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

Abstract

Background: Autoantibodies are critical elements in RA pathogenesis and clinical assessment. The anti-malondialdehyde-acetaldehyde (anti-MAA) antibodies are potentially useful because of their claimed high sensitivity for all RA patients, including those lacking RF and anti-CCP antibodies. Therefore, we aimed to replicate these findings.

Methods: We independently attempted replication in Santiago and Barcelona using sera from 517 and 178 RA patients and 272 and 120 healthy controls, respectively. ELISA protocols for anti-MAA antibodies included five antigens (human serum albumin in three formulations, fibrinogen, and a synthetic peptide) and assays for the IgG, IgM, and IgA isotypes. We integrated our results with information found by searching the Web of Science for reports of anti-MAA antibodies in RA. The available patients (4989 in 11 sets) were included in a meta-analysis aimed at heterogeneity between studies. Factors accounting for heterogeneity were assessed with meta-regression.

Results: The sensitivity of anti-MAA antibodies in our RA patients was low, even in seropositive patients, with the percentage of positives below 23% for all ELISA conditions. Our results and bibliographic research showed IgG anti-MAA positive patients ranging from 6 to 92%. The extreme between-studies heterogeneity could be explained (up to 43%) in univariate analysis by sex, African ethnicity, the site of study, or recruitment from the military. The best model, including African ancestry and smoking, explained a high heterogeneity fraction (74%).

Conclusion: Anti-MAA antibody sensitivity is extremely variable between RA patient collections. A substantial fraction of this variability cannot be attributed to ELISA protocols. On the contrary, heterogeneity is determined by complex factors that include African ethnicity, smoking, and sex.

Keywords: Autoantibodies; Biomarker; Heterogeneity; Meta-analysis; Post-translational modifications; Rheumatoid arthritis.

Fig. 1

Anti-MAA antibody levels in healthy controls, anti-CCP- RA patients, and anti-CCP + RA patients. The results in A and B were obtained with complete independence at Santiago and Barcelona, respectively. In A 272 healthy controls, 185 anti-CCP⁻ and 332 anti-CCP⁺ RA patients were included. In B the numbers were 120, 52, and 127, respectively. Each dot represents a subject; the red horizontal lines represent the median anti-MAA antibody levels

Fig. 2

Random effect meta-analysis of the frequency of IgG anti-MAA⁺ in RA patients. The patient sets are identified by the first author and year of publication. The four RA patient sets in de Moel (2023) [5] are FNS, First Nations People from Canada; SA, South Africans; NLD, Dutch from the Netherlands; and JPN, Japanese. The size of the squares is proportional to the weight of each patient collection (provided in the last column). The X-axis is on the logit scale. RE, random effects. 95% CI, 95% confidence interval