Background/Purpose: To identify predictive parameters for the progression of skin fibrosis in patients with diffuse cutaneous SSc (dcSSc) to enable 1) risk-stratification in clinical practice and 2) improved cohort enrichment in clinical trials with skin fibrosis as the primary endpoint.

Methods: An observational prospective study using the EUSTAR database was performed. Worsening of skin fibrosis was defined as increase in modified Rodnan skin score (mRSS) >5 points and ≥25% from the 1^st to the 2^nd visit. Inclusion criteria: dcSSc, ACR criteria fulfilled, mRSS≥7 at 1^st visit, valid data for mRSS at 2^ndvisit, period in between visits 12±2 months. In the univariate analysis, patients with progressive skin fibrosis were compared to non-progressive patients. Predictive markers with p<0.2 were included in the multivariate logistic regression analysis. For validation of the regression models, a second cohort with new patients was extracted from the EUSTAR database 11 months after the first data extraction.

Results:

Out of 637 patients fulfilling the inclusion criteria of the original cohort, 9.7% had progressive skin disease. Univariate analysis suggested the following prediction parameters: presence of joint synovitis (p=0.009), disease duration (p=0.023), mRSS at baseline (p=0.015), and the interaction between disease duration (≤15/>15 months, cut-off defined by ROC analysis) and sex (p=0.020) as well as the interaction between disease duration and CK elevation (p=0.047).

In the multivariate analysis, different prediction models with varying numbers and combinations of the predictors identified in the univariate analysis were compared. The model with the highest prediction success rate (n=8/18, 44.4%) showed an area under the ROC curve of 0.73 (95% CI=0.66-0.79, p<0.0001) with an overall accuracy of 89.9% (98.1% for no progression, 14.3% for progression) (Table1).

Tabl.1 Prediction model for skin progression in dcSSc

Predictors	p-value	OR	95%-CI
Joint synovitis	0.016	2.123	1.147-3.927
Female sex	0.143	0.541	0.238-1.230
Short disease duration* (≤15 months)	0.689	0.752	0.186-3.036
Female sex*short disease duration (≤15 months)	0.033	5.380	1.142-25.342
Low mRSS at baseline (≤22/51)	0.001	6.027	2.113-17.189

Other models with broader inclusion criteria revealed lower prediction success rates, but would simplify the recruiting process (e.g. prediction success rate 23.8% (n=20/84) for a model including low mRSS at baseline (≤22/51) and short disease duration (≤15 months)).

In the validation cohort, out of 188 patients, 6.5% had progressive skin disease. In the multivariate analysis, essentially the findings from the original cohort were confirmed, including the model in Table 1.

Conclusion: These data from a large cohort analysis including a 2^nd verification cohort clearly have an important impact on the future clinical study design in SSc. The identified and validated criteria allow the enrichment for dcSSc patients with progressive active skin fibrosis by up to 4.5-fold.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/prediction-of-worsening-of-skin-fibrosis-in-patients-with-diffuse-systemic-sclerosis-using-the-eular-scleroderma-trials-and-research-eustar-registry/