Early Diffuse Cutaneous Systemic Sclerosis Research Articles

Reliability and Validity of the Tender and Swollen Joint Counts and the Modified Rodnan Skin Score in Early Diffuse Cutaneous Systemic Sclerosis: Analysis from the Prospective Registry of Early Systemic Sclerosis Cohort.

To determine the inter/intraobserver reliability of the tender and swollen joint counts (TJC, SJC) and the modified Rodnan Skin Score (mRSS) in diffuse cutaneous systemic sclerosis (dcSSc) and to assess content validity of the TJC/SJC. Ten rheumatologists completed the SJC, TJC, and mRSS on 7 patients. Musculoskeletal ultrasound (MSUS) was performed. Interobserver and intraobserver reliability for the TJC was 0.97 and 0.99, for the SJC was 0.24 and 0.71, and for the mRSS was 0.81 and 0.94, respectively. MSUS abnormalities did not correspond with SJC/TJC. We demonstrate excellent inter- and intraobserver reliability for the mRSS and TJC in dcSSc. However, the SJC and TJC did not correspond to MSUS.

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

ObjectivesThe rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.MethodsThis...

Hand Impairment in Systemic Sclerosis: Various Manifestations and Currently Available Treatment.

Systemic sclerosis (SSc) is an autoimmune disease initially recognized by hand involvement due to characteristic Raynaud's phenomenon (RP), puffy hands, skin thickening, and contractures resembling claw deformities. SSc contributes to hand impairment through inflammatory arthritis, joint contractures, tendon friction rubs (TFRs), RP, digital ulcers (DU), puffy hands, skin sclerosis, acro-osteolysis, and calcinosis. These manifestations, which often co-exist, can contribute to difficulty with occupational activities and activities of daily living (ADL), which can result in impaired quality of life. However, despite this knowledge, most diagnostic and treatment principles in SSc are focused on visceral manifestations due to known associations with morbidity and mortality. Treatment of inflammatory arthritis is symptom based and involves corticosteroids ≤10mg daily, methotrexate, tumor necrosis factor inhibitors, tocilizumab, and abatacept. Small joint contractures are managed by principles of occupational hand therapy and rarely surgical procedures. TFRs may be treated similar to inflammatory arthritis with corticosteroids. All patients with RP and DU should keep digits covered and warm and avoid vasoconstrictive agents. Pharmacologic management of RP begins with use of calcium channel blockers, but additional agents that may be considered are fluoxetine and phosphodiesterase 5 (PDE5) inhibitors. DU management also involves vasodilators including calcium channel blockers and PDE5 inhibitors; bosentan has also been shown to prevent DU. In patients with severe RP and active DU, intravenous epoprostenol or iloprost can be used and surgical procedures, such as botulinum injections and digital sympathectomies, may be considered. For those with early diffuse cutaneous SSc needing immunosuppression for skin sclerosis, methotrexate or mycophenolate mofetil can be used, but the agent of choice depends on co-existing manifestations, such as inflammatory arthritis and/or lung involvement. Various pharmacologic agents for calcinosis have been considered but are generally ineffective; however, surgical options, including excision of areas of calcinosis, can be considered. Overall management of hand impairment for all patients with SSc should include occupational hand therapy techniques such as range of motion exercises, paraffin wax, and devices to assist in ADL. Thus, treatment options for the various manifestations contributing to hand impairment in SSc are limited and often modestly efficacious at best. Robust studies are needed to address the manifestations of SSc that contribute to hand impairment.

Derivation and External Validation of a Prediction Rule for Five-Year Mortality in Patients With Early Diffuse Cutaneous Systemic Sclerosis.

Although diffuse cutaneous systemic sclerosis (dcSSc) is associated with a reduction in life expectancy, there are no validated prognostic models for determining 5-year mortality in patients with dcSSc. The objective of this study was to derive and validate a rule for predicting 5-year mortality in patients with early dcSSc. We studied an inception cohort of 388 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom). Predefined baseline variables were analyzed in a stepwise logistic regression model in order to identify factors independently associated with 5-year all-cause mortality. We rounded the beta weights to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk (<0 points), moderate-risk (1-2 points), and high-risk (≥3 points) groups. We then applied this rule to an external validation cohort of 144 Caucasian patients with early dcSSc from the Royal Free Hospital cohort and compared stratum-specific 5-year mortality. Six independent predictors (rounded beta weight) comprised the model: age at first visit (points allotted: -1, 0, or 1), male sex (points allotted: 0 or 1), tendon friction rubs (points allotted: 0 or 1), gastrointestinal involvement (points allotted: 0 or 1), RNA polymerase III antibodies (points allotted: 0 or 1), and anemia (points allotted: 0 or 1). The 3-level risk stratification model performed well, with no significant differences between the US derivation cohort and the UK validation cohort. We derived and externally validated, in US and UK cohorts, an easy-to-use 6-variable prediction rule that assigns low-risk, moderate-risk, and high-risk categories for 5-year mortality in patients with early dcSSc. Only history, physical examination, and basic laboratory assessments are required.

The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis.

Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs). We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT. Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02). We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.

Progranulin Overproduction Due to Fli-1 Deficiency Contributes to the Resistance of Dermal Fibroblasts to Tumor Necrosis Factor in Systemic Sclerosis.

Progranulin is a growth factor that is active in wound repair and is an antagonist of tumor necrosis factor (TNF) receptors, regulating fibroblast activation, angiogenesis, and inflammation. Because long-standing activation of gene programs related to wound healing is a hallmark of systemic sclerosis (SSc), we sought to investigate the role of progranulin in SSc. Progranulin expression levels in human and murine skin samples were determined by immunohistochemical analysis and quantitative reverse transcription-polymerase chain reaction. The role of progranulin in fibroblast activation was examined using a gene-silencing technique. Progranulin levels in serum obtained from 60 patients with SSc and 16 healthy control subjects were determined by enzyme-linked immunosorbent assay. Progranulin expression was increased in SSc dermal fibroblasts compared with normal dermal fibroblasts, both in vivo and in vitro. Transcription factor Fli-1, a deficiency of which is involved in the activation of SSc dermal fibroblasts, served as a potent repressor of the progranulin gene, and Fli-1(+/-) mice and bleomycin-treated wild-type mice exhibited up-regulated expression of progranulin in dermal fibroblasts. SSc dermal fibroblasts were resistant to the antifibrotic effect of TNF, but this resistance was reversed by gene silencing of progranulin. Serum progranulin levels were elevated in patients with early diffuse cutaneous SSc (dcSSc), especially in those with inflammatory skin symptoms, and were positively correlated with the C-reactive protein level. Progranulin overproduction due to Fli-1 deficiency may contribute to the constitutive activation of SSc dermal fibroblasts by antagonizing the antifibrotic effect of TNF. Progranulin may also be involved in the inflammatory process associated with progressive skin sclerosis in early dcSSc.

Serum amyloid A is a marker for pulmonary involvement in systemic sclerosis.

Inflammation in systemic sclerosis (SSc) is a prominent, but incompletely characterized feature in early stages of the disease. The goal of these studies was to determine the circulating levels, clinical correlates and biological effects of the acute phase protein serum amyloid A (SAA), a marker of inflammation, in patients with SSc. Circulating levels of SAA were determined by multiplex assays in serum from 129 SSc patients and 98 healthy controls. Correlations between SAA levels and clinical and laboratory features of disease were analyzed. The effects of SAA on human pulmonary fibroblasts were studied ex vivo. Elevated levels of SAA were found in 25% of SSc patients, with the highest levels in those with early-stage disease and diffuse cutaneous involvement. Significant negative correlations of SAA were found with forced vital capacity and diffusion capacity for carbon monoxide. Patients with elevated SAA had greater dyspnea and more frequent interstitial lung disease, and had worse scores on patient-reported outcome measures. Incubation with recombinant SAA induced dose-dependent stimulation of IL-6 and IL-8 in normal lung fibroblasts in culture. Serum levels of the inflammatory marker SAA are elevated in patients with early diffuse cutaneous SSc, and correlate with pulmonary involvement. In lung fibroblasts, SAA acts as a direct stimulus for increased cytokine production. These findings suggest that systemic inflammation in SSc may be linked to lung involvement and SAA could serve as a potential biomarker for this complication.

Derivation and Validation of a Prediction Rule for Two‐Year Mortality in Early Diffuse Cutaneous Systemic Sclerosis

Systemic sclerosis (SSc) is associated with a reduction in life expectancy, but there are no validated prognostic models for determining short-term mortality. The objective of this study was to derive and validate a prediction rule for 2-year mortality in patients with early diffuse cutaneous SSc (dcSSc). We studied a prospectively enrolled cohort of 387 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom), randomly divided into a derivation cohort (n = 260) and a validation cohort (n = 127). Predefined baseline predictor variables were analyzed in a stepwise multivariable logistic regression model in order to identify factors independently associated with 2-year all-cause mortality using a cutoff of P < 0.05. We rounded the beta values to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk, moderate-risk, and high-risk groups. We then applied this rule to an external validation cohort of 110 Caucasian patients with early dcSSc from a single UK center and compared stratum-specific mortality using chi-square statistics. Four independent predictor variables (with assigned integer values) comprised the model: age at first visit (points allotted: -1, 0, or 1), skin thickness progression rate (points allotted: 0 or 1), gastrointestinal tract severity (points allotted: 0, 1, or 2), and anemia (points allotted: 0 or 2). The prediction model performed well, with no significant differences between the derivation cohort and the US or UK validation cohorts in the low-risk and moderate-risk groups. We derived a 4-variable prediction rule that can be used to stratify patients with early dcSSc into groups by risk of 2-year mortality, and we validated that prediction rule in US and UK cohorts.

Estimating Benefits from Immunesuppressive Treatment in Diffuse Cutaneous Systemic Sclerosis: Data from the Canadian Scleroderma Research Group

Objective: To determine the efficacy of immunesuppressive treatment over 1 year in early diffuse cutaneous systemic sclerosis (dcSSc). Methods: dcSSc patients with less than 3 years disease duration and at least one year of data enrolled in the CSRG database were included. Regression analyses for achieving at least minimal important differences (MID) for 5 outcomes over one year were done to determine baseline predictors of change and if immunesuppressive treatment yielded the attainment of the MID. Results: 124 patients (mean age 52.3 years; 79.2% female) were included. Variables associated with MID at one year were often the baseline variable and for some outcomes, age, sex, smoking, restrictive lung disease and treatment type. Treatment with immunesuppressive was not found to be associated with achieving MIDs in multivariate analyses. Conclusion: Treatment was associated with achieving a MID change at 1 year using univariate statistics, but not in multivariate models. These observational data do not support improvement with immunesuppressives over one year but there could be confounding or biases comparing with those prescribed immunesuppressives vs. those who don’t.

Significance of Palpable Tendon Friction Rubs in Early Diffuse Cutaneous Systemic Sclerosis

Palpable tendon friction rubs (TFRs) in systemic sclerosis (SSc; scleroderma) have been associated with diffuse skin thickening, increased disability, and poor survival. Our objective was to quantify the prognostic implications of palpable TFRs on the development of disease complications and longer-term mortality in an incident cohort of early diffuse cutaneous SSc (dcSSc) patients. We identified early dcSSc patients (disease duration <2 years from the first SSc symptom) first evaluated at the University of Pittsburgh Scleroderma Center between 1980 and 2006 and found to have palpable TFRs. These patients were matched 1:1 with the next consecutive early dcSSc patient without TFRs as a control. All had ≥2 clinic visits and 5 years of followup from the first visit. A total of 287 early dcSSc patients with TFR were identified and matched to 287 controls. The median disease duration was 0.83 years in TFR patients and 1.04 years in controls. The median followup was 10.1 years in TFR patients and 7.9 years in controls. Over the course of their illness, patients with TFRs had a >2-fold risk of developing renal crisis and cardiac and gastrointestinal disease complications, even after adjustment for other known risk factors. Patients with TFRs had poorer 5- and 10-year survival rates. Patients with early dcSSc having ≥1 TFRs are at an increased risk of developing renal, cardiac, and gastrointestinal involvement before and after their first Scleroderma Center visit and have reduced survival. Patients presenting with TFRs should be carefully monitored for serious internal organ involvement.

LB0002 The astis trial: Autologous stem cell transplantation versus IV pulse cyclophosphamide in poor prognosis systemic sclerosis, first results

BackgroundPilot studies have shown durable responses in two thirds of patients with poor prognosis diffuse cutaneous systemic sclerosis (dcSSc) treated with high dose immunosuppressive therapy and haematopoietic stem cell transplantation...

SP0035 Raynaud’s phenomenon and systemic sclerosis: An update

Systemic sclerosis (SSc) is a multisystem auto-immune disease. The two main subtypes of SSc (limited and diffuse cutaneous subsets) typically have differing courses and prognoses. However, new classification criteria are...

Autologous Hematopoietic Stem Cell Transplantation Versus Intravenous Pulse Therapy Cyclophosphamide for Severe or Rapidly Progressive Systemic Sclerosis, the Astis Trial

AbstractAbstract ▪964▪This icon denotes a clinically relevant abstract Background:High dose immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) has shown efficacy in severe or rapidly progressive systemic sclerosis (SSc) in phase 1 and 2 trials with durable responses in two thirds of patients (pts), while a recent phase 2 randomised trial in 19 SSc pts showed superior benefit of HSCT over iv pulse cyclophosphamide (Cy) on skin score and lung function. Methods:The ASTIS-trial (Autologous Stem cell Transplantation International Scleroderma trial) is a multinational prospective randomized controlled phase 3 trial, comparing safety and efficacy of HSCT versus Cy in early progressive dcSSc pts with disease duration of a) 4 years or less and evidence of organ involvement or b) of 2 years or less and evidence of systemic inflammation with or without major organ involvement. Major exclusion criteria were: concomitant severe SSc disease (mean PAP > 50 mmHg, DLCO < 40% predicted, creatinine clearance (CCl) <40 ml/min, LVEF <45%, uncontrolled arythmia, infection, previous Cy (>5gr iv or >3months oral) treatment), liver failure. Pts randomized to the transplant arm underwent mobilization with Cy 2×2 g/m2 + G-CSF 10mcg/kg/d, conditioning with Cy 200 mg/kg, rbATG 7.5 mg/kg, followed by reinfusion of CD34+ autologous HSCT. Controls were treated with 12× monthly iv pulse Cy 750 mg/m2. Crossing over was allowed after 2 years. The primary endpoint was event-free survival (EFS), defined as survival until death or development of major organ failure at 2 yrs. Toxicity according to WHO criteria and progression free survival (defined as worsening of modified Rodnan skin score, functional ability, major organ function) were the main secondary endpoints. The effects of treatment were analyzed on an ITT basis and by comparing EFS using the KM survival curves (using log-rank test) and Cox models. Results:156 pts (female 59%), from 27 centers were enrolled in 10 countries from March 2001 until October 2009 and randomized to HSCT (n=79) or iv pulse Cy (n=77). Seventy-five pts in each arm started treatment, 70 pts in HSCT and 58 pts in control groups completed treatment. The median time (Interquartile Range (IR)) from randomization to completion of treatment was 93 (43.0) days in the HSCT and 338 (41.75) days in the control groups respectively. Baseline characteristics (mean (SD)) of the pts were: age 44 (11.2) yrs, SSc duration 1.4 (1.3) yrs, BMI 24 (14.4), Rodnan skin score 25 (8), HAQ 1.35 (0.8), prior Cy therapy 22%, creat cl 116 (39.5) ml/min, LVEF 65% (8.5), DLCO 59% (14), with no significant differences between the 2 arms.With data cut at 1 May 2012, median follow-up (IR) are 33 (42.0) and 27 (34.0) months in the HSCT and control groups respectively. Forty two events occurred : 18 in the HSCT group (16 deaths and 2 irreversible renal failures) and 24 in the control group (24 deaths). Event-free survival was time-dependent with a hazard ratio at 84 months of 0.22 (95% CI 0.08–0.58, P= 0.002). Eight deaths (including 1 during mobilization and 1 after conditioning) in the HSCT group were deemed treatment-related by the independent data monitoring committee with heart failure (3), ARDS (2), multiple organ failure (2) and pulmonary oedema (1) as the causes of death. In the control group, none died from treatment causes and most deaths were due to progressive disease. Eight pts in the control arm received rescue HSCT treatment, one of whom later died from secondary acute myeloid leukaemia. Two HSCT pts received rescue iv Cy therapy. Conclusions:The ASTIS-trial is the first international, investigator-initiated, phase 3 HSCT trial in early diffuse cutaneous systemic sclerosis. The data show that despite 10% treatment-related mortality, long term event-free survival and overall survival were better in the HSCT group than in the group treated with iv pulse cyclophosphamide.(Funded by the European Group for Blood and Marrow Transplantation, European League Against Rheumatism, AP-HP, NIHR, DIGR, Imtix-Sangstat, Miltenyi-Biotec, Amgen Europe; Current Controlled Trials number, ISRCTN 54371254). Disclosures:No relevant conflicts of interest to declare.

Augmented ICOS expression in patients with early diffuse cutaneous systemic sclerosis

Inducible costimulator (ICOS), expressed on activated T cells, and its ligand, ICOS ligand (ICOSL), expressed on antigen-presenting cells, have been considered a single receptor-ligand pair. Here we investigated the expression of ICOS and ICOSL in patients with SSc. ICOS expression on peripheral blood T cells, and ICOSL expression on B cells and macrophages was determined by flow cytometry. Expression of ICOS and ICOSL was assessed by immunohistological staining and real-time PCR of lesional skin. ICOS expression levels were specifically increased on both peripheral blood memory T cells and Tregs from early dcSSc patients compared with those from healthy controls. Mean ICOSL expression on B cells or macrophages was comparable between SSc patients and healthy controls. ICOS-expressing T cells, ICOSL-expressing macrophages and mRNA levels of ICOS and ICOSL were increased in the lesional skin of patients with early dcSSc. In vitro ICOS costimulation enhanced production of IFN-γ, IL-4 and IL-17A from T cells in SSc patients vs normal controls. Soluble ICOS levels were significantly increased in SSc patients and were negatively associated with the presence of ACAs and positively associated with CRP values. Serum levels of soluble ICOS were more closely associated with clinical features compared with levels of soluble IL-2 receptor. Augmented ICOS signalling may contribute to the pathogenesis of SSc during early progressive disease. Soluble ICOS levels may be used as a serum marker for the activity and severity of SSc.

Observational Study of Treatment Outcome in Early Diffuse Cutaneous Systemic Sclerosis

Randomized clinical trials in early diffuse cutaneous systemic sclerosis (dcSSc) are challenging. We used an observational approach to estimate the relative effectiveness of different current treatment approaches, capturing entry and outcome data in a standardized way. Patients with dcSSc within 3 years of the onset of skin thickening were included. Standardized entry and followup data were collected in relation to the first disease-modifying treatment at baseline and 4-6 weeks, then 3, 6, 12, 18, 24, 30, and 36 months. The 5 different protocols were (1) intravenous cyclophosphamide followed by mycophenolate mofetil (MMF); (2) antithymocyte globulin followed by MMF; (3) MMF alone; (4) no disease-modifying treatment; (5) other immunosuppressant treatment. The primary outcome measure was the modified Rodnan skin score (mRSS). Inverse probability of treatment weights were used to allow for differing patient characteristics between groups. The study included 147 patients from 12 centers. Numbers of patients starting on Protocols 1 to 5 were 29, 25, 61, 19, and 13, respectively. mRSS decreased over time from 24 (IQ 19-32) at baseline to 15.5 (IQ 9-24.5) at 3 years. Although there were differences in the magnitude of the change for different protocols, there were no significant differences between protocols in the rate of change of mRSS over time (p = 0.43). When inverse probability weights were applied, the results remained nonsignificant (p = 0.41). Using this observational approach, there were no obvious differences in outcome between groups after allowing as far as possible for baseline differences in treatment allocations.

Thymoglobulin and Cyclophosphamide as Treatment for Diffuse Cutaneous Systemic Sclerosis

To the Editor: Systemic sclerosis (SSc) is an autoimmune disease associated with the development of organ fibrosis and vasculopathy1. Patients with severe, early diffuse cutaneous SSc and significant internal organ involvement have a mortality rate of 50% at 5 years2. There are many aspects of SSc that support the hypothesis that it is an autoimmune disease and might respond to immunosuppressive therapy3,4. Immunosuppressive agents like cyclophosphamide have been investigated as treatment for SSc. Cyclophosphamide can affect immune function by decreasing circulating B and T cells5. A retrospective, open, controlled study of 103 SSc patients with multiple cycles suggested improved survival6. To date, the immunomodulatory effect of thymoglobulin is not fully understood but includes increased T cell clearance from blood, modulation of T cell activation, elimination of cytotoxic T cells, and increased T regulatory cells. In a pilot study, thymoglobulin was studied as single-agent therapy7. Matteson, et al 8 treated 10 patients with Atgam® (antithymocyte globulin) alone, at total dose … Address correspondence to Dr. L. Holmberg, Fred Hutchison Cancer Research Center, 1100 Fairview Ave N., D5-390, PO Box 19024, Seattle, WA 98109-1024. E-mail: lholmber{at}fhcrc.org

Molecular framework for response to imatinib mesylate in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRbeta and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10(-8)). The response of these patients and the findings of the analyses suggest that PDGFRbeta and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.

Validity, reliability, and feasibility of durometer measurements of scleroderma skin disease in a multicenter treatment trial

To determine the validity, reliability, and feasibility of durometer measurements of skin hardness as an outcome measure in clinical trials of scleroderma. Skin hardness was measured during a multicenter treatment trial for scleroderma using handheld digital durometers with a continuous scale. Skin thickness was measured by modified Rodnan skin score (MRSS). Other outcome data collected included the Scleroderma Health Assessment Questionnaire. In a reliability exercise in advance of the trial, 9 investigators examined the same 5 scleroderma patients by MRSS and durometry. Forty-three patients with early diffuse cutaneous systemic sclerosis were studied at 11 international centers (mean age 49 years [range 24-76], median disease duration 6.4 months [range 0.3-23], and median baseline MRSS 22 [range 11-38]). The reliability of durometer measurements was excellent, with high interobserver intraclass correlation coefficients (ICCs) (0.82-0.92), and each result was greater than the corresponding skin site ICCs for MRSS (0.54-0.85). Baseline durometer scores correlated well with MRSS (r = 0.69, P < 0.0001), patient self-assessments of skin disease (r = 0.69, P < 0.0001), and Health Assessment Questionnaire (HAQ) disability scores (r = 0.34, P = 0.03). Change in durometer scores correlated with change in MRSS (r = 0.70, P < 0.0001), change in patient self-assessments of skin disease (r = 0.52, P = 0.003), and change in HAQ disability scores (r = 0.42, P = 0.017). The effect size was greater for durometry than for MRSS or patient self-assessment. Durometer measurements of skin hardness in patients with scleroderma are reliable, simple, accurate, demonstrate good sensitivity to change compared with traditional skin scoring, and reflect patients' self-assessments of their disease. Durometer measurements are valid, objective, and scalable, and should be considered for use as a complementary outcome measure to skin scoring in clinical trials of scleroderma.

Low‐dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease

Objective: To investigate the efficacy of a treatment with low‐dose intravenous cyclophosphamide (CYC) and low‐dose prednisone in early diffuse cutaneous systemic sclerosis (dcSSc).Methods: Patients with dcSSc and a disease duration <24 months consecutively admitted to a tertiary centre underwent a prospective 1‐year study. They were treated with i.v. CYC 500 mg/pulses, 10 mg prednisone equivalent, and supportive therapy. Modified Rodnan skin score (mRss), Health Assessment Questionnaire – Disability Index (HAQ‐DI), forced vital capacity (FVC), and diffusing lung capacity for CO (DLCO) were assessed as outcome measures. In addition, the nine Medsger severity scale scores were evaluated.Results: mRss and DLCO significantly improved at both 6 (p = 0.002 and 0.012, respectively) and 12 months (p = 0.002 and 0.003, respectively). HAQ‐DI showed a nearly significant reduction at 12 months (p = 0.06). Medsger's severity scores also improved for general condition (p = 0.001), peripheral vascular (p = 0.05), skin (p = 0.02), joint/tendon (p = 0.001), muscle (p = 0.05), and lung (p = 0.02). No treatment interruption was needed.Conclusions: This preliminary study suggests a role for low‐dose i.v. CYC in the treatment of early dcSSc. Controlled studies are warranted.

Elevated serum BAFF levels in patients with systemic sclerosis: Enhanced BAFF signaling in systemic sclerosis B lymphocytes

To determine serum levels of BAFF, a potent B cell survival factor, in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc. Serum BAFF levels in 83 patients with SSc were examined by enzyme-linked immunosorbent assay (ELISA). In a longitudinal study, 131 serum samples obtained from 21 patients with SSc were analyzed. The expression of BAFF messenger RNA (mRNA) in the skin was quantified by real-time reverse transcription-polymerase chain reaction. The expression of BAFF receptor (BAFFR) on CD19+ B cells was assessed by flow cytometry. The production of IgG and interleukin-6 (IL-6) by isolated B cells was examined by ELISA. Serum BAFF levels were elevated in SSc patients compared with healthy controls and correlated positively with the extent of skin fibrosis. Among the 21 patients with SSc in the longitudinal study, 7 had decreased BAFF levels, 11 had levels that remained unchanged, and 3 patients had increased levels. Decreasing BAFF levels were accompanied by regression of skin sclerosis, whereas increasing levels of BAFF were associated with the new onset or worsening of organ involvement. BAFF mRNA expression was up-regulated in the affected skin of patients with early diffuse cutaneous SSc. BAFFR expression on B cells was increased in SSc patients relative to healthy controls. Furthermore, SSc B cells that were stimulated by BAFF exhibited an enhanced ability to produce IgG and IL-6. These results suggest that BAFF and its signaling in B cells contribute to B cell abnormalities and disease development in patients with SSc.