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Allogeneic stem cell transplantation for the treatment of refractory scleromyxedema
FEATURED NEW INVESTIGATOR Allogeneic stem cell transplantation for the treatment of refractory scleromyxedema NONA SHAYEGI, NAEL ALAKEL, JAN MORITZ MIDDEKE, J. SCHETELIG, € € LUISA MANTOVANI-LOFFLER, and MARTIN BORNHAUSER DRESDEN AND LEIPZIG, GERMANY
Scleromyxedema is a rare disorder of connective tissue with unknown etiology. Its manifestation includes a generalized mucin deposition, which is frequently associated with paraproteinemia. The course of scleromyxedema is progressive and often lethal. As a result of its poorly understood pathogenesis, there is no causative treatment option. The efficacy of cytoreductive agents and autologous stem cell transplantation has been reported, but so far allografting as a treatment option has not yet been documented. Herein, we report on a patient with severe neurologic involvement and refractory course attaining durable remission after receiving an allogeneic hematopoietic cell transplant from an human leukocyte antigen-matched sibling. This case not only illustrates a potential new treatment option for selected patients, but also provides insights into the pathogenesis of this rare disease. (Translational Research 2015;165:321–324) Abbreviations: G-CSF ¼ Granulocyte-colony stimulating factor; GvD ¼ Graft versus disease; GVHD ¼ Graft-versus-host disease; HLA ¼ Human leukocyte antigen; IgG kappa ¼ Immunoglobulin G kappa; MRI ¼ Magnetic resonance imaging; SCT ¼ Stem cell transplantation; SM ¼ Scleromyxedema; WBC ¼ White blood cell
INTRODUCTION
T
he clinical manifestation of scleromyxedema (SM) involves a generalized papular and sclerodermoid eruption. This condition was first described in 1906 by Dubreuilh, and its association with monoclonal gammopathy has been known since the early 1960s.1,2 The diagnosis of SM requires the histology of the involved areas showing a triad of a marked interstitial mucin deposition, increased fibroblasts, and collagen.3
Nona Shayegi, MD, is a resident physician in the Department of Internal Medicine, University Hospital Carl Carus, Dresden, Germany. Dr Shayegi's research goals include expanding the applications of hematopoietic cell transplantation. From the Medizinische Klinik und Poliklinik I, Universit€atsklinikum Carl Gustav Carus der, Technischen Universit€at, Dresden, Germany; Praxisklinik am Johannisplatz Leipzig, Leipzig, Germany. Submitted for publication April 19, 2014; revision submitted June 6, 2014; accepted for publication June 11, 2014.
Mild perivascular lymphoplasmacytic inflammatory infiltrates can also be observed. These patients often have monoclonal gammopathy, in the absence of thyroid disease.4 Systemic implications including neurologic, hematologic, and cardiologic involvement are common and determine the prognosis.5 In particular the outcome is poor if neurologic impairment such as encephalopathy, convulsions, and coma occur. Recent case series report a fatal outcome for most patients with SM with systemic disease
Reprint requests: Nona Shayegi, Medizinische Klinik und Poliklinik I, Universit€atsklinikum Carl Gustav Carus der Technischen Universit€at, Fetscherstrasse 74, 01307 Dresden, Germany; e-mail: nshayegi@ hotmail.com. 1931-5244/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2014.06.002
321
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Shayegi et al
AT A GLANCE COMMENTARY Shayegi N, et al. Background
Scleromyxedema is a rare disorder of connective tissue. Its course is progressive and often lethal. Because of its poorly understood pathogenesis, there is no causative treatment option. Translational Significance
The successful clinical course in our patient provides direct evidence that there is a rationale for allografting in otherwise fatal cases of scleromyxedema. It can be hypothesized that cellular components of the bone marrow and secondary lymphatic organs may be involved. The combination of immunomodulation induced by allogeneic effector cells (graft-vs-disease effect) with unspecific cytoreductive conditioning therapy may be a strategy inducing stable remission in carefully selected patients.
manifestations.5,6 Among the 26 cases of SM with neurologic involvement reported in the literature, 8 patients died during neurologic episodes.6 To the best of our knowledge, we report the first patient with SM successfully treated by allogeneic hematopoietic cell transplantation. The procedure provided long-term remission after an otherwise refractory course with severe neurologic involvement. CASE REPORT
We report the case of a 44-year-old man, developing sclerodermoid skin changes unknown etiology. Two months later because of the onset of coma he was admitted to the intensive care unit. The patient immediately received supportive care, mechanical ventilation, and thrombolytic therapy on suspicion of a stroke. Magnetic resonance imaging (MRI) did not support the suspected diagnosis of a stroke. Findings of an extensive workup including analysis of autoimmune markers, thyroid studies, and urine were unrevealing except for immunoglobulin G kappa (IgG kappa) monoclonal gammopathy. Echocardiography, chest radiograph, and abdominal ultrasound showed no abnormalities. Bone marrow aspiration and biopsy were nondiagnostic. Furthermore, cerebrospinal fluid analysis indicated pleocytosis (20 white blood cell/mL; normal range, ,5/mL), and positivity for monoclonal
Translational Research February 2015
IgG kappa. Physical examination revealed progression of the sclerodermoid skin changes. Biopsy specimens of the papular and sclerodermoid eruptions from abdominal wall and forearms led to the diagnosis of SM, showing histologically with fibroblast proliferation, fibrosis, and mucin deposition in the upper reticular dermis without evidence of amyloidosis. The abnormalities of a second MRI performed 10 days after admission were consistent with the diagnosis of limbic encephalitis. Tracheotomy had to be performed because the patient still presented with significantly illness. A treatment regimen was initiated with high-dose steroids and plasmapheresis, which rapidly resolved the monoclonal gammopathy. Five weeks later, the MRI findings disappeared and his condition began to ameliorate so that he finally could be released from the intensive care unit. Four months later, he presented again with rapidly progressive skin changes. High-dose steroids, intravenous immunoglobulins, mycophenolate mofetil, and finally plasmapheresis were not able to stop the progressive course. The treatment of his refractory disease with 2 courses of doxorubicin, bortezomib, and dexamethasone showed no response, and because of that the regimen was switched to bortezomib and bendamustine. Meanwhile, his mental functions deteriorated progressively, leading to dysarthria. Fortunately, the patient achieved complete remission after cyclophosphamide stem cell mobilization and conditioning with high-dose melphalan for autologous stem cell transplant. Maintenance therapy with mycophenolate mofetil was initiated. One year after the stem cell transplant, he developed serious central nervous system (CNS) disturbances, characterized by tetraplegia and generalized seizures, followed by coma. His condition was temporarily stabilized by high-dose immunoglobulins, steroids, and continuous bortezomib and bendamustine infusion. To prevent further deterioration and a fatal outcome, the patient received allogeneic hematopoietic cells from an human leukocyte antigen-matched sister, after conditioning therapy with 150 mg/m2 fludarabine and 140 mg/m2 melphalan. Graft-vs-host-disease prophylaxis consisted of tacrolimus, bortezomib, and methotrexate. He achieved rapid hematologic engraftment associated with clinical remission and full and longlasting lymphohematopoietic donor chimerism during at least 530 days (Figs 1 and 2). At his latest followup, 18 months after allografting, the skin changes had dissipated completely, and he remained free of CNS disturbance. Ten months after allografting, when tacrolimus was tapered, there was an isolated flare of hepatic GvD that was successfully treated with prednisolone. During steroid therapy, infectious complications included 2 episodes of pneumonia (Pneumocystis
Translational Research Volume 165, Number 2
Shayegi et al
323
Fig 1. Clinical course from initial diagnosis to allogeneic transplantation. HLA, human leukocyte antigen; SCT, stem cell transplantation.
Fig 2. Monitoring of hematopoietic chimerism by short tandem repeats.
jiroveci and Streptococcus pneumoniae as well as Haemophilus parainfluenzae). DISCUSSION
For the first time, we demonstrate that allogeneic stem cell transplantation provides complete and long-term clinical remission in a patient with SM with severe neurologic involvements. So far an established consensus on the treatment of SM has not been reached because of its unknown origin and limited information on disease pathogenesis. Mostly the literature reports are restricted to single cases or small case series.5 The mechanism underlying mucin overproduction is unclear. There is no evidence to support a specific therapeutic strategy. Nonspecific antiinflammatory therapies including steroids, immunoglobulins, and plasmapheresis have been used, with varying outcomes.7 Given the association between SM and plasma cell dyscrasia, therapies for multiple myeloma have been proposed, including low-dose melphalan, prednisolone, high-dose chemotherapy with autologous stem cell support, and proteasome inhibitors to suppress the paraproteinemia.7-11 The pathogenetic significance of the monoclonal
gammopathy associated with SM remains a matter of debate because paraprotein levels are not consistent with disease severity or progression. Moreover, serum from patients with SM was shown to enhance fibroblast proliferation in vitro, but the involvement of the paraprotein was ruled out.12 Other possible causative agents currently considered include cytokines (ie, interleukin 1, interleukin 6, tumor necrosis factor a, and transforming growth factor b) known to stimulate mucin production, but functional evidence remains unavailable.13 Because clinical remissions are observed after autologous stem cell transplantation, it can be hypothesized that cellular components of the bone marrow and secondary lymphatic organs may be a source of these factors. This assumption is consistent with our finding and one published case of SM with hematologic involvement. The treatment with granulocyte-colony stimulating factor (G-CSF) in a patient with SM developing chronic idiopathic neutropenia not only led to normalization of the neutrophil count, but also was associated with a significant improvement of the skin and decrease in mucin deposition.14 Nevertheless this observation can be a result of the pleiotropic effects of G-CSF executing
324
Translational Research February 2015
Shayegi et al
immunomodulatory actions such as reduction of proinflammatory cytokines, induction of antiapoptotic pathways, and stimulation of angiogenesis as well as bone marrow mobilization.15 The largest multicenter case series on SM identified 30 patients, including 19 patients presenting extracutaneous manifestations: neurologic (30%), rheumatoid (23.3%), or cardiac (20%).5 Two patients developed hematologic malignancies: acute myeloid leukemia and Hodgkin disease. The review of the English literature reports on 26 cases of SM with severe neurologic presentation. Eight of these 26 cases had a lethal outcome during their neurologic episodes. Most of the remaining patients had complete recovery from the neurologic complications.6 Of note, although many systemic involvements may occur, autopsy results indicated that mucin overproduction is not detected in all affected organs.3 For example, patients with SM with CNS disturbances show no mucin accumulation in the brain. From systemic sclerosis, it is well known that T cell and B cell activation as well as macrophages induce fibrosis and fibroproliferation. Because inadequate fibroblast activation is the key feature of SM, it can be hypothesized that this disease is probably of immunologic origin. The resolution of the mucinosis in our patient supports the existence of a graft-vs-disease (GvD) effect and may be similar to the resolution of myelofibrosis after allografting for myeloproliferative malignancies. The term ‘‘GvD’’ effect is referring on to the observation in experimental animal models and patients showing that transplanted allogeneic immunocompetent cells or donor lymphocyte infusions are able to eliminate leukemic cells without further cytotoxic treatment. The biology of the GvD effect has been poorly defined but donor T cells are thought to be the main mediators and the target antigens are for the most part unidentified. In conclusion, we provide evidence that allogeneic stem cell transplantation can lead to complete remission in patients with SM with severe neurologic involvements, whereas the low incidence of SM is insufficient to support prospective clinical trials, the successful clinical course of our patient provides direct evidence for the rationale of allografting in otherwise fatal cases of SM.
ACKNOWLEDGMENTS
We offer our deepest gratitude to Christiane Gl€aser and Christian Thiede for collecting the data and performing the chimerism analysis. Conflict of interests: None. REFERENCES
1. Dubreuilh W. Fibromes miliares folliculaires: sclerodermie consecutive. Arch Derm Syph 1908;569–72. 2. Perry HO, Montgomery H, Stickney JM. Further observations on lichen myxedematosus. Ann Intern Med 1960;53:955–69. 3. Rongioletti F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 2001;44:273–81. 4. Mccarthy JT, Osserman e, Lombardo PC, Takatsuki K. An abnormal serum globulin in lichen myxedematosus. Arch Dermatol 1964;89:446–50. 5. Rongioletti F, Merlo G, Cinotti E, et al. Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients. J Am Acad Dermatol 2013;69:66–72. 6. Fleming KE, Virmani D, Sutton E, et al. Scleromyxedema and the dermato-neuro syndrome: case report and review of the literature. J Cutan Pathol 2012;39:508–17. 7. Rongioletti F, Hazini A, Rebora A. Coma associated with scleromyxoedema and interferon alfa therapy. Full recovery after steroids and cyclophosphamide combined with plasmapheresis. Br J Dermatol 2001;144:1283–4. 8. Marshall K, Klepeiss SA, Ioffreda MD, Helm KF. Scleromyxedema presenting with neurologic symptoms: a case report and review of the literature. Cutis 2010;85:137–40. 9. Nieves DS, Bondi EE, Wallmark J, Raps EC, Seykora JT. Scleromyxedema: successful treatment of cutaneous and neurologic symptoms. Cutis 2000;65:89–92. 10. Ataergin S, Arpaci F, Demiriz M, Ozet A. Transient efficacy of double high-dose chemotherapy and autologous peripheral stem cell transplantation, immunoglobulin, thalidomide, and bortezomib in the treatment of scleromyxedema. Am J Clin Dermatol 2008;9:271–3. 11. Ca~nueto J, Labrador J, Roman C, et al. The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights. Eur J Haematol 2012;88:450–4. 12. Harper RA, Rispler J. Lichen myxedematosus serum stimulates human skin fibroblast proliferation. Science 1978;199:545–7. 13. Rongioletti F, Rebora A, eds. Dermatology: mucinoses. 3rd ed. Philadelphia: Elsevier, 2012. 14. Cohen AM, Hodak E, David M, Mittelman M, Gal R, Stern R. Beneficial effect of granulocyte-colony stimulating factor in scleromyxoedema associated with severe idiopathic neutropenia. Br J Dermatol 1996;135:626–9. 15. Minnerup J, Sevimli S, Sch€abitz W. Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies. Exp Transl Stroke Med 2009;1:2.
Scleromyxedema is a rare disorder of connective tissue with unknown etiology. Its manifestation includes a generalized mucin deposition, which is frequently associated with paraproteinemia. The course of scleromyxedema is progressive and often lethal. As a result of its poorly understood pathogenesis, there is no causative treatment option. The efficacy of cytoreductive agents and autologous stem cell transplantation has been reported, but so far allografting as a treatment option has not yet been documented. Herein, we report on a patient with severe neurologic involvement and refractory course attaining durable remission after receiving an allogeneic hematopoietic cell transplant from an human leukocyte antigen-matched sibling. This case not only illustrates a potential new treatment option for selected patients, but also provides insights into the pathogenesis of this rare disease. (Translational Research 2015;165:321–324) Abbreviations: G-CSF ¼ Granulocyte-colony stimulating factor; GvD ¼ Graft versus disease; GVHD ¼ Graft-versus-host disease; HLA ¼ Human leukocyte antigen; IgG kappa ¼ Immunoglobulin G kappa; MRI ¼ Magnetic resonance imaging; SCT ¼ Stem cell transplantation; SM ¼ Scleromyxedema; WBC ¼ White blood cell
INTRODUCTION
T
he clinical manifestation of scleromyxedema (SM) involves a generalized papular and sclerodermoid eruption. This condition was first described in 1906 by Dubreuilh, and its association with monoclonal gammopathy has been known since the early 1960s.1,2 The diagnosis of SM requires the histology of the involved areas showing a triad of a marked interstitial mucin deposition, increased fibroblasts, and collagen.3
Nona Shayegi, MD, is a resident physician in the Department of Internal Medicine, University Hospital Carl Carus, Dresden, Germany. Dr Shayegi's research goals include expanding the applications of hematopoietic cell transplantation. From the Medizinische Klinik und Poliklinik I, Universit€atsklinikum Carl Gustav Carus der, Technischen Universit€at, Dresden, Germany; Praxisklinik am Johannisplatz Leipzig, Leipzig, Germany. Submitted for publication April 19, 2014; revision submitted June 6, 2014; accepted for publication June 11, 2014.
Mild perivascular lymphoplasmacytic inflammatory infiltrates can also be observed. These patients often have monoclonal gammopathy, in the absence of thyroid disease.4 Systemic implications including neurologic, hematologic, and cardiologic involvement are common and determine the prognosis.5 In particular the outcome is poor if neurologic impairment such as encephalopathy, convulsions, and coma occur. Recent case series report a fatal outcome for most patients with SM with systemic disease
Reprint requests: Nona Shayegi, Medizinische Klinik und Poliklinik I, Universit€atsklinikum Carl Gustav Carus der Technischen Universit€at, Fetscherstrasse 74, 01307 Dresden, Germany; e-mail: nshayegi@ hotmail.com. 1931-5244/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2014.06.002
321
322
Shayegi et al
AT A GLANCE COMMENTARY Shayegi N, et al. Background
Scleromyxedema is a rare disorder of connective tissue. Its course is progressive and often lethal. Because of its poorly understood pathogenesis, there is no causative treatment option. Translational Significance
The successful clinical course in our patient provides direct evidence that there is a rationale for allografting in otherwise fatal cases of scleromyxedema. It can be hypothesized that cellular components of the bone marrow and secondary lymphatic organs may be involved. The combination of immunomodulation induced by allogeneic effector cells (graft-vs-disease effect) with unspecific cytoreductive conditioning therapy may be a strategy inducing stable remission in carefully selected patients.
manifestations.5,6 Among the 26 cases of SM with neurologic involvement reported in the literature, 8 patients died during neurologic episodes.6 To the best of our knowledge, we report the first patient with SM successfully treated by allogeneic hematopoietic cell transplantation. The procedure provided long-term remission after an otherwise refractory course with severe neurologic involvement. CASE REPORT
We report the case of a 44-year-old man, developing sclerodermoid skin changes unknown etiology. Two months later because of the onset of coma he was admitted to the intensive care unit. The patient immediately received supportive care, mechanical ventilation, and thrombolytic therapy on suspicion of a stroke. Magnetic resonance imaging (MRI) did not support the suspected diagnosis of a stroke. Findings of an extensive workup including analysis of autoimmune markers, thyroid studies, and urine were unrevealing except for immunoglobulin G kappa (IgG kappa) monoclonal gammopathy. Echocardiography, chest radiograph, and abdominal ultrasound showed no abnormalities. Bone marrow aspiration and biopsy were nondiagnostic. Furthermore, cerebrospinal fluid analysis indicated pleocytosis (20 white blood cell/mL; normal range, ,5/mL), and positivity for monoclonal
Translational Research February 2015
IgG kappa. Physical examination revealed progression of the sclerodermoid skin changes. Biopsy specimens of the papular and sclerodermoid eruptions from abdominal wall and forearms led to the diagnosis of SM, showing histologically with fibroblast proliferation, fibrosis, and mucin deposition in the upper reticular dermis without evidence of amyloidosis. The abnormalities of a second MRI performed 10 days after admission were consistent with the diagnosis of limbic encephalitis. Tracheotomy had to be performed because the patient still presented with significantly illness. A treatment regimen was initiated with high-dose steroids and plasmapheresis, which rapidly resolved the monoclonal gammopathy. Five weeks later, the MRI findings disappeared and his condition began to ameliorate so that he finally could be released from the intensive care unit. Four months later, he presented again with rapidly progressive skin changes. High-dose steroids, intravenous immunoglobulins, mycophenolate mofetil, and finally plasmapheresis were not able to stop the progressive course. The treatment of his refractory disease with 2 courses of doxorubicin, bortezomib, and dexamethasone showed no response, and because of that the regimen was switched to bortezomib and bendamustine. Meanwhile, his mental functions deteriorated progressively, leading to dysarthria. Fortunately, the patient achieved complete remission after cyclophosphamide stem cell mobilization and conditioning with high-dose melphalan for autologous stem cell transplant. Maintenance therapy with mycophenolate mofetil was initiated. One year after the stem cell transplant, he developed serious central nervous system (CNS) disturbances, characterized by tetraplegia and generalized seizures, followed by coma. His condition was temporarily stabilized by high-dose immunoglobulins, steroids, and continuous bortezomib and bendamustine infusion. To prevent further deterioration and a fatal outcome, the patient received allogeneic hematopoietic cells from an human leukocyte antigen-matched sister, after conditioning therapy with 150 mg/m2 fludarabine and 140 mg/m2 melphalan. Graft-vs-host-disease prophylaxis consisted of tacrolimus, bortezomib, and methotrexate. He achieved rapid hematologic engraftment associated with clinical remission and full and longlasting lymphohematopoietic donor chimerism during at least 530 days (Figs 1 and 2). At his latest followup, 18 months after allografting, the skin changes had dissipated completely, and he remained free of CNS disturbance. Ten months after allografting, when tacrolimus was tapered, there was an isolated flare of hepatic GvD that was successfully treated with prednisolone. During steroid therapy, infectious complications included 2 episodes of pneumonia (Pneumocystis
Translational Research Volume 165, Number 2
Shayegi et al
323
Fig 1. Clinical course from initial diagnosis to allogeneic transplantation. HLA, human leukocyte antigen; SCT, stem cell transplantation.
Fig 2. Monitoring of hematopoietic chimerism by short tandem repeats.
jiroveci and Streptococcus pneumoniae as well as Haemophilus parainfluenzae). DISCUSSION
For the first time, we demonstrate that allogeneic stem cell transplantation provides complete and long-term clinical remission in a patient with SM with severe neurologic involvements. So far an established consensus on the treatment of SM has not been reached because of its unknown origin and limited information on disease pathogenesis. Mostly the literature reports are restricted to single cases or small case series.5 The mechanism underlying mucin overproduction is unclear. There is no evidence to support a specific therapeutic strategy. Nonspecific antiinflammatory therapies including steroids, immunoglobulins, and plasmapheresis have been used, with varying outcomes.7 Given the association between SM and plasma cell dyscrasia, therapies for multiple myeloma have been proposed, including low-dose melphalan, prednisolone, high-dose chemotherapy with autologous stem cell support, and proteasome inhibitors to suppress the paraproteinemia.7-11 The pathogenetic significance of the monoclonal
gammopathy associated with SM remains a matter of debate because paraprotein levels are not consistent with disease severity or progression. Moreover, serum from patients with SM was shown to enhance fibroblast proliferation in vitro, but the involvement of the paraprotein was ruled out.12 Other possible causative agents currently considered include cytokines (ie, interleukin 1, interleukin 6, tumor necrosis factor a, and transforming growth factor b) known to stimulate mucin production, but functional evidence remains unavailable.13 Because clinical remissions are observed after autologous stem cell transplantation, it can be hypothesized that cellular components of the bone marrow and secondary lymphatic organs may be a source of these factors. This assumption is consistent with our finding and one published case of SM with hematologic involvement. The treatment with granulocyte-colony stimulating factor (G-CSF) in a patient with SM developing chronic idiopathic neutropenia not only led to normalization of the neutrophil count, but also was associated with a significant improvement of the skin and decrease in mucin deposition.14 Nevertheless this observation can be a result of the pleiotropic effects of G-CSF executing
324
Translational Research February 2015
Shayegi et al
immunomodulatory actions such as reduction of proinflammatory cytokines, induction of antiapoptotic pathways, and stimulation of angiogenesis as well as bone marrow mobilization.15 The largest multicenter case series on SM identified 30 patients, including 19 patients presenting extracutaneous manifestations: neurologic (30%), rheumatoid (23.3%), or cardiac (20%).5 Two patients developed hematologic malignancies: acute myeloid leukemia and Hodgkin disease. The review of the English literature reports on 26 cases of SM with severe neurologic presentation. Eight of these 26 cases had a lethal outcome during their neurologic episodes. Most of the remaining patients had complete recovery from the neurologic complications.6 Of note, although many systemic involvements may occur, autopsy results indicated that mucin overproduction is not detected in all affected organs.3 For example, patients with SM with CNS disturbances show no mucin accumulation in the brain. From systemic sclerosis, it is well known that T cell and B cell activation as well as macrophages induce fibrosis and fibroproliferation. Because inadequate fibroblast activation is the key feature of SM, it can be hypothesized that this disease is probably of immunologic origin. The resolution of the mucinosis in our patient supports the existence of a graft-vs-disease (GvD) effect and may be similar to the resolution of myelofibrosis after allografting for myeloproliferative malignancies. The term ‘‘GvD’’ effect is referring on to the observation in experimental animal models and patients showing that transplanted allogeneic immunocompetent cells or donor lymphocyte infusions are able to eliminate leukemic cells without further cytotoxic treatment. The biology of the GvD effect has been poorly defined but donor T cells are thought to be the main mediators and the target antigens are for the most part unidentified. In conclusion, we provide evidence that allogeneic stem cell transplantation can lead to complete remission in patients with SM with severe neurologic involvements, whereas the low incidence of SM is insufficient to support prospective clinical trials, the successful clinical course of our patient provides direct evidence for the rationale of allografting in otherwise fatal cases of SM.
ACKNOWLEDGMENTS
We offer our deepest gratitude to Christiane Gl€aser and Christian Thiede for collecting the data and performing the chimerism analysis. Conflict of interests: None. REFERENCES
1. Dubreuilh W. Fibromes miliares folliculaires: sclerodermie consecutive. Arch Derm Syph 1908;569–72. 2. Perry HO, Montgomery H, Stickney JM. Further observations on lichen myxedematosus. Ann Intern Med 1960;53:955–69. 3. Rongioletti F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 2001;44:273–81. 4. Mccarthy JT, Osserman e, Lombardo PC, Takatsuki K. An abnormal serum globulin in lichen myxedematosus. Arch Dermatol 1964;89:446–50. 5. Rongioletti F, Merlo G, Cinotti E, et al. Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients. J Am Acad Dermatol 2013;69:66–72. 6. Fleming KE, Virmani D, Sutton E, et al. Scleromyxedema and the dermato-neuro syndrome: case report and review of the literature. J Cutan Pathol 2012;39:508–17. 7. Rongioletti F, Hazini A, Rebora A. Coma associated with scleromyxoedema and interferon alfa therapy. Full recovery after steroids and cyclophosphamide combined with plasmapheresis. Br J Dermatol 2001;144:1283–4. 8. Marshall K, Klepeiss SA, Ioffreda MD, Helm KF. Scleromyxedema presenting with neurologic symptoms: a case report and review of the literature. Cutis 2010;85:137–40. 9. Nieves DS, Bondi EE, Wallmark J, Raps EC, Seykora JT. Scleromyxedema: successful treatment of cutaneous and neurologic symptoms. Cutis 2000;65:89–92. 10. Ataergin S, Arpaci F, Demiriz M, Ozet A. Transient efficacy of double high-dose chemotherapy and autologous peripheral stem cell transplantation, immunoglobulin, thalidomide, and bortezomib in the treatment of scleromyxedema. Am J Clin Dermatol 2008;9:271–3. 11. Ca~nueto J, Labrador J, Roman C, et al. The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights. Eur J Haematol 2012;88:450–4. 12. Harper RA, Rispler J. Lichen myxedematosus serum stimulates human skin fibroblast proliferation. Science 1978;199:545–7. 13. Rongioletti F, Rebora A, eds. Dermatology: mucinoses. 3rd ed. Philadelphia: Elsevier, 2012. 14. Cohen AM, Hodak E, David M, Mittelman M, Gal R, Stern R. Beneficial effect of granulocyte-colony stimulating factor in scleromyxoedema associated with severe idiopathic neutropenia. Br J Dermatol 1996;135:626–9. 15. Minnerup J, Sevimli S, Sch€abitz W. Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies. Exp Transl Stroke Med 2009;1:2.