Update on the pathogenesis of Scleroderma: focus on circulating progenitor cells [version 1; referees: 2 approved]

In systemic sclerosis (SSc), the development of fibrosis seems to be a consequence of the initial ischemic process related to an endothelial injury. The initial trigger event in SSc is still unknown, but circulating progenitor cells (CPCs) might play a key role. Such cells have the ability to traffic into injury sites, exhibiting inflammatory features of macrophages, tissue remodeling properties of fibroblasts, and vasculogenesis functions of endothelial cells. The different subsets of CPCs described thus far in SSc arise from a pool of circulating monocyte precursors (CD14+ cells) and probably correspond to a different degree of differentiation of a single cell of origin. Several subsets of CPCs have been described in patients with SSc, all have a monocytic origin but may or may not express CD14, and all of these cells have the ability to give origin to endothelial cells, or collagen (Col)-producing cells, or both. We were able to identify six subsets of CPCs: pluripotent stem cells (CD14+, CD45+, and CD34+), monocyte-derived multipotential cells (MOMCs) or monocyte-derived mesenchymal progenitors (CD14+, CD45+, CD34+, Col I+, CD11b+, CD68+, CD105+, and VEGFR1+), early endothelial progenitor cells (EPCs) or monocytic pro-angiogenic hematopoietic cells or circulating hematopoietic cells (CD14+, CD45+, CD34low/−, VEGFR2+/−, CXCR4+, c-kit+, and DC117+), late EPCs (CD14−, CD133+, VEGFR2+, CD144+ [VE-cadherin+], and CD146+), fibroblast-like cells (FLCs)/circulating Col-producing monocytes (CD14+, CD45+, CD34+/−, and Col I+), and fibrocytes (CD14−, CD45+, CD34+, Col I+, and CXCR4+). It has been demonstrated that circulating CD14+ monocytes with an activated phenotype are increased in patients with SSc when compared with normal subjects. CD14+, CD34+, and Col I+ spindle-shaped cells have been found in increased numbers in lungs of SSc patients with interstitial lung disease. Elevated blood amounts of early EPCs have been found in patients with SSc by different groups of researchers and such levels correlate directly with the interstitial lung involvement. The prevalence of hematopoietic markers expressed by CPCs that migrate from blood into injury sites in SSc differs and changes according to the degree of differentiation. CXCR4 is the most commonly expressed marker, followed by CD34 and CD45 at an end stage of differentiation. Such difference also indicates a continuous process of cell differentiation that might relate to the SSc clinical phenotype (degree of fibrosis and vascular involvement). A deeper understanding of the role of each subtype of CPCs in the development of the disease will help us to better classify patients in order to offer them targeted approaches in the future

New Onset of Dermatomyositis/Polymyositis during Anti-TNF-α Therapies: A Systematic Literature Review

We performed a systematic search of databases from 1990 to 2013 to identify articles concerning the new onset of dermatomyositis/polymyositis (DM/PM) in patients treated with anti-TNF-α therapy. We retrieved 13 publications describing 20 patients where the new onset of DM/PM after anti-TNF-α therapy was recorded. 17 patients were affected by rheumatoid arthritis (RA), one by Crohn’s disease, one by ankylosing spondilytis, and one by seronegative arthritis. In 91% of the cases antinuclear autoantibodies were detected after the introduction of anti-TNF-α therapy. In 6 patients antisynthetase antibodies were detected and other clinical findings as interstitial lung disease (ILD) were recorded. Improvement of DM/PM after anti-TNF suspension (with the concomitant use of other immunosuppressors) was recorded in 94% of cases. The emergence of DM/PM and antisynthetase syndrome seem to be associated with the use of anti-TNF-α agents, especially in patients with chronic inflammatory diseases (mainly RA) with positive autoantibodies before therapy initiation. In particular, physicians should pay attention to patients affected by RA with positive antisynthetase antibodies and/or history of ILD. In those cases, the use of the TNF-α blocking agents may trigger the onset of PM/DM or antisynthetase syndrome or may aggravate/trigger the lung disease

Teledermatopathology: Current status and perspectives

Teledermatopathology allows remote diagnosis of skin specimens at remote locations by using computer and communications technology, and it can be performed with real-time (dynamic) transmission of images or the store-and-forward (SAF; static) option [3,16,23]. The first method provides remote consultation via a robotic microscope, which can be controlled by the consulting pathologist [3,16,23]. On the contrary, using the SAF system, each image is captured and transmitted as a single file. The fields to be examined are selected by the referring pathologist and then transmitted by an e-mail or a file transfer protocol (FTP) connection or using a specific web application [3,16,23]. In the last several years, virtual slide systems (VSSs) have been introduced in telepathology. With these systems, the whole slide can be digitized at high resolutions, which allows the user to view any part of the specimen at any magnification [8]. In this way, the limitations imposed by capturing small preselected areas can be overcome. Moreover, the acquired images can be stored on a virtual slide (VS) server that makes them available on the web, and an integrated VS client enables the users to browse the VS [8,23]. Recently, new ultrarapid VS processors have been developed [24]. In dermatopathology, the knowledge of skin physiology and semiotics should always be integrated with a clinical background to arrive at a correct diagnosis. The study of histopathologic specimens from inflammatory skin diseases and equivocal melanocytic lesions can be particularly difficult, and a strict correlation with clinical parameters becomes mandatory. Two examples of der-matopathologic entities that might be problematic in routine dermatopathology are inflammatory dermatoses, characterized by subtle pattern arrangements of inflammatory cells and dysplastic nevi, where subtle changes in architectural and cytologic appearance can lead astray to a more malignant behavior.This issue is of major concern for achieving correct diagnoses in teledermatopathology [2, 16, 18]. The feasibility of both SAF and real-time teledermatopathology has already been proved in few studies, mainly on nonmelanoma skin cancer or melanocytic lesions, with less emphasis on inflammatory skin diseases [1, 2, 4, 6, 7, 16-19, 22]. These studies suggest that diagnostic efficacy and accuracy in teledermatopathology may be particularly weak when examining entities that require the identification of subtle architectural arrangements or delicate cytologic features, as in inflammatory skin diseases [1, 2, 4, 6, 7, 16-19, 22]. Recent applications of VSS in teledermatopathology both on melanocytic lesions and on inflammatory skin diseases confirmed the intrinsic difficulty of dermatopathology and teledermatopathology [11, 15]. Further development of the VSS and new studies using the new VS processor, as well as training with the virtual microscope, might improve the diagnostic performance of teleconsultants

Teledermatopathology

Teledermatopathology may involve real-time transmission of images from distant locations to consulting pathologists by the remote manipulation of a robotic microscope. Alternatively, the static store-and-forward (SAF) option involves the single file transmission of subjectively preselected and captured areas of microscopic images by a referring physician. The recent introduction of virtual slide systems (VSS) involves the digitization of whole slides at high resolution thus enabling the user to view any part of the specimen at any magnification. Such technology has surmounted previous restrictions caused by the size of preselected areas and specimen sampling for telepathology. In terms of client access, these VSS may be stored on a virtual slide (VS) server, made available on the web for remote consultation by pathologists via an integrated VS client network. Despite SAF teledermatopathology being the most frequently used and less expensive approach to teledermatopathology, VSS represents the future in this discipline. The recent pilot studies suggest that the use of remote expert consultants in diagnostic dermatopathology can be integrated into daily routine, teleconsultation and teleteaching. The new technology enables rapid and reproducible diagnoses, but despite its usability, VSS are not completely feasible for teledermatopathology of inflammatory skin diseases as the performance seems to be influenced by the availability of complete clinical data. Improvements in the diagnostic facility will no doubt follow from further development of the VSS, the slide processor and of course training in the use virtual microscope. Undoubtedly as technology becomes even more sophisticated in the future VSS will overcome the present drawbacks and find its place in all facets of teledermatopathology

Clinicopathologic and Dermoscopic Features of 20 Cases of Spark's Nevus, a Dermoscopic Simulator of Melanoma

Spark's nevus is a particular type of melanocytic nevus, with histology that shows features of both Spitz and Clark nevus. Detailed dermoscopic features in a series of Spark nevi have not been described yet. We performed a monocentric retrospective observational study on 20 lesions of Spark nevus excised from 19 patients (M:F = 10:9; mean age: 37,6 years), reviewed by 5 experts in dermoscopy and 2 dermatopathologists. A histologic review confirmed that Spark nevi were mostly symmetric (80%), well circumscribed (100%), mainly compound (65%) melanocytic lesions with either epithelioid (55%) or spitzoid (45%) cell morphology and bridging of the nests (100%). Spark nevi were more frequently found on the trunk (85%) in patients with a history of sunburns in childhood (84%), with skin phototype III (79%), and with high nevus count (>100 nevi, 7 patients (36%)). On dermoscopy, we observed different general patterns: multicomponent (40%), reticular-globular-homogeneous (15%), globular homogeneous (15%), reticular (15%), reticular-globular (5%), homogeneous (5%), and globular (5%). Spark nevi showed frequently dermoscopic asymmetry (63%), brown color (90%) with areas of central hyperpigmentation (41%) and peripheral hypopigmentation (28%), atypical pigment network (48%), irregular globules (42%), irregular dots (31%), irregular blotches (16%), blue-whitish veil (13%), peripheral island (25%), irregular hyperpigmented areas (12%), and regression (33%). BRAF mutation was present in 7 of the 10 analyzed cases (70%); all these cases presented a history of evolution. In conclusion, Spark nevi occur on the trunk of young adults with high nevus count and history of sunburns; dermoscopic features are protean, often atypical and suspicious of melanoma