Sputum Autoantibodies in Patients With Established Rheumatoid Arthritis and Subjects at Risk of Future Clinically Apparent Disease

Abstract

Objective To evaluate the generation of rheumatoid arthritis (RA)–related autoantibodies in the lung. Methods Simultaneous collection of serum and induced sputum was performed in 21 healthy controls, 49 at-risk subjects without inflammatory arthritis but at risk of RA due to family history or seropositivity for anti–citrullinated protein antibodies, and 14 subjects with early RA. Samples were tested for anti–cyclic citrullinated peptide 2 (anti-CCP2), anti-CCP3, anti-CCP3.1, rheumatoid factor isotypes IgM, IgG, and IgA, and total IgM, IgG, and IgA. Results One or more autoantibodies were present in sputum of 39% of at-risk seronegative subjects, 65% of at-risk seropositive subjects, and 86% of subjects with early RA. In at-risk seronegative subjects, the rate of anti-CCP3.1 positivity and the median number of autoantibodies were elevated in sputum versus serum. In subjects with early RA, the rate of positivity for several individual autoantibodies and the median number of autoantibodies were higher in serum than in sputum. Results in at-risk seropositive subjects were intermediate between these groups. In at-risk subjects with autoantibody positivity in sputum, the ratios of autoantibody to total Ig were higher in sputum than in serum, suggesting that these autoantibodies are generated or sequestered in the lung. Conclusion RA-related autoantibodies are detectable in sputum in subjects at risk of RA and in subjects with early RA. In a subset of at-risk subjects, the presence of sputum autoantibodies in the absence of seropositivity, and the increased autoantibody-to–total Ig ratios in sputum, suggest that the lung may be a site of autoantibody generation in the early development of RA. These findings suggest an important role of the lung in the pathogenesis of RA.

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…This finding is reminiscent of our recent observation showing that nearly 40% of ACPA -FDRs already had detectable levels of APCA in their sputum (62). It will be of great interest to examine if the presence of APCA in sputum correlates with the impaired induction of PTPN22 in PBMCs of ARIs.…”

Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention

“…Structural and immunologic abnormalities have also been reported in the lungs of individuals at-risk for RA (28)(29)(30). At-risk individuals without arthritis who were seropositive for ACPAs were found to have a similar prevalence of airway abnormalities on HRCT when compared to matched RA patients (28), and rheumatoid-type lung disease was found in seropositive individuals who later progressed to develop RA (30).…”

“…Similar to PD, the presence of lung mucosal abnormalities in seropositive individuals raises the possibility that the mucosae could simply precede the joints as a downstream target, rather than providing the initial trigger for autoimmunity. However, some at-risk individuals who are seronegative for autoantibodies have evidence of well-established localized autoimmunity at the lung mucosa (29); the discovery of RA-related autoantibodies in the sputum of these patients supports the role of the lung as a potential initiating site of RA autoimmunity.…”

“…Harvey et al (24) Anti-CCP antibodies (28) Airways disease on HRCT imaging Seropositive individuals without arthritis had higher prevalence of airways disease on HRCT imaging compared to seronegative matched controls. Willis et al (29) Sputum autoantibodies (ACPAs and RF) 39% of seronegative at-risk individuals were positive for $1 RA-related autoantibody in the sputum; at-risk seropositive subjects had similar prevalence of RA-related autoantibodies in the sputum and serum; patients with early RA had higher autoantibody prevalence in the serum than in the sputum.…”

Citrullination: A Specific Target for the Autoimmune Response in Rheumatoid Arthritis

“…These observations have led to hypotheses that the formation of ACPAs provides a link between the risk factors for RA and the pathway that ultimately leads to clinical arthritis. Notably, smoking can lead to formation of citrullinated proteins in the lung, the presence of ACPAs is associated with lung inflammation in RA, and ACPAs can be measured in sputum not only in those with RA, but even in individuals at risk for RA who do not yet have ACPAs in their serum (34)(35)(36)(37)(38). Periodontitis, which is bidirectionally associated with RA, is driven by the bacterium Porphyromonas gingivalis, which uniquely among oral flora expresses PAD and thus generates local protein citrullination, leading to formation of ACPAs (33,(39)(40)(41).…”