Prognostic and predictive markers of systemic sclerosis-associated interstitial lung disease in a clinical trial and long-term observational cohort.

OBJECTIVES: To explore prognostic and predictive markers of SSc-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART). METHODS: The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan-Meier estimation and Cox regression were used for time-to-event analyses. RESULTS: In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P = 0.0001). FVC was 9.8% lower in patients with CRP >6 mg/ml vs those with CRP ≤6 mg/ml (P = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease (<2 years duration), had IL-6 levels <10 pg/ml, or had anti-topoisomerase antibodies (ATA). In the SMART cohort, prognostic factors for ppFVC <70% were male sex, ATA, and low baseline FVC. Males had 3.3% lower FVC 1 year after disease onset (P < 0.001) and 0.6% faster yearly decline (P = 0.03) than females. CONCLUSION: Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but IL-6 ≥10 pg/ml was not predictive of response to tocilizumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02453256.

Autoantibody predictors of gastrointestinal symptoms in systemic sclerosis.

OBJECTIVES: To assess the prevalence and burden of SSc-related gastrointestinal dysfunction (SSc-GI) and to evaluate associations with demographic, clinical and serological characteristics. METHODS: Patients completed the UCLA SCTC GIT 2.0 questionnaire for SSc-GI disease to assess the burden of GI disease across multiple functional and psychological domains. Questionnaire scores were assessed using non-parametric and quantile regression analyses. RESULTS: Our cohort included 526 patients with SSc, with a typical distribution of disease-associated autoantibodies (ACA, ARA, ATA, PM-Scl, U1RNP, U3RNP). We demonstrated associations between hallmark antibodies and the domain-specific burden of GI disease. In particular, ACA, ARA and ENA-negative demonstrated increased SSc-GI disease burden, while PM-Scl conferred relative protection. In a distributional analysis, associations with autoantibodies were particularly marked in those with the highest burden of GI disease. CONCLUSION: There is a significant burden of SSc-GI disease in patients with SSc; reflux and bloating symptoms are most prominent. SSc hallmark antibodies may predict increased risk of SSc-GI disease, in particular ACA and ARA, while PM-Scl may be protective.

Outcomes linked to eligibility for stem cell transplantation trials in diffuse cutaneous systemic sclerosis.

OBJECTIVES: The aim of this study was to explore outcomes in a cohort of dcSSc patients fulfilling eligibility criteria for stem cell transplantation (SCT) studies but receiving standard immunosuppression. METHODS: From a large single-centre dcSSc cohort (n = 636), patients were identified using the published SCT trials' inclusion criteria. Patients meeting the trials' exclusion criteria were excluded. RESULTS: Of the 227 eligible patients, 214 met the inclusion criteria for ASTIS (Autologous Stem Cell Transplantation International Scleroderma), 82 for SCOT (Scleroderma: Cyclophosphamide Or Transplantation) and 185 for the UPSIDE (UPfront autologous haematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) trial, and 66 were excluded based on age >65 years, low diffusing capacity of the lungs for carbon monoxide (DLco), pulmonary hypertension or creatinine clearance <40 ml/min. The mean follow-up time was 12 years (s.d. 7). Among the eligible patients, 103 (45.4%) died. Survival was 96% at 2 years, 88% at 5 years, 73% at 10 years and 43% at 20 years. Compared with this 'SCT-eligible' cohort, those patients who would have been excluded from SCT trials had a worse long-term survival (97% at 2 years, 77% at 5 years, 52% at 10 years and 15% at 20 years, log rank P < 0.001). Excluded patients also had a significantly worse long-term event-free survival. Hazard of death was higher in patients with higher age at onset [hazard ratio (HR) 1.05, P < 0.001], higher ESR at baseline (HR 1.01, P = 0.025) and males (HR 2.12, P = 0.008). CONCLUSION: SCT inclusion criteria identify patients with poor outcome despite current best practice treatment. Patients meeting the inclusion criteria for SCT but who would have been excluded from the trials because of age, pulmonary hypertension, poor kidney function or DLco <40% had worse outcomes.

High proton pump inhibitor exposure increases risk of calcinosis in systemic sclerosis.

OBJECTIVE: To investigate the association between proton pump inhibitor (PPI) use and the presence and severity of calcinosis in SSc. METHODS: We analysed data from two SSc cohorts from a single centre. Cohort 1 included 199 patients reviewed over 10 years, for whom retrospective data on PPI use and calcinosis were available. Cohort 2 was recruited prospectively and included 215 consecutive patients, who underwent clinical assessment. Outcomes of interest were presence of current calcinosis (CC) or calcinosis at any time (CAT). RESULTS: The cohort 1 data analysis showed that among patients on standard dose PPI 20% had calcinosis, while in those on high doses of PPI calcinosis was present in 39% (P = 0.003). Analysis of the data from cohort 2 confirmed these findings, demonstrating that the odds of CAT increased significantly with longer PPI exposure [odds ratio (OR) 1.04, 95% CI: 1.02, 1.06; P < 0.001], longer disease duration (OR 1.08, 95% CI: 1.05, 1.12; P < 0.001) and greater age (OR 1.03, CI: 1.01, 1.05; P = 0.010). Multivariable logistic regression showed that higher exposure to PPI remained a significant predictor of calcinosis, with PPI exposure >10 years increasing the risk of CAT >6-fold, compared with no PPI (OR 6.37, 95% CI: 1.92, 21.17; P = 0.003) after adjusting for disease duration and antibodies. CONCLUSION: We confirm a significant association between high PPI exposure with severity of calcinosis in SSc. Given the clinical impact of calcinosis and reflux in SSc, PPI exposure as a potentially modifiable risk factor for calcinosis requires further evaluation.

Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis.

OBJECTIVE: IVIG is known to confer significant benefit in rheumatologic conditions, including inflammatory myopathy. This study aimed to assess the efficacy of IVIG across different aspects of internal organ involvement in refractory active SSc, particularly the gastrointestinal (GI) system. METHODS: SSc patients with overlap polymyositis who remained active and unresponsive to conventional disease-modifying agents and who subsequently received IVIG were identified. GI symptoms were assessed using validated questionnaires. The Medical Research Council Sum Score for muscle strength and modified Rodnan skin score (mRSS) were assessed. Serial measurements were undertaken at baseline prior to the first IVIG treatment and post-treatment in the most recent assessment. RESULTS: Fifteen SSc patients were consecutively recruited into this observational study. The mean duration of IVIG treatment was 2.3 years, with treatment frequency ranging from every 6 weeks to 4 months. Compared with baseline, there was a significant reduction in gastro-oesophageal reflux frequency and intensity mean scores (P = 0.006 and P = 0.013, respectively). Significant improvement in the Gastrointestinal Tract (GIT) 2.0 score from a baseline mean score of 1.07 (s.d. 0.67) to 0.60 (0.46) (P = 0.002) was observed. There was regression in the markers of muscle disease with a reduction in the mean (s.d.) Medical Research Council sum score and the median creatine kinase level (P = 0.001 and P = 0.025, respectively). Significant amelioration of the mean basal modified Rodnan skin score from 21.5 (s.d. 13.8) to 10 (10.6) (P = 0.005) was observed. CONCLUSION: IVIG may be a helpful adjunctive therapy in the amelioration of some key clinical aspects in refractory SSc. Sustained benefit from IVIG suggests a specific immunomodulatory effect on those with established SSc GI complications.

Current management strategies for systemic sclerosis.

Systemic sclerosis remains a challenging disease despite progress that has taken place in the management of organ-based complications. Overall management strategies need to take into account the features of the disease that are common to almost all patients such as skin involvement, gastro-oesophageal manifestations and secondary Raynaud's, as well as identify less frequent but critical manifestations that impact on survival including heart, lung, renal and more severe GI involvement. Treatments can be considered to be disease-modifying or symptomatic. In addition, it is important to address more generic problems such as the emotional, psychological and economic impact of a chronic autoimmune rheumatic disease. This article reviews general approaches to disease assessment and management and relates this to subset and stage of the condition.

Revisiting ANCA-associated vasculitis in systemic sclerosis: clinical, serological and immunogenetic factors.

OBJECTIVES: To define the clinical, serological, histological and immunogenetic features of patients with scleroderma and ANCA-associated vasculitis (AAV). METHODS: We examined a clinical database of 2,200 patients with either limited or diffuse cutaneous systemic sclerosis (SSc). Patients with a confirmed diagnosis of vasculitis who were ANCA positive with either MPO or PR3 reactivity had their clinical features, serology, histology and HLA haplotypes examined in detail. RESULTS: From this SSc cohort, 35 patients (1.6%) had evidence of vasculitis, and the SSc autoantibody profiles in this group were comparable to those previously published from the whole cohort. Of these 35 patients, 8 (0.4% of whole SSc cohort) had either anti-MPO or anti-PR3 antibodies and two further patients were ANCA positive without defined specificities. Of the eight ANCA-positive patients, seven had limited cutaneous SSc and anti-MPO antibodies and only one had anti-PR3 antibodies, associated with diffuse cutaneous SSc. Two ANCA-positive patients had anti-U3RNP antibodies, usually associated with overlap disease. None of the patients had granulomatous disease. The majority had glomerulonephritis, renal arteritis and pulmonary fibrosis. There were several shared HLA haplotypes from the DP and DQ loci in these overlap patients. CONCLUSION: SSc in overlap with ANCA-associated vasculitis is rare, and clinical features are more mixed than when either of these two conditions occurs separately. From our database, U3RNP antibodies may be more associated with overlap AAV than the other scleroderma-specific antibodies.

Dynamic Prediction of Pulmonary Hypertension in Systemic Sclerosis Using Landmark Analysis.

OBJECTIVE: Pulmonary hypertension (PH) is a serious complication of systemic sclerosis (SSc). In this study, we explored the prediction of short-term risk for PH using serial pulmonary function tests (PFTs) and other disease features. METHODS: SSc patients in whom disease onset occurred ≥10 years prior to data retrieval and for whom autoantibody specificity and PFT data were available were included in this study. Mixed-effects modeling was used to describe changes in PFTs over time. Landmarking was utilized to include serial assessments and stratified Cox proportional hazards regression analysis with landmarks as strata was used to develop the PH prediction models. RESULTS: We analyzed data from 1,247 SSc patients, 16.3% of whom were male and 35.8% of whom had diffuse cutaneous SSc. Anticentromere, antitopoisomerase, and anti-RNA polymerase antibodies were observed in 29.8%, 22.0%, and 11.4% of patients, respectively, and PH developed in 13.6% of patients. Over time, diffusing capacity for carbon monoxide (DLco) and carbon monoxide transfer coefficient (Kco) declined in all SSc patients (up to 1.5% per year) but demonstrated much greater annual decline (up to 4.5% and 4.8%, respectively) in the 5-7 years preceding PH diagnosis. Comparisons between multivariable models including either DLco, Kco, or forced vital capacity (FVC)/DLco ratio, demonstrated that both absolute values and change over the preceding year in those measurements were strongly associated with the risk of PH (hazard ratio [HR] 0.93 and 0.76 for Kco and its change; HR 0.90 and 0.96 for DLco and its change; and HR 1.08 and 2.01 for FVC/DLco ratio and its change; P < 0.001 for all). The Kco-based model had the greatest discriminating ability (Harrell's C-statistic 0.903). CONCLUSION: Our findings strongly support the importance of PFT trends over time in identifying patients at risk of developing PH.

Comparing paediatric- and adult-onset linear morphoea in a large tertiary-referral scleroderma centre.

Background: Linear morphoea is a severe morphoea subtype associated with extracutaneous manifestations, potentially permanent disfigurement and functional impairment. Linear morphoea is more prevalent in paediatric patients, and knowledge of disease in adults is limited. The objective of this study was to compare paediatric- and adult-onset linear morphoea, in an exclusively adult population. Methodology: This was a retrospective cohort study of adult patients with linear morphoea seen over a 3-year period at a single-site adult tertiary-referral Connective Tissue Disease centre. Clinical markers of disease severity and course, including anatomical distribution, extracutaneous manifestations, cutaneous symptoms, associated autoimmunity, inflammatory blood parameters, Dermatology Life Quality Index scores, treatment requirements and modified Localised Scleroderma Activity Tool were assessed and compared in paediatric- and adult-onset linear morphoea. Results: Of 298 patients with morphoea seen during the study period, 135 had linear morphoea and 133 were included in the study. Most were female (78.9%), the mean age was 36.5 years and almost half (43.6%) had adult-onset disease. Disease was similarly severe between groups with regard to anatomical distribution, cutaneous symptoms (n = 89, 66.9%), extracutaneous manifestations (n = 76, 57.1%), antinuclear antibody-positivity (n = 40, 40.4%), raised erythrocyte sedimentation rate (n = 27, 25.0%) and associated autoimmune diagnoses (n = 15, 11.3%). Prescribed treatments were similar between groups; 73.7% receiving methotrexate and almost one-third (32.3%) requiring more than one steroid-sparing agent. Those with paediatric-onset had more disease-related damage, with a mean modified Localised Scleroderma Skin Damage Index score of 19.5 (95% confidence interval: 17.0-22.0) versus 8.1 (95% confidence interval: 4.4-11.8; p < 0.001). Significantly more patients with adult-onset linear morphoea had quiescent disease (p = 0.0332), and even after correcting for disease duration, paediatric-onset patients still had 2.6 times greater odds of active disease (odds ratio = 2.59, 95% confidence interval: 0.9-7.6; p = 0.083). Conclusion: Linear morphoea in adults can be a severe disease with extracutaneous, autoimmune and systemic features. Adults with paediatric-onset disease appear to have more severe cumulative damage, greater functional impairment and ongoing disease activity. This patient subgroup may require particularly close monitoring and more aggressive therapy.

Pathogenesis of systemic sclerosis associated interstitial lung disease.

Systemic sclerosis is an autoimmune disease leading to vasculopathy and fibrosis of skin and internal organs. Despite likely shared pathogenic mechanisms, the patterns of skin and lung fibrosis differ. Pathogenesis of interstitial lung disease, a major cause of death in systemic sclerosis, reflects the intrinsic disease pathobiology and is associated with distinct clinical phenotypes and laboratory characteristics. The commonest histological pattern of systemic sclerosis-interstitial lung disease is non-specific interstitial pneumonia. Systemic sclerosis-interstitial lung disease pathogenesis involves multiple components, including susceptibility and triggering factors, which could be genetic or environmental. The process is amplified likely through ongoing inflammation and the link between inflammatory activity and fibrosis with IL6 emerging as a key mediator. The disease is driven by epithelial injury, reflected by markers in the serum, such as surfactant proteins and KL-6. In addition, mediators that are produced by epithelial cells and that regulate inflammatory cell trafficking may be important, especially CCL2. Other factors, such as CXCL4 and CCL18, point towards immune-mediated damage or injury response. Monocytes and alternatively activated macrophages appear to be important. Transforming growth factor beta appears central to pathogenesis and regulates epithelial repair and fibroblast activation. Understanding pathogenesis may help to unravel the stages of systemic sclerosis-interstitial lung disease, risks of progression and determinants of outcome. With this article, we set out to review the multiple factors, including genetic, environmental, cellular and molecular, that may be involved in the pathogenesis of systemic sclerosis-interstitial lung disease and the mechanisms leading to sustained fibrosis. We propose a model for the pathogenesis of systemic sclerosis-interstitial lung disease, based on the available literature.

Using Autoantibodies and Cutaneous Subset to Develop Outcome-Based Disease Classification in Systemic Sclerosis.

OBJECTIVE: To describe the associations between autoantibodies, clinical presentation, and outcomes among patients with systemic sclerosis (SSc) in order to develop a novel SSc classification scheme that would incorporate both antibodies and the cutaneous disease subset as criteria. METHODS: Demographic and clinical characteristics, including cutaneous subset, time of disease and organ complication onset, and autoantibody specificities, were determined in a cohort of SSc subjects. Survival analysis was used to assess the effect of the autoantibodies on organ disease and death. RESULTS: The study included 1,325 subjects. Among the antibody/skin disease subsets, anticentromere antibody-positive patients with limited cutaneous SSc (lcSSc) (n = 374) had the highest 20-year survival (65.3%), lowest incidence of clinically significant pulmonary fibrosis (PF) (8.5%) and scleroderma renal crisis (SRC) (0.3%), and lowest incidence of cardiac SSc (4.9%), whereas the frequency of pulmonary hypertension (PH) was similar to the mean value in the SSc cohort overall. The anti-Scl-70+ groups of patients with lcSSc (n = 138) and patients with diffuse cutaneous SSc (dcSSc) (n = 149) had the highest incidence of clinically significant PF (86.1% and 84%, respectively, at 15 years). Anti-Scl-70+ patients with dcSSc had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years. In contrast, in anti-Scl-70+ patients with lcSSc, other complications were rare, and these patients demonstrated the lowest incidence of PH (6.9%) and second highest survival (61.8%) at 20 years. Anti-RNA polymerase antibody-positive SSc patients (n = 147) had the highest incidence of SRC (28.1%) at 20 years. The anti-U3 RNP+ SSc group (n = 56) had the highest incidence of PH (33.8%) and cardiac SSc (13.2%) at 20 years. Among lcSSc patients with other autoantibodies (n = 295), the risk of SRC and cardiac SSc was low at 20 years (2.7% and 2.4%, respectively), while the frequencies of other outcomes were similar to the mean values in the full SSc cohort. Patients with dcSSc who were positive for other autoantibodies (n = 166) had a poor prognosis, demonstrating the second lowest survival (33.6%) and frequent organ complications. CONCLUSION: These findings highlight the importance of autoantibodies, cutaneous subset, and disease duration when assessing morbidity and mortality in patients with SSc. Our novel classification scheme may improve disease monitoring and benefit future clinical trial designs in SSc.

Analysis of Anti-RNA Polymerase III Antibody-positive Systemic Sclerosis and Altered GPATCH2L and CTNND2 Expression in Scleroderma Renal Crisis.

OBJECTIVE: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC. METHODS: ARA-positive patients (n = 99) with at least 5 years' follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort. RESULTS: Analysis of 641,489 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10-5), CTNND2 (rs1859082; P = 5.58 × 10-5), HECW2 (rs16849716; P = 1.2 × 10-4), and GPATCH2L (rs935332; P = 4.92 × 10-5) with SRC. Further, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC (P = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L (P = 0.026) and glomerular expression of CTNND2 (P = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP. CONCLUSION: Increased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.

A longitudinal study of anti-RNA polymerase III antibody levels in systemic sclerosis.

OBJECTIVES: Anti-RNA-polymerase antibodies (ARAs) are associated with the diffuse cutaneous subset of SSc (dcSSc) and particularly with scleroderma renal crisis (SRC). We analysed serial ARA levels and explored the relationship with clinical features and disease outcome. METHODS: A commercially available ELISA method with a recombinant peptide of RNA polymerase III was used and ARA levels were measured in a well-characterized cohort of SSc cases. RESULTS: ARA levels were measured in 64 SSc patients. Of them, 78% (n = 50) were females and 92% (n = 59) had dcSSc, 39% (n = 25) had SRC, 20% (n = 13) had pulmonary fibrosis (PF), 9% (n = 6) had pulmonary arterial hypertension and 3% (n = 2) had cardiac involvement. There was considerable inter- and intra-patient variability in ARA levels (11-210 U/ml). There was no correlation between absolute ARA levels (at baseline or throughout the disease course) and outcome. There was a moderate correlation between time to peak ARA level and development of significant PF (Pearson correlation = 0.669, P = 0.034), but no correlation between peak ARA levels and onset of SRC. ARA levels change correlated with change in skin score (correlation coefficient within subjects = 0.236, P = 0.011). CONCLUSIONS: The pathogenic significance of ARA is unclear. Despite the very strong association of ARA with SRC, we could not show the clinically significant association between absolute levels of antibody and development of internal organ complications, which makes repeated measurements of ARA levels unnecessary. However, changes in ARA level over time occur and may reflect changes in skin score.

Current approaches to the management of early active diffuse scleroderma skin disease.

Skin sclerosis is a clinical hallmark of systemic sclerosis (SSc) and provides a means to classify and evaluate patients. In the diffuse cutaneous subset, skin involvement is often extensive and warrants direct therapy. Currently, broad spectrum immunosuppressive strategies are used, but more targeted specific approaches are now emerging. This article reviews the evidence for efficacy of current treatment approaches and future developments for managing skin disease in early diffuse cutaneous SSc.

Distinctive clinical phenotype of anti-centromere antibody-positive diffuse systemic sclerosis.

OBJECTIVES: The aim was to define clinical characteristics and long-term survival of patients with dcSSc and positive ACA. METHODS: We identified all cases of ACA+ SSc in our cohort (n = 1313). Those with dcSSc (ACA+ diffuse) were compared with representative groups of consecutive ACA+ patients with limited subset (ACA+ limited) and ACA- dcSSc (non-ACA diffuse). RESULTS: Thirty-five patients (2.7%) were ACA+ diffuse. The peak modified Rodnan skin score was not significantly different between the dcSSc subgroups, but it occurred later in the disease course in ACA+ diffuse (88.54 vs 30.65 months, P < 0.001). Patterns of organ involvement were different between the groups. ACA+ diffuse had a higher incidence of interstitial lung disease than ACA+ limited (22.86 vs 4.43%, P = 0.001), but lower than non-ACA diffuse (41.18%, P = 0.042). More patients developed pulmonary hypertension in the ACA+ diffuse group (28.5 vs 12.0% ACA+ limited or 12.0% non-ACA diffuse), although this was attributable to the longer follow-up in these patients. The cumulative incidence of pulmonary hypertension was not different from the other two groups. The incidence of cardiac involvement was similar between the dcSSc groups, and scleroderma renal crisis was more frequent in the non-ACA diffuse group. Survival in ACA+ patients was similar in both subsets, whereas non-ACA diffuse had higher mortality. CONCLUSION: ACA+ dcSSc is uncommon and has a distinct clinical phenotype, with a more insidious onset of skin and organ involvement. Even in dcSSc, ACA appears protective for organ-based complications, namely interstitial lung disease and scleroderma renal crisis, and is associated with a better survival than expected in dcSSc.

Characteristics and Survival of Anti-U1 RNP Antibody-Positive Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). This study aimed to investigate the clinical and hemodynamic characteristics and survival of anti-U1 RNP-positive patients with CTD-associated PAH, with a focus on systemic sclerosis (SSc)-associated PAH. METHODS: We implemented a prospective database that included patients with CTD-associated PAH for whom there were clinical, autoantibody, and mortality data. We compared clinical and hemodynamic characteristics to anti-U1 RNP antibody status. We then assessed whether anti-U1 RNP antibodies could be a prognostic factor in CTD-associated PAH with a focus on SSc-associated PAH. RESULTS: We studied a total of 342 patients with CTD-associated PAH, of whom 36 (11%) were anti-U1 RNP antibody positive. Anti-U1 RNP-positive patients were younger and less functionally impaired than were anti-U1 RNP-negative patients in CTD- and SSc-associated PAH. Hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients. In CTD-associated PAH, anti-U1 RNP positivity was associated with decreased mortality in univariable analysis (hazard ratio 0.34 [95% confidence interval 0.18-0.65], P < 0.001). In multivariable analysis, anti-U1 RNP positivity was also associated with decreased mortality (hazard ratio 0.44 [95% confidence interval 0.20-0.97], P = 0.043) independently of age, sex, functional parameters, lung involvement, and hemodynamic parameters. Results were similar in SSc-associated PAH, although the association between anti-U1 RNP positivity and survival did not reach significance in univariable (hazard ratio 0.47 [95% confidence interval 0.22-1.02], P = 0.055) and multivariable (hazard ratio 0.47 [95% confidence interval 0.20-1.11], P = 0.085) analyses. CONCLUSION: Anti-U1 RNP positivity was associated with distinct clinical characteristics and survival in CTD- and SSc-associated PAH. While hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients, our results suggest that anti-U1 RNP positivity could be a factor protecting against mortality in CTD- and SSc-associated PAH.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prediction of pulmonary complications and long-term survival in systemic sclerosis.

OBJECTIVE: To assess survival and incidence of organ-based complications in a large single-center cohort of unselected systemic sclerosis (SSc) patients, and to explore predictors of survival and clinically significant pulmonary fibrosis (PF) and pulmonary hypertension (PH). METHODS: The study cohort consisted of 398 consecutive SSc patients, followed up for up to 15 years. Cox proportional hazards analysis with demographic, clinical, and laboratory characteristics as predictor variables was used to develop prediction models for pulmonary complications and survival. RESULTS: The overall survival estimate at the end of followup was 57% among patients with limited cutaneous SSc (lcSSc) and 50% among patients with diffuse cutaneous SSc (dcSSc) (P = 0.017). We found that greater age at disease onset, dcSSc, lower diffusing capacity for carbon monoxide (DLco), lower hemoglobin levels, higher serum creatinine levels, and the presence of PH or cardiac involvement were independent predictors of worse survival. Over the entire followup period, 42% of dcSSc patients and 22% of lcSSc patients developed clinically significant PF (P < 0.001). The variables that predicted clinically significant PF development were dcSSc, greater age at onset, lower forced vital capacity and DLco, and the presence of anti-topoisomerase I antibody, while the presence of anticentromere antibody was protective. There was no difference in cumulative incidence of PH between the 2 subsets-24% in lcSSc and 18% in dcSSc (P = 0.558). Incidence rates were 1-2% per year. The PH prediction model demonstrated that greater age at onset, increase in serum creatinine levels, lower DLco, and the presence of anti-RNA polymerase III or anti-U3 RNP antibodies were associated with increased risk of PH, while anti-topoisomerase I antibody positivity reduced the hazard. CONCLUSION: Our study provides data on long-term outcome of SSc and the timing and frequency of major organ complications. The predictive models we present could be used as clinical tools for patient risk stratification and could facilitate cohort enrichment for event-driven studies.