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Concept: Systemic scleroderma


Systemic sclerosis (scleroderma) is unique among the rheumatic diseases because it presents the challenge of managing a chronic multisystem autoimmune disease with a widespread obliterative vasculopathy of small arteries that is associated with varying degrees of tissue fibrosis. The hallmark of scleroderma is clinical heterogeneity with subsets that vary in the degree of disease expression, organ involvement, and ultimate prognosis. Thus, the term scleroderma is used to describe patients who have common manifestations that link them together, whereas a highly variable clinical course exists that spans from mild and subtle findings to aggressive, life-threatening multisystem disease. The physician needs to carefully characterize each patient to understand the specific manifestations and level of disease activity to decide appropriate treatment. This is particularly important in treating a patient with scleroderma because there is no treatment that has been proven to modify the overall disease course, although therapy that targets specific organ involvement early before irreversible damage occurs improves both quality of life and survival. This review describes our approach as defined by evidence, expert opinion, and our experience treating patients. Scleroderma is a multisystem disease with variable expression; thus, any treatment plan must be holistic, yet at the same time focus on the dominant organ disease. The goal of therapy is to improve quality of life by minimizing specific organ involvement and subsequent life-threatening disease. At the same time the many factors that alter daily function need to be addressed, including nutrition, pain, deconditioning, musculoskeletal disuse, comorbid conditions, and the emotional aspects of the disease, such as fear, depression, and the social withdrawal caused by disfigurement.

Concepts: Medicine, Diseases and disorders, Rheumatology, Autoimmune disease, Lupus erythematosus, Systemic disease, Scleroderma, Systemic scleroderma


Significant advances have been made in understanding the genetic basis of systemic sclerosis (scleroderma) in recent years. Can these discoveries lead to individualized monitoring and treatment? Besides robustly replicated genetic susceptibility loci, several genes have been recently linked to various systemic sclerosis disease manifestations. Furthermore, inclusion of genetic studies in design and analysis of drug trials could lead to development of genetic biomarkers that predict treatment response. Future genetic studies in well-characterized systemic sclerosis cohorts paired with advanced analytic approaches can lead to development of genetic biomarkers for targeted diagnostic and therapeutic interventions in systemic sclerosis.

Concepts: DNA, Medicine, Gene, Genetics, Genomics, Rheumatology, Scleroderma, Systemic scleroderma


Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive fibrosis of the skin and the internal organs. In a previous work we suggested a correlation between levels of salivary psoriasin (S100A7) and pulmonary involvement in SSc patients. The goals of this study are to determine the distribution characteristics of psoriasin in whole saliva (WS) of SSc and healthy donor populations and define its predictive value on diffusion capacity of carbon monoxide (DLCO), along with others clinical parameters.

Concepts: Epidemiology, Heart, Skin, Carbon monoxide, Autoimmune diseases, Organs, Scleroderma, Systemic scleroderma


To compare the characteristics of patients with systemic sclerosis who died within 2 years of diagnosis to those who died after 2 years of diagnosis. A retrospective chart review of all medical records of deceased systemic sclerosis (SSc) patients who had been followed at our institution from 1985 to 2007 was performed. We identified 87 deceased SSc patients within this period. From the 87 deceased individuals, 20 had died within 2 years after they were diagnosed, and 67 had died after 2 years of their diagnosis. Patients who died within 2 years of diagnosis were more likely to be anticentromere antibody negative when compared to the patients who died after 2 years (17/20 vs. 48/67, P = 0.03). The time from the first appearance of non-Raynaud’s symptoms to diagnosis was significantly shorter in the group who died within 2 years than in the group who died after 2 years of diagnosis (11.8 ± 10.3 vs. 60.7 ± 64.9 months, P = 0.002). According to the Medsger severity score, there was more severe muscle (0.82 ± 1.13 vs. 1.8 ± 1.28, P = 0.0014) and heart (0.86 ± 1.37 vs. 2.1 ± 1.71, P = 0.0013) involvement at the initial evaluation in patients who died before 2 years of diagnosis when compared to the group of patients who died after 2 years of diagnosis. The time from the first symptoms to treatment initiation was significantly shorter in patients who died early (9.43 ± 6.3 vs. 38.3 ± 54.4 months, P = 0.05). The interval between treatment initiation and death was also significantly shorter (15.1 ± 9.48 vs. 60.7 ± 49.7 months, P = 0.001), reflecting greater severity of disease. Patients who died within the first 2 years of SSc diagnosis were typically anticentromere negative and had significant muscle and cardiac involvement. The time from the first appearance of non-Raynaud phenomenon symptoms to death was much shorter in the patients who died within 2 years of diagnosis, suggesting a very fulminant form of systemic sclerosis.

Concepts: Disease, Death, Medical terms, Demography, Heart, Rheumatology, Scleroderma, Systemic scleroderma


To investigate whether women with systemic sclerosis (SSc) have an increased risk of osteoporosis (OP) and related fractures compared to a high-risk population with rheumatoid arthritis (RA) and also healthy controls, and to determine putative specific OP and fracture risk factors.

Concepts: Osteoporosis, Bone fracture, Rheumatoid arthritis, Rheumatology, Systemic lupus erythematosus, Arthritis, Scleroderma, Systemic scleroderma


Background  A disintegrin and metalloprotease (ADAM) 12 is one of the metalloproteinase-type ADAMs and possesses extracellular metalloprotease and cell-binding functions. ADAM12 is expressed in two alternative forms, such as a membrane-anchored form (ADAM12-L) and a short secreted form (ADAM12-S). Objective  To investigate the clinical significance of serum ADAM12-S levels in systemic sclerosis (SSc). Methods  Serum ADAM12-S levels were determined by a specific enzyme-linked immunosorbent assay in 61 SSc patients and 18 healthy controls. Results  Serum ADAM12-S levels were significantly increased in diffuse cutaneous SSc (dcSSc) patients than in healthy controls (0.417 ± 0.389 vs. 0.226 ± 0.065 ng/mL; P < 0.05), while being comparable between limited cutaneous SSc (0.282 ± 0.258 ng/mL) and healthy controls. Serum ADAM12-S levels significantly elevated in dcSSc patients with disease duration of ≤6 years (0.537 ± 0.449 ng/mL, P < 0.05), but not in dcSSc with disease duration of >6 years (0.225 ± 0.049 ng/mL), compared to healthy controls. Furthermore, in dcSSc patients with disease duration of ≤6 years, serum ADAM12-S levels correlated positively with modified Rodnan total skin thickness score, ground glass score, and serum C-reactive protein values, while showed inverse correlation with fibrosis score. Conclusion  Elevated serum ADAM12-S levels are associated with elevated serum inflammatory marker, severity of skin fibrosis, and activity of interstitial lung disease in dcSSc, suggesting the possible contribution of ADAM12-S to the pathological events in this disorder.

Concepts: Inflammation, ELISA, ELISPOT, Assay, Skin, Eva Engvall, Scleroderma, Systemic scleroderma


Background  Scleroderma is a connective tissue disease that includes localized and systemic forms. Our recent encounter with a morphea case exhibiting prominent perineural inflammation microscopically prompted us to assess the features of all patients diagnosed with morphea/scleroderma at our institution. Objective/methods  To describe the clinicopathological features of all patients diagnosed with morphea/scleroderma at American University of Beirut Medical Center (AUB-MC) between 1999 and 2010, and compare our findings with those published in the literature. Results  A total of 81 cases (63 women and 18 men) were identified, of which 73 were localized (morphea) and eight were systemic scleroderma. Clinically, plaque type morphea was the most common variant both in adults and children, and seven (9%) cases of morphea were associated with lichen sclerosis et atrophicus (LSA). Histopathologically, perineural inflammation was observed in 49% of cases, and may serve, in addition to other features including lichen sclerosis-like changes (observed in exclusively nine cases of morphea), more diffuse dermal and less subcutaneous sclerosis, and intense inflammation, as clues favouring diagnosis of morphea over systemic sclerosis. Conclusion  The features of morphea/scleroderma patients in this study are generally comparable to those published in the literature, with few differences. Clinically, plaque type morphea was the most common variant both in adults and children and LSA was a frequent association. Histopathologically, perineural inflammation was commonly observed and may serve in addition to lichen sclerosis-like changes and intense inflammation as clues favouring diagnosis of morphea over systemic sclerosis.

Concepts: Rheumatology, Scleroderma, Systemic scleroderma, Lichen sclerosus


Wnt-, Hedgehog- and Notch-signaling cascades are morphogen pathways that play crucial roles in development and tissue homeostasis. While morphogen pathways are tightly regulated at multiple levels, inappropriate activation of Wnt, Hedgehog and Notch signaling has been implicated into the pathogenesis of various diseases. In particular, Wnt, Hedgehog and Notch signaling have emerged as central players in the pathogenesis of fibrotic diseases. Here, we will review the pro-fibrotic effects of Wnt, Hedgehog and Notch signaling in systemic sclerosis (SSc), prototypical systemic fibrotic disease. Wnt, Hedgehog and Notch pathways are activated in SSc. They potently stimulate fibroblasts to differentiate into myofibroblasts and to release collagen and other extracellular matrix components. Genetic or pharmacological inhibition of morphogen pathways effectively prevents experimental fibrosis in different preclinical models and induces regression of pre-established fibrosis. As several inhibitors of Wnt, Hedgehog and Notch have recently been developed with first ones being already approved for clinical trials, morphogen pathways maybe a novel approach for the treatment of fibrosis.

Concepts: Wound healing, Collagen, Extracellular matrix, Fibrosis, Rheumatology, Tissue, Scleroderma, Systemic scleroderma


Raynaud’s phenomenon often precedes the diagnosis of systemic sclerosis and is the first symptom of the disease in many cases. Antinuclear antibody positivity can assist in the early identification of cases of isolated Raynaud’s phenomenon likely to progress to systemic sclerosis. However, the specific differences between rate of progression for different scleroderma hallmark antibodies is less clear. We review the predictive potential of ANA positivity and nailfold capillaroscopy for identifying cases of Raynaud’s phenomenon which may progress to connective tissue diseases. We also have reviewed data from our own large scleroderma cohort to explore the relationship between antibody subtype and time to development of SSc. Duration of pre-existing Raynaud’s phenomenon may be an important determinant of the profile of systemic sclerosis cases identified through screening. Ninety-five percent of our patients with isolated Raynaud’s phenomenon, negative autoimmune serology on more than one visit and normal capillaroscopy score showed no progression to connective tissue disease. Duration of antecedent Raynaud’s phenomenon differs between disease subsets and scleroderma-specific ANA patterns.

Concepts: Immune system, Blood, Rheumatology, Autoimmune diseases, Scleroderma, Systemic scleroderma, Raynaud's phenomenon, CREST syndrome


To identify the incidence rate (IR) and risk factors of osteoporotic fractures (OFs) among systemic sclerosis (SSc) patients.

Concepts: Osteoporosis, Epidemiology, Medical statistics, Risk, Rheumatology, Scleroderma, Systemic scleroderma, Mucinoses