Geo-epidemiology of autoantibodies in rheumatoid arthritis: comparison between four ethnically diverse populations

Abstract

Background Rheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether differences exist in autoantibody responses at different geographic locations and between different ethnic groups, which could provide new clues regarding factors underlying autoantibody development. We therefore investigated AMPA prevalence and association with HLA DRB1 alleles and smoking in four ethnically diverse populations on four different continents. Methods Anti-carbamylated (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (anti-AcVim) IgG were determined in anti-citrullinated protein antibody-positive Dutch (NL, n = 103), Japanese (JP, n = 174), First Nations Peoples in Canada (FN, n = 100), and black South African (SA, n = 67) RA patients. Ethnicity-matched local healthy controls were used to calculate cut-offs. Risk factors associated with AMPA seropositivity in each cohort were identified using logistic regression. Results Median AMPA levels were higher in First Nations Peoples in Canada and especially South African patients, as reflected by percentage seropositivity: NL, JP, FN, and SA: anti-CarP: 47%, 43%, 58%, and 76% (p < 0.001); anti-MAA: 29%, 22%, 29%, and 53% (p < 0.001); and anti-AcVim: 20%, 17%, 38%, and 28% (p < 0.001). Total IgG levels also differed markedly, and when autoantibody levels were normalized to total IgG, differences between cohorts became less pronounced. Although there were some associations with AMPA and HLA risk alleles and smoking, none was consistent across all four cohorts. Conclusions AMPA against various post-translational modifications could consistently be detected on different continents across ethnically diverse RA populations. Differences in AMPA levels corresponded to differences in total serum IgG levels. This suggests that, despite differences in risk factors, a common pathway may be involved in AMPA development across geographic locations and ethnicities.

Assessment of anti-malondialdehyde-acetaldehyde antibody frequencies in rheumatoid arthritis with new data from two independent cohorts, meta-analysis, and meta-regression

“…Therefore, only the IgG isotype was considered for meta-analysis. Five publications included a patient collection; the remaining publication contained four patient sets, each from a different continent [ 5 ]. Therefore, we considered nine patient sets from previous studies and the two collections reported here.…”

“…Analysis of the bibliography of these publications did not reveal any additional sources. One of the publications was a meeting abstract at the time of the search [ 33 ], but the full article became available before the final analyses [ 5 ]. This article includes four patient sets that join the five previously published studies and our two RA collections.…”

“…The demand for biomarkers is particularly acute in seronegative patients, lacking the validated RA autoantibodies rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies because these antibodies are valuable for RA diagnosis and prognosis. Therefore, the 2015 discovery of autoantibodies with high sensitivity for this subset of patients was received with keen interest [ 3 , 4 ], although this claim has been questioned more recently [ 5 – 8 ]. The antibodies in the 2015 study recognized malondialdehyde-acetaldehyde (MAA) protein adducts in more than 80% of seronegative patients and 92% of the whole set of RA patients [ 4 ].…”

“…An obstacle to anti-MAA antibody use is the incomplete validation in subsequent RA studies [ 5 , 6 , 8 , 18 , 22 , 23 ]. Some studies replicated the high sensitivity in seropositive and seronegative RA patients [ 18 , 23 ], but others reported lower frequencies of positive RA patients [ 5 , 6 , 8 , 22 ]. Here, we present our anti-MAA results and attempts to increase anti-MAA sensitivity in the first part of the current article.…”

“…We complemented it by integrating our results with previous studies in the second part. The integration was done with a meta-analysis of the frequency of IgG anti-MAA + patients in all available studies [ 5 , 6 , 8 , 18 , 23 ]. This meta-analysis was aimed at quantifying and defining heterogeneity.…”