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... Show moreBackground: 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. Show less
Moel, E.C. de; Trouw, L.A.; Terao, C.; Govind, N.; Tikly, M.; El-Gabalawy, H.; ... ; Woude, D. van der 2023
BackgroundRheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether... Show moreBackgroundRheumatoid 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.MethodsAnti-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.ResultsMedian 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.ConclusionsAMPA 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. Show less
Amkreutz, J.A.M.P.; Moel, E.C. de; Theander, L.; Willim, M.; Heimans, L.; Nilsson, J.A.; ... ; Woude, D. van der 2021
Objective Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral... Show moreObjective Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts.Methods Dual x-ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow-up and in 198 Swedish patients with early RA during 10 years of follow-up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations.Results In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA-positive patients compared to ACPA-negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm(2) (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm(2) (95% CI 0.93-0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA-positive group compared to the ACPA-negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies). In the Swedish cohort, ACPA-positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time.Conclusion The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well-managed. Show less
Moel, E.C. de; Rech, J.; Mahler, M.; Roth, J.; Vogl, T.; Schouffoer, A.; ... ; Woude, D. van der 2019
Objective: To investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA)... Show moreObjective: To investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA) patients who are in stable remission on disease-modifying anti-rheumatic drugs (DMARDs) and serve as a marker for disease flare after DMARD tapering.Methods: We used data from two trials. Patients from the IMPROVED study had early (< 2 years) RA, and when they achieved disease activity score remission (DAS44 < 1.6), they stopped methotrexate to attempt drug-free remission. Patients from the RETRO study had established RA in stable remission (DAS28 < 2.6) and either tapered by 50% or stopped (biological or conventional) DMARDs. Circulating calprotectin at the tapering time point was determined by ELISA, and its predictive value for flare (loss of remission) within 12 months of DMARD tapering/stopping was determined.Results: In both IMPROVED (n = 104) and RETRO (n = 57), patients that flared within 12 months had higher calprotectin at the moment of DMARD tapering/stopping. Twofold higher calprotectin at the moment of DMARD tapering/stopping was associated with an increased risk (odds ratio) of flare of 1.07 (95% CI 0.98-1.18, p = 0.14) in the IMPROVED and 3.62 (95% CI 1.76-7.46, p < 0.001) in the RETRO. Correcting for clinical predictors of flare (DAS at study inclusion, anti-CCP2 positivity, gender) did not change these estimates. The area under the receiver operating curve of calprotectin levels for predicting flare within 12 months was 0.63 (95% CIs 0.51-0.76) in the IMPROVED study and 0.80 (95% CIs 0.69 to 0.92) in the RETRO study.Conclusion: Circulating calprotectin levels in RA patients in remission on DMARDs are higher in patients that will flare upon DMARD tapering/stopping. Since the differences between the cohorts precluded definitive conclusions, more research is needed to determine whether calprotectin has prognostic value in predicting flare after attempting drug tapering in RA. Show less
Moel, E.C. de; Rozeman, E.A.; Kapiteijn, E.H.; Verdegaal, E.M.E.; Grummels, A.; Bakker, J.A.; ... ; Woude, D. van der 2019
