur J Haematol 2007;78:524-6. 3. Ntaios G, Chatzinikolaou A, Saouli Z, et al. Discrimination indices as screening tests for beta-thalassemic trait. Ann Hematol 2007;86:487-91. 4. Elliot DL, Goldberg L, Loprinzi M. Management of suspected iron deficiency: a cost-effectiveness model. Med Sci Sports Exerc 1991;23:1332-7. DOI: 10.1056/NEJMc1413161
Remission of Recalcitrant Dermatomyositis Treated with Ruxolitinib To the Editor: We report a case of recalcitrant dermatomyositis in a 72-year-old woman with skin lesions typical for the disease (heliotropic periorbital erythema and rash in sun-exposed areas, with a score of 30 on the activity section of the Cutaneous Dermatomyositis Disease Area and Severity Index [CDASI]) and extensive muscle weakness (tetraplegia, dysphagia, a characteristic pattern on electromyography, and biopsy-confirmed myositis). (The CDASI includes four measures of activity [erythema, scale, excoriation, and ulceration], with the total activity score ranging from 0 to 116 and higher scores indicating more severe disease.) Systemic treatment with high-dose glucocorticoids and azathioprine was not effective. Treatment was then escalated to include intravenous immune globulin (IVIG) (2 g per kilogram of body weight over 5 consecutive days), mycophenolate mofetil (2 g per day), and prednisone (5 mg per day), which achieved partial disease control (CDASI activity-section score of 12). Approximately 1 year after her initial visit, the
patient presented with fever and marked splenomegaly. Testing for the Janus kinase 2 mutation JAK2 V617F was positive, and the patient received a diagnosis of post–polycythemia vera myelofibrosis (with staging based on the International Prognostic Scoring System). We initiated treatment with the JAK inhibitor ruxolitinib at a reduced dose of 5 mg twice a day because of grade 2 thrombocytopenia. No dose-limiting side effects developed, and the dosage was gradually raised to 15 mg twice a day, at which point platelet recovery was observed (after 2 months of treatment). As expected, the fever and night sweats completely resolved, and the spleen size decreased. Unexpectedly, however, the symptoms of dermatomyositis were also rapidly reduced during ruxolitinib treatment. The patient regained muscle strength and body weight, and her skin lesions completely resolved (CDASI activitysection score of 0). Glucocorticoids, mycophenolate mofetil, and IVIG were tapered and eventually discontinued (Fig. 1). At a 12-month follow-up
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNL on April 8, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2537
correspondence
12
Start ruxolitinib Prednisone (mg/day) MMF (g/day) IVIG (time points)
10
Dosage
8 6 4
University of Bonn Bonn, Germany [email protected]
2 0
0
2
4
6
8
10
12
14
16
18
20
Months
Figure 1. The Immunosuppressive-Sparing Effect of Ruxolitinib. Oral prednisone was administered once daily and mycophenolate mofetil (MMF) twice daily. Intravenous immune globulin (IVIG [Privigen]) (2 g per kilogram of body weight) was administered over 5 consecutive days. Ruxolitinib was started at a dose of 5 mg twice daily and was gradually increased to 15 mg twice daily during the next 2 months.
visit, ruxolitinib was reduced to 10 mg twice daily. Currently, the patient is able to walk short distances and climb stairs independently, and the dermatomyositis has remained in remission while she receives monotherapy with ruxolitinib. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 that was developed for the treatment of neoplastic diseases, particularly myelofibrosis. However, ruxolitinib has also been shown to be a potent immunomodulator. It affects circulating cytokine levels and regulates the activation of dendritic cells and T lymphocytes,1,2 factors that have been shown to play a fundamental role in dermatomyositis. Activation of interferon-regulated pro-inflammatory cytokines is a pathological hallmark of dermatomyositis.3 Ruxolitinib blocks the interferon-beta–induced signal transducers and activators of transcription 1 (STAT1) in vitro, thereby blocking phosphorylation and inhibiting the pathway used by type I interferons to induce targeted gene expression that may drive inflammation in dermatomyositis.4 Most recently, JAK inhibition has been shown to be therapeutic in other autoimmune diseases (e.g., rheumatoid arthritis5 and alopecia areata2), thus confirming the antiinflammatory and immunosuppressive activity of this class of compounds. We therefore assume that the antiinflammatory potential of ruxolitinib directly interfered with dermatomyositis 2538
disease activity in this case, suggesting that the drug has potent antiinflammatory properties that may provide powerful new options for the treatment of dermatomyositis and related autoimmune diseases. Thorsten Hornung, M.D. Viktor Janzen, M.D. Joerg Wenzel, M.D.
and Others A complete list of authors is available with the full text of this letter at NEJM.org. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immu-
nity, immunodeficiency, and cancer. N Engl J Med 2013;368:161-70. 2. Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 2014;20:1043-9. 3. Hornung T, Wenzel J. Innate immune-response mechanisms in dermatomyositis: an update on pathogenesis, diagnosis and treatment. Drugs 2014;74:981-98. 4. Pattison MJ, Mackenzie KF, Arthur JS. Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback. J Immunol 2012; 189:2784-92. 5. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014;370:2377-86. DOI: 10.1056/NEJMc1412997 Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. • Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNL on April 8, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
discrimination indices in differential diagnosis between iron deficiency anemia and β-thalassemia minor. Int J Hematol Oncol Stem Cell Res 2014;8:27-32. 4. Aslan D, Gumruk F, Gurgey A, Altay C. Importance of RDW value in differential diagnosis of hypochrome anemias. Am J Hematol 2002;69:31-3. DOI: 10.1056/NEJMc1413161
The Author Replies: I agree with Brodzik et al. about the role of H. pylori infection in inducing refractory iron deficiency. When there is no response to oral iron supplementation, patients should be screened for infection.1 Although there are no prospective data to prove that PPI use leads to iron deficiency, the need for this therapy should be reevaluated in patients with iron deficiency. I also strongly agree with the comments of Aviner et al. regarding the detrimental effect of iron deficiency in infants and toddlers. Their letter reinforces the concept that replete iron stores are beneficial across all age groups. Differentiating between iron deficiency and thalassemia as causes of anemia is important,
but most of the data show that neither the redcell distribution width nor combinations of redcell indexes can make this distinction reliably.2,3 For some patients, a trial of oral iron may be cost-effective, but the results can be confounded by a lack of adherence to treatment and concurrent illness.4 Thomas G. DeLoughery, M.D. Oregon Health and Science University Portland, OR [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Hershko C, Camaschella C. How I treat unexplained refrac-
tory iron deficiency anemia. Blood 2014;123:326-33. 2. Beyan C, Kaptan K, Ifran A. Predictive value of discrimination indices in differential diagnosis of iron deficiency anemia and beta-thalassemia trait. Eur J Haematol 2007;78:524-6. 3. Ntaios G, Chatzinikolaou A, Saouli Z, et al. Discrimination indices as screening tests for beta-thalassemic trait. Ann Hematol 2007;86:487-91. 4. Elliot DL, Goldberg L, Loprinzi M. Management of suspected iron deficiency: a cost-effectiveness model. Med Sci Sports Exerc 1991;23:1332-7. DOI: 10.1056/NEJMc1413161
Remission of Recalcitrant Dermatomyositis Treated with Ruxolitinib To the Editor: We report a case of recalcitrant dermatomyositis in a 72-year-old woman with skin lesions typical for the disease (heliotropic periorbital erythema and rash in sun-exposed areas, with a score of 30 on the activity section of the Cutaneous Dermatomyositis Disease Area and Severity Index [CDASI]) and extensive muscle weakness (tetraplegia, dysphagia, a characteristic pattern on electromyography, and biopsy-confirmed myositis). (The CDASI includes four measures of activity [erythema, scale, excoriation, and ulceration], with the total activity score ranging from 0 to 116 and higher scores indicating more severe disease.) Systemic treatment with high-dose glucocorticoids and azathioprine was not effective. Treatment was then escalated to include intravenous immune globulin (IVIG) (2 g per kilogram of body weight over 5 consecutive days), mycophenolate mofetil (2 g per day), and prednisone (5 mg per day), which achieved partial disease control (CDASI activity-section score of 12). Approximately 1 year after her initial visit, the
patient presented with fever and marked splenomegaly. Testing for the Janus kinase 2 mutation JAK2 V617F was positive, and the patient received a diagnosis of post–polycythemia vera myelofibrosis (with staging based on the International Prognostic Scoring System). We initiated treatment with the JAK inhibitor ruxolitinib at a reduced dose of 5 mg twice a day because of grade 2 thrombocytopenia. No dose-limiting side effects developed, and the dosage was gradually raised to 15 mg twice a day, at which point platelet recovery was observed (after 2 months of treatment). As expected, the fever and night sweats completely resolved, and the spleen size decreased. Unexpectedly, however, the symptoms of dermatomyositis were also rapidly reduced during ruxolitinib treatment. The patient regained muscle strength and body weight, and her skin lesions completely resolved (CDASI activitysection score of 0). Glucocorticoids, mycophenolate mofetil, and IVIG were tapered and eventually discontinued (Fig. 1). At a 12-month follow-up
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNL on April 8, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2537
correspondence
12
Start ruxolitinib Prednisone (mg/day) MMF (g/day) IVIG (time points)
10
Dosage
8 6 4
University of Bonn Bonn, Germany [email protected]
2 0
0
2
4
6
8
10
12
14
16
18
20
Months
Figure 1. The Immunosuppressive-Sparing Effect of Ruxolitinib. Oral prednisone was administered once daily and mycophenolate mofetil (MMF) twice daily. Intravenous immune globulin (IVIG [Privigen]) (2 g per kilogram of body weight) was administered over 5 consecutive days. Ruxolitinib was started at a dose of 5 mg twice daily and was gradually increased to 15 mg twice daily during the next 2 months.
visit, ruxolitinib was reduced to 10 mg twice daily. Currently, the patient is able to walk short distances and climb stairs independently, and the dermatomyositis has remained in remission while she receives monotherapy with ruxolitinib. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 that was developed for the treatment of neoplastic diseases, particularly myelofibrosis. However, ruxolitinib has also been shown to be a potent immunomodulator. It affects circulating cytokine levels and regulates the activation of dendritic cells and T lymphocytes,1,2 factors that have been shown to play a fundamental role in dermatomyositis. Activation of interferon-regulated pro-inflammatory cytokines is a pathological hallmark of dermatomyositis.3 Ruxolitinib blocks the interferon-beta–induced signal transducers and activators of transcription 1 (STAT1) in vitro, thereby blocking phosphorylation and inhibiting the pathway used by type I interferons to induce targeted gene expression that may drive inflammation in dermatomyositis.4 Most recently, JAK inhibition has been shown to be therapeutic in other autoimmune diseases (e.g., rheumatoid arthritis5 and alopecia areata2), thus confirming the antiinflammatory and immunosuppressive activity of this class of compounds. We therefore assume that the antiinflammatory potential of ruxolitinib directly interfered with dermatomyositis 2538
disease activity in this case, suggesting that the drug has potent antiinflammatory properties that may provide powerful new options for the treatment of dermatomyositis and related autoimmune diseases. Thorsten Hornung, M.D. Viktor Janzen, M.D. Joerg Wenzel, M.D.
and Others A complete list of authors is available with the full text of this letter at NEJM.org. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immu-
nity, immunodeficiency, and cancer. N Engl J Med 2013;368:161-70. 2. Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 2014;20:1043-9. 3. Hornung T, Wenzel J. Innate immune-response mechanisms in dermatomyositis: an update on pathogenesis, diagnosis and treatment. Drugs 2014;74:981-98. 4. Pattison MJ, Mackenzie KF, Arthur JS. Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback. J Immunol 2012; 189:2784-92. 5. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014;370:2377-86. DOI: 10.1056/NEJMc1412997 Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. • Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNL on April 8, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
