Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenisis
Session Type: Abstract Submissions (ACR)
The presence of antibodies against cyclic citrullinated peptides (ACPA) has been demonstrated to precede the development of rheumatoid arthritis (RA) by several years. The gene-environment interaction for these antibodies has not been elucidated.
The aim was to analyse for the development of reactivity against citrullinated peptides during the pre-disease phase of RA and after disease onset in relation to genetic and environmental factors.
Methods: This study comprised 406 individuals, providing 717 samples, who were identified before onset of symptoms of RA (median (IQR) 7.4 (9.3) years), as donors to the Medical Biobank of Northern Sweden. Among these, 204 were also sampled at the time of diagnosis. Population controls (1305) were identified from the Medical Biobank. Analysis of antibodies against 10 different citrullinated peptides; fibrinogen (Fib) ß36‑52, Fib α72, Fib α74, Fib α573, Fib α591, α-enolase (CEP-1), collagen citC1, filaggrin, vimentin (Vim) 2-17, and Vim 60-75 was performed using a microarray system developed in collaboration with Phadia AB/Thermofisher, Uppsala, based on their ISAC platform. All samples were also analysed for anti-CCP2 antibodies by ELISA (Euro-Diagnostica). HLA-DRB1 alleles were genotyped using polymerase chain reaction sequence-specific primers. Genotyping of the PTPN22 1858C/T polymorphism was performed using a Taqman instrument.
The frequency of antibodies against Fibß36-52, CEP-1, and filaggrin and anti-CCP2 increased significantly during the pre-dating time with the highest frequency of all antibodies before onset of symptoms. The number of positive antibodies against citrullinated peptides increased the closer to onset of symptoms and was significantly higher in individuals carrying HLA-SE or T-variant compared with those without. Individually antibodies against Fibß36-52, CEP-1, and filaggrin were in combination with HLA-SE, PTPN22 T variant and smoking associated with the development of RA, even stronger than for anti-CCP2 antibodies. Development of antibodies against the various citrullinated peptides after disease onset in individuals who were negative for these antibodies prior to onset of symptoms was associated with the presence of HLA-SE and smoking e.g. antibodies against Fib ß36-52, CEP-1, Fib α74, and Vim 60-75 were significantly associated with HLA-SE. Positivity for antibodies against Fib β36-52, CEP-1, Vim 60-75, collagen citC1, Fib α591, and Fib α573 was all significantly associated with smoking.
These results indicate that the development of an ACPA immune response is restricted to individuals carrying HLA-SE or the PTPN22 1858T variant, is strengthened by smoking and conversion to positivity for several of the antibodies is associated with the presence of HLA-SE and/or smoking
P. J. Jakobsson,
S. M. Rantapaa-Dahlqvist,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interaction-of-antibodies-against-citrullinated-peptides-with-hla-shared-epitope-ptpn22-1858t-variant-and-smoking-in-individuals-prior-to-and-after-the-development-of-rheumatoid-arthritis/