METHODS: We explored a collection of 4,392 well-characterized incident patients with RA of White European descent from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) new-onset RA study, as well as 1,199 cases of patients with RA of Southeast Asian origin from the Malaysian EIRA study. We focused on a quantitative analysis of the levels of anti-cyclic citrullinated peptide IgG antibodies, including those falling below the diagnostic threshold.
RESULTS: Our data show that non-shared epitope alleles HLA-DRB1*09 and *15 exhibit significant associations with ACPA levels. Notably, these novel associations were independent of ethnicity. To validate our findings, we conducted an additional replication study in an independent pool of 4,109 patients with RA of White European origin.
CONCLUSION: These results indicate a new, previously overlooked, role for the HLA locus in the regulation of the levels of ACPA RA-specific autoantibodies that goes beyond the shared epitope-defined gene variants.
METHODS: Flare was defined using the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI flare index), and PAD was defined as an SLEDAI-2K score of ≥4, excluding serology only, on two or more consecutive visits with a maximum six-month interval. Multivariable logistic regression was used to develop predictive models for flare and PAD, which were tested in an independent validation subset.
RESULTS: Among 3,811 patients over 2.8 (interquartile range 1.0-5.3) years of follow-up, 2,142 (56.2%) experienced flare and 1,786 (46.9%) had PAD, with 368 (9.7%) experiencing PAD but not flare. The most common flare features were nephritis and arthritis, whereas PAD was most commonly characterized by renal or mucocutaneous activity. After adjusting for prednisone dose and use of antimalarials and immunosuppressants, low gross domestic product in country of residence, smoking, arthritis, nephritis, and low complement levels were predictive for flare, whereas being in a low disease activity state for ≥50% of follow-up time (LLDAS50) was a protective factor. Renal activity and higher time-adjusted mean SLEDAI-2K were predictive of PAD, whereas LLDAS50 was protective. The models developed gave 72.1% and 83.8% correct classification of flare and PAD, respectively, in the validation cohort.
CONCLUSION: Both flare and PAD are common disease activity patterns in SLE; both predict organ damage accrual but differ in disease features and predictive factors. Because 9.7% of patients experience PAD but not flare, flare measures alone do not adequately capture all patients in whom disease control is suboptimal.