*3.2. Serum S100A6 in Ssc Patients*

Serum S100A6 levels were statistically significant higher in the Ssc group compared to controls (median 81.06 ng/mL (18.80) versus median 13.24 ng/mL (4.85), Mann Whitney U test, *p* < 0.001, Figure 3).

**Figure 3.** Serum S100A6 levels were higher in Ssc (systemic sclerosis) patients compared to healthy controls (*p* < 0.001, Mann Whitney U test). The circle, stars and numbers in figure represent the patient ID in the database that are considered outliers by the statistical software used.

Higher circulatory S100A6 levels were associated with digital ulcer presence (median 91.83 ng/mL in Ssc patients with digital ulcers (17.79) versus median 79.28 ng/mL in Ssc patients without digital ulcers (10.77), Mann Whitney U test, *p* = 0.002). Also, S100A6 levels were positively correlated with the number of active digital ulcers (r = 0.33, *p* = 0.02)

There were no significant differences between serum S100A6 levels in diffuse versus localized Ssc patients, nor with current Ssc medication.

#### *3.3. Serum Cytohesin 2 in Ssc Patients*

Serum cytohesin 2 levels were statistically significant higher in Ssc patients compared to controls (median 45.02 ng/mL (17.07) versus median 37.02 ng/mL (7.15), Mann Whitney U test, *p* = 0.003, Figure 4).

**Figure 4.** Serum cytohesin 2 levels were higher in Ssc (systemic sclerosis) patients compared to healthy controls (*p* < 0.001, Mann Whitney U test). The circle and numbers in figure represent the patient ID in the database that are considered outliers by the statistical software used.

Higher serum cytohesin 2 levels were observed in patients with telangiectasia presence (median 45.11 ng/mL (19.53) versus 40.46 ng/mL (11.68), Mann Whitney U test, *p* = 0.025).

Palpable tendon friction rubs were associated with lower circulating levels of cytohesin 2 (median 38.63 ng/mL (19.64) versus 46.06 (16.26), Mann Whitney U test, *p* = 0.021). Serum cytohesin 2 levels were positively correlated with inflammatory markers (ESR r = 0.324, *p* = 0.024, CRP r = 0.486, *p* = 0.001). There was a tendency for higher cytohesin 2 levels in patients with active disease, but without statistical significance (*p* = 0.22).

A cut-off value (53.97 ng/mL) defined as mean + two standard deviations of cytohesin 2 value of healthy controls was used to divide Ssc patients into two groups: high cytohesin 2 level and normal cytohesin 2 level. A total number of 13 Ssc patients (24.5%) had high cytohesin 2 levels. These patients had statistically significant higher PAP (pulmonary artery pressure) compared with patients with normal cytohesin 2 levels (median 28 mm Hg (20) versus median 25 mm Hg (2), Mann Whitney U test, *p* = 0.03). There were no significant differences between serum cytohesin 2 levels in diffuse versus localized Ssc patients, nor with current Ssc medication.
