Rheumatoid arthritis (RA) exhibits common characteristics with numerous other autoimmune diseases, including the presence of susceptibility genes and the presence of disease-specific autoantibodies... Show moreRheumatoid arthritis (RA) exhibits common characteristics with numerous other autoimmune diseases, including the presence of susceptibility genes and the presence of disease-specific autoantibodies. Anti-citrullinated protein antibodies (ACPA) are the hallmarking autoantibodies in RA and the anti-citrullinated protein immune response has been implicated in disease pathogenesis. Insight into the immunological pathways leading to anti-citrullinated protein immunity will not only aid understanding of RA pathogenesis, but may also contribute to elucidation of similar mechanisms in other autoantibody-positive autoimmune diseases. Similarly, lessons learnt in other human autoimmune diseases might be relevant to understand potential drivers of RA. In this review, we will summarise several novel insights into the biology of the anti-citrullinated protein response and their clinical associations that have been obtained in recent years. These insights include the identification of glycans in the variable domain of ACPA, the realisation that ACPA are polyreactive towards other post-translational modifications on proteins, as well as new awareness of the contributing role of mucosal sites to the development of the ACPA response. These findings will be mirrored to emerging concepts obtained in other human (autoimmune) disease characterised by disease-specific autoantibodies. Together with an updated understanding of genetic and environmental risk factors and fresh perspectives on how the microbiome could contribute to antibody formation, these advancements coalesce to a progressively clearer picture of the B cell reaction to modified antigens in the progression of RA. Show less
Beukel, M.D. van den; Wesemael, T.J. van; Hoogslag, A.T.W.; Borggreven, N.; Huizinga, T.W.J.; Helm-van Mil, A.H.M. van der; ... ; Trouw, L.A. 2023
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... Show moreObjective 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. Show less
