Morphea and systemic sclerosis are fibrosing disorders of the skin that share common inflammatory and immunologic pathways that are responsible for the vascular changes, increased collagen production, and extracellular matrix proliferation seen in both conditions. Recent advances in molecular biology techniques have furthered our knowledge of the potential underlying pathogenic mechanisms and offer new and provocative areas of research for novel diagnostic and therapeutic interventions. This review focuses on the role of vascular injury in the development of morphea, the use of ultrasonography as a diagnostic modality, and well-established and newly proposed treatments. 1. Introduction Morphea is an inflammatory, fibrosing skin disorder that leads to sclerosis of the dermis and subcutaneous tissue but in some cases may also extend to the fascia, muscle, and underlying bone. Clinically, morphea has an asymmetric distribution and is usually confined to one body area; hence it is also referred to as localized scleroderma. Systemic sclerosis (SSc), however, in addition to symmetric skin changes is characterized by internal organ involvement, sclerodactyly, presence of Raynaud’s phenomenon, and nailfold capillary abnormalities. Despite these differences, both entities share common inflammatory and immunologic pathways that are ultimately responsible for the vascular changes, increased collagen production, and extracellular matrix proliferation seen in both conditions. Although the etiology and precise mechanisms that trigger the cascade of molecular events that culminate in skin fibrosis are not fully understood, advances in molecular biology techniques have furthered our knowledge of the potential culprits and offer new and provocative areas of research for novel diagnostic and therapeutic interventions. This brief review will focus on the role of vascular injury in the development of morphea with emphasis on recent basic research data as well as use of ultrasonography as a diagnostic method. Lastly, well-established and newly proposed treatments will be discussed. 2. Clinical Features Several classification systems have been developed in attempt to grasp the breath of the various forms of presentation of morphea [1, 2]. They are largely based on clinical findings and include, with minor differences, at least four major variants: plaque-type, linear, generalized and a miscellaneous group of morphologically distinct phenotypes. Plaque-Type Morphea (Morphea en Plaque or Circumscribed). It is the most common subtype overall and the most common variant in
References
[1]
R. M. Laxer and F. Zulian, “Localized scleroderma,” Current Opinion in Rheumatology, vol. 18, no. 6, pp. 606–613, 2006.
[2]
L. S. Peterson, A. M. Nelson, and W. P. D. Su, “Classification of morphea (localized scleroderma),” Mayo Clinic Proceedings, vol. 70, no. 11, pp. 1068–1076, 1995.
[3]
Y. E. Chiu, S. Vora, E. K. Kwon, and M. Maheshwari, “A significant proportion of children with morphea en coup de sabre and Parry-Romberg syndrome have neuroimaging findings,” Pediatric Dermatology, vol. 29, pp. 738–748, 2012.
[4]
T. M. Frech, M. P. Revelo, S. G. Drakos, et al., “Vascular leak is a central feature in the pathogenesis of systemic sclerosis,” The Journal of Rheumatology, vol. 39, pp. 1385–1391, 2012.
[5]
M. Hasegawa, S. Sato, T. Nagaoka, M. Fujimoto, and K. Takehara, “Serum levels of tumor necrosis factor and interleukin-13 are elevated in patients with localized scleroderma,” Dermatology, vol. 207, no. 2, pp. 141–147, 2003.
[6]
H. Higley, K. Persichitte, S. Chu, W. Waegell, R. Vancheeswaran, and C. Black, “Immunocytochemical localization and serologic detection of transforming growth factor β1: association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon,” Arthritis and Rheumatism, vol. 37, no. 2, pp. 278–288, 1994.
[7]
H. Ihn, S. Sato, M. Fujimoto, K. Kikuchi, and K. Takehara, “Demonstration of interleukin-2, interleukin-4 and interleukin-6 in sera from patients with localized scleroderma,” Archives of Dermatological Research, vol. 287, no. 2, pp. 193–197, 1995.
[8]
V.-M. Kahari, M. Sandberg, H. Kalimo, T. Vuorio, and E. Vuorio, “Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization,” Journal of Investigative Dermatology, vol. 90, no. 5, pp. 664–670, 1988.
[9]
R. Sgonc, M. S. Gruschwitz, H. Dietrich, H. Recheis, M. E. Gershwin, and G. Wick, “Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma,” The Journal of Clinical Investigation, vol. 98, no. 3, pp. 785–792, 1996.
[10]
P. Cipriani, A. Marrelli, V. Liakouli, P. Di Benedetto, and R. Giacomelli, “Cellular players in angiogenesis during the course of systemic sclerosis,” Autoimmunity Reviews, vol. 10, no. 10, pp. 641–646, 2011.
[11]
D. Hamamdzic, R. A. Harley, D. Hazen-Martin, and E. C. LeRoy, “MCMV induces neointima in IFN-γR-/- mice: intimal cell apoptosis and persistent proliferation of myofibroblasts,” BMC Musculoskeletal Disorders, vol. 2, article 1, 2001.
[12]
C. M. Magro, A. N. Crowson, and C. Ferri, “Cytomegalovirus-associated cutaneous vasculopathy and scleroderma sans inclusion body change,” Human Pathology, vol. 38, no. 1, pp. 42–49, 2007.
[13]
C. M. Magro, G. Nuovo, C. Ferri, A. N. Crowson, D. Giuggioli, and M. Sebastiani, “Parvoviral infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma,” Journal of Cutaneous Pathology, vol. 31, no. 1, pp. 43–50, 2004.
[14]
S. S. Koca, A. Isik, I. H. Ozercan, B. Ustundag, B. Evren, and K. Metin, “Effectiveness of etanercept in bleomycin-induced experimental scleroderma,” Rheumatology, vol. 47, no. 2, pp. 172–175, 2008.
[15]
C. Lunardi, M. Dolcino, D. Peterlana et al., “Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach,” PLoS Medicine, vol. 3, no. 1, article e2, 2006.
[16]
R. Pastano, C. Dell'Agnola, C. Bason, et al., “Antibodies against human cytomegalovirus late protein UL94 in the pathogenesis of scleroderma-like skin lesions in chronic graft-versus-host disease,” International Immunology, vol. 24, pp. 583–591, 2012.
[17]
V. Ratanatharathorn, L. Ayash, C. Reynolds et al., “Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody,” Biology of Blood and Marrow Transplantation, vol. 9, no. 8, pp. 505–511, 2003.
[18]
T. C. Barnes, D. G. Spiller, M. E. Anderson, S. W. Edwards, and R. J. Moots, “Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signalling: a novel target for systemic sclerosis?” Annals of the Rheumatic Diseases, vol. 70, no. 2, pp. 366–372, 2011.
[19]
R. Sgonc, M. S. Gruschwitz, G. Boeck, N. Sepp, J. Gruber, and G. Wick, “Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95,” Arthritis and Rheumatism, vol. 43, pp. 2550–2562, 2000.
[20]
J. H. W. Distler, A. Akhmetshina, C. Dees et al., “Induction of apoptosis in circulating angiogenic cells by microparticles,” Arthritis and Rheumatism, vol. 63, no. 7, pp. 2067–2077, 2011.
[21]
S. Guiducci, J. H. W. Distler, A. Jüngel et al., “The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis,” Arthritis and Rheumatism, vol. 58, no. 9, pp. 2845–2853, 2008.
[22]
J. H. W. Distler, L. C. Huber, S. Gay, O. Distler, and D. S. Pisetsky, “Microparticles as mediators of cellular cross-talk in inflammatory disease,” Autoimmunity, vol. 39, no. 8, pp. 683–690, 2006.
[23]
S. Chabaud, M.-P. Corriveau, T. Grodzicky et al., “Decreased secretion of MMP by non-lesional late-stage scleroderma fibroblasts after selection via activation of the apoptotic fas-pathway,” Journal of Cellular Physiology, vol. 226, no. 7, pp. 1907–1914, 2011.
[24]
G. H. Samuel, S. Lenna, A. M. Bujor, R. Lafyatis, and M. Trojanowska, “Acid sphingomyelinase deficiency contributes to resistance of scleroderma fibroblasts to Fas-mediated apoptosis,” Journal of Dermatological Science, vol. 67, pp. 166–172, 2012.
[25]
C. Mihai and J. W. C. Tervaert, “Anti-endothelial cell antibodies in systemic sclerosis,” Annals of the Rheumatic Diseases, vol. 69, no. 2, pp. 319–324, 2010.
[26]
D. Abraham and O. Distler, “How does endothelial cell injury start? The role of endothelin in systemic sclerosis,” Arthritis Research and Therapy, vol. 9, supplement 2, article S2, 2007.
[27]
H. Dib, M. C. Tamby, G. Bussone, et al., “Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma,” European Respiratory Journal, vol. 39, pp. 1405–1414, 2012.
[28]
K. Lewandowska, M. Ciurzynski, E. Gorska, et al., “Antiendothelial cells antibodies in patients with systemic sclerosis in relation to pulmonary hypertension and lung fibrosis,” Advances in Experimental Medicine and Biology, vol. 756, pp. 147–153, 2013.
[29]
J. Avouac, N. Cagnard, J. H. Distler et al., “Insights into the pathogenesis of systemic sclerosis based on the gene expression profile of progenitor-derived endothelial cells,” Arthritis and Rheumatism, vol. 63, no. 11, pp. 3552–3562, 2011.
[30]
C. Selmi, C. A. Feghali-Bostwick, A. Lleo, et al., “X chromosome gene methylation in peripheral lymphocytes from monozygotic twins discordant for scleroderma,” Clinical & Experimental Immunology, vol. 169, pp. 253–262, 2012.
[31]
M. Bielecki, K. Kowal, A. Lapinska, S. Chwiesko-Minarowska, L. Chyczewski, and O. Kowal-Bielecka, “Peripheral blood mononuclear cells from patients with systemic sclerosis spontaneously secrete increased amounts of vascular endothelial growth factor (VEGF) already in the early stage of the disease,” Advances in Medical Sciences, vol. 56, no. 2, pp. 255–263, 2011.
[32]
V. Carrai, I. Miniati, S. Guiducci, et al., “Evidence for reduced angiogenesis in bone marrow in SSc: immunohistochemistry and multiparametric computerized imaging analysis,” Rheumatology, vol. 51, pp. 1042–1048, 2012.
[33]
N. Del Papa, N. Quirici, C. Scavullo et al., “Antiendothelial cell antibodies induce apoptosis of bone marrow endothelial progenitors in systemic sclerosis,” The Journal of Rheumatology, vol. 37, no. 10, pp. 2053–2063, 2010.
[34]
M. Bielecki, K. Kowal, A. Lapinska et al., “Diminished production of TWEAK by the peripheral blood mononuclear cells is associated with vascular involvement in patients with systemic sclerosis,” Folia Histochemica et Cytobiologica, vol. 47, no. 3, pp. 465–469, 2009.
[35]
X. Wortsman, J. Wortsman, I. Sazunic, and L. Carre？o, “Activity assessment in morphea using color Doppler ultrasound,” Journal of the American Academy of Dermatology, vol. 65, no. 5, pp. 942–948, 2011.
[36]
K. A. Nezafati, R. L. Cayce, J. S. Susa et al., “14-MHz ultrasonography as an outcome measure in morphea (localized scleroderma),” Archives of Dermatology, vol. 147, no. 9, pp. 1112–1115, 2011.
[37]
S. C. Li, M. S. Liebling, K. A. Haines, J. E. Weiss, and A. Prann, “Initial evaluation of an ultrasound measure for assessing the activity of skin lesions in juvenile localized scleroderma,” Arthritis Care and Research, vol. 63, no. 5, pp. 735–742, 2011.
[38]
E. Szymańska, M. Maj, M. Majsterek, J. Litniewski, A. Nowicki, and L. Rudnicka, “The usefulness of high frequency ultrasonography in dermatologlcal practice—ultrasound features of selected cutaneous lesions,” Polski Merkuriusz Lekarski, vol. 31, no. 181, pp. 37–40, 2011.
[39]
A. Iagnocco, F. Ceccarelli, C. Vavala, et al., “Ultrasound in the assessment of musculoskeletal involvement in systemic sclerosis,” Medical Ultrasonography, vol. 14, pp. 231–234, 2012.
[40]
T. M. Fernandes, B. E. Bica, N. R. Villela, et al., “Evaluation of endothelial function in patients with limited systemic sclerosis by use of brachial artery Doppler ultrasound,” Revista Brasileira de Reumatologia, vol. 52, pp. 561–568, 2012.
[41]
A. Osmola-Mankowska, W. Silny, A. Danczak-Pazdrowska, et al., “Assessment of chronic sclerodermoid Graft-versus-Host Disease patients, using 20 MHz high-frequency ultrasonography and cutometer methods,” Skin Research and Technology, vol. 19, no. 1, pp. e417–e422, 2013.
[42]
S. C. Li, M. S. Liebling, and K. A. Haines, “Ultrasonography is a sensitive tool for monitoring localized scleroderma,” Rheumatology, vol. 46, no. 8, pp. 1316–1319, 2007.
[43]
R. Buense, I. A. Duarte, and M. Bouer, “Localized scleroderma: assessment of the therapeutic response to phototherapy,” Anais Brasileiros de Dermatologia, vol. 87, pp. 63–69, 2012.
[44]
E. Pope, A. S. Doria, M. Theriault, A. Mohanta, and R. M. Laxer, “Topical imiquimod 5% cream for pediatric plaque morphea: a prospective, multiple-baseline, open-label pilot study,” Dermatology, vol. 223, no. 4, pp. 363–369, 2011.
[45]
S. Schanz, G. Fierlbeck, A. Ulmer et al., “Localized scleroderma: MR findings and clinical features,” Radiology, vol. 260, no. 3, pp. 817–824, 2011.
[46]
S. Schanz, J. Henes, A. Ulmer, et al., “Magnetic resonance imaging findings in patients with systemic scleroderma and musculoskeletal symptoms,” European Radiology, vol. 23, pp. 212–221, 2013.
[47]
S. Schanz, J. Henes, A. Ulmer, et al., “Response evaluation of musculoskeletal involvement in patients with deep morphea treated with methotrexate and prednisolone: a combined MRI and clinical approach,” American Journal of Roentgenology, vol. 200, pp. 376–382, 2013.
[48]
F. Zulian, C. Vallongo, A. Patrizi, et al., “A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea),” Journal of the American Academy of Dermatology, vol. 67, pp. 1151–1156, 2012.
[49]
K. S. Torok and T. Arkachaisri, “Methotrexate and corticosteroids in the treatment of localized scleroderma: a standardized prospective longitudinal single-center study,” The Journal of Rheumatology, vol. 39, no. 2, pp. 286–294, 2012.
[50]
Y. Inamo and T. Ochiai, “Successful combination treatment of a patient with progressive Juvenile Localized Scleroderma (Morphea) using Imatinib, Corticosteroids, and Methotrexate,” Pediatric Dermatology, 2012.
[51]
S. Reitamo, A. Remitz, J. Varga et al., “Demonstration of interleukin 8 and autoantibodies to interleukin 8 in the serum of patients with systemic sclerosis and related disorders,” Archives of Dermatology, vol. 129, no. 2, pp. 189–193, 1993.
[52]
S. Visvanathan, J. C. Marini, J. S. Smolen et al., “Changes in biomarkers of inflammation and bone turnover and associations with clinical efficacy following infliximab plus methotrexate therapy in patients with early rheumatoid arthritis,” The Journal of Rheumatology, vol. 34, no. 7, pp. 1465–1474, 2007.
[53]
J. E. Pope, N. Bellamy, J. R. Seibold, et al., “A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma,” Arthritis and Rheumatism, vol. 44, pp. 1351–1358, 2001.
[54]
F. H. J. van den Hoogen, A. M. T. Boerbooms, A. J. G. Swaak, J. J. Rasker, H. J. J. van Lier, and L. B. A. van de Putte, “Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial,” British Journal of Rheumatology, vol. 35, no. 4, pp. 364–372, 1996.
[55]
C. T. Derk, E. Grace, M. Shenin, M. Naik, S. Schulz, and W. Xiong, “A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis,” Rheumatology, vol. 48, no. 12, pp. 1595–1599, 2009.
[56]
N. Fett and V. P. Werth, “Update on morphea: part II. Outcome measures and treatment,” Journal of the American Academy of Dermatology, vol. 64, no. 2, pp. 231–242, 2011.
[57]
L. George, B. George, D. J. Gottlieb, M. Hertzberg, and P. Fernandez-Pe？as, “Lack of efficacy of rituximab in refractory sclerodermatous chronic GVHD,” Bone Marrow Transplantation, vol. 47, pp. 737–738, 2012.
[58]
M. S. Chimenti, M. Teoli, A. D. Stefani, A. Giunta, M. Esposito, and R. Perricone, “Resolution with rituximab of localized scleroderma occurring during etanercept treatment in a patient with rheumatoid arthritis,” European Journal of Dermatology, vol. 23, no. 2, pp. 273–274, 2013.
[59]
M. Kerscher, M. Vokenandt, M. Meurer, P. Lehmann, G. Plewig, and M. Rocken, “Treatment of localised scleroderma with PUVA bath photochemotherapy,” The Lancet, vol. 343, no. 8907, p. 1233, 1994.
[60]
M. El-Mofty, W. Mostafa, S. Esmat et al., “Suggested mechanisms of action of UVA phototherapy in morphea: a molecular study,” Photodermatology Photoimmunology and Photomedicine, vol. 20, no. 2, pp. 93–100, 2004.
[61]
A. Morita, K. Kobayashi, I. Isomura, T. Tsuji, and J. Krutmann, “Ultraviolet A1 (340-400 nm) phototherapy for scleroderma in systemic sclerosis,” Journal of the American Academy of Dermatology, vol. 43, no. 4, pp. 670–674, 2000.
[62]
K. Scharffetter, M. Wlaschek, A. Hogg et al., “UVA irradiation induces collagenase in human dermal fibroblasts in vitro and in vivo,” Archives of Dermatological Research, vol. 283, no. 8, pp. 506–511, 1991.
[63]
B. Stein, H. J. Rahmsdorf, A. Steffen, M. Litfin, and P. Herrlich, “UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein,” Molecular and Cellular Biology, vol. 9, no. 11, pp. 5169–5181, 1989.
[64]
M. El-Mofty, W. Mostafa, M. El-Darouty et al., “Different low doses of broad-band UVA in the treatment of morphea and systemic sclerosis. A clinico-pathologic study,” Photodermatology Photoimmunology and Photomedicine, vol. 20, no. 3, pp. 148–156, 2004.
[65]
M. El-Mofty, H. Zaher, M. Bosseila, R. Yousef, and B. Saad, “Low-dose broad-band UVA in morphea using a new method for evaluation,” Photodermatology Photoimmunology and Photomedicine, vol. 16, no. 2, pp. 43–49, 2000.
[66]
A. Kreuter, J. Hyun, M. Stücker, A. Sommer, P. Altmeyer, and T. Gambichler, “A randomized controlled study of low-dose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma,” Journal of the American Academy of Dermatology, vol. 54, no. 3, pp. 440–447, 2006.
[67]
B. A. Zwischenberger and H. T. Jacobe, “A systematic review of morphea treatments and therapeutic algorithm,” Journal of the American Academy of Dermatology, vol. 65, no. 5, pp. 925–941, 2011.
[68]
A. Kreuter, F. Breuckmann, A. Uhle et al., “Low-dose UVA1 phototherapy in systemic sclerosis: effects on acrosclerosis,” Journal of the American Academy of Dermatology, vol. 50, no. 5, pp. 740–747, 2004.
[69]
C. Tuchinda, H. A. Kerr, C. R. Taylor et al., “UVA1 phototherapy for cutaneous diseases: an experience of 92 cases in the United States,” Photodermatology Photoimmunology and Photomedicine, vol. 22, no. 5, pp. 247–253, 2006.
[70]
N. Pereira, F. Santiago, H. Oliveira, and A. Figueiredo, “Low-dose UVA1 phototherapy for scleroderma: what benefit can we expect?” Journal of the European Academy of Dermatology and Venereology, vol. 26, no. 5, pp. 619–626, 2012.
[71]
H. Xu, M. Zaidi, J. Struve et al., “Abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic sclerosis,” American Journal of Physiology—Cell Physiology, vol. 300, no. 3, pp. C550–C556, 2011.
[72]
E. Tinazzi, M. Dolcino, A. Puccetti et al., “Gene expression profiling in circulating endothelial cells from systemic sclerosis patients shows an altered control of apoptosis and angiogenesis that is modified by iloprost infusion,” Arthritis Research and Therapy, vol. 12, no. 4, article R131, 2010.
[73]
C. Ferri, D. Giuggioli, A. Manfredi et al., “Recombinant human erythropoietin stimulates vasculogenesis and wound healing in a patient with systemic sclerosis complicated by severe skin ulcers,” Clinical and Experimental Dermatology, vol. 35, no. 8, pp. 885–887, 2010.
