Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: Localized scleroderma, systemic sclerosis and overlap syndromes.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this consensus provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes.

Prospective evaluation of treatment response and disease reversibility of paediatric localized scleroderma (morphoea) to steroids and methotrexate using multi-modal imaging.

BACKGROUND: Paediatric localized scleroderma is a severe inflammatory disorder associated with tissue atrophy, often leading to disability. Assessing disease activity and response to treatment has always been challenging and remains an important difficulty in clinical practice. OBJECTIVES: To investigate prospectively the efficacy of systemic treatment with corticosteroids and methotrexate in children with localized scleroderma and the validity of infrared thermography, laser Doppler flowmetry and high-frequency ultrasound in assessing disease activity. METHODS: Children with localized scleroderma were prospectively treated with corticosteroids (initially pulsed IV methylprednisolone 30 mg/kg/day, maximum 500 mg/day and/or oral prednisolone 0.5-1 mg/kg/day) and methotrexate (15 mg/m2 weekly). Treatment response was evaluated using a clinical activity score. Skin temperature, blood flow, dermal thickness and dermal echogenicity of clinically active skin lesions were determined in relation to the unaffected contralateral site at baseline and after 3, 6, 12 and 18 months. Patient charts were later reviewed for long-term follow-up. RESULTS: Twenty-two patients were included [age 6.0 (0.2-14.4] years; female-to-male ratio 3.4 : 1) All responded well to therapy. Disease reversibility was demonstrated in the majority of children with partial resolution of skin sclerosis and regrowth of hair. Laser Doppler flowmetry and high-frequency ultrasound findings correlated with disease activity at baseline. Thermography had no added value in this cohort. The recurrence rate was 36% in the follow-up period. CONCLUSIONS: Corticosteroids and methotrexate are highly effective as first-line therapy in paediatric localized scleroderma, leading to partial reversal of skin manifestations. However, the recurrence rate is substantial and affected children require long-term follow-up. Laser Doppler flowmetry and high-frequency ultrasound correlate with disease activity in the acute phase and may assist decision-making in these patients.

Sidestream Dark Field (SDF) imaging of oral microcirculation in the assessment of systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a systemic disease characterised by abnormalities in small blood vessels, skin and organ fibrosis. It is assessed using generalised skin thickening scores, autoantibodies and nailfold capillaroscopy. Sidestream Dark Field imaging (SDF) is a non-invasive imaging tool that assesses microcirculation. This study aims to investigate the potential of using SDF as a diagnostic tool in SSc. METHOD: Oral microcirculation of 20 patients with SSc was compared to 20 age and gender matched controls using SDF imaging. Sublingual, buccal and incisor regions of the mouth were examined. All volunteers were female averaging 48.0 (24-64) years old. Vasculature was assessed by calculating the De Backer score and Functional Capillary Density (FCD) on an imaging software. RESULTS: At all regions of the mouth, SSc patients had a significantly lower De Backer score compared to controls (SSc 3.484 ±â€¯0.1361/mm vs Control 5.184 ±â€¯0.1896/mm, unpaired t-test p < 0.0001). The SSc patients showed significantly lower FCDs compared to controls at all areas as well (SSc 19.65 ±â€¯0.9445% vs Control 29.45 ±â€¯1.681%, unpaired t-test, p < 0.0001). The incisor regions had significantly higher De Backer and FCD scores than buccal and sublingual regions in both control and SSc patients (one way anova, p < 0.05). De Backer/FCD scores showed significant correlation against Rodnan Skin Scores in patients with SSc (Pearson correlation, p < 0.05). CONCLUSIONS: SSc patients showed decreased oral vasculature compared to controls. SDF imaging has shown the ability to be a useful diagnostic tool in the assessment of SSc.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

The molecular pathogenesis of morphoea: from genetics to future treatment targets.

A number of immunoinflammatory and profibrotic mechanisms are recognized in the pathogenesis of broad sclerotic skin processes and, more specifically, morphoea. However, the precise aetiopathogenesis is complex and remains unclear. Morphoea is clinically heterogeneous, with variable anatomical patterning, depth of tissue involvement and sclerotic, inflammatory, atrophic and dyspigmented morphology. Underlying mechanisms determining these reproducible clinical subsets are poorly understood but of great clinical and therapeutic relevance. Regional susceptibility mechanisms (e.g. environmental triggers, mosaicism and positional identity) together with distinct pathogenic determinants (including innate, adaptive and imbalanced pro- and antifibrotic signalling pathways) are likely implicated. In the age of genetic profiling and personalized medicine, improved characterization of the environmental, systemic, local, genetic and immunopathological factors underpinning morphoea pathogenesis may open the door to novel targeted therapeutic approaches.

European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy).

European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.

Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): a phase II double-blind placebo-controlled trial.

OBJECTIVE: The primary objective of the study was to explore safety and tolerability of hyperimmune caprine serum (AIMSPRO) in established diffuse cutaneous systemic sclerosis (SSc). Secondary objectives included assessment of potential efficacy and biological activity and exploration of candidate biomarkers. METHODS: This was a double-blind parallel group randomised placebo-controlled clinical trial. After informed consent 20 patients with established diffuse cutaneous SSc of greater than 3 years duration not receiving immunosuppressive therapy were randomised to receive either active (n=10) or placebo formulation (n=10) by subcutaneous twice weekly injection over 26 weeks. Clinical assessments were evaluated over 26 weeks. RESULTS: There were no safety concerns during this study. Frequency of adverse events was not different between active and placebo groups. Mean modified Rodnan Skin Score (mRSS) fell by 1.4±4.7 units with active treatment but increased by 2.1±6.4 units on placebo when baseline values were compared with 26 weeks and responder analysis showed clinically meaningful improvement in mRSS at 26 weeks in 5 (50%) of actively treated patients compared with 1 (10%) in the control group (p=0.062). PIIINP (µg/L) showed a comparatively larger increase in the treatment group compared with the placebo group, (p=0.0118). CONCLUSIONS: These results confirm tolerability and safety of this novel biological agent in established diffuse SSc. The value of a placebo treated control group in small clinical trials evaluating skin disease in SSc is confirmed. Potential improvement in mRSS and changes in PIIINP in cases receiving active therapy suggest that this intervention may be of clinical benefit and warrants further evaluation.

Sputnik Planitia as an impactor remnant indicative of an ancient rocky mascon in an oceanless Pluto.

Pluto's surface is dominated by the huge, pear-shaped basin Sputnik Planitia. It appears to be of impact origin, but modelling has not yet explained its peculiar geometry. We propose an impact mechanism that reproduces its topographic shape while also explaining its alignment near the Pluto-Charon axis. Using three-dimensional hydrodynamic simulations to model realistic collisions, we provide a hypothesis that does not rely upon a cold, stiff crust atop a contrarily liquid ocean where a differentiated ~730 km ice-rock impactor collides at low-velocity into a subsolidus Pluto-like target. The result is a new geologic region dominated by impactor material, namely a basin that (in a 30° collision) closely reproduces the morphology of Sputnik Planitia, and a captured rocky impactor core that has penetrated the ice to accrete as a substantial, strength-supported mascon. This provides an alternative explanation for Sputnik Planitia's equatorial alignment and illustrates a regime in which strength effects, in low-velocity collisions between trans-Neptunian objects, lead to impactor-dominated regions on the surface and at depth.

Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials. METHODS: Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture. RESULTS: The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = -0.27, P < 0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty-three percent of patients with "early" disease (disease duration <18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty-one percent of patients with "late" disease (disease duration ≥ 18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome. CONCLUSION: Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.

A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators.

OBJECTIVE: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). METHODS: We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. RESULTS: In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001). CONCLUSION: Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.

The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis.

Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 × 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.

Biomarkers for skin involvement and fibrotic activity in scleroderma.

Systemic sclerosis (scleroderma, SSc) is characterized as a severe and very heterogeneous disease with a bright variation of skin and organ manifestations in individual patients. The pathogenesis is still not fully elucidated; however, it is known that this disease starts with an initial vascular damage, which then leads to an inflammatory process and finally promotes the development of an accumulation of collagen and other extracellular matrix (ECM) components. As a result of the heterogeneous characteristics of this multisystem, autoimmune disease, it is always a challenge to identify high-risk patients and to monitor the fibrotic activity also in response to therapies. This can be achieved by several physical methods including the mRSS, the durometer and ultrasound determination of skin thickness. However, this also requires the use of laboratory biomarkers, which are easily detectable and that reflect the inflammatory and/or fibrotic activity. As skin correlates well with the extent of fibrosis also in other organs, we focused in this review on biomarkers which reflect skin involvement of scleroderma patients. These include growth factors, cytokines and proteases as well as their inhibitors. Moreover, several ECM proteins, especially the collagens have been determined in skin biopsies and in blood/serum samples. Determination of proteins has been supported by mRNA levels using PCR techniques and expression analysis of gene expression patterns. This review summarizes all non-invasive physical and laboratory examinations, which permit a better understanding of the fibrotic activity of the disease, can be effectively used to assess potential therapeutic response and help to find better treatment options.

Increased epithelial permeability in pulmonary fibrosis in relation to disease progression.

Epithelial injury contributes to pathogenesis in idiopathic pulmonary fibrosis (IPF) but its role in the interstitial lung disease (ILD) of systemic sclerosis (SSc) is uncertain. We quantified the prognostic significance of inhaled technetium-99m ((99m)Tc)-labelled diethylene triamine pentacetate (DTPA) pulmonary clearance, a marker of the extent of epithelial injury, in both diseases. Baseline (99m)Tc-DTPA pulmonary clearance was evaluated retrospectively in patients with SSc-ILD (n = 168) and IPF (n = 97) against mortality and disease progression. In SSc-ILD, the rapidity of total clearance (hazard ratio (HR) 1.02, 95% CI 1.01-1.03; p = 0.001) and the presence of abnormally rapid clearance (HR 2.10; 95% CI 1.25-3.53; p = 0.005) predicted a shorter time to forced vital capcity (FVC) decline, independent of disease severity. These associations were robust in both mild and severe disease. By contrast, in IPF, delayed clearance of the slow component, an expected consequence of honeycomb change, was an independent predictor of a shorter time to FVC decline (HR 1.01, 95% CI 1.00-1.02; p<0.01). Epithelial injury should be incorporated in pathogenetic models in SSc-ILD. By contrast, outcome is not linked to the overall extent of epithelial injury in IPF, apart from abnormalities ascribable to honeycombing, suggesting that core pathogenetic events may be more spatially focal in that disease.

Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis.

OBJECTIVE: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). METHOD: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. RESULTS: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). CONCLUSION: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

The psychological impact of facial changes in scleroderma.

The physical disabilities associated with scleroderma are well known but the psychological impact of the condition has received less attention. Few studies have examined appearance related issues, most notably of the face. The aim of this study is to evaluate the psychological impact of facial, aesthetic and functional changes in scleroderma. One hundred seventy-one patients with a clinical diagnosis of scleroderma were recruited into the study. Digital photographs were objectively graded into groups based on severity of disfigurement as judged by an observer. Facial movement was recorded using a modified House-Brackmann Grading Scale. Psychological evaluation comprised the Derriford Appearance Scale short-form (DAS), the Noticeability and Worry score and the Hospital Anxiety and Depression Scale (HADS). Severity of disfigurement predicted decreased mouth opening, the extent to which participants judged their appearance as noticeable to others, and the level of appearance-related concern as measured by the DAS24. There was an inverse relationship with age. Facial changes were ranked as the most worrying aspect of the condition. This study shows facial disfigurement impacts on patient with scleroderma independent of functional changes related to systemic disease. The major difficulty is with the perceived noticeably of the condition to other people and the resulting self-consciousness in social encounters.

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.

INTRODUCTION: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.