Extent Of Skin Sclerosis Research Articles

Controversies: molecular vs. clinical systemic sclerosis classification

Systemic sclerosis (SSc) is a multisystem chronic disease characterized by the three cardinal pathological features, including autoimmunity/inflammation, vasculopathy, and fibrosis, with unknown etiology. Individual patients manifest these three components to variable degrees, resulting in the diverse heterogeneity of clinical presentation. The classification of SSc patients into relatively homogenous subtypes is helpful in the setting of daily clinical practice and the field of clinical and basic research. The classification of SSc has been continuously discussed over four decades based on the clinical and laboratory features, especially the extent of skin sclerosis and disease-related autoantibodies. This clinical classification system enables clinicians to provide general advice regarding prognosis and risk for internal organ disease, but only permits estimates of outcomes informed by population-based studies. On the other hand, the recent decade has seen much progress in the understanding of molecular aspects of SSc complex pathology, raising a discussion on molecular classification of SSc. The development of molecular targeting therapies, especially biologics, further strengthens the importance of molecular classification which aids the identification of potential responders for each treatment. Although a careful validation study is required for molecular classification of SSc due to its large heterogeneity, the advance of molecular classification would introduce a further modification into SSc classification system in the near future. Importantly, clinical and molecular classifications are not mutually exclusive, therefore the combination would facilitate the development of a better classification system of this complex heterogeneous disorder that is useful in both the clinical setting and research studies.

Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: Association with extent of skin sclerosis.

The interaction of programmed death-1 (PD-1) with its ligand, programmed death ligand-1 (PD-L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD-1 (sPD-1) than those with limited cutaneous SSc and healthy individuals. Serum sPD-1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD-L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD-L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD-1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD-1/PD-L1 interaction may contribute to the development of skin sclerosis in SSc.

Interleukin-33 in systemic sclerosis: correlation with clinical manifestations and disease subset

Background Systemic sclerosis (SSc) is a generalized connective tissue disorder characterized by sclerotic changes in the skin and internal organs. Interleukin-33 (IL-33) is a newly reported cytokine of the IL-1 family. Aim of the work The aim of this study was to determine serum levels of IL-33 in SSc patients and evaluate its association with clinical manifestations and disease subset. Patients and methods The patients in this study were divided into group A and group B. Group A included 30 adult patients with SSc, which was subdivided into diffuse systemic sclerosis (dSSc) and limited systemic sclerosis (lSSc). All cases were diagnosed according to the American College of Rheumatology criteria for SSc. Group B included 15 healthy adults (age and sex matched) who served as controls. Serum IL-33 levels were examined by means of enzyme-linked immunosorbent assay in 30 patients with SSc and in 15 healthy individuals. Skin assessment was done using the modified Rodnan skin score. Results IL-33 was increased in all SSc patients compared with controls. The levels of IL-33 were significantly higher in the dSSc subset compared with the lSSc subset. IL-33 is highly correlated to the presence of pulmonary fibrosis, Raynaud’s phenomenon, pitting scars and ulcers, pulmonary hypertension, joint contracture, and modified Rodnan skin score. Thus, IL-33 levels were increased in SSc patients and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. Therefore, IL-33 possibly plays a role in cutaneous and pulmonary fibrosis in SSc patients. Conclusion IL-33 may have a significant role in the pathogenesis of SSc. IL-33 serum levels paralleled the severity of the disease subset. Understanding of IL-33 functions is important for the development of new therapeutic approaches including IL-33 inhibitors and IL-33 receptor blockers as a therapeutic target.

SP0179 Biological Changes in Early Systemic Sclerosis

Early systemic sclerosis (SSc) is a newly identified condition characterized by the association of Raynaud's phenomenon (RP) with SSc marker autoantibodies and/or with a scleroderma pattern at nailfold videocapillaroscopy (NVC),...

SP0056 Raynaud's Phenomenon and Systemic Sclerosis

Systemic sclerosis has high mortality and morbidity and is diverse in clinical manifestations. In approaching management it is important to consider baseline assessment that must include confirmation of diagnosis, ascertainment...

Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity

Objective To determine serum growth differentiation factor-15 (GDF-15) levels and their clinical associations in patients with systemic sclerosis (SSc).Methods Serum GDF-15 levels were examined by enzyme-linked immunosorbent assay in 61 patients with SSc and 24 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (duration of follow-up 1.2–7.2 years).Results Serum GDF-15 levels were significantly elevated in SSc patients (1340 ± 910 pg/ml) compared with healthy individuals (213 ± 79 pg/ml; P < 0.001). Among SSc patients, patients with diffuse cutaneous SSc (n = 31) had higher levels of serum GDF-15 (1609 ± 1069 pg/ml) than those with limited cutaneous SSc (n = 30; 1142 ± 646 pg/ml; P < 0.05). SSc patients with high GDF-15 levels (≥1000 pg/ml) had pulmonary fibrosis, decreased vital capacity, and decreased diffusion capacity for carbon monoxide more often than those with low GDF-15 levels (<1000 pg/ml). GDF-15 levels correlated positively with the extent of skin sclerosis and inversely with percentage vital capacity and diffusion capacity for carbon monoxide in patients with SSc. In a longitudinal study, serum GDF-15 levels were generally decreased during the follow-up.Conclusion Serum GDF-15 levels were increased in patients with SSc and associated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that GDF-15 may play a role in the development of cutaneous and pulmonary fibrosis in SSc. Measurement of serum GDF-15 may be useful for risk stratification in early disease stage.

Increased serum levels and tissue expression of MMP-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage

Background and objectiveSystemic sclerosis (SSc) is a life-threatening connective tissue disease characterised by widespread vasculopathy, lack of angiogenesis and fibrosis of the skin, lung and other internal organs. Increasing evidence...

Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity

To determine serum growth differentiation factor-15 (GDF-15) levels and their clinical associations in patients with systemic sclerosis (SSc). Serum GDF-15 levels were examined by enzyme-linked immunosorbent assay in 61 patients with SSc and 24 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (duration of follow-up 1.2-7.2 years). Serum GDF-15 levels were significantly elevated in SSc patients (1340 ± 910 pg/ml) compared with healthy individuals (213 ± 79 pg/ml; P < 0.001). Among SSc patients, patients with diffuse cutaneous SSc (n = 31) had higher levels of serum GDF-15 (1609 ± 1069 pg/ml) than those with limited cutaneous SSc (n = 30; 1142 ± 646 pg/ml; P < 0.05). SSc patients with high GDF-15 levels (≥1000 pg/ml) had pulmonary fibrosis, decreased vital capacity, and decreased diffusion capacity for carbon monoxide more often than those with low GDF-15 levels (<1000 pg/ml). GDF-15 levels correlated positively with the extent of skin sclerosis and inversely with percentage vital capacity and diffusion capacity for carbon monoxide in patients with SSc. In a longitudinal study, serum GDF-15 levels were generally decreased during the follow-up. Serum GDF-15 levels were increased in patients with SSc and associated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that GDF-15 may play a role in the development of cutaneous and pulmonary fibrosis in SSc. Measurement of serum GDF-15 may be useful for risk stratification in early disease stage.

Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis

To determine serum interleukin-33 (IL-33) levels and their associations with clinical parameters in patients with systemic sclerosis (SSc). Serum IL-33 levels were examined by enzyme-linked immunosorbent assay in 69 patients with SSc and 30 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (follow-up, 1-7years). Serum IL-33 levels were elevated in SSc patients (261.7 ± 141.9pg/ml) compared with healthy individuals (174.9 ± 72.4pg/ml; P < 0.001). Patients with diffuse cutaneous SSc had higher levels of IL-33 (287.5 ± 146.6pg/ml) than those with limited cutaneous SSc (221.5 ± 126.5pg/ml; P < 0.05). Pulmonary fibrosis and decreased forced vital capacity were more commonly found in patients with elevated IL-33 levels than in those with normal IL-33 levels. IL-33 levels correlated positively with the extent of skin sclerosis, and inversely with percent predicted forced vital capacity. IL-33 levels were increased in SSc patients and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. Therefore, IL-33 possibly plays a role in cutaneous and pulmonary fibrosis in SSc patients.

Serum CXCL16 Concentrations Correlate with the Extent of Skin Sclerosis in Patients with Systemic Sclerosis

To determine serum concentrations of soluble CXCL16 and its clinical associations in patients with systemic sclerosis (SSc). Serum CXCL16 levels from 89 patients with SSc were examined by ELISA. In a retrospective longitudinal study, 68 sera from 28 patients with SSc were analyzed (followup 1.3 to 7.3 yrs). Serum CXCL16 levels were elevated in patients with SSc compared with healthy controls (n = 42). Patients with diffuse cutaneous SSc (n = 52) had higher levels of CXCL16 than those with limited cutaneous SSc (n = 37). Serum CXCL16 levels correlated positively with the extent of skin sclerosis. In the longitudinal study, CXCL16 levels generally decreased on a parallel with the improvement in skin sclerosis. CXCL16 levels were increased in patients with SSc, and correlated with the extent of skin sclerosis, suggesting that CXCL16 may have a role in the development of skin fibrosis in SSc. Blockade of CXCL16 interaction might be a potential therapeutic target in patients with SSc.

Clonal T-cell populations are frequent in the skin and blood of patients with systemic sclerosis

Pilot studies were suggestive for a role of clonal T cells in the pathogenesis of systemic sclerosis (SSc). To investigate the presence of clonal T cells in both peripheral blood and skin of a large collection of patients with SSc. Polymerase chain reaction and high-resolution capillary electrophoresis for detecting T-cell clonality were performed in a series of 126 patients with SSc. Seventy-seven (61%) of 126 patients had clonal T cells in their peripheral blood. In contrast, a clonal T-cell population was present in only four of 29 (14%) age-matched healthy controls (P = 0.03). Older patients were more likely to have clonal T cells than younger patients with SSc (P < 0.0001). Clonal T cells were more commonly detected in the blood of patients with limited cutaneous SSc (48 of 65 patients, 74%) than in those with diffuse cutaneous disease (29 of 61, 48%; P = 0.0002). Lesional skin specimens from 20 of 44 patients (45%) had detectable clonal T-cell populations. There was no correlation between the presence of circulating clonal T cells and lesional clonal T cells, sex, disease duration, extent of skin sclerosis, digital ulcers, organ involvement (e.g. interstitial lung disease, kidney disease, oesophagus involvement), treatment of SSc, or autoantibody profile. Many patients with SSc have expanded clonal T cells in their peripheral blood and skin. These clonal T cells could play a critical role in the pathogenesis of SSc, especially in limited cutaneous disease.

Skin sclerosis is only of limited value to identify SSc patients with severe manifestations--an analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register

In SSc, diagnosis and classification is based mainly on skin sclerosis. Herein, we investigated in a large multicentre cohort, to what extent skin sclerosis reflects organ involvement and additional clinical symptoms. A total of 1200 SSc patients from the register of the German Systemic Sclerosis Network (DNSS), classified as either lcSSc or dcSSc, were analysed for their serological characteristics, clinical symptoms and organ manifestations in relation to skin involvement measured by the modified Rodnan skin score (mRSS). SSc patients with different mRSS did not differ significantly in their disease duration and in most of the clinical symptoms. They showed a similar distribution of most organ manifestations such as pulmonary arterial hypertension as well as cardiac, renal and nervous system involvement. More severe skin thickening was found to be associated with pulmonary fibrosis and gastrointestinal symptoms, as well as with digital ulcers and musculoskeletal involvement. In patients with SSc, potentially life-threatening complications and clinical symptoms with high impact on the quality of life occur independently from the extent of skin sclerosis. The diagnosis in SSc patients with a low mRSS could be missed or they could be insufficiently treated.

Circulating Tissue Inhibitor of Matrix Metalloproteinase‐4 (TIMP‐4) in Systemic Sclerosis Patients with Elevated Pulmonary Arterial Pressure

Decreased levels of matrix metalloproteinases (MMPs) or excess levels of their tissue inhibitors (TIMPs) may contribute to dysregulation of extracellular matrix turnover in systemic sclerosis (SSc). In a cross-sectional study of 106 SSc patients, we measured serum levels of TIMP-4 which is preferentially expressed in cardiovascular structures and searched for correlations with simultaneously performed echocardiography measurements of pulmonary artery systolic pressure (PASP), myocardial performance, and pulmonary function tests. TIMP-4, but not MMP-9, levels were significantly raised in patients with SSc than controls. However, in the subgroup of patients with PASP measurements lower to 40 mmHg (n = 69), TIMP-4 levels were comparable to controls irrespective of the presence of diffuse or limited skin involvement, or lung fibrosis. Individual PASP measurements suggestive of pulmonary hypertension were associated with increased TIMP-4 serum levels (P = .03), independently of age, extent of skin sclerosis, or lung fibrosis, suggesting a cardiopulmonary vasculature-specific role of TIMP-4 activation in SSc.

Influence de l'âge sur les caractéristiques cliniques et biologiques de la sclérodermie systémique

The present study was aimed at assessing the influence of age on clinical and biological features of systemic sclerosis. This retrospective study included 151 consecutive patients with systemic sclerosis. The median age at diagnosis was 50.0 years (range: 10-84 years). Patients were divided into two groups according to their age (lower than 50.0 years of age: 73 patients, equal to or above 50 years of age: 78 patients). The following features were compared between the two groups: gender, disease duration, extent of skin sclerosis, Crest syndrome, lung fibrosis, secondary Sjögren's syndrome, antinuclear, anticentromere, and anti-Scl70 antibodies. The disease duration was significantly higher in patients over 50 years of age (7.1 +/- 6.8 years vs 5.5 +/- 5.0 years, P < 0.05). Crest syndrome, secondary Sjögren's syndrome and anticentromere antibodies were significantly more common in patients over 50 years of age (17/73 vs 30/78, P < 10(-2); 9/73 vs 20/78, P < 10(-2), and 19/73 vs 31/78, P < 0.05; respectively). Anti-Scl70 antibodies were significantly more common in patients under 50 years of age (17/73 vs 10/78, P < 10(-2)). No significant difference was found in regard to the other features. The clinical and biological patterns of systemic sclerosis are different according to the age at disease onset. Crest syndrome including anticentromere antibodies and Sjögren's syndrome is more common in elderly patients, while anti- Scl-70 antibodies are more common in younger patients. This suggests the involvement of various mechanisms in the pathogenesis of systemic sclerosis, and that these mechanisms may depend on the age.

Mortality and causes of death of 344 Danish patients with systemic sclerosis (scleroderma)

To determine survival, mortality and causes of death in Danish patients with systemic sclerosis (scleroderma), and to analyse how these parameters are influenced by demographic variables and the extent of skin involvement. A cohort of 344 patients with incident systemic sclerosis (SSc) after 1 January 1960 was retrospectively identified, representing 3716 patient-years of follow-up. The vital status at the end of the study ultimo 1996 was established by reviewing the clinical charts and by contacting the Danish Central Person Register. The causes of death were based on information obtained from the hospital charts and the autopsy reports (80%) and death certificates (20%). The extent of skin sclerosis was described by means of a two-subset model (limited and diffuse involvement) and a three-subset model (digital, extremity and truncal involvement) in all patients. Expected numbers of deaths were calculated by means of age- and sex-specific mortality rates of the general Danish population. Crude mortality rates were 6.5 and 3.9%/yr, respectively, in men and women. The standardized mortality ratio (SMR) was 2.9 (95% CI 2.5-3.4) and was not significantly influenced by sex or age at disease onset. Mortality rates were significantly increased in patients with diffuse skin sclerosis (SMR 4.5, 95% CI 3.5-5.7) and patients under the age of 35 yr (SMR 13, 95% CI 2.7-37). Of the 160 patients who died during the study, 41 deaths (26%) were SSc related, accounting for one-third of the excess mortality. We found a significantly increased mortality in patients with SSc, particularly in the subset of patients with diffuse skin sclerosis and in young patients. The excess mortality was due to an increase in both the SSc-related mortality and the unrelated mortality. However, all other subsets also had a significantly increased risk of death, mainly due to an increased risk of death due to causes unrelated to SSc, cancer among others. The fact that the unrelated mortality in SSc was found to be 2-fold increased suggests that the excess mortality that was classified as unrelated should more appropriately be termed indirectly SSc related.

Determination of procollagen type I carboxyterminal propeptide in Japanese patients with systemic sclerosis

Our objective was to clarify the relationship between the serum levels of procollagen type I carboxyterminal propeptide (PICP) and the extent of skin sclerosis or pulmonary fibrosis in patients with systemic sclerosis (SSc). Thirty-eight SSc patients and 36 control subjects were examined for serum PICP levels using enzyme-linked immunosorbent assay. SSc patients were divided into two subgroups according to the grade of skin sclerosis. Mean PICP level in the SSc patients was significantly higher than that in the normal controls. In 53% of the SSc patients, the serum PICP levels were elevated more than 3 SD above the mean control value. The SSc patients with elevated serum PICP levels showed a high incidence of pulmonary fibrosis of diffuse skin sclerosis compared to those with normal PICP levels. Moreover, in 17 patients with pulmonary fibrosis there was an increase in the percentage of patients with elevated PICP levels in the group with diffuse SSc compared to that in the limited SSc group. Furthermore, there was a significant negative correlation between PICP levels and partial pressure of arterial oxygen levels ( r=−0.744). We conclude that serum PICP levels may be a useful parameter for the evaluation of skin sclerosis and pulmonary fibrosis of SSc patients.

Determination of procollagen type I carboxyterminal propeptide in Japanese patients with systemic sclerosis

Our objective was to clarify the relationship between the serum levels of procollagen type I carboxyterminal propeptide (PICP) and the extent of skin sclerosis or pulmonary fibrosis in patients with systemic sclerosis (SSc). Thirty-eight SSc patients and 36 control subjects were examined for serum PICP levels using enzyme-linked immunosorbent assay. SSc patients were divided into two subgroups according to the grade of skin sclerosis. Mean PICP level in the SSc patients was significantly higher than that in the normal controls. In 53% of the SSc patients, the serum PICP levels were elevated more than 3 SD above the mean control value. The SSc patients with elevated serum PICP levels showed a high incidence of pulmonary fibrosis of diffuse skin sclerosis compared to those with normal PICP levels. Moreover, in 17 patients with pulmonary fibrosis there was an increase in the percentage of patients with elevated PICP levels in the group with diffuse SSc compared to that in the limited SSc group. Furthermore, there was a significant negative correlation between PICP levels and partial pressure of arterial oxygen levels (r=−0.744). We conclude that serum PICP levels may be a useful parameter for the evaluation of skin sclerosis and pulmonary fibrosis of SSc patients.

Changes in skin disaccharide components correlate with the severity of sclerotic skin in systemic sclerosis.

The disaccharide contents of chondroitinase-digestible glycosaminoglycans extracted from a 6-mm punch biopsy of the forearm skin were determined using high-performance liquid chromatography after 1-phenyl-3-methyl-5-pyrasolone labelling. In 9 patients with systemic sclerosis, the amounts of both the main disaccharide unit of dermatan sulfate and chondroitin sulfate C increased significantly, as compared with 7 site-matched controls. Furthermore, the increase in dermatan sulfate was significantly correlated with both the clinical severity and the extent of skin sclerosis, while the main disaccharide unit of hyaluronic acid tended to decrease. These results confirm that changes in skin glycosaminoglycans are closely related to fibrotic processes and suggest that the alterations of disaccharide components may play a role in the collagen deposition in systemic sclerosis.

Clinical evaluation of scleroderma spectrum disorders using a points system.

We have established a new diagnostic method using a points system to evaluate patients with early scleroderma and those with scleroderma spectrum disorders (SSD). To examine the clinical usefulness of this method, it was applied to a total of 215 cases including 97 patients with scleroderma, 32 with SSD, 28 with presumed primary Raynaud's phenomenon (RP) and 58 with other connective tissue disorders (CTD). A total score was obtained for each patient as the sum of the following five factors: (1) extent of skin sclerosis (maximum, 10 points); (2) pulmonary changes (maximum, 4 points); (3) antinuclear antibodies (maximum, 5 points); (4) pattern of Raynaud's phenomenon (maximum, 3 points); and (5) nailfold bleeding (maximum, 2 points). Of the 97 scleroderma patients, 86 (89%) had 9 or more points, and of the 32 SSD patients, 28 (88%) had 5 to 8 points. In contrast, all patients with presumed primary RP and 54 of 58 (93%) patients with other CTD had 0 to 4 points. These data suggest that this diagnostic method is very useful not only for clinical evaluation of SSD, but also for the differentiation of scleroderma and SSD from other CTD and primary RP.