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. 2023 Apr 3;62(4):1543-1551.
doi: 10.1093/rheumatology/keac501.

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

Robyn T Domsic  1 , Thomas A Medsger  1 , Shiyao Gao  2 , Maureen Laffoon  1 , Suiyuan Huang  3 , Stephen Wisniewski  2 , Cathie Spino  4 , Virginia Steen  5 , Robert Lafyatis  1 , Dinesh Khanna  6
Affiliations

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

Robyn T Domsic et al. Rheumatology (Oxford). .

Abstract

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.

Keywords: SSc; clinical trial design; early diffuse scleroderma; scleroderma.

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Figures

Figure 1.
Figure 1.
mRSS trajectory patterns for patients. (A) The five mRSS trajectory groups over 5 years of follow-up in those presenting with <18 months of disease. The corresponding colour % represents the percentage of patients falling into that trajectory. (B) The six mRSS trajectory groups that appear in patients presenting with <36 months of disease. Similarly, the corresponding number depicts the percentage of patients falling into that trajectory. mRSS: modified Rodnan skin score
Figure 2.
Figure 2.
mRSS change in the ASSET trial re-analysed by RNAP3 and TFR presence. (A) The original ASSET trial analysis comparing abatacept (dotted line) and placebo (solid line). (B) mRSS change stratified by RNAP3 positivity (solid line) and negativity (dotted line). (C) mRSS change adjusted for RNAP3: placebo/RNAP3+ (solid dark), abatacept/RANP3– (solid dotted), abatacept/RNAP3 (solid grey) and abatacept/RNAP3– (dotted grey line). (D) mRSS change stratified by TFR presence (solid) and absence (dotted line). (E) mRSS change adjusted for TFR: placebo/TFR+ (solid dark), abatacept/TFR+ (dotted dark), placebo/TFR absence (solid grey), abatacept/TFR absence (dotted grey). All analyses are adjusted for the stratum (disease duration ≤18 months vs 18–36 months). mRSS: modified Rodnan skin score; ASSET: abatacept in early diffuse systemic sclerosis; RNAP3: RNA polymerase III; TFR: tendon friction rubs
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