The onset site of rheumatoid arthritis: the joints or the lung?

Abstract

The etiopathogenesis of rheumatoid arthritis (RA) is not yet fully elucidated and the site of inflammation onset is still a matter of debate. The presence of autoantibodies as well as clinical manifestations, such as interstitial lung disease, before the onset of arthritis seems to be in favour of the hypothesis that initial pathogenic events take place in tissues other than the joint. In this review article we summarize the most recent literature on extra-synovial autoimmunity triggers eventually leading to RA, with particular focus on the role of the lung. To date, anti-cyclic citrullinated peptide antibodies (ACPAs) are considered central players in RA pathogenesis and represent the gold-standard for disease diagnosis. Lungs and mucosae are exposed to environmental stimuli such as dusts and smoke which have been shown to foster citrullination of peptides in lungs thereby triggering the production of ACPA. In addition, other mechanisms of disease pathogenesis independent of citrullination play an important role. Deeper knowledge of these processes could represent a huge step forward in the management of RA, with dramatic impact on diagnosis, prevention, prognostic stratification and treatment of the disease.

Systematic Review and Meta-analysis on the Association of Occupational Exposure to Free Crystalline Silica and Rheumatoid Arthritis

“…Since both FCS and tobacco smoke are inhaled through the airways and are deposited at the lung level, it has been speculated that both can act synergistically in the establishment of RA [10]. To perform this meta-analysis, we considered ever smokers/RA+ cases who had been occupationally exposed to FCS.…”

“…This assumption has been hypothesized in particular in ACPA-positive RA [3,10] that manifests with early inflammatory lung changes, even many years before joint inflammation, suggesting that autoimmunity starts right in the lung [9].…”

“…Among environmental risk factors, the main suspects are for cigarette smoke, FCS, and viral infections [1]. Although the molecular pathogenesis of RA remains to date not fully understood, an increasing number of studies hypothesize that the lung might be a possible starting site of immuno-molecular alterations, alternative to joints [9,10].…”

Elevated Anti–Citrullinated Protein Antibodies Prior to Rheumatoid Arthritis Diagnosis and Risks for Chronic Obstructive Pulmonary Disease or Asthma

“…Smoking is a known RA risk factor, perhaps in part due to increasing pulmonary mucosal inflammation leading to ACPA production particularly for individuals with the HLA-DRB1 shared epitope (2,(6)(7)(8)(9)(10)(11). ACPA may originate at mucosal surfaces in the airways (12) and is central to RA pathogenesis. Inflammation, citrullination, ACPA formation, and autoimmunity leading to clinical RA may be important in the development of pulmonary abnormalities (13).…”

Contribution of pulmonary function tests (PFTs) to the diagnosis and follow up of connective tissue diseases

“…The pathogenesis of the disease is currently not fully understood, but the lung seems to be a possible source of autoimmunity. Exposure to dust and smoke can lead to the citrullination of peptides, provoking an autoimmune response, with the production of Anti Cyclic Citrullinated Antibodies (ACPA) which represent one of the most specific items for the diagnosis [5, 6]. Probably due to autoimmune mechanisms, RA can be directly associated with respiratory system damage not only with ILD, but also with bronchiectasis, pleural effusion, rheumatoid parenchymal nodules and, rarely, vascular disease.…”