Tissue factor–thrombin signaling enhances the fibrotic activity of myofibroblasts in systemic sclerosis through up‐regulation of endothelin receptor A

Objective

The extrinsic coagulation cascade is involved in the fibrotic process, via thrombin‐dependent induction of CCN2 (connective tissue growth factor) expression. Given the previously reported activation of the coagulation system in systemic sclerosis (SSc), we undertook the present study to investigate the involvement of cross‐talk between the tissue factor (TF)–thrombin axis and endothelin 1 (ET‐1) signaling in the fibrotic activity of SSc.

Methods

Human colonic myofibroblasts (HCMFs) from 6 patients with SSc and gastrointestinal symptoms and from 6 control subjects were isolated and cultured under various conditions. Messenger RNA and protein levels of TF, CCN2, and endothelin receptor A (ET_A) were investigated. Collagen production and migratory activity of HCMFs were further assessed.

Results

HCMFs from SSc patients demonstrated increased basal CCN2 production, collagen deposition, and migration rate, in a thrombin‐dependent manner. Increased TF expression was also observed in SSc HCMFs. Subsequent activation of the extrinsic coagulation system resulted in thrombin‐dependent enhancement of ET_A expression. ET_A overexpression led to further increases in both TF expression and fibrotic activity in HCMFs. Moreover, inhibition of ET‐1 signaling by bosentan abolished the TF‐mediated fibrotic capacity of HCMFs.

Conclusion

Tissue factor–thrombin signaling is involved in the increased fibrotic activity of HCMFs from patients with SSc. Moreover, the up‐regulation of ET_A expression by thrombin and the effect of ET‐1 in the induction of TF expression indicate an amplification loop for enhanced collagen deposition. Therapeutic interventions targeting the extrinsic coagulation system or ET‐1 signaling may provide clinical benefit by breaking this vicious circle.

     

BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4

Objective

To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene–gene interactions between BANK1 and IRF5 as well as STAT4.

Methods

BANK1 single‐nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls.

Results

The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64–0.93) and an OR of 0.73 (95% CI 0.61–0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A‐T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57–0.86], P = 3.39 × 10⁻⁴) and the G‐C haplotype to be a risk factor (OR 1.25 [95% CI 1.06–1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43‐fold.

Conclusion

Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

     

Contribution of activin receptor–like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts

Objective

To use a specific transforming growth factor β receptor type I (TGFβRI; activin receptor–like kinase 5 [ALK‐5]) kinase inhibitor (SD208) to determine the role of activation of the TGFβRI kinase (ALK‐5) in maintaining the profibrotic phenotype of dermal fibroblasts in systemic sclerosis (SSc).

Methods

The effect of SD208 on the expression of key biochemical markers of the fibrotic phenotype was compared in fibroblasts cultured from clinically involved (lesional) and clinically uninvolved skin of patients with diffuse cutaneous SSc (dcSSc) and in fibroblasts from healthy controls matched for age, sex, and anatomic site. Protein expression was compared together with the ability of fibroblasts to adhere to the extracellular matrix and to remodel and contract a free‐floating fibroblast–populated type I collagen lattice.

Results

Inhibiting TGFβRI kinase reduced the expression of a cohort of fibrotic markers by dermal fibroblasts from patients with dcSSc, including type I collagen and β1 integrin. Moreover, inhibition also attenuated the elevated adhesive and contractile abilities of dcSSc fibroblasts.

Conclusion

Our data suggest that some of the key profibrotic features of lesional SSc fibroblasts are dependent upon ALK‐5 activity. Thus, TGFβRI kinase–mediated signaling may contribute to dermal fibrosis in dcSSc.

     

C8orf13–BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: Results from a large french cohort and meta‐analysis

Objective

Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13–BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype–phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta‐analysis of the available data, this study was undertaken to determine whether the C8orf13–BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc.

Methods

The C8orf13–BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta‐analysis of the 3 available data sets (6,078 individuals) was also performed.

Results

Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta‐analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06–1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08–1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻⁵, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13–BLK and BANK1, mainly in the dcSSc subset.

Conclusion

These results confirm C8orf13–BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13–BLK and BANK1 in the dcSSc subset.

     

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Objective

T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell–derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc.

Methods

To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4+ and CD8+ T cell subsets to produce cytokines following in vitro activation.

Results

High levels of the profibrotic type 2 cytokine interleukin‐13 (IL‐13) were produced following activation of peripheral blood effector CD8+ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4+ T cells showed a lower and more variable level of IL‐13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients.

Conclusion

Dysregulated IL‐13 production by effector CD8+ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target.

     

Health‐related quality of life in systemic sclerosis as measured by the short form 36: Relationship with clinical and biologic markers

Objective

To evaluate health‐related quality of life (HRQOL) in patients with systemic sclerosis (SSc) using the Short Form 36 (SF‐36) and to correlate SF‐36 scores with clinical and biologic markers.

Methods

The SF‐36 was administered to 24 controls and 24 SSc patients. SSc patients also were evaluated for subset (limited SSc [lSSc] and diffuse SSc [dSSc]), age, disease duration, angiotensin‐converting enzyme (ACE) levels, autoantibodies, and skin and internal organ involvement.

Results

The physical summary score (PSS) was lower in SSc patients than in controls (P < 0.05), whereas the mental summary score (MSS) was higher in dSSc than in lSSc patients (P < 0.05). Five of 8 single SF‐36 domain scores were lower in SSc patients than in controls (P < 0.05). Vitality was higher in dSSc than in controls (P < 0.001). In SSc, elder age correlated with lower PSS; low ACE levels and high skin score correlated with higher general mental health and role limitations due to physical problems, respectively (P < 0.05). Patients with heart involvement had higher scores in general health perceptions (P < 0.05).

Conclusion

The SF‐36 shows that HRQOL is impaired in patients with SSc. Higher scores in MSS and vitality in patients with dSSc and correlations of high SF‐36 scores with specific organ involvement suggest that SSc patients with severe disease are more able to cope with HRQOL modification.

     

Clinical subsets,skin thickness progression rate,and serum antibody levels in systemic sclerosis patients with anti–topoisomerase I antibody

Objective

To describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti–topoisomerase I (anti–topo I) antibody who have different skin thickness progression rates (STPRs).

Methods

SSc patients (n = 212) who were anti–topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti–topo I IgG antibody levels were determined.

Results

Sixty patients who were anti–topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10‐year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti–topo I antibody levels correlated with the STPR and the MRSS.

Conclusion

Anti–topo I antibody–positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti–topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.

     

Hemorheologic profile in systemic sclerosis: Role of NOS3 −786T>C and 894G>T polymorphisms in modulating both the hemorheologic parameters and the susceptibility to the disease

Objective

Microvascular disorders are relevant in systemic sclerosis (SSc). Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of microcirculatory disorders. An impaired availability of nitric oxide, related to polymorphisms in NOS3, the gene for endothelial cell nitric oxide synthase, might influence erythrocyte deformability. We undertook this study to investigate the hemorheologic profile in SSc and the role of NOS3 polymorphisms in modulating the hemorheologic status of SSc patients.

Methods

We studied 113 consecutive SSc patients (75 with limited cutaneous SSc [lcSSc] and 38 with diffuse cutaneous SSc [dcSSc]) and 113 healthy controls. The hemorheologic profile was obtained by assessing whole blood viscosity (WBV; at shear rates of 0.512 and 94.5 seconds⁻¹), plasma viscosity (PLV; at a shear rate of 94.5 seconds⁻¹), and erythrocyte deformability index (DI). We determined NOS3 polymorphisms by molecular analysis.

Results

A marked alteration of hemorheologic parameters was found both in patients with lcSSc and in those with dcSSc compared with controls (P < 0.0001). In multivariate analysis, rheologic variables were significantly associated with the disease (for WBV at a shear rate of 94.5 seconds⁻¹, odds ratio [OR] 5.4, 95% confidence interval [95% CI] 1.4–19.9, P = 0.01; for PLV, OR 2.8, 95% CI 1.2–6.5, P = 0.01; for DI, OR 3.9, 95% CI 1.4–10.8, P = 0.007), and NOS3 −786C and 894T alleles significantly affected the DI (for −786C allele, OR 2.3, 95% CI 1.01–5.4, P = 0.04; for 894T allele, OR 2.2, 95% CI 1.01–4.8, P = 0.04). The simultaneous presence of the −786C and 894T alleles represented a susceptibility factor for SSc (OR 2.8, 95% CI 1.4–5.7, P = 0.004).

Conclusion

Our findings document an altered rheologic profile in SSc and demonstrate a relationship between this alteration and NOS3 polymorphisms, thus shedding light on a potential novel mechanism influencing the microcirculation in this disease.

     

Endothelin is a downstream mediator of profibrotic responses to transforming growth factor β in human lung fibroblasts

Objective

Fibrosis is excessive scarring caused by the accumulation and contraction of extracellular matrix proteins and is a common end pathway in many chronic diseases, including scleroderma (systemic sclerosis [SSc]). Indeed, pulmonary fibrosis is a major cause of death in SSc. Transforming growth factor β (TGFβ) induces endothelin 1 (ET‐1) in human lung fibroblasts by a Smad‐independent, JNK‐dependent mechanism. The goal of this study was to assess whether ET‐1 is a downstream mediator of the profibrotic effects of TGFβ in lung fibroblasts.

Methods

We used a specific endothelin receptor antagonist to determine whether ET‐1 is a downstream mediator of TGFβ responses in lung fibroblasts, using microarray technology, real‐time polymerase chain reaction, and Western blot analyses.

Results

The ability of TGFβ to induce the expression of a cohort of profibrotic genes, including type I collagen, fibronectin, and CCN2, and to contract a collagen gel matrix, depends on ET‐1.

Conclusion

ET‐1 contributes to the ability of TGFβ to promote a profibrotic phenotype in human lung fibroblasts, consistent with the notion that endothelin receptor antagonism may be beneficial in controlling fibrogenic responses in lung fibroblasts.

     

Association of the FAM167A–BLK region with systemic sclerosis

Objective

An association of single‐nucleotide polymorphisms (SNPs) in the FAM167A (previously referred to as C8orf13)–BLK region with systemic lupus erythematosus (SLE) has been demonstrated in Caucasians and in Asians. Recent studies have shown that many genes, including IRF5, STAT4, and PTPN22, are shared susceptibility genes in multiple autoimmune diseases. We undertook the current study to examine whether the FAM167A–BLK region is also associated with susceptibility to systemic sclerosis (SSc).

Methods

Japanese patients with SSc (n = 309) and healthy controls (n = 769) were enrolled in a 2‐tiered case–control association study. In tier 1, 124 patients and 412 controls were tested to determine association of 16 tag SNPs encompassing the FAM167A–BLK region with SSc. In tier 2, an additional 185 patients and 357 controls were analyzed for SNP rs13277113.

Results

Two haplotype blocks that correspond approximately to FAM167A and BLK were observed. In tier 1 of the study, the rs13277113A allele in the BLK block exhibited the most significant association with SSc after correction for multiple testing (permutated P = 0.024). Two SNP haplotypes formed by rs13277113 and the most significant SNP in the FAM167A block did not exhibit stronger association. When samples from tier 1 and tier 2 were combined, the rs13277113A allele was significantly associated with SSc (odds ratio 1.45 [95% confidence interval 1.17–1.79], P = 6.1 × 10⁻⁴). Association or a tendency toward association of rs13277113A with SSc was observed regardless of a patient's autoantibody profile or whether a patient had diffuse cutaneous or limited cutaneous SSc.

Conclusion

Our findings indicate that the rs13277113A allele is associated not only with SLE but also with SSc and that the FAM167A–BLK region is a common genetic risk factor for both SLE and SSc.

     

Randomized comparison of a multidisciplinary team care program with usual care in patients with systemic sclerosis

Objective

To compare the effectiveness of a multidisciplinary team care program with usual outpatient care in patients with systemic sclerosis (SSc; scleroderma).

Methods

We performed a randomized controlled trial comparing a 12‐week multidisciplinary team care program (1 day per week; individual treatments, group exercises, and group education) with outpatient clinic care. Outcome measures included the Hand Mobility in Scleroderma (HAMIS) test, grip strength, maximal mouth opening (MMO), 6‐minute walk distance (6MWD), maximum aerobic capacity (VO _2max), Checklist Individual Strength 20 (CIS‐20), SSc Health Assessment Questionnaire (HAQ), and Short Form 36 (SF‐36), assessed at 0, 12, and 24 weeks. Statistical comparisons of change scores were done by analysis of covariance.

Results

Twenty‐eight patients were assigned to the intervention group (mean age 53.9 years, 15 of 28 with diffuse SSc) and 25 were assigned to the control group (mean age 51.7 years, 15 of 25 with diffuse SSc). Twenty‐five patients (89%) in the intervention group completed the treatment program. At 12 weeks, there was a significantly greater improvement in grip strength (2.2 versus ?1.8 kg; P = 0.001), MMO (1.4 versus ?0.9 mm; P = 0.011), 6MWD (42.8 versus 3.9 meters; P = 0.021), and HAQ score (?0.18 versus 0.13; P = 0.025) in the intervention group, whereas differences for the other outcome measures did not reach significance. At 24 weeks, the effect on grip strength persisted.

Conclusion

In patients with SSc, a 12‐week multidisciplinary day patient treatment program was more effective than regular outpatient care with respect to 6MWD, grip strength, MMO, and HAQ score, but not for VO _2max, HAMIS test, CIS‐20, SF‐36, and visual analog scale for pain. This study provides a first step in quantifying the effect of a multidisciplinary team care program and warrants the conduct of further intervention studies.

     

Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: A randomized,double‐blind,placebo‐controlled trial

Objective

A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 μg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double‐blind, placebo‐controlled clinical trial to compare placebo with 10 μg/kg/day and 25 μg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate‐to‐severe SSc.

Methods

Men and women ages 18–70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 μg/kg/day or 25 μg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28.

Results

The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo.

Conclusion

Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

     

Soluble CD90 as a potential marker of pulmonary involvement in systemic sclerosis

Objective

Vascular injury and endothelial cell (EC) activation are pathogenic hallmarks of systemic sclerosis (SSc; scleroderma). Human CD90 is highly expressed on activated ECs and can be shed from the cell surface. This study was conducted to examine whether soluble CD90 (sCD90) is elevated in the sera of patients with SSc and linked to pulmonary involvement and in particular, pulmonary arterial hypertension (PAH).

Methods

sCD90 serum concentrations were assessed in 76 patients with SSc and related to clinical data, lung function, 6‐minute walk distance, echocardiography, bronchoalveolar lavage fluid, and laboratory parameters. Thirty‐one healthy volunteers and 29 patients with idiopathic retroperitoneal fibrosis (IRF) served as controls.

Results

sCD90 serum concentrations were elevated in patients with SSc compared to healthy volunteers (P = 0.001) and patients with IRF (P = 0.01). SSc patients with pulmonary fibrosis (P = 0.006) and patients with PAH (P < 0.001) had increased sCD90 serum concentrations compared to patients without the respective pulmonary manifestation of SSc. sCD90 levels correlated with diffusing capacity for carbon monoxide (n = 65; r = ?0.348, P = 0.005) and systolic pulmonary artery pressure (n = 53; r = 0.469, P < 0.001). Receiver operating characteristic curve testing determined an optimal cutoff value of ≥626 ng/ml with a sensitivity of 68% and a specificity of 83% for PAH (area under the curve 0.773, 95% confidence interval 0.648–0.898; P < 0.001).

Conclusion

sCD90 concentrations were increased in the sera of SSc patients, particularly in patients with vascular involvement of the lungs. These data suggest that sCD90 should be further evaluated as a marker for diagnosis of PAH in SSc.

     

Signaling pathways regulating intercellular adhesion molecule 1 expression by endothelin 1: Comparison with interleukin‐1β in normal and scleroderma dermal fibroblasts

Objective

Endothelin 1 (ET‐1) has been implicated in the pathogenesis of fibrotic and inflammatory diseases, including scleroderma. In addition to modulating vascular tone and extracellular matrix turnover, ET‐1 up‐regulates cell surface adhesion molecules including intercellular adhesion molecule 1 (ICAM‐1), which is key to cell–cell and cell–matrix adhesion and leukocyte infiltration. This study was undertaken to delineate the signal transduction pathways utilized by ET‐1 and compare them with those adopted by proinflammatory cytokine interleukin‐1β (IL‐1β) in normal and scleroderma dermal fibroblasts.

Methods

Protein expression induced by ET‐1 and IL‐1β on normal dermal fibroblasts, with or without signaling inhibitors, was detected by enzyme‐linked immunosorbent assay, while messenger RNA (mRNA) levels were analyzed by LightCycler polymerase chain reaction. Expression of protein kinase Cδ (PKCδ) and PKCϵ protein in normal dermal fibroblasts and scleroderma dermal fibroblasts was determined by Western blotting, and PKCϵ involvement in ET‐1 signaling was confirmed through transfection of an ICAM‐1 promoter construct into murine PKCϵ^−/− fibroblasts. NF‐κB activation was confirmed via electrophoretic mobility supershift assay, and analysis of the ICAM‐1 promoter region was achieved via transfection of deletion constructs into human dermal fibroblasts.

Results

In normal dermal fibroblasts, ET‐1 induced ICAM‐1 mRNA and surface protein expression in a dose‐ and time‐dependent manner via both receptor subtypes, ET_A and ET_B; antagonism of both abolished the ET‐1 response. MEK was involved in the signaling cascade, but phosphatidylinositol 3‐kinase and p38 MAPK were not. Key to the cascade was activation of NF‐κB, achieved by ligation of either receptor subtype. PKCϵ activation led to downstream activation of MEK and, in part, NF‐κB. IL‐1β signaling required NF‐κB and MEK activation, along with activation of PKCδ. ET‐1 and IL‐1β each utilized the same ICAM‐1 promoter region and the same NF‐κB site at –157 bp. Responses to ET‐1 and IL‐1β differed in scleroderma dermal fibroblasts, with ET‐1 sensitivity decreasing and IL‐1β responses remaining intact. Expression of PKCϵ and PKCδ in scleroderma dermal fibroblasts was also altered.

Conclusion

The findings of this study indicate that differences in sensitivity to ET‐1 and IL‐1β in scleroderma dermal fibroblasts may be explained by altered expression of the PKC isoforms and cytokine receptors.

     

Course of the modified Rodnan skin thickness score in systemic sclerosis clinical trials: Analysis of three large multicenter,double‐blind,randomized controlled trials

Objective

To assess the course of the modified Rodnan skin thickness score (MRSS) in 3 large, multicenter, double‐blind, randomized controlled trials (RCTs) of patients with diffuse cutaneous systemic sclerosis (dcSSc) with different baseline disease durations, as defined from the date of onset of the first dcSSc symptom (excluding Raynaud's phenomenon) or from the date of onset of the first dcSSc‐related symptom (including Raynaud's phenomenon).

Methods

Data from 3 RCTs examining high‐dose versus low‐dose D‐penicillamine (D‐Pen Trial), recombinant human relaxin versus placebo (Relaxin Trial), and oral bovine type I collagen versus placebo (Collagen Trial) treatment in patients with dcSSc were pooled and analyzed. Patients were divided into 5 groups according to their disease duration at baseline. The linear mixed model for correlated data was used to model the 2 predictors of MRSS: time in study (expressed in months after baseline) and baseline disease duration (expressed in months, calculated from the date of onset of the first symptom characteristic of dcSSc with and without Raynaud's phenomenon).

Results

At study entry, the mean MRSS value was 21.0 in the D‐Pen Trial cohort, 27.3 in the Relaxin Trial cohort, and 26.1 in the Collagen Trial cohort. Time in study was a significant predictor of improvement in MRSS regardless of the disease duration at baseline (P < 0.0001). Patients with a disease duration of ≥24 months showed a greater rate of decline as compared with patients with a disease duration of <24 months (P < 0.05). Similar results were obtained when disease duration was reclassified by including the time of the first Raynaud's phenomenon symptom in the definition.

Conclusion

Our study confirms recent findings that in patients entered into these 3 RCTs, skin thickening did not follow the same trend in natural history as that seen in the dcSSc populations entered into early, open longitudinal studies previously reported. These findings have important implications for study design, in which “prevention of worsening” is the main objective.