Molecular Signatures in Skin Associated with Clinical Improvement during Mycophenolate Treatment in Systemic Sclerosis

Abstract

Heterogeneity in systemic sclerosis/SSc confounds clinical trials. We previously identified ‘intrinsic’ gene expression subsets by analysis of SSc skin. Here we test the hypotheses that skin gene expression signatures including intrinsic subset are associated with skin score/MRSS improvement during mycophenolate mofetil (MMF) treatment. Gene expression and intrinsic subset assignment were measured in 12 SSc patients’ biopsies and ten controls at baseline, and from serial biopsies of one cyclophosphamide-treated patient, and nine MMF-treated patients. Gene expression changes during treatment were determined using paired t-tests corrected for multiple hypothesis testing. MRSS improved in four of seven MMF-treated patients classified as the inflammatory intrinsic subset. Three patients without MRSS improvement were classified as normal-like or fibroproliferative intrinsic subsets. 321 genes (FDR <5%) were differentially expressed at baseline between patients with and without MRSS improvement during treatment. Expression of 571 genes (FDR <10%) changed between pre- and post-MMF treatment biopsies for patients demonstrating MRSS improvement. Gene expression changes in skin are only seen in patients with MRSS improvement. Baseline gene expression in skin, including intrinsic subset assignment, may identify SSc patients whose MRSS will improve during MMF treatment, suggesting that gene expression in skin may allow targeted treatment in SSc.

Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity

“…Given the repeatedly observed clinical and molecular heterogeneity in SSc patients across multiple independent cohorts (8,(10)(11)(12), the robustness of the SSc signatures identified in our analysis is unexpected and significant. Until now, the lack of such a robust signature has hampered development of novel diagnostics and prognostics for monitoring SSc patients in clinics.…”

“…A growing body of evidence supports the use of skin, lung, and peripheral blood transcriptomes as SSc biomarkers to quantify interpatient heterogeneity, to identify dysregulated molecular pathways underlying disease, and to identify appropriate patients for specific SSc therapies (6)(7)(8)(9). These studies have identified remarkable homogeneity in skin biopsies obtained from the same patient such that transcriptomic profiles of clinically unaffected back and clinically affected forearm biopsies are nearly identical (10)(11)(12).…”

“…For instance, strict inclusion and exclusion criteria restrict study participation to reduce the number and effects of confounding factors (8,10). However, this controlled experimental approach typically does not capture the heterogeneity observed in the real-world SSc patient population.…”

A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis

“…7 More importantly, patients with inflammatory skin transcript signature are more likely to respond to immunosuppressive therapy and demonstrated clinical improvement. 8 However, no effective treatment has yet been approved to cure SSc. The study of SSc is hindered by a lack of animal models that recapitulate the etiology of this complex disease.…”

Prospects for Using Tocilizumab in Systemic Sclerosis

“…При изу-чении экспрессии палитры генов в коже больных ССД бы-ли выявлены подгруппы с разными профилями, условно классифицированными как пролиферативный, фиброз-ный, ограниченный и «нормоподобный» [48]. Возникло предположение об ассоциации этих субтипов с ответом на иммуносупрессивную терапию [49]. Недавнее изучение интерстициальной жидкости из пораженной кожи боль-ных ССД с помощью мультиплексного анализа показало существенные различия в локальной концентрации воспа-лительных и профиброзных белков [50].…”