CONCISE COMMUNICATION Systemic sclerosis with multiple nodules: characterization of the extracellular matrix P. Moinzadeh • P. Agarwal • W. Bloch • C. Orteu • N. Hunzelmann • B. Eckes • T. Krieg Received: 28 December 2012 / Revised: 17 June 2013 / Accepted: 20 June 2013 / Published online: 9 July 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract Systemic sclerosis (SSc) is still an enigmatic disease of unknown etiology, although the pathophysiology is thought to be based on vascular alterations as well as immunological and fibrotic processes. Here we present the case of a female patient with diffuse SSc (dSSc), who developed multiple subcutaneous nodules. Histologic eval- uation confirmed the diagnosis of nodular scleroderma, a very rare condition. Histological analysis of biopsies was combined with ultrastructural analysis by transmission electron microscopy and immunohistochemistry/immuno- fluorescence, using antibodies against different collagens and non-collagenous ECM proteins. Collagen fibrils were deposited at very high density in nodules as well as in adjacent extra nodular skin. Within nodules, a large fraction of immature collagen fibrils was detected with smaller and highly variable diameter. Activated fibroblasts were present, however no myofibroblasts were identified. Cartilage Olig- omeric Matrix Protein (COMP), collagen XII and fibrillin-1 were all deposited at increased amounts within nodules and their distribution differed markedly from that in healthy skin. The excessive deposition of COMP within nodules closely resembled the distribution of COMP in keloids. Nodules—like keloids—were characterized by lack of myofibroblasts. By virtue of its structural properties and the capacity to avidly bind collagen I and XII, COMP is thought to reorganize and compact the collagen network, leading to a tissue with locally increased biomechanical tension acting on fibroblasts. In addition, COMP may present active TGFb to fibroblasts. Both mechanisms in concert can activate fibroblast proliferation and production of extracellular matrix, resulting in a sustained activation loop. Keywords Systemic sclerosis Á Scleroderma Á Nodules Á Extracellular matrix Á Fibrosis Introduction Systemic sclerosis (SSc) is a rare and very heterogeneous disease. Its pathophysiology is based on (1) immunologic processes, (2) vascular endothelial cell injury and (3) activation of fibroblasts resulting in excessive deposition of extracellular matrix (ECM), skin thickening and fibrotic changes in internal organs, e.g. cardio-pulmonary system, gastrointestinal tract, kidneys as well as the musculoskel- etal system [13, 39]. Skin manifestation includes dermal thickening, hyperpigmentation, and loss of appendageal structures. A rare group of scleroderma patients develop additional subcutaneous nodules. These can occur in a P. Moinzadeh and P. Agarwal are the combined first authorship. P. Moinzadeh (&) Á P. Agarwal Á N. Hunzelmann Á B. Eckes Á T. Krieg Department of Dermatology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany e-mail: pia.moinzadeh@uk-koeln.de W. Bloch Department of Molecular and Cellular Sport Medicine, German Sport University, Cologne, Germany C. Orteu Department of Dermatology, Royal Free Hospital, Medical School, UCL, London, UK T. Krieg Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated, Diseases (CECAD), University of Cologne, Cologne, Germany T. Krieg Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany 123 Arch Dermatol Res (2013) 305:645–652 DOI 10.1007/s00403-013-1383-0