Clinical Features and Disease Phenotypes as Study Entry Criteria for Scleroderma Encompass Patients with Significant Biological Heterogeneity

Objectives Clinical trials in systemic sclerosis (SSc) define strict eligibility criteria to overcome the known heterogeneity of the disease. We evaluated baseline circulating cytokines in participants of the Phase I/II Randomized Controlled Clinical Trial of Umbilical Cord-Derived Mesenchymal Stromal Cells in Systemic Sclerosis (CARE-SSc, NCT04356287 ) to verify this. Methods CARE-SSc is a randomized, double-blind, placebo-controlled trial testing the safety and generating preliminary evidence of the efficacy of umbilical cord-derived mesenchymal stromal cells in SSc. The inclusion criteria for CARE-SSc are adults who meet SSc criteria according to the ACR/EULAR 2013 classification criteria with: either a) disease duration of < 2 years with a modified Rodnan skin score (mRSS) > 20 and erythrocyte sedimentation rate > 25 mm and/or hemoglobin < 11 g/dL, or b) mRSS > 15 with at least 1 major organ involvement (lung, heart or kidneys); inadequate response or adverse effects with standard therapy; and, ineligibility or unwillingness to undergo autologous hematopoietic stem cell transplant. Baseline sera of the first 6 trial participants were analyzed with an extended cytokine/chemokine assay (Human Cytokine/ Chemokine 96-Plex Discovery Assay Array®, Eve Technologies). A non-clustered heatmap was generated using the Matplotlib coding library in Python. Results Five women and 1 man with median age of 46 (range 38-67) years, median disease duration of 3.5 (range 1-14) years and median mRSS of 18 (range 16-22) were included. Four subjects had lung disease and 4 had cardiac involvement. None had renal involvement. Five subjects had anti-topoisomerase I and 1 had anti-RNA polymerase III antibodies. At baseline, 5 patients were on mycophenolate, 2 on nintedanib and 3 on low-dose prednisone (< 10 mg/d). Among the 96 analytes, only 5 (IL-23, SCF, 6CKine, IL-17E, sCD40L) were consistently elevated among all 6 participants. Twenty-one analytes (TSLP, MIP-1β, MIG, MDC, TRAIL, RANTES, M-CSF, IL-27, TGFα, IL-15, IL-12p40, IL-10, PDGF-AA, IL-8, IL-7, IL-5, IL-3, IL-28A, TPO, FLT-3L, and IL-20) were within normal levels in all patients. Of the 3 components of the serum interferon inducible protein score tested (IP-10, MCP-2, MIG/CXCL9), only MCP-2 was above normal in 5 of 6 participants. Although individual pro-inflammatory cytokines were elevated in all participants, the patterns of elevation varied from patient to patient (Figure 1). Conclusion Selecting SSc patients based on clinical features results in varied cytokine endotypes. Whether this is associated with variability in treatment responses requires further investigation. If so, it could inform eligibility criteria in future SSc clinical trials.

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