Molecular and epidemiological investigations of lung involvement in very early rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory joint disease with at least two distinct clinical phenotypes defined by the presence or absence of antibodies, i.e. rheumatoid factor (RF) and/or anti-­citrullinated protein antibodies (ACPAs). These two phenotypes differ both with respect to risk factors and disease outcome, with seropositive disease being more likely associated with extra-­articular manifestations, such as lung manifestations, and tobacco exposure. Both ACPA and RF can be detected in the blood years prior to the onset of joint inflammation suggesting that these antibodies are initially generated outside the joints. The current thesis investigates the pathogenic link between lungs and joints with a focus on the potential role of the lung as an initiating site for the RA-­associated autoimmunity.

We investigated a cohort of patients with early, untreated RA, who underwent high resolution computed tomography and conducted lung function tests. A subgroup of these patients was subjected to bronchoscopy with retrieval of bronchoalveolar lavage (BAL) and bronchial biopsies. All investigations were repeated after six months of anti-­rheumatic treatment. We found more prevalent lung abnormalities, both parenchymal (54%) and airway (66%) in RA patients as compared to controls. The parenchymal abnormalities were significantly more frequent in the subgroup of ACPA-­positive RA patients compared to ACPA-­negative patients. The same was true after compensating for smoking. Signs of inflammation and immune activation with more lymphocytic infiltration and expression of citrullinated proteins were found in the lungs of ACPA-­positive as compared to ACPA-­negative patients. ACPAs were enriched in the BAL as compared to the blood compartment of ACPA-­positive patients. Using mass spectrometry we were able to identify two novel citrullinated vimentin peptides that were present in a majority of bronchial (n=6) and RA synovial biopsies (n=7) tested. Immune reactivity against these targets was specifically detected in the blood of RA patients. At 6 months follow-­up one third of patients with lung fibrosis (11%) at baseline had progressed and additionally 3 patients had developed new radiological changes suggestive of early interstitial lung disease. Moreover, there was an increase in airway obstruction, with a decline in forced expiratory volume in one second in all patients, more prominent in smokers.

In conclusion, lung changes in early RA are prevalent and may be progressive despite anti-­rheumatic treatment. Taken together our results support the hypothesis that the lung may be an early important player in the pathogenesis of RA in a subset of patients. These findings encourage new therapeutic strategies to target the local inflammation in the lungs, with the aim to prevent the progress of autoimmunity in ACPA-­positive healthy individuals.

List of scientific papers

I. Reynisdottir G, Karimi R, Joshua V, Olsen H, Hensvold AH, Harju A, Engstrom M, Grunewald J, Nyren S, Eklund A, Klareskog L, Skold CM, Catrina AI. Structural changes and antibody enrichment in the lungs are early features of anti-­citrullinated protein antibody-­positive rheumatoid arthritis. Arthritis & Rheumatology. 2014;66(1):31-­39.
https://doi.org/10.1002/art.38201

II. Reynisdottir G, Olsen H, Joshua V, Engstrom M, Forsslund H, Karimi R, Skold CM, Nyren S, Eklund A, Grunewald J, Catrina AI. Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis. Annals of the Rheumatic Diseases. 2015 Nov 3.
https://doi.org/10.1136/annrheumdis-2015-208216

III. Ytterberg AJ, Joshua V, Reynisdottir G, Tarasova NK, Rutishauser D, Ossipova E, Haj Hensvold A, Eklund A, Skold CM, Grunewald J, Malmstrom V, Jakobsson PJ, Ronnelid J, Padyukov L, Zubarev RA, Klareskog L, Catrina AI. Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis : identification and validation. Annals of the Rheumatic Diseases. 2015;74(9):1772-­7.
https://doi.org/10.1136/annrheumdis-2013-204912

IV. Olsen H, Reynisdotir G*, Pawlowski J, Harju A, Karimi R, Klareskog L, Skold CM, Nyren S, Catrina AI, Eklund A, Grunewald J. Pulmonary manifestations in early rheumatoid arthritis: Features at baseline and after six months of standard treatment. [Manuscript]