Lupus Arthritis: Muscoloskeletal Ultrasound as Clinical Outcome of Peripheral Blood and Synovial Deep Phenotyping

Musculoskeletal involvement, defined as arthritis/arthralgia, is the most common manifestation of patients with systemic lupus erythematosus (SLE). It accounts for decreased quality of life and can lead to unemployment and disability.

Lupus arthritis is divided into non-erosive, with up to 80% of the cases, erosive, also known as Rhupus, with up to 5% of cases, and deforming, or Jaccoud's arthropathy which can involve up to 15% of the patients. Initially, these 3 forms can present similarly, therefore identifying early on their specific characteristics, can guide better treatments and improve outcomes.

Muscoloskeletal ultrasound (MSK-US) is an established modality to diagnose and investigate joint involvement in inflammatory arthropathies. While for these conditions, well-defined MSK-US approaches exist, much less, if any, for SLE.

The research hypothesis is that a longitudinal standardized prospective MSK-US evaluation coupled with deep phenotyping in patients with SLE peripheral musculoskeletal involvement, will allow us to:

1. better define the systemic nature of this manifestation and
2. yield novel biomarkers that accurately capture this important feature of SLE. In this monocenter study consecutive SLE patients with inflammatory MSK symptoms will recruited and followed prospectively. Patients will undergo MSK ultrasound, blood sample collection, synovial biopsy, for histological assessment. A subgroup of the study cohort will have synovial, Peripheral Blood Mononuclear Cells (PBMCs), serum and omic analysis. Patients will be followed for at least 6 months and up to 18 months with clinical and US evaluation.

Aims and methods

The following two aims are proposed:

1. to define the prevalence and evolution of MSK involvement in SLE patients with inflammatory arthralgia using a standardized US evaluation according with the Outcome Measures in Rheumatology (OMERACT) definition and scoring system In this Aim, a systematic characterization of joint, tendons and enthesis status will be performed through a clinical and US evaluation in order to demonstrate the role of US as an objective tool to better characterize MSK involvement in SLE patients. A MSK-US assessment will be conducted at the beginning and subsequently at each defined time table for all patients.
2. To investigate lupus arthritis with MSK-US, multi-omics technologies including single cell RNA sequencing and proteomics, with the aim to characterize disease activity.

For this Aim, blood and synovial multi-omics analysis will be performed exclusively in a subgroup of 10 SLE recruited patients. A US-guided synovial tissue biopsy will be performed for all patients enrolled in the study, regardless of multi-omics inclusion.

Patients will be longitudinally evaluated to identify clinical articular and systemic flares. The baseline US evaluation and the multi-omics approach will be correlated with the longitudinal manifestations to identify possible biomarkers of flares, both at the joint and systemic levels.

Expected results:

The combined achievement of the above-mentioned aims will address the need to standardize the MSK-US approach and pathogenic mechanisms via biomarkers' discovery of lupus arthritis, a yet still poorly understood SLE manifestation.

expectations:

• To enhance the characterization of joint involvement by reducing the heterogeneity associated with clinical examination through a standardized US evaluation.
• To identify systemic and synovial disease biomarkers in SLE patients that can predict different joint patterns, systemic manifestations and response to therapy through multi-omics technologies.