Background/Purpose: Elevations of rheumatoid arthritis (RA)-related autoantibodies (Abs) prior to the symptomatic onset of inflammatory arthritis (IA) suggest that autoimmunity in RA is initiated outside of the joints.  Furthermore, emerging data suggest a potential site may be the lung, supported by the association of inhaled factors such as smoking with RA, our published findings that inflammatory airways abnormalities can precede the onset of symptomatic IA in RA, and known mechanisms for generation of autoimmunity in the lung such as bronchus-associated lymphatic tissue (BALT) (Rangel-Moreno et al 2006). Prior work suggests that comparison of sputa and sera can be used to identify lung generation of autoantibodies (Schiotz et al 1979); therefore, to investigate the role of the lung as a site of initial generation of RA-related autoimmunity, we tested RA-related Abs from sera and sputa from subjects with established RA and subjects at-risk for future RA due to a family history of RA.

Methods: Simultaneous collection of sera and induced sputa (5% nebulized saline) was performed in 17 healthy controls, 29 first-degree relatives (FDR) of RA probands without IA by clinical examination, and 12 subjects with early seropositive RA (1987 criteria; <1 year from diagnosis).  Samples were tested for CCP2 (IgG), CCP3.1 (IgG/IgA), and IgM, IgG and IgA rheumatoid factors (RFs) using commercial ELISAs. In sera, CCP positivity was set from kit standards, and RF positivity was determined as a level elevated in <5% of 491 blood donors. Sputa positivity for each Ab was determined using the control mean plus 2 standard deviations.  Chi-squared testing was used to compare groups, and matched-pair analyses were used to compare the frequency of Ab positivity in sputa and sera.

Results: There were no significant differences in age, sex, smoking status or history of lung disease between Early RA and FDR subjects. All of the Early RA and 8/29 (28%) of FDR subjects were positive in their sera for at least 1 Ab. Overall, a greater proportion of Early RA subjects were positive for each Ab in their sera vs. sputa. However, 8 of the 21 seronegative FDRs were positive in their sputa for at least 1 Ab. Specifically, the assays that detected IgA were elevated in significantly more FDR subjects’ sputa than sera: CCP3.1 31% positive in sputa vs. 7% positive in sera, p=0.03; RF-IgA 14% vs. 0%, p=0.03).

Conclusion: Sputa elevations of RA-related Abs in seronegative FDRs without IA suggest that in some cases RA-related autoimmunity may be initially generated in the lung. Because sputum largely reflects airway responses, these findings also suggest that RA-related autoimmunity may be initially limited to the airways, and IgA predominant. However, the higher number of patients with RA with sera vs. sputa Ab positivity also suggests that after the symptomatic onset of RA the generation of Abs occurs at other sites, leading to autoantibodies in the circulation instead of sputa. These findings show the utility of sputa testing to assess RA-related autoimmunity in the lung, as well as demonstrate a need for prospective studies of subjects at-risk for future RA to determine the role of immunologic responses in the lung in the earliest phases of RA development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sputa-autoantibodies-in-patients-with-established-rheumatoid-arthritis-and-subjects-at-risk-for-future-clinically-apparent-disease/