Antibodies against advanced glycation end-products and malondialdehyde-acetaldehyde adducts identify a new specific subgroup of hitherto patients with seronegative arthritis with a distinct clinical phenotype and an HLA class II association

Abstract

Objective: In rheumatoid arthritis (RA) around two-thirds of patients are autoantibody positive for rheumatoid factor, anti-citrullinated protein antibodies and/or anti-carbamylated protein antibodies. The remaining seronegative subgroup of patients is clinically heterogeneous and thus far, biomarkers predicting the disease course are lacking. Therefore, we analysed the value of other autoantibodies in RA directed against malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE).

Methods: In sera of 648 patients with RA and 538 patients without RA from the Leiden Early Arthritis Clinic, anti-MAA and anti-AGE IgG antibody levels were measured using ELISA. Associations between genetic risk factors, acute phase reactants, radiological joint damage, remission and anti-PTM positivity were investigated using regression, correlation and survival analyses.

Results: Anti-AGE and anti-MAA were most prevalent in RA (44.6% and 46.1% respectively) but were also present in non-RA arthritis patients (32.9% and 30.3% respectively). Anti-AGE and anti-MAA antibodies were associated with HLA-DRB1*03 within seronegative RA (OR=1.98, p=0.003, and OR=2.37, p<0.001, respectively) and, for anti-AGE also in non-RA arthritis patients (OR=2.34, p<0.001). Presence of anti-MAA antibodies was associated significantly with markers of inflammation, erythrocyte sedimentation rate and C reactive protein, in all groups independent of anti-AGE. Interestingly, the presence of anti-AGE and anti-MAA antibodies was associated with radiological progression in patients with seronegative RA, but not evidently with sustained drug-free remission.

Conclusions: Anti-AGE and anti-MAA were present in around 45% of RA patients and 30% of non-RA arthritis patients, and although not specific for RA, their presence associated with HLA, inflammation and, for RA, with clinical outcomes especially in patients with seronegative RA.

Keywords: Anti-Citrullinated Protein Antibodies; Arthritis; Arthritis, Rheumatoid; Autoantibodies.

Figure 1

Anti-AGE and anti-MAA show higher levels in RA and occur in a subgroup of patients with anti-CarP anti-CCP2 negative RA. IgG antibody levels of anti-AGE (A) and anti-MAA (B) in patients with (n=648) and without (n=538) RA. Early patients with arthritis were separately depicted as groups: AI without RA (including psoriatic arthritis, paraneoplastic arthritis, SLE, sarcoidosis and spondyloarthritis) and non-AI (including septic arthritis, gout, pseudogout). (C) Upset plots of groups of patients with RA (n=499*) positive for anti-PTM combinations; anti-AGE, anti-MAA, anti-CarP, anti-CCP2 and RF. *Data for anti-CarP was missing for 149 patients with RA. AGE, advanced glycation end-product; AI, autoimmune; aU/mL, arbitrary units per mL; CarP, carbamylated protein; CCP2, citrullinated cyclic peptide 2; MAA, malondialdehyde acetaldehyde adduct; RA, rheumatoid arthritis; RF, rheumatoid factor.

Figure 2

Anti-AGE and anti-MAA associate with radiological progression in patients with RA (n=600). (A) Radiological progression in anti-AGE positive and negative RA. (B) Data stratified for CCP2. (C) Data stratified for anti-CarP in anti-CCP2-negative stratum. (D) Radiological progression in anti-MAA positive and negative RA. (E) Data stratified for CCP2. Data presented as estimate (95% CI), p value. AGE, advanced glycation end-product; CarP, carbamylated protein; CCP2, citrullinated cyclic peptide 2; MAA, malondialdehyde acetaldehyde adduct.