Opinion
EDITORIAL
Low-Dose Interleukin 2 to Reverse Alopecia Areata Maria Hordinsky, MD; Daniel H. Kaplan, MD, PhD
Cytokines have long been postulated to play a role in alopecia areata (AA), and antigen-specific scalp T cells from patients with extensive AA have been found to have an intrinsic defect in the production of TH1 cytokines such as interferon gamma and interleukin 2 (IL-2). 1,2 In Related article page 748 the interesting study presented by Castela et al,3 5 patients with extensive AA were treated with low-dose IL-2, and 4 of the 5 patients attained considerable hair regrowth. This was accompanied by an increase in regulatory T (Treg) cells; cells defined by the expression of CD4, CD25, and transcription factor forkhead box P3 (FOXP3) in skin biopsy specimens; and no significant change in circulating Treg cells. Adverse effects in this study were reported to be minimal. The investigators in the Department of Dermatology at University Hospital in Nice, France, continue to enroll research participants and list this study as a clinical trial on ClinicalTrials.gov (NCT01840046). Dysfunctional Treg cells have been identified and characterized in autoimmune diseases, such as psoriasis, multiple sclerosis, and autoimmune polyglandular syndrome type 1, suggesting that normal Treg function is important to the prevention of autoimmune disease. In the mouse model for AA, the C3H/HeJ mouse, a low level of skin CD4+CD25+ Treg cells has been found in the skin, and in this same model, injection of CD4+CD25+Treg cells was found to prevent the induction of AA by CD4+CD25– T cells as well as CD8+ T-cell–induced localized hair loss.4-6
So Why IL-2, and What Are the Risks, if Any? Interleukin 2 is a highly pleiotropic cytokine that signals via 2 ligand-binding receptors (the high-affinity IL-2Rα and low-affinity IL-2Rβ) that combine with the common cytokine receptor γ chain for signaling. Interleukin 2 has classically been associated with inducing T-cell proliferation. Naïve T cells do not express the high-affinity IL-2Rα chain and require relatively high levels of IL-2 for proliferation. In contrast, activated T cells and Treg cells in particular express the high-affinity IL-2Rα and are sensitive to low levels of IL-2. The low doses of IL-2 used in this study may preferentially expand Treg cells, thus suppressing autoimmunity.7 Interleukin 2 is marketed in the United States as Proleukin (aldesleukin) and is a registered indication for metastatic renal cell carcinoma and metastatic melanoma in adults using a dosing schedule that is much higher than was used in this study. As the authors note, a low-dose schedule of IL-2 was recently studied and found to be beneficial for 696
the treatment of chronic graft vs host disease as well as hepatitis C virus–induced vasculitis resistant to standard therapy.8,9 The potential of IL-2 as a therapeutic tool for human autoimmune diseases, such as AA, has been fairly limited, most likely owing to perceived risks of therapy with this approach. For example, the use of high-dose Proleukin has been associated with exacerbation of preexisting or initial presentation of autoimmune disease and inflammatory disorders (according to the package insert10). The low-dose regimen used in this study (subcutaneous IL-2, 1.5 MIU/d for 5 days, followed by three 5-day courses of 3 MIU/d at weeks 3, 6, and 9) suggests that the use of low-dose IL-2 favors the Treg-effector T-cell balance in favor of Treg cells and that administration of IL-2 on this protocol is associated with very few adverse reactions in contrast to the high-dose regimen (a 15-minute intravenous infusion every 8 hours for up to 5 days [for a maximum of 14 doses] and no treatment on days 6 to 14 with dosing repeated for up to 5 days on days 15 to 19 [maximum of 14 doses]). Of note, only the high-dose schedule was approved, and not the low-dose regimen, for the treatment of metastatic renal cell carcinoma or metastatic melanoma. Also, treatments with the high-dose schedule are restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and normal pulmonary function testing. Proleukin treatment may also be associated with impaired neutrophil chemotaxis.
Need for New Tools and Confounding Factors For the physician treating a patient with extensive AA, there are many therapies to choose from, and treatment choices are frequently based on disease extent, the duration of the disease, and age of the patient. In the United States there is no approved drug for this disease, and there is no universally proven therapy that induces and sustains remission.11 There is a hint from the study by Castela et al3 that the clinical response may be durable, but this remains to be proven; maybe the response will be as with prednisone, excellent for some but not sustained for many. There are relatively few published randomized controlled trials in AA, and most of these studies are only of moderate quality. A major limitation in most of the studies is that there is either a very small number of participants, as in this study, or significant disease heterogeneity in study design. In 1999 and 2004, the AA Investigational Assessment Guidelines were published and, when used, provide some standardization to the description of disease extent and percentage of improvement in response to therapy.12,13 These guidelines are now commonly being implemented in AA clinical trials, as they
JAMA Dermatology July 2014 Volume 150, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Grand Valley State University User on 06/09/2015
jamadermatology.com
Editorial Opinion
were in this study. Long-term monitoring of successfully treated patients from this study is needed not only to determine the sustainability of the response but also to monitor whether IL-2–treated patients develop other autoimmune diseases over time. This needed safety and efficacy information will only be obtained with an appropriately powered study. Other confounding issues include that IL-2 increases natural killer (NK) cell activity, which would be expected to make AA worse. Also, JAK3 (Janus kinase) signals downstream of the IL-2 receptor. Currently, a JAK inhibitor, ruxolitinib, is in a clinical trial for AA (NCT01950780) because Jak inhibitors may target other key pathways, such as IL-15, a cytokine which is also in ARTICLE INFORMATION Author Affiliations: Department of Dermatology, University of Minnesota, Minneapolis (Hordinsky); Department of Dermatology and Immunology Center, University of Minnesota, Minneapolis (Kaplan). Corresponding Author: Maria Hordinsky, MD, Department of Dermatology, 420 Delaware St, MMC 98, University of Minnesota, Minneapolis, MN 55455 ([email protected]). Published Online: May 28, 2014. doi:10.1001/jamadermatol.2014.510. Conflict of Interest Disclosures: None reported. REFERENCES 1. Deeths MJ, Endrizzi BT, Irvin ML, Steiner LP, Ericson ME, Hordinsky MK. Phenotypic analysis of T-cells in extensive alopecia areata scalp suggests partial tolerance. J Invest Dermatol. 2006;126(2): 366-373. 2. Gilhar A, Paus R, Kalish RS. Lymphocytes, neuropeptides, and genes involved in alopecia areata. J Clin Invest. 2007;117(8):2019-2027. 3. Castela E, Le Duff F, Butori C, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata [published
jamadermatology.com
the IL-2 family and one that is considered to be the key cytokine for NK cells even more so than IL-2.14
Future Treatment Further investigations are required to confirm and to optimize the protocol of IL-2 therapy to enhance the Treg response in AA. Of note, a long-standing and accepted immunotherapy for AA, topical diphenylcyclopropenone, also alters cytokine profiles in treated patients with AA and, in particular, increases IL-2 and IL-10.15 Optimizing this therapy could be another, perhaps safer and more conservative treatment modality for patients with AA.
online May 28, 2014]. JAMA Dermatol. doi:10.1001 /jamadermatol.2014.504.
10. Proleukin (aldesleukin) [package insert]. San Diego, CA: Prometheus Laboratories Inc; 2012.
4. Shin BS, Furuhashi T, Nakamura M, Torii K, Morita A. Impaired inhibitory function of circulating CD4+CD25+ regulatory T cells in alopecia areata. J Dermatol Sci. 2013;70(2):141-143.
11. Delamere FM, Sladden MM, Dobbins HM, Leonardi-Bee J. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008;(2):CD004413.
5. Valsecchi R, Imberti G, Martino D, Cainelli T. Alopecia areata and interleukin-2 receptor. Dermatology. 1992;184(2):126-128.
12. Olsen E, Hordinsky M, McDonald-Hull S, et al; National Alopecia Areata Foundation. Alopecia areata investigational assessment guidelines. J Am Acad Dermatol. 1999;40(2, pt 1):242-246. 13. Olsen EA, Hordinsky MK, Price VH, et al; National Alopecia Areata Foundation. Alopecia areata investigational assessment guidelines, part II. J Am Acad Dermatol. 2004;51(3):440-447.
6. McElwee KJ, Freyschmidt-Paul P, Hoffmann R, et al. Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model. J Invest Dermatol. 2005;124(5):947-957.
14. Waldmann TA. The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders. J Investig Dermatol Symp Proc. 2013;16(1): S28-S30.
7. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13-25. 8. Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365(22):2067-2077.
15. Hoffmann R, Wenzel E, Huth A, et al. Cytokine mRNA levels in alopecia areata before and after treatment with the contact allergen diphenylcyclopropenone. J Invest Dermatol. 1994; 103(4):530-533.
9. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055-2066.
JAMA Dermatology July 2014 Volume 150, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Grand Valley State University User on 06/09/2015
697
EDITORIAL
Low-Dose Interleukin 2 to Reverse Alopecia Areata Maria Hordinsky, MD; Daniel H. Kaplan, MD, PhD
Cytokines have long been postulated to play a role in alopecia areata (AA), and antigen-specific scalp T cells from patients with extensive AA have been found to have an intrinsic defect in the production of TH1 cytokines such as interferon gamma and interleukin 2 (IL-2). 1,2 In Related article page 748 the interesting study presented by Castela et al,3 5 patients with extensive AA were treated with low-dose IL-2, and 4 of the 5 patients attained considerable hair regrowth. This was accompanied by an increase in regulatory T (Treg) cells; cells defined by the expression of CD4, CD25, and transcription factor forkhead box P3 (FOXP3) in skin biopsy specimens; and no significant change in circulating Treg cells. Adverse effects in this study were reported to be minimal. The investigators in the Department of Dermatology at University Hospital in Nice, France, continue to enroll research participants and list this study as a clinical trial on ClinicalTrials.gov (NCT01840046). Dysfunctional Treg cells have been identified and characterized in autoimmune diseases, such as psoriasis, multiple sclerosis, and autoimmune polyglandular syndrome type 1, suggesting that normal Treg function is important to the prevention of autoimmune disease. In the mouse model for AA, the C3H/HeJ mouse, a low level of skin CD4+CD25+ Treg cells has been found in the skin, and in this same model, injection of CD4+CD25+Treg cells was found to prevent the induction of AA by CD4+CD25– T cells as well as CD8+ T-cell–induced localized hair loss.4-6
So Why IL-2, and What Are the Risks, if Any? Interleukin 2 is a highly pleiotropic cytokine that signals via 2 ligand-binding receptors (the high-affinity IL-2Rα and low-affinity IL-2Rβ) that combine with the common cytokine receptor γ chain for signaling. Interleukin 2 has classically been associated with inducing T-cell proliferation. Naïve T cells do not express the high-affinity IL-2Rα chain and require relatively high levels of IL-2 for proliferation. In contrast, activated T cells and Treg cells in particular express the high-affinity IL-2Rα and are sensitive to low levels of IL-2. The low doses of IL-2 used in this study may preferentially expand Treg cells, thus suppressing autoimmunity.7 Interleukin 2 is marketed in the United States as Proleukin (aldesleukin) and is a registered indication for metastatic renal cell carcinoma and metastatic melanoma in adults using a dosing schedule that is much higher than was used in this study. As the authors note, a low-dose schedule of IL-2 was recently studied and found to be beneficial for 696
the treatment of chronic graft vs host disease as well as hepatitis C virus–induced vasculitis resistant to standard therapy.8,9 The potential of IL-2 as a therapeutic tool for human autoimmune diseases, such as AA, has been fairly limited, most likely owing to perceived risks of therapy with this approach. For example, the use of high-dose Proleukin has been associated with exacerbation of preexisting or initial presentation of autoimmune disease and inflammatory disorders (according to the package insert10). The low-dose regimen used in this study (subcutaneous IL-2, 1.5 MIU/d for 5 days, followed by three 5-day courses of 3 MIU/d at weeks 3, 6, and 9) suggests that the use of low-dose IL-2 favors the Treg-effector T-cell balance in favor of Treg cells and that administration of IL-2 on this protocol is associated with very few adverse reactions in contrast to the high-dose regimen (a 15-minute intravenous infusion every 8 hours for up to 5 days [for a maximum of 14 doses] and no treatment on days 6 to 14 with dosing repeated for up to 5 days on days 15 to 19 [maximum of 14 doses]). Of note, only the high-dose schedule was approved, and not the low-dose regimen, for the treatment of metastatic renal cell carcinoma or metastatic melanoma. Also, treatments with the high-dose schedule are restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and normal pulmonary function testing. Proleukin treatment may also be associated with impaired neutrophil chemotaxis.
Need for New Tools and Confounding Factors For the physician treating a patient with extensive AA, there are many therapies to choose from, and treatment choices are frequently based on disease extent, the duration of the disease, and age of the patient. In the United States there is no approved drug for this disease, and there is no universally proven therapy that induces and sustains remission.11 There is a hint from the study by Castela et al3 that the clinical response may be durable, but this remains to be proven; maybe the response will be as with prednisone, excellent for some but not sustained for many. There are relatively few published randomized controlled trials in AA, and most of these studies are only of moderate quality. A major limitation in most of the studies is that there is either a very small number of participants, as in this study, or significant disease heterogeneity in study design. In 1999 and 2004, the AA Investigational Assessment Guidelines were published and, when used, provide some standardization to the description of disease extent and percentage of improvement in response to therapy.12,13 These guidelines are now commonly being implemented in AA clinical trials, as they
JAMA Dermatology July 2014 Volume 150, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Grand Valley State University User on 06/09/2015
jamadermatology.com
Editorial Opinion
were in this study. Long-term monitoring of successfully treated patients from this study is needed not only to determine the sustainability of the response but also to monitor whether IL-2–treated patients develop other autoimmune diseases over time. This needed safety and efficacy information will only be obtained with an appropriately powered study. Other confounding issues include that IL-2 increases natural killer (NK) cell activity, which would be expected to make AA worse. Also, JAK3 (Janus kinase) signals downstream of the IL-2 receptor. Currently, a JAK inhibitor, ruxolitinib, is in a clinical trial for AA (NCT01950780) because Jak inhibitors may target other key pathways, such as IL-15, a cytokine which is also in ARTICLE INFORMATION Author Affiliations: Department of Dermatology, University of Minnesota, Minneapolis (Hordinsky); Department of Dermatology and Immunology Center, University of Minnesota, Minneapolis (Kaplan). Corresponding Author: Maria Hordinsky, MD, Department of Dermatology, 420 Delaware St, MMC 98, University of Minnesota, Minneapolis, MN 55455 ([email protected]). Published Online: May 28, 2014. doi:10.1001/jamadermatol.2014.510. Conflict of Interest Disclosures: None reported. REFERENCES 1. Deeths MJ, Endrizzi BT, Irvin ML, Steiner LP, Ericson ME, Hordinsky MK. Phenotypic analysis of T-cells in extensive alopecia areata scalp suggests partial tolerance. J Invest Dermatol. 2006;126(2): 366-373. 2. Gilhar A, Paus R, Kalish RS. Lymphocytes, neuropeptides, and genes involved in alopecia areata. J Clin Invest. 2007;117(8):2019-2027. 3. Castela E, Le Duff F, Butori C, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata [published
jamadermatology.com
the IL-2 family and one that is considered to be the key cytokine for NK cells even more so than IL-2.14
Future Treatment Further investigations are required to confirm and to optimize the protocol of IL-2 therapy to enhance the Treg response in AA. Of note, a long-standing and accepted immunotherapy for AA, topical diphenylcyclopropenone, also alters cytokine profiles in treated patients with AA and, in particular, increases IL-2 and IL-10.15 Optimizing this therapy could be another, perhaps safer and more conservative treatment modality for patients with AA.
online May 28, 2014]. JAMA Dermatol. doi:10.1001 /jamadermatol.2014.504.
10. Proleukin (aldesleukin) [package insert]. San Diego, CA: Prometheus Laboratories Inc; 2012.
4. Shin BS, Furuhashi T, Nakamura M, Torii K, Morita A. Impaired inhibitory function of circulating CD4+CD25+ regulatory T cells in alopecia areata. J Dermatol Sci. 2013;70(2):141-143.
11. Delamere FM, Sladden MM, Dobbins HM, Leonardi-Bee J. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008;(2):CD004413.
5. Valsecchi R, Imberti G, Martino D, Cainelli T. Alopecia areata and interleukin-2 receptor. Dermatology. 1992;184(2):126-128.
12. Olsen E, Hordinsky M, McDonald-Hull S, et al; National Alopecia Areata Foundation. Alopecia areata investigational assessment guidelines. J Am Acad Dermatol. 1999;40(2, pt 1):242-246. 13. Olsen EA, Hordinsky MK, Price VH, et al; National Alopecia Areata Foundation. Alopecia areata investigational assessment guidelines, part II. J Am Acad Dermatol. 2004;51(3):440-447.
6. McElwee KJ, Freyschmidt-Paul P, Hoffmann R, et al. Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model. J Invest Dermatol. 2005;124(5):947-957.
14. Waldmann TA. The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders. J Investig Dermatol Symp Proc. 2013;16(1): S28-S30.
7. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13-25. 8. Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365(22):2067-2077.
15. Hoffmann R, Wenzel E, Huth A, et al. Cytokine mRNA levels in alopecia areata before and after treatment with the contact allergen diphenylcyclopropenone. J Invest Dermatol. 1994; 103(4):530-533.
9. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055-2066.
JAMA Dermatology July 2014 Volume 150, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Grand Valley State University User on 06/09/2015
697
