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

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.

Association Between Bone Mineral Density and Autoantibodies in Patients With Rheumatoid Arthritis.

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 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/cm2 (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm2 (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.

Circulating calprotectin (S100A8/A9) is higher in rheumatoid arthritis patients that relapse within 12 months of tapering anti-rheumatic drugs.

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) 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. TRIAL REGISTRATION: IMPROVED, ISRCTN11916566. RETRO, 2009-015740-42.

In rheumatoid arthritis, changes in autoantibody levels reflect intensity of immunosuppression, not subsequent treatment response.

BACKGROUND: Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies like rheumatoid factor (RF), anti-cyclic citrullinated peptide-2 (anti-CCP2), and anti-carbamylated protein (anti-CarP) antibodies. It is currently unclear whether changes in autoantibody levels are associated with disease activity/treatment outcomes and whether they are modified by treatment intensity. Therefore, we determined longitudinal changes in RA-autoantibody levels, the association between these changes and activity score (DAS) and treatment outcomes, and the effect of intensity of immunosuppressive treatment on levels. METHODS: In 381 seropositive RA patients from the IMPROVED study, we measured IgG, IgM, and IgA of anti-CCP2 and anti-CarP; IgM and IgA of RF; and IgG against four citrullinated and two acetylated peptides at 4-month intervals over the first year of treatment. Following initial prednisone and methotrexate (MTX), treatment was changed every 4 months aiming for DAS < 1.6. We investigated changes in autoantibody levels following treatment escalation versus tapering, and the association of levels with DAS over time, EULAR response, and drug-free remission (DFR) ≥ 1 year. RESULTS: For all 14 autoantibodies, levels decreased from 0 to 4 months and then rose until 12 months. Following treatment escalation, autoantibody levels dropped markedly, while they rose following tapering: RF IgM levels, a representative autoantibody, dropped 10% after restarting prednisone and rose 15% aU/mL after tapering MTX (p < 0.0001). There was no association between autoantibody levels and DAS over time or EULAR response. Greater relative changes between 0 and 12 months did not predict DFR (0-12-month relative change RF IgM, - 39% for no DFR (n = 126) and - 16% for DFR (n = 18)). CONCLUSIONS: Changes in RA-autoantibody levels are not associated with DAS or long-term treatment response, but reflect intensity of immunosuppression. This suggests that autoantibody levels are modifiable by current therapies, but that modifying levels is in itself of limited clinical relevance. TRIAL REGISTRATION: ISRCTN11916566 . Registered on 7 November 2006.

Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors.

Immune-checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and posttreatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival. Autoantibodies developed in 19.2% (19/99) of patients who were autoantibody-negative pretreatment. A nonsignificant association was observed between development of any autoantibodies and any irAEs [OR, 2.92; 95% confidence interval (CI) 0.85-10.01]. Patients with antithyroid antibodies after ipilimumab had significantly more thyroid dysfunction under subsequent anti-PD-1 therapy: 7/11 (54.6%) patients with antithyroid antibodies after ipilimumab developed thyroid dysfunction under anti-PD1 versus 7/49 (14.3%) patients without antibodies (OR, 9.96; 95% CI, 1.94-51.1). Patients who developed autoantibodies showed a trend for better survival (HR for all-cause death: 0.66; 95% CI, 0.34-1.26) and therapy response (OR, 2.64; 95% CI, 0.85-8.16). We conclude that autoantibodies develop under ipilimumab treatment and could be a potential marker of ICI toxicity and efficacy.

Baseline autoantibody profile in rheumatoid arthritis is associated with early treatment response but not long-term outcomes.

BACKGROUND: The autoantibody profile of seropositive rheumatoid arthritis (RA) is very diverse and consists of various isotypes and antibodies to multiple post-translational modifications. It is yet unknown whether this varying breadth of the autoantibody profile is associated with treatment outcomes. Therefore, we investigated whether the composition of the autoantibody profile in RA, as a marker of the underlying immunopathology, influences initial and long-term treatment outcomes. METHODS: In serum from 399 seropositive patients with RA in the IMPROVED study, drawn at baseline and at the moment of drug tapering, we measured IgG, IgM, and IgA isotypes for anti-cyclic citrullinated peptide-2 and anti-carbamylated protein antibodies, IgM and IgA rheumatoid factor, and reactivity against four citrullinated and two acetylated peptides (anti-modified protein antibodies (AMPAs)). We investigated the effect of the breadth of the autoantibody profile on (1) change in disease activity score (DAS)44 between 0 and 4 months, (2) initial drug-free remission (DFR, drug-free DAS44 < 1.6) achieved between 1 and 2 years of follow up, and (3) long-term sustained DFR until last follow up. RESULTS: Patients with a broad autoantibody profile at baseline had a significantly better early treatment response: ΔDAS 0-4 months of 1-2, 3-4, and 5-6 vs 7-8 isotypes, -1.5 (p < 0.001), -1.7 (p = 0.03), and -1.8 (p = 0.04) vs -2.2. Similar results were observed for AMPA number. However, patients with a broad baseline autoantibody profile achieved less initial DFR. For long-term sustained DFR there was no longer an association with the breadth of the autoantibody response. When assessing autoantibodies at the moment of tapering, similar trends were observed. CONCLUSIONS: A broad baseline autoantibody profile is associated with a better early treatment response. The breadth of the baseline autoantibody profile, reflecting a break in tolerance against several different autoantigens and extensive isotype switching, may indicate a more active humoral autoimmunity, which could make the underlying disease processes initially more suppressible by medication. The lack of association with long-term sustained DFR suggests that the relevance of the baseline autoantibody profile diminishes over time. TRIAL REGISTRATION: ISRCTN11916566 . Registered on 7 November 2006. EudraCT, 2006- 06186-16. Registered on 16 July 2007.