A data-driven approach finds RNA polymerase III antibody and tendon friction rubs as enrichment tools for early diffuse scleroderma trials.

OBJECTIVE: Clinical trials in early diffuse SSc have consistently shown a placebo group response with a declining modified Rodnan skin score (mRSS), with negative outcomes. Our objective was to identify strategies using clinical characteristics or laboratory values to improve trial design. METHODS: We identified early diffuse SSc patients first seen at the University of Pittsburgh from 1980-2015. Eligible patients had ≥3 visits, with at least two mRSS scores within the first year of follow-up. We performed Kaplan-Meier analyses, group-based trajectory analysis of mRSS scores, followed by multivariable regression analysis and classification tree analysis. We applied the results to the abatacept in early diffuse systemic sclerosis (ASSET) trial outcome data. RESULTS: We identified 403 patients with <18 months, and 514 with <36 months disease duration. The median number of mRSS follow-up scores was 14 (interquartile range 8, 25). All methodologic approaches identified skin thickness progression rate, RNA polymerase III (RNAP3) antibody positivity and presence of tendon friction rubs (TFR) as predictors of mRSS trajectory over 5 years of follow-up, and thereby as potential enrichment variables. When applied to the ASSET data, adjustment for both RNAP3 and TFR demonstrated reduction of the placebo mRSS response, particularly at 6 months. A significant difference in the ACR Composite Response Index in Systemic Sclerosis (CRISS) score was found with adjustment by RNAP3 at 6 months, and TFR or RNAP3 at 12 months. CONCLUSION: Adjustment for both RNAP3 and TFR predicts mRSS trajectory and diminished the mRSS decline in ASSET placebo group, and identified significant differences in CRISS. RNAP3, particularly, is a stratification or enrichment approach to improve early diffuse SSc trial design.

Defining the optimal disease duration of early diffuse systemic sclerosis for clinical trial design.

OBJECTIVES: Clinical trials in early diffuse cutaneous systemic sclerosis (SSc) using the modified Rodnan skin score (mRSS) as the primary outcome measure have most often been negative. We wanted to assess how the definition of disease onset (first SSc manifestation vs first non-Raynaud manifestation) and varying lengths of disease duration at trial entry as an inclusion criteria functioned. Our objective was to optimize trial inclusion criteria. METHODS: We used the prospective, observational University of Pittsburgh Scleroderma Cohort to identify early diffuse SSc patients first evaluated between 1980 and 2015. All had <3 years from first SSc (n = 481) or first non-Raynaud manifestation (n = 514) and three or more mRSS scores. We used descriptive, survival and group-based trajectory analyses to compare the different definitions of disease onset and disease duration as inclusion criteria for clinical trials. RESULTS: There was no appreciable difference between using first SSc manifestation compared with first non-Raynaud manifestation as the definition of disease onset. Compared with other disease durations, <18 months of disease had >70% of patients fitting into trajectories with worsening cutaneous disease over 6 months of follow-up. Longer disease durations demonstrated the majority of patients with trajectories showing an improvement in mRSS (regression to the mean) over 6 months. CONCLUSIONS: Regardless of whether the first SSc or first non-Raynaud manifestation is used to define disease onset, duration of <18 months at enrolment is preferable. A longer disease duration criterion more frequently results in regression to the mean of the mRSS score, and likely contributes to negative trial outcomes.

Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course.

OBJECTIVES: We examined whether an array of scleroderma autoantibodies associates with risk of cancer and could be useful tools for risk stratification. METHODS: Scleroderma cancer cases and scleroderma controls without cancer from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center were studied. Sera were assayed by Lineblot and enzyme-linked immunosorbent assay (ELISA) for autoantibodies against centromere, topoisomerase 1, RNA polymerase (POLR) 3, PM/Scl, Th/To, NOR90, U3 RNP, Ku, Ro52, U1RNP, and RNPC3. Logistic regression models were constructed to examine whether distinct autoantibodies associated with overall cancer at any time and cancer-associated scleroderma (cancer occurring three years before and after scleroderma onset). The effects of having more than one autoantibody on cancer were further examined using random forest analysis. RESULTS: A total of 676 cases and 687 controls were studied. After adjusting for relevant covariates, anti-POLR3 (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.03-2.11) and monospecific anti-Ro52 (OR 2.19, 95% CI 1.29-3.74) were associated with an increased overall cancer risk, whereas anticentromere (OR 0.69, 95% CI 0.51-0.93) and anti-U1RNP (OR 0.63, 95% CI 0.43-0.93) were associated with lower risk. When examining risk of cancer-associated scleroderma, these immune responses remained associated with increased or decreased risk: anti-POLR3 (OR 2.28, 95% CI 1.33-3.91), monospecific anti-Ro52 (OR 2.58, 95% CI 1.05-6.30), anticentromere (OR 0.39, 95% CI 0.20-0.74), and anti-U1RNP (OR 0.32, 95% CI 0.11-0.93). Anti-Ro52 plus anti-U1RNP or anti-Th/To was associated with decreased cancer risk compared with anti-Ro52 alone. CONCLUSIONS: These data suggest that five distinct scleroderma immune responses, alone or in combination, may be useful tools to stratify the risk of cancer for scleroderma patients. Further study examining cancer risk in autoantibody subgroups relative to the general population is warranted.

Development of Pulmonary Hypertension in Over One-Third of Patients With Th/To Antibody-Positive Scleroderma in Long-Term Follow-Up.

OBJECTIVE: This study was undertaken to describe clinical manifestations in patients with Th/To antibody-positive systemic sclerosis (SSc) during long-term follow-up. METHODS: We performed a case-control study involving anti-Th/To antibody-positive patients with SSc who were newly referred to the University of Pittsburgh Medical Center and the Pittsburgh Scleroderma Center from 1980 to 2015. For every case, 2 anti-Th/To antibody-negative SSc patients (the first 2 consecutively seen after a case) were used as controls. Long-term disease manifestations and survival were then compared between cases and controls. RESULTS: A total of 204 anti-Th/To antibody-positive SSc patients and 408 controls were identified. The cohort had a mean ± SD age of 52 ± 12.9 years, and 76% of individuals were women. Anti-Th/To antibody-positive patients more often presented without skin thickening (P < 0.0001) and had a higher rate of pulmonary hypertension (PH) (P < 0.0001) and interstitial lung disease (P = 0.05) compared to anti-Th/To antibody-negative SSc controls. Anti-Th/To antibody-positive SSc patients also had less frequent muscle and joint involvement than anti-Th/To antibody-negative SSc controls (P < 0.0001). After a median clinical follow-up period of 6.1 years (interquartile range 2.4-12.7), 38% of anti-Th/To-positive patients had developed PH compared to 15% of anti-Th/To antibody-negative SSc controls (P < 0.0001). The rate of PH classified as World Health Organization (WHO) Group 1 pulmonary arterial hypertension [PAH] was 23% in anti-Th/To-positive patients compared to 9% in anti-Th/To antibody-negative SSc controls (P < 0.0001). After adjusting for age and sex, anti-Th/To antibody positivity was associated with a hazard ratio (HR) of 3.3 (95% confidence interval 2.3-4.9) for increased risk of developing PH at 10 years of follow-up from the first scleroderma center visit. CONCLUSION: This is the largest cohort of patients with anti-Th/To antibody-positive SSc with long-term follow-up data. The very high rate (38%) and associated independent risk of anti-Th/To antibody-positive patients developing PH in follow-up, particularly in WHO Group 1 PAH patients, is striking. Patients presenting with limited skin involvement should be tested for Th/To antibodies, and if present, careful monitoring for PH is warranted.

Estradiol levels are elevated in older men with diffuse cutaneous SSc and are associated with decreased survival.

BACKGROUND: Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity in disease incidence, estradiol (E2), an estrogen form with pro-fibrotic effects, may play a role in SSc. We reported that post-menopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males with SSc tend to have more severe disease, we examined serum E2 in dcSSc males in relation to disease characteristics and survival. METHODS: We measured serum E2 in 83 dcSSc men > 50 years old from the University of Pittsburgh Scleroderma Center and similar aged healthy controls. Using statistical modeling, we examined the associations between serum E2, internal organ involvement, autoantibody profiles, and survival. RESULTS: Male dcSSc patients had significantly higher serum E2 levels compared to healthy males and similar aged dcSSc post-menopausal women. Male dcSSc patients with high serum E2 had significantly more heart involvement, a trend for higher skin thickness progression rate, and worse survival. Using Cox regression modeling, increased serum E2 levels in anti-Scl-70 antibody-positive dcSSc males were associated with an increased risk of death. CONCLUSIONS: dcSSc males > 50 years old have higher levels of serum E2 compared to healthy controls and dcSSc post-menopausal women. Elevated serum E2 levels in dcSSc males are associated with heart involvement, trend to progression of dermal fibrosis, and, if anti-Scl-70 antibody positive, worse survival. Our study expands on previous work implicating E2 in dermal fibrosis in SSc and associates E2 levels with internal organ involvement and survival. These data suggest a role for estrogen imbalance in dcSSc.