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Abstract

We thank Dr Castellanos-Moreira and colleagues for their thoughtful comments on our article about the elevation of IgA anti-citrullinated protein antibodies (ACPA) in subjects with idiopathic pulmonary fibrosis (IPF).1Solomon J.J. Matson S. Kelmenson L.B. et al.IgA antibodies directed against citrullinated protein antigens are elevated in patients with idiopathic pulmonary fibrosis.Chest. 2020; 157: 1513-1521Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar We read with interest their work on anti-carbamylated protein antibodies (Anti-CarP)2Castellanos-Moreira R. Rodriguez-Garcia S.C. Gomara M.J. et al.Anti-carbamylated proteins antibody repertoire in rheumatoid arthritis: evidence of a new autoantibody linked to interstitial lung disease.Ann Rheum Dis. 2020; 79: 587-594Crossref PubMed Scopus (15) Google Scholar in rheumatoid arthritis-associat4ed interstitial lung disease (RA-ILD), and like them, we are intrigued by the finding that the IgA subtype of anti-CarP was associated with the highest OR for ILD in their subjects with RA. These findings further support the hypotheses that, in RA, autoantibodies are generated at mucosal surfaces and may play a role in the pathogenesis of RA-ILD. In unpublished data, we have followed 162 serum anti-cyclic citrullinated protein (CCP) positive subjects (without RA but with airways disease or ILD) over time for the development of RA. Anti-CCP positivity was determined clinically, and in most subjects, was measured using CCP3.1 (IgG/IgA Inova), which detects both IgG and IgA anti-CCP antibodies. Over a median 1,810 days of follow-up, 17% developed joint inflammation and were clinically diagnosed with RA. Among the subjects followed, 32 had a usual interstitial pneumonia (UIP) pattern of ILD on high-resolution CT, and only two of 32 (6.25%) developed RA over a median 185 days. Given the retrospective approach, small number, and relatively short follow-up, we caution against drawing any firm conclusions from these data. However, this lower rate of development of RA among subjects with UIP compared with rates reported for serum anti-CCP positivity in non-ILD cohorts3Ramos-Remus C. Castillo-Ortiz J.D. Aguilar-Lozano L. et al.Autoantibodies in prediction of the development of rheumatoid arthritis among healthy relatives of patients with the disease.Arthritis Rheum. 2015; 67: 2837-2844Crossref Scopus (41) Google Scholar,4van de Stadt L.A. Witte B.I. Bos W.H. van Schaardenburg D. A prediction rule for the development of arthritis in seropositive arthralgia patients.Ann Rheum Dis. 2013; 72: 1920-1926Crossref PubMed Scopus (123) Google Scholar suggests that ACPA-positive UIP is not necessarily a “pre-RA” phenotype destined to develop RA. We posit the that anti-CCP isotype present is highly relevant to risk of developing RA. We also speculate that the ACPA-IgA positive subset of IPF/UIP share certain lung-based pathogenetic mechanisms with RA that may not necessarily be related to joint-based pathogenic mechanisms. We believe that elucidating these mechanisms could lead to effective prevention and treatment strategies against these progressive and morbid clinical entities. What role members of the anti-modified protein antibody family other than ACPA and anti-CarP may play in this proposed shared pathogenesis scenario is also worthy of exploration. We suspect there are multiple pathways that end with UIP-pattern lung injury, some involving auto-antibody formation and some not. Regardless, we agree with Castellanos-Moreira and colleagues; future research into autoimmune mechanisms involved in the development or progression of IPF or RA-ILD ought not be confined to ACPA and should include other candidate pathways. IgA Antibodies Directed Against Citrullinated Protein Antigens Are Elevated in Patients With Idiopathic Pulmonary FibrosisCHESTVol. 157Issue 6PreviewThe etiology of idiopathic pulmonary fibrosis (IPF) is unknown. Because it shares genetic, histopathologic, and radiographic features with the fibrosing interstitial lung disease seen in rheumatoid arthritis (RA), the goal of this study was to investigate RA-related autoantibodies in IPF. Full-Text PDF Is Auto-Antibody Expansion the Turning Point Between Idiopathic Pulmonary Fibrosis and Rheumatoid Arthritis?CHESTVol. 158Issue 4PreviewWe read with interest the article by Solomon et al1 in a previous issue of CHEST (June 2020), which reports for the first time that the high prevalence of anti-citrullinated protein antibodies (ACPA) in idiopathic pulmonary fibrosis (IPF) is mostly attributed to IgA. ACPA are part of the family of anti-modified protein antibodies (AMPA) that also includes the anti-acetylated and anti-carbamylated protein antibodies (anti-AceP and anti-CarP, respectively). Both anti-AceP and anti-CarP have been found to be associated with interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Full-Text PDF