Journal Information
Vol. 109. Issue 3.
Pages 241-247 (April 2018)
Visits
...
Vol. 109. Issue 3.
Pages 241-247 (April 2018)
Original Article
DOI: 10.1016/j.adengl.2018.01.002
Full text access
Sclerodermatous Chronic Graft-versus-Host Disease Treated With Imatinib: A Dermatological Perspective
Tratamiento de la enfermedad de injerto contra huésped crónica esclerodermiforme con imatinib: una perspectiva dermatológica
Visits
...
P. Molés-Povedaa,b,
Corresponding author
paula.moles@gmail.com

Corresponding author.
, P. Montesinosa, J. Sanz-Caballera,c, B. de Unamunoa,b,d, J.L. Piñanaa,c, A. Sahuquilloa,b,e, R. Botella-Estradaa,e
a Departamento de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
b Instituto de Investigación Sanitaria La Fe, Valencia, España
c Grupo de Investigación en Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
d Grupo de Investigación Clínica y Traslacional del Cáncer, Hospital Universitario y Politécnico La Fe, Valencia, Spain
e Grupo de Investigación de Dermatología y Regeneración Tisular, Hospital Universitario y Politécnico La Fe, Valencia, Spain
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Tables (3)
Table 1. Patient and transplantation characteristics.
Table 2. Organs affected by chronic GVHD.
Table 3. Response at 1, 3, 6, 9, 12 and 18 months after start of imatinib.
Show moreShow less
Abstract
Introduction

Chronic graft-versus-host disease (cGVHD) is the most important cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Sclerodermatous cGVHD is usually steroid refractory and remains a therapeutic challenge. Activating antibodies against the PDGFR have been reported in patients with sclerodermatous cGVHD. These antibodies induce PDGFR phosphorylation and lead to fibrosis. There is increasing evidence of successful treatment of sclerodermatous cGVHD with imatinib, a tyrosine kinase inhibitor.

Objective

To evaluate the response of cutaneous sclerodermatous cGVHD to imatinib.

Materials and methods

Retrospective study of 18 patients with sclerodermatous cGVHD refractory to immunosuppressants treated with imatinib in a single center. Evaluation of treatment response was performed by clinicians’ assessment and patients’ subjective response at one, 3, 6, 9, 12 and 18 months after initiation of imatinib. Response was assessed as complete, partial, significant, no change or progression. Tapper off steroids was complete, partial or not possible.

Results

In our series, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and one (6%) patient progressive disease at last follow-up. Mean time from initiation of imatinib to any degree of response was 2,75 months (range 1-9 months).

Conclusions

This study provides further evidence of the role of imatinib for the treatment of steroid refractory sclerodermatous cGVHD.

Keywords:
Graft-versus-host disease
Chronic sclerodermatous graft versus host disease
Cutaneous graft versus host disease
Imatinib
Treatment
Platelet-derived growth factor receptor
Resumen
Introducción

La enfermedad de injerto contra huésped crónica (EICHc) es la causa más importante de mortalidad tardía no relacionada con la recidiva del trasplante alogénico de células progenitoras hematopoyéticas. La EICHc esclerodermiforme suele ser refractaria a los corticosteroides y supone todo un reto terapéutico. Se han descrito anticuerpos activadores contra el RFCDP en pacientes con EICHc esclerodermiforme. Estos anticuerpos inducen la fosforilación del RFCDP, produciendo fibrosis. Hay cada vez más evidencias de la efectividad de imatinib, un inhibidor de la tirosina cinasa, en el tratamiento de la EICHc esclerodermiforme.

Objetivo

Evaluar la respuesta de la EICHc esclerodermiforme al imatinib.

Materiales y métodos

Estudio retrospectivo de 18 pacientes con EICHc cutánea esclerodermiforme refractaria a inmunosupresores tratada con imatinib en un único centro. La evaluación de la respuesta al tratamiento se realizó mediante valoración clínica del dermatólogo y percepción subjetiva del paciente tras uno, 3, 6, 9, 12 y 18 meses de iniciar el tratamiento con imatinib. La respuesta fue valorada como completa, parcial, significativa, sin cambios o progresión. El descenso de la dosis de esteroides se catalogó como completo, parcial o no posible.

Resultados

En nuestra serie, 4 (22%) pacientes lograron una respuesta completa, 9 (50%) alcanzaron una respuesta parcial, 2 (11%) tuvieron un grado significativo de respuesta, 2 (11%) no presentaron ningún cambio y uno (6%) experimentó avance de la enfermedad en el último seguimiento que se llevó a cabo. El tiempo medio transcurrido desde el inicio del imatinib hasta mostrar algún grado de respuesta fue de 2,75 meses (rango 1-9 meses).

Conclusiones

Este estudio apoya la evidencia de la utilidad del imatinib en el tratamiento de la EICHc esclerodermiforme.

Palabras clave:
Enfermedad de injerto contra huésped
Enfermedad de injerto contra huésped crónica esclerodermiforme
Enfermedad de injerto contra huésped cutánea
Imatinib
Tratamiento
Receptor del factor de crecimiento derivado de plaquetas
Full Text

Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative treatment for several diseases. The increasing use of this procedure, including more unrelated donors, older patients, the use of peripheral blood, and less treatment related mortality have raised the prevalence of chronic graft-versus-host disease (cGVHD).1 Chronic GVHD accounts for 20-40% of deaths2–4 and it is a major determinant in the survival and quality of life of patients after HSCT, not only due to the symptoms, but also resulting from the complications of long-term immunosuppression.5

Chronic GVHD results from auto, alloimmune and immunodeficiency processes. Alloreactivity is induced by histocompatibility complex incompatibilities between donor and recipient. It often mimics autoimmune diseases, with loss of immune tolerance by impaired thymic negative selection that allows expansion and activation of autoreactive T and B cells.6

Sclerodermatous GVHD is a rare and severe form of cGVHD that accounts for 10-15% of cases7 frequently refractory to treatment with steroids and other immunosuppressants. Activating antibodies against the PDGFR8 have been described in patients with sclerodermatous cGVHD. These antibodies trigger an intracellular loop, involving a-Ras-extracellular-signal-regulated kinases 1 and 2 - reactive oxygen species, which leads to increased type 1 collagen expression and myofibroblast phenotype conversion of normal fibroblasts.4 Likewise, other pro-fibrotic cytokines, such as TGF-β have been identified and anti-TGF-β antibodies prevented the development of skin fibrosis in a murine model.9

Imatinib mesylate (IM) (Glivec and Gleevec; Novartis, Basel, Switzerland) is a potent inhibitor of the tyrosine kinases BCR-ABL, PDGFR α and β, c-KIT and ABL, among others, that has proven effective for treatment of malignancies that harbor a constitutive activation of these kinases. Recent studies have shown that IM also strongly inhibits TGF-β.10 In view that IM is a dual inhibitor of the PDGFR and TGF-β pathways, it has been used in patients with fibrotic features with most cases presenting complete or partial response.11 We describe the outcome of 15 patients treated with IM for refractory sclerodermatous cGVHD.

Materials and methodsPatient selection

A retrospective study was conducted in a single allo-SCT center. All patients with cutaneous sclerodermatous cGVHD treated with IM and referred to the Dermatology department between 2001 and 2016 were included.

Data collection

Data were collected from electronic charts. Demographic data, past medical history and type of transplant were recorded including conditioning regimen and GVHD prophylaxis.

Response criteria

Evaluation of treatment response was performed by clinicians’ assessment and patients’ subjective response at 1, 3, 6, 9, 12 and 18 months after initiation of IM. Clinical response was assessed as: “complete response”, “partial response”, “significant response”, “no change”, or “progression”. Complete response was defined as resolution of all manifestations, partial response as an improvement of more than 50% without any new organ involvement or progression in a previously involved organ, and significant response as less than 50% improvement. No change was defined as the absence of improvement. Steroid dose tapper off was evaluated as “complete”, “partial”, or “not possible”. Treatment duration was at the discretion of the physician.

ResultsPatient characteristics

In total 18 patients were included (10 male and 8 female). Patient and transplant characteristics are summarized in Table 1. Acute myeloid leukemia was the most frequent preceding diagnosis. Median age at time of HSCT was 39 years (range 13-63). Fifteen (83%) transplants were HLA-identic sibling. All patients received GVHD prophylaxis, in which cyclosporine plus short course methotrexate was the most common regimen. Nine (50%) patients had history of acute GVHD. The mean number of affected organs by cGVHD was 3.5. Skin, eyes and liver were the most frequently involved (Table 2).

Table 1.

Patient and transplantation characteristics.

  Sex  Age (y)  Condition  Conditioning  Type  Cell source  GVHD profilaxis  aGVHD sites (grade)  cGVHD sites  Immunosuppression before imatinib 
63  AML  MAC  HLA id  PBSC  CS-TAC  No  Skin, intestine, lung, joint contracture  MMF 
24  AML  MAC  HLA id  BM  CSA-MTX  Skin (1), liver (3)  Skin, mouth, liver  CS, MMF, PT 
23  CML  MAC  NRD  UCSC  CS-CSA  No  Skin, intestine, lung  MMF, CS 
43  AML  MAC  HLA id  PBSC  CS-CSA  Skin (3)  Skin, mouth, eyes  TAC, CS, PT, ETN 
35  CLL  RIC  HLA id  PBSC  CSA-MMF  No  Skin, mouth, eyes, liver  CS 
37  ALL  MAC  HLA id  PBSC  CSA-MTX  No  Skin, eyes, liver, joint contracture  CS 
54  AML  MAC  HLA id  PBSC  CSA-MTX  No  Skin, mouth, eyes, liver  CS, CSA 
34  AA  MAC  HLA id  PBSC  CSA-MTX  No  Skin, mouth, eyes, lung  TAC, CS, PT 
27  AML  MAC  HLA id  PBSC  CSA-MTX  No  Skin, mouth, eyes, liver, lung  CS 
10  31  AML  MAC  HLA id  PBSC  CSA-MTX  Skin (1)  Skin, mouth, eyes, intestine, liver, lung,  MMF 
11  48  AML  MAC  NRD  UCSC  CS-CSA  Skin (1)  Skin, eyes, intestine, lung  CS 
12  52  CLL  RIC  HLA id  PBSC  CSA-MTX  Skin (2)  Skin, mouth, eyes, intestine  CS, CSA, ATG, MMF 
13  46  NHL  RIC  HLA id  PBSC  CSA-MTX  Skin (2)  Skin, nails, eyes  CS 
14  13  ALL  MAC  Haplo  PBSC  CY-MMF-TAC  Skin (3)  Skin, mouth, eyes, liver  No 
15  30  AML  MAC  HLA id  PBSC  CSA-MTX  Liver (1), intestine (1)  Skin, mouth, liver  CS, PT 
16  50  AML  MAC  HLA id  PBSC  CSA-MTX  No  Skin, eyes  No 
17  55  AML  IR  HLA id  PBSC  CSA-MTX  No  Skin, liver, hematopoyetic  CS, TAC 
18  43  ALL  MAC  HLA id  PBSC  CSA-MTX  Skin (2) GI  Skin, intestine  No 

M: male, F: female, Y: years, AML: acute myeloid leukemia, CML: chronic myeloid leukemia, CLL: chronic lymphocytic leukemia, ALL: acute lymphoblastic leukemia, AA: aplastic anemia, NHL: non-Hodgkin lymphoma, MAC: myeloablative conditioning, RIC: reduced intensity conditioning, NE: not evaluable, HLA id: HLA identical, Haplo: HLA haploidentical, NRD: non-related donor, PBSC: peripheral blood stem source, BM: bone marrow, UCSC: umbilical cord stem cell, CS: corticosteroids, CSA: cyclosporine A, MMF: Mycofenolate mofetil, MTX: methotrexate, CY: cyclophosphamide, TAC: tacrolimus, PT: phototherapy, ETN: etanercept, ATG: antitimoglobuline.

Table 2.

Organs affected by chronic GVHD.

Skin  18 
Eyes  12 
Liver 
Mouth 
Gastrointestinal tract 
Lung 
Musculoskeletal system 
Nails 
Hematopoietic system 

Patients received an average of 1.6 immunosuppressants before IM. The overall median follow-up until treatment suspension because of no further improvement or treatment failure was 27 months (range 1-89 months). Only patient No. 6 received IM intermittently, the remaining were on the drug continuously. IM dose was between 100-300mg daily (in two doses).

Treatment response

Mean time from initiation of IM to any degree of response was 2,75 months (range 1-9 months). After 1 month, 10 (66.7%) patients had partial or significant response but none achieved a complete response and 6 (33.3%) showed no changes. Of the 13 (86.7%) patients evaluated at 6 months, only 1 (7.7%) patient had a complete response, 5 (38.5%) had partial or significant response, 6 (46%) patients had no change, and in 1 (7.7%) patient the symptoms progressed. Ten (55.6%) patients were assessed at 12 months, with 1 (10%) complete response, 7 (70%) significant or partial response, 1 (10%) no change and 1 (10%) progression. Only 8 (44.4%) patients achieved 18 months follow up, 3 (37.5%) with a complete response, 4 (50%) with partial response and 1 patient (12.5%) showed no change.

Overall, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and 1 (6%) patient showed progressive disease at last follow-up. A complete suspension of steroids was achieved in 4 (22%) patients, partial reduction in 10 (55.6%) patients and no dose reduction was possible in 4 (22%) patients.

It is noteworthy that patients with early response to IM maintained it through all follow up, and those without response in the first months did not show improvement later. Only patient No. 12 had initially a partial response but progression at 12 months follow up.

Seven (39%) patients presented adverse reactions consisting of cramps, headache, hypophosphatemia, edema and thrombocytopenia. There were no withdrawals due to adverse effects. All patients (93.3%) except No. 12 are alive and 11 (61%) remain indefinitely on IM (Table 3).

Table 3.

Response at 1, 3, 6, 9, 12 and 18 months after start of imatinib.

Case no.  Maximal tolerated daily dose of IM (mg)  IM therapy duration at last follow-up (mo)  Side effects  IM discontinuation at last follow-up  cGVHD status at 1 mo of IM  cGVHD status at 3 mo of IM  cGVHD status at 6 mo of IM  cGVHD status at 9 mo of IM  cGVHD status at 12 mo of IM  cGVHD status at 18 mo of IM  Tapper off CS  Patient status 
200  10  No  Yes  NC  NC  NC  SR  Treatment suspended    Partial  Alive 
100  No  Yes  SR  Treatment suspended          Complete  Alive 
200  No  Yes  PR  PR  Treatment suspended        Partial  Alive 
200  32  Hypophosphatemia  No  NC  NC  NC  SR  PR  PR  Partial  Alive 
200  Cramps  Yes  SR  NC  NC  PR  Not achieved  Not achieved  Partial  Alive 
200  24  Cramps, headache  No  PR  PR  PR  PR  PR  PR  Partial  Alive 
200  48  Edema  No  PR  PR  PR  PR  PR  CR  Complete  Alive 
200  No  Yes  PR  Treatment suspended          No  Alive 
200  15  No  No  NC  SR  SR  SR  NC  CR  Partial  Alive 
10  200  No  Yes  NC  NC  Treatment suspended        No  Alive 
11  200  14  No  No  SR  CR  CR  CR  CR  Not achieved  Partial  Alive 
12  200  21  No  No  PR  PR  Prog  NC  Prog  NC  No  Dead 
13  200  16  Cramps  Yes  NC  SR  PR  PR  PR  Not achieved  No  Alive 
14  300  Trombocitopenia  Yes  PR  Treatment suspended          Partial  Alive 
15  200  No  No  NC  NC  NC  Treatment suspended      Partial  Alive 
16  200  84  Cramps  No  SR  SR  SR  SR  SR  PR  Complete  Alive 
17  100  58  No  No  SR  SR  NC  SR  SR  PR  Complete  Alive 
18  200  89  No  No  SR  SG  NC  NC  PR  CR  Partial  Alive 

Mo: months, IM: imatinib, NC: no change, PR: partial response, SR: significant response, CR: complete response, Prog: progression.

Discussion

Sclerodermatous cGVHD is characterized by chronic inflammation and fibrosis of the skin, lung and gastrointestinal tract that resembles systemic sclerosis. Topical and systemic steroids are the standard treatment. However, second line therapy is required in 50% of cases, such as cyclosporine, tacrolimus, mycophenolate mofetil, methotrexate, sirolimus, phototherapy and extracorporeal photopheresis.12 These treatments are limited by their adverse effects and have not showed improvement in the long-term outcome. Therefore, no current therapies used for cGVHD are approved by the Food and Drug Administration therefore it is recommended that refractory cGVHD should be treated under experimental protocols.11

This study shows that IM is effective in sclerodermatous cGVHD even at low doses. In our series, 15 of 18 (83%) patients achieved complete, partial or significant response, 2 (11%) had no change and 1 (6%) experimented progressive disease at last follow-up. Our results are similar to the study by Olivieri et al, in which 19 patients were treated with IM for refractory cGVHD with fibrotic features. IM dose was 100-400mg/day. Fifteen patients (79%) responded at 6 months, and overall survival rate was 84% at 18 months.11 Subsequently, Magro et al reported an overall response of 50% in a retrospective study of 14 patients with refractory sclerotic cGVHD.13 In contrast, de Masson et al. reported limited efficacy and tolerance of IM in the setting of severe sclerodermatous cGVHD in 39 patients. They attributed the poorer outcomes to patients’ older age, more severe disease and longest follow-up period.14

It has been reported that about 10% of patients do not tolerate IM.15 Its most common side effects reported in series of cGVHD are fluid retention and cytopenias. In our study, IM was reasonably well tolerated by almost all patients. However, the doses used were lower than that of CML (400mg/day).

Another benefit of treatment with IM is the reduction in steroids dose, which was possible in 14 (77.8%) of patients to some degree. Hitherto, it is not known if the immune process is linked to the resolution of fibrosis neither if IM may be useful in the absence of sclerotic features. Additionally, it is not possible to discriminate patients who will benefit from those who will not improve.

Two other more potent kinase and PDGFR inhibitors (dasatinib and nilotinib) are in the early stages of investigation.16 Besides the PDGFR pathways, EGFR is also implicated in fibrotic diseases. In this context, erlotinib is a potent EGFR tyrosine kinase inhibitor used to treat advanced non-small-cell lung cancer, and has recently been tested to prevent skin and visceral sclerodermatous lesions in a mouse model of cGVHD.7

In summary, IM represents a valuable option for patients with sclerodermatous cGVHD, it is a simple treatment that requires neither hospitalization nor central venous access with an acceptable safety profile. Nonetheless, IM is not effective in all patients with cGVHD, and the response is often partial. Further evidence from well-controlled randomized multicenter prospective trials using the National Institute of Health Consensus Response Criteria is needed to confirm the true efficacy of IM.

The limitations of this study are the reduced number of patients and the retrospective design. Cutaneous sclerosis and treatment response were subjectively assessed, and grading of IM toxicity was not recorded in patients’ charts.

As there is greater understanding of the pathophysiology treatment for cGVHD will rapidly develop. Novel strategies such as therapies that target B lymphocytes, expand regulatory cells and target the fibrotic process are under investigation.17 In the future, we may be able to provide tailored therapies for individual patients and separate the graft versus tumor effect from the debilitating symptoms of this disease.18

Funding

This study was supported in part by the Health Research Institute La Fe for having granted the project (IISLaFe 2015/0369).

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Bibliografía
[1]
E.A. Copelan.
Hematopoietic stem-cell transplantation.
N Engl J Med., 354 (2006), pp. 1813-1826
[2]
G. Socié, J.V. Stone, J.R. Wingard, Weisdorf D., P.J. Henslee-Downey, C. Bredeson, et al.
Long-term survival and late deaths after allogeneic bone marrow transplantation: Late effects working committee of the International Bone Marrow Transplant Registry.
N Engl J Med., 34 (1999), pp. 14-21
[3]
J.A. Moreno-Romero, F. Fernández-Avilés, E. Carreras, M. Rovira, C. Martínez, J.M. Mascaró, et al.
Imatinib as a potential treatment for sclerodermatous chronic graft-vs-host disease.
Arch Dermatol., 144 (2008), pp. 1106-1109
[4]
S. Svegliati, A. Olivieri, N. Campelli, M. Luchetti, A. Poloni, S. Trappolini, et al.
Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease.
[5]
J.H. Lee, J.H. Lee, S.J. Choi, S. Kim, M. Seol, Y.S. Lee, et al.
Graft-versus-host disease (GVHD)-specific survival and duration of systemic immunosuppressive treatment in patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation.
Br J Haematol., 122 (2003), pp. 637-644
[6]
H. Nishimori, Y. Maeda, M. Tanimoto.
Chronic graft-versus-host disease: Disease biology and novel therapeutic strategies.
Acta Med Okayama., 67 (2013), pp. 1-8
[7]
F. Morin, N. Kavian, W. Marut, C. Chéreau, O. Cerles, P. Grange.
Inhibition of EGFR tyrosine kinase by erlotinib prevents sclerodermatous graft-versus-host disease in a mouse model.
J Invest Dermatol., 135 (2015), pp. 2385-2393
[8]
S. Svegliati, A. Olivieri, N. Campelli, M. Luchetti, A. Poloni, S. Trappolini, et al.
Stimulatory autoantibodies to the PDGF receptor in patients with extensive chronic graft-versus-host disease.
[9]
L.L. McCormick, Y. Zhang, E. Tootell, A.C. Gilliam.
Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: A model for human scleroderma.
J Immunol., 163 (1999), pp. 5693-5699
[10]
J.H. Distler, A. Jungel, L.C. Huber, U. Schulze-Horsel, J. Zwerina, R.E. Gay, et al.
Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis.
Arthritis Rheum., 56 (2007), pp. 311-322
[11]
A. Olivieri, F. Locatelli, M. Zecca, A. Sanna, M. Cimminiello, R. Raimondi, et al.
Imatinib for refractory chronic graft-versus-host disease with fibrotic features.
[12]
D. Wolff, M. Schleuning, S. von Harsdorf, U. Bacher, A. Gerbitz, M. Stadler, et al.
Consensus conference on clinical practice in chronic GVHD: Second-line treatment of chronic graft-versus-host disease.
Biol Blood Marrow Transplant., 17 (2011), pp. 1-17
[13]
L. Magro, B. Catteau, V. Coiteux.
Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous shronic GVHD.
Bone Marrow Transplant., 42 (2008), pp. 757-760
[14]
A. De Masson, J.D. Bouaziz, R.P. Latour.
Limited efficacy and tolerance of imatinib mesylate in steroid-refractory sclerodermatous chronic GVHD.
Blood., 120 (2012), pp. 5089-5090
[15]
L. Caldemeyer, M. Dugan, J. Edwards, L. Akard.
Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia.
Curr Hematol Malig Rep., 11 (2016), pp. 71-79
[16]
J.H. Distler, O. Distler.
Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: Towards molecular targeted therapies.
Ann Rheum Dis., 69 (2010), pp. i48-i51
[17]
Y. Inamoto, M.E. Flowers.
Treatment of chronic graft-versus-host disease in 2011.
Curr Opin Hematol., 18 (2011), pp. 414-420
[18]
R. Seggewiss, K. Loré, E. Greiner, M.K. Magnusson, D.A. Price, D.C. Douek, et al.
Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner.
Blood., 6 (2005), pp. 2473-2479

Please cite this article as: Molés-Poveda P, Montesinos P, Sanz-Caballer J, de Unamuno B, Piñana JL, Sahuquillo A, et al. Tratamiento de la enfermedad de injerto contra huésped crónica esclerodermiforme con imatinib: una perspectiva dermatológica. Actas Dermosifiliogr. 2018;109:241–247.

Copyright © 2017. Elsevier España, S.L.U. and AEDV
Idiomas
Actas Dermo-Sifiliográficas (English Edition)

Subscribe to our newsletter

Article options
    NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
    NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
    NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
    NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
  • Additional material
Tools
NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
NOTICE Undefined index: tipo (includes_ws_v2/librerias/html/item.php[1273])
Supplemental materials
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.