Search for Diagnostic and Prognostic Biomarkers in Systemic Sclerosis and Inflammatory Myopathies

Search for Diagnostic and Prognostic Biomarkers (Molecular Signatures) in Systemic Sclerosis and Inflammatory Myopathies by a Multi-OMIC Strategy Integrating a Single Cell Analysis Approach

Systemic sclerosis and inflammatory myopathies, which sometimes combine (scleromyositis), have shared pathophysiological elements. In both diseases, many cell subtypes are involved in damage to organs such as T lymphocytes, B lymphocytes, and unconventional (non-B, non-T) lymphocytes called innate lymphoid cell (ILC). The increasing complexity of our understanding of the immune system (multiplication of recognized cell subtypes) also makes the strategies for analyzing pathophysiological mechanisms more complex. Currently, no biomarker perfectly predicts the phenotype and evolution of patients. Multi-OMIC analyzes will be performed (identification of cell populations as well as genomic, transcriptomic and proteomic characterization) in blood and tissue samples (skin and muscle biopsy) in patients with systemic sclerosis and inflammatory myopathies, with the objective of identifying discriminating molecular signatures (biomarkers) according to the characteristics of the disease and its evolution.

Cohort study, monocentric, comparative, non-randomized, open-label, prospective and longitudinal, quasi-experimental.

Participating subjects will be classified according to their clinical, biological and additional investigations into one of the 4 populations presented in the eligibility criteria.

A 1st sampling point will be carried out at inclusion visit (baseline). Prospective follow-up of participating patients will be carried out as part of their routine care (1 to 2 visits per year or more if disease complications appear).

During the 5-year follow-up, the investigating physician will remain attentive to the appearance of a new clinical element which will mark the course of the disease.

During the follow-up, 2 more sampling points will be carried out (blood and / or skin) on each participating patient.

Blood samples and muscle biopsies will be carried out in the usual way during diagnostic and therapeutic management. An additional volume of blood, an additional muscle biopsy (on the occasion of the one performed for diagnosis) and two superficial skin biopsies (1 sclerotic tissue & 1 healthy tissue) will be taken for research purposes.

Inclusion in this cohort will not change the management of the patient, either with regard to his treatment or his follow-up.

Multi-omics analyzes will include single cell RNAseq, as well as proteomics and genomics analysis:

• Transcriptomic analysis will be performed on PMBC, muscle and skin.
• Genomic analysis (exome & whole genome) will be performed on PMBC, muscle and skin.
• Proteomic analysis will be performed on serum, PMBC, muscle and skin.
• Single cell analysis will be performed on PMBC, muscle and skin. During the analysis, the clinical characteristics of baseline, the treatments and the evolutions during the follow-up will be compared to reveal the clinical relevance of the multi-OMIC signatures.

Inclusion Criteria:

• Control population without inflammatory myopathy (population 1), suspected myopathy for whom a blood test and muscle biopsy are required to confirm the diagnosis
• Confirmed inflammatory myopathy (population 2)
• Control population without systemic sclerosis (population 3), with primary Raynaud's phenomenon
• Early diffuse systemic cutaneous scleroderma (population 4)
• Male or female (age ≥ 18, no upper age limit)

Exclusion Criteria:

Populations 1 & 2

• Contraindication to muscle biopsy
• Diagnosed for another neuromuscular disease
• Taking an immunosuppressant / immunomodulator treatment within 3 months before inclusion
• Unbalanced cardiovascular pathology

Population 3 & 4

• Contraindication to skin biopsy
• Capillaroscopic and / or immunological anomaly suggesting scleroderma
• Suspicion of scleroderma but diagnosed for another connectivitis
• Immunosuppressive treatment (corticosteroids> 15 mg, methotrexate, mycophenolate mofetil) introduced for more than 1 month
• Active or recent cancer <3 years (apart from non-melanoma skin cancer).

For all

- Pregnancy or breast feeding