Malondialdehyde–Acetaldehyde Adducts and Antibody Responses in Rheumatoid Arthritis–Associated Interstitial Lung Disease

Abstract

Objective To compare serum anti–malondialdehyde–acetaldehyde (anti‐MAA) antibody levels and MAA expression in lung tissue from patients with rheumatoid arthritis–associated interstitial lung disease (RA‐ILD) to those found in controls. Methods Anti‐MAA antibody (IgA, IgM, IgG) concentrations were measured in patients with RA‐ILD and compared to those of RA patients with chronic obstructive pulmonary disease (COPD) and RA patients without lung disease. Associations between anti‐MAA antibody with RA‐ILD were assessed using multivariable logistic regression. Lung tissue from patients with RA‐ILD, other ILD, or emphysema, and from controls (n = 3 per group) were stained for MAA, citrulline, macrophages (CD68), T cells (CD3), B cells (CD19/CD27), and extracellular matrix proteins (type II collagen, fibronectin, vimentin). Tissue expression and colocalization with MAA were quantified and compared. Results Among 1,823 RA patients, 90 had prevalent RA‐ILD. Serum IgA and IgM anti‐MAA antibody concentrations were higher in RA‐ILD than in RA with COPD or RA alone (P = 0.005). After adjustment for covariates, the highest quartiles of IgA anti‐MAA antibody concentration (odds ratio 2.09 [95% confidence interval 1.11–3.90]) and IgM (odds ratio 2.23 [95% confidence interval 1.19–4.15]) were significantly associated with the presence of RA‐ILD. MAA expression in RA‐ILD lung tissue was greater than in tissue from all other groups (P < 0.001), and it colocalized with citrulline (r = 0.79), CD19+ B cells (r = 0.78), and extracellular matrix proteins (type II collagen [r = 0.72] and vimentin [r = 0.77]) to the greatest degree in RA‐ILD. Conclusion Serum IgA and IgM anti‐MAA antibody is associated with ILD among RA patients. MAA is highly expressed in RA‐ILD lung tissue, where it colocalizes with other RA autoantigens, autoreactive B cells, and extracellular matrix proteins, highlighting its potential role in the pathogenesis of RA‐ILD.

Anti-carbamylated proteins antibody repertoire in rheumatoid arthritis: evidence of a new autoantibody linked to interstitial lung disease

“…Various novel candidates have been proposed for RA-ILD screening, including imaging techniques such as positron emission tomography and pulmonary ultrasound,22 23 or serum biomarkers such as the matrix metalloproteinases 7, surfactant protein D and Krebsvon del Lungen-6 4 5. RA-ILD has been associated with different antimodified protein antibodies (AMPAs) based on citrulline24 25 and more recently, malondialdehyde–acetaldehyde adducts 26. Screening techniques can increase RA-ILD diagnostic accuracy, although a model based on features used in clinical practice such as age, sex, smoking, RF and ACPA has a potent screening capacity for symptomatic and subclinical RA-ILD 4.…”

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

“…79 MAA (the antigen) can also be found in higher concentrations in lung tissue of RA patients with interstitial lung disease (ILD) as compared to ILD patients without RA. 80 Unlike AAPA and anti-CarP, anti-MAA were not shown to be cross-reactive with ACPA (discussed below), which could indicate that this response is less related to the other AMPA ( Figure 3). 79 Anti-MAA antibodies have furthermore been reported in patients with osteoarthritis, systemic lupus erythematosus, and even alcohol use disorders, indicating that they lack RA specificity.…”

“…Anti‐MAA antibodies are associated with coronary artery disease and are furthermore found in RA patients, mainly but not exclusively within the seropositive group . MAA (the antigen) can also be found in higher concentrations in lung tissue of RA patients with interstitial lung disease (ILD) as compared to ILD patients without RA . Unlike AAPA and anti‐CarP, anti‐MAA were not shown to be cross‐reactive with ACPA (discussed below), which could indicate that this response is less related to the other AMPA (Figure ) .…”

Lung inflammation in the pathogenesis of rheumatoid arthritis

“…Several studies have also identified male sex as a risk factor for RA‐ILD, including Bongartz and colleagues who reported that the risk of RA‐ILD was 4.4‐fold higher in men vs women . In addition, there is growing evidence associating RA, ILD, and the presence of multiple autoantibodies, including RF, ACPA, and other autoantibody systems including antibodies to heat‐shock protein‐90 (anti‐HSP90), malondialdehyde‐acetaldehyde adducts (anti‐MAA), and anti‐PAD antibodies …”

“…Several studies have also identified male sex as a risk factor for RA-ILD, including Bongartz and colleagues who reported that the risk of RA-ILD was 4.4-fold higher in men vs women. 48 In addition, there is growing evidence associating RA, ILD, and the presence of multiple autoantibodies, including RF, ACPA, and other autoantibody systems including antibodies to heat-shock protein-90 (anti-HSP90), 49,50 malondialdehyde-acetaldehyde adducts (anti-MAA), 51 and anti-PAD antibodies. 52 While several studies have suggested a relationship between the genetic factor the shared epitope and ILD in RA, 36 that relationship may be confounded by other associations between the shared epitope, smoking (another risk factor for lung disease), and autoantibody positivity in RA.…”