A symposium at EULAR 2016, held in London in June, addressed the targeting of unmet needs in autoantibody-driven inflammatory diseases, with a focus on seropositive rheumatoid arthritis (RA).
The symposium, sponsored by Bristol-Myers Squibb, was chaired by Professor Paul Emery from the University of Leeds, UK.
Professor Tom Huizinga, from the Department of Rheumatology at Leiden University Medical Center in The Netherlands, discussed the potential for autoantibody status to identify patients more likely to respond to specific biological therapies. Rheumatoid factor (RF) is a traditional marker, but anti-citrullinated protein antibodies (ACPA) have attracted increasing attention in recent years.
“Seropositive RA, especially ACPA+ RA, is associated with poor prognosis,” Professor Huizinga said. “There is a better response for seropositive vs seronegative patients with some biologics, and interference with autoantigen presentation, as demonstrated by seroconversion, appears to correlate with better outcomes.”
ACPA positivity can often be identified some years before the onset of clinical symptoms and signs of RA.1 Increasing ACPA titres and epitope spreading occur as undifferentiated arthritis develops, but ACPA maturation plateaus as RA becomes established. More ACPA isotypes are associated with a higher risk of radiographic damage, and each additional isotype increases the risk by 40%.2 ACPA isotypes, therefore, provide additional prognostic information compared to ACPA status alone.2
The BRASS Registry includes American patients with established RA who have been evaluated annually using clinical measures and semi-annually using patient-reported outcomes and data on resource use.3 A study presented at EULAR 2016 reported that among 1,309 patients with data on ACPA status, the odds ratio for erosive disease was 2.72 (95% CI: 1.77, 4.18) for ACPA+. The association was stronger than for RF+ (odds ratio 1.36, 95% CI 0.88, 2.08). “The presence of ACPA+ and erosions…is associated with higher disease activity, lower odds of remission and lower work productivity, even when treated with standard-of-care biological DMARDs,” the study’s authors concluded.3
A meta-analysis of 2,331 patients with early RA included in three registries found the hazard ratio for all-cause mortality was 1.48 for ACPA+ and 1.47 for RF+.4 ACPA+ was associated with increased cardiovascular death (HR 1.52), and RF+ with increased neoplasm-related death (HR 1.64) and death related to respiratory disease (HR 1.71).
Response to treatment
Autoantibody status is a marker of response to biological DMARD therapy. A Japanese post-marketing study evaluated the safety and effectiveness of abatacept in RA over 6 months.5 Disease activity, assessed by DAS28-CRP, improved significantly overall. Multivariate logistic regression analysis indicated that positive serology (RF+ or ACPA+) in patients with moderate disease activity was significantly associated with improvement.
The CORRONA RA registry (www.corrona.org) is the largest RA real-world prospective cohort study in the world. Another study presented at EULAR 2016, based on the registry, confirmed that ACPA+ and RF+ status are associated with higher rates of low disease activity at 6 months among patients treated with abatacept.6 No such association was found for patients treated with TNF inhibitors. The change in the Clinical Disease Activity Index (CDAI) was -8.5 in ACPA+ patients commencing abatacept, compared to -4.1 in ACPA- patients (p<0.001). In those commencing a TNF inhibitor, the change was -7.4 in ACPA+ patients and -6.4 in ACPA- patients (p=0.071).6
“These real-world data suggest that anti-CCP+ [ACPA+] patients with RA show incremental improvements in response while receiving abatacept therapy compared with anti-CCP- [ACPA-] patients,” the study’s authors concluded.6
The absence of an association between ACPA+ and RF+ status and the response to TNF inhibitors was confirmed in meta-analysis of 14 studies involving 5561 patients.7 The relative risk for the predictive effects of RF+ status was 0.98 (p=0.54), and 0.88 (p=0.11) for ACPA+ status.
Neither ACPA nor RF status predict the response to tocilizumab,8 but seropositivity is associated with more rapid discontinuation of tocilizumab therapy.9
A modest association has been identified between ACPA+ or RF+ status at baseline and response to rituximab.10 A meta-analysis of four placebo-controlled phase II or III clinical trials found the reduction in DAS28-ESR at week 24 was, on average, 0.35 units greater in seropositive compared to seronegative patients treated with rituximab. This effect was not seen in patients randomised to placebo.
Several recent studies have specifically explored relationships between autoantibody status and responses to treatment of RA with abatacept. A pooled analysis of nine European RA registries found that persistence with abatacept treatment was higher in patients who were ACPA+ or RF+, compared to those who were negative for the autoantibodies.11
Even after adjustment for sociodemographic and disease- and treatment-related confounders, RF and ACPA positivity were each associated with a lower risk of abatacept discontinuation for any reason (HR 0.79, p<0.001, and HR 0.78, p<0.001, respectively), compared to RF-negative and ACPA-negative patients. Similar associations with RF and ACPA were observed for discontinuation of abatacept treatment due to ineffectiveness.
“Our results strongly suggest that positivity for RF or ACPA is associated with better effectiveness of abatacept therapy,” the study’s authors stated.11
In addition, Professor Huizinga and colleagues have reported that abatacept in combination with methotrexate has greater clinical efficacy in patients who were ACPA IgM-positive at baseline than those who were ACPA IgM-negative at baseline, and in those who seroconverted over time than those who did not.12
Presenting results from the AVERT study at EULAR 2015 in Rome, they described how a similar trend was not observed in patients treated with either abatacept or methotrexate as monotherapy.
In addition, a numerically higher proportion of patients who seroconverted from ACPA IgM-positive at baseline to negative at month 12 achieved remission compared to those who remained seropositive in the abatacept plus methotrexate and abatacept monotherapy arms.12
- Willemze A et al. The influence of ACPA status and characteristics on the course of RA. Nat Rev Rheumatol 2012; 8: 144-52.
- van der Woude D et al. The ACPA isotype profile reflects long-term radiographic progression in rheumatoid arthritis. Ann Rheum Dis 2010; 69: 1110-6.
- Alemao E et al. Association of the rheumatoid arthritis prognostic factors anti-citrullinated peptide antibodies, rheumatoid factor and erosions with disease activity and work productivity. Ann Rheum Dis 2016; 75 (Suppl 2): 211.
- Ajeganova S et al. Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts. Ann Rheum Dis 2016 Jan 12. pii: annrheumdis-2015-208579.
- Harigai M et al. Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis. Mod Rheumatol 2016; 26: 491-8.
- Harrold LR et al. Relationship between anti-citrullinated protein antibody status and response to abatacept or anti-tumour necrosis factor therapy in patients with rheumatoid arthritis: A US national observational study. Ann Rheum Dis 2016; 75 (Suppl 2): 505.
- Lv Q et al. The status of rheumatoid factor and anti-cyclic citrullinated peptide antibody are not associated with the effect of anti-TNFα agent treatment in patients with rheumatoid arthritis: a meta-analysis. PLoS One 2014; 9: e89442.
- Pers YM et al. Predictors of response and remission in a large cohort of rheumatoid arthritis patients treated with tocilizumab in clinical practice. Rheumatology (Oxford) 2014; 53: 76-84.
- Gabay C et al. Effectiveness of tocilizumab with and without synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a European collaborative study. Ann Rheum Dis 2016; 75: 1336-42.
- Isaacs JD et al. Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis. Ann Rheum Dis 2013; 72: 329-36.
- Gottenberg JE et al. Brief report: Association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: Results from the Pan-European Registry Analysis. Arthritis Rheumatol 2016; 68: 1346-52.
- Huizinga TWJ et al. Effect of anti-cyclic citrullinated peptide 2 immunoglobulin M serostatus on efficacy outcomes following treatment with abatacept plus methotrexate in the AVERT trial. Ann Rheum Dis 2015; 74 (Suppl 2): 234.
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