Lung Involvement in Rheumatoid Arthritis from initiation to chronic disease (LIRA study)

Background: Autoantibody-positive (seropositive) rheumatoid arthritis (RA) is a disease where autoimmunity appears many years prior to clinical onset. In contrast to others autoimmune diseases, RA provides a unique setting due to recent insights in the longitudinal development of the disease, suggesting that pathogenic autoimmunity first develops in the lungs of genetic susceptible individuals exposed to environmental challenges.

In a second step this autoimmunity will target the joints and others organs (often the lungs) to generate an autoimmune chronic systemic disease.

Aim. The overall purpose of the current project is to quantify and target pathogenic lung-associated events in individuals at risk for and those already having RA.

Work plan. We will investigate the lung function in RA by detailed studies of the lung in well characterized cohorts covering different stages of RA development (using high resolution computer tomography, pulmonary function tests and lung function questionnaires). We will further perform register linkage studies to identify and characterize lung comorbidities specific for each disease phase.

We will map and characterize in detail how environmental and immune factors contribute to initiation and perpetuation of autoimmunity in the lungs by high through put cell-phenotyping (single cell transcriptomics and mass cytometry), antibody profiling (custom-made immunochip, Nimblegene assay) and microbiome analysis (16S rRNA gene high-throughput sequencing). Finally, we will test how targeting of either environmental or immune factors in the lungs could modulate disease evolution in RA.

Significance. Results from the current studies will have immediate impact on management of RA patients promoting early investigation of the lung function and smoking cessation. They will also enable discovery of new disease and therapeutic biomarkers increasing the chance of better personalized medicine in both early and late stages of the disease. Such a development would diminish the risk for long term handicap and suffering for the individual, as well as the societal costs for this disease.