Abstract
IntroductionIt has previously been shown that an increased number of antibodies against citrullinated peptides/proteins (ACPA) predate the onset of rheumatoid arthritis (RA). Over time antibody positivity expands, involving more specific responses when approaching the onset of symptoms. We investigated the impact of human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking on the development of ACPA, as well as in combination with ACPA during the state of quiescent autoimmunity (before the onset of symptoms), on the development of RA.MethodsBlood samples donated to the Medical Biobank of Northern Sweden from individuals prior to the onset of symptoms of RA (n = 370) and after onset (n = 203) and from population-based controls (n = 585) were used. Antibodies against 10 citrullinated peptides, fibrinogen (Fibα561-583, α580-600, ß62-81a, ß62-81b, ß36-52), vimentin (Vim2-17, 60-75), filaggrin (CCP-1/Fil307-324), α-enolase (CEP-1/Eno5-21), collagen type II (citC1359-369), and anti-cyclic citrullinated peptide (CCP)2 antibodies were analysed.ResultsHLA-SE-positive individuals were more frequently positive for ACPA compared with HLA-SE-negative individuals prior to the onset of symptoms of RA, particularly for antibodies against CEP-1 and Fibß62-81a (72). Smoking was associated with antibodies against Vim2-17 and citC1359-369. HLA-SE and smoking showed increasing association to the presence of the antibodies closer to disease onset. The highest odds ratio (OR) for development of RA was for the combination of HLA-SE alleles and ACPA positivity, especially for antibodies against Fibß62-81b, CCP-1/Fil307-324, and Fibβ36-52. A gene-environment additive interaction between smoking and HLA-SE alleles for the risk of disease development was found, with the highest OR for individuals positive for antibodies against Fibβ36-52, CEP-1, and Fibα580-600.ConclusionsThe relationships between antibodies against the different ACPA specificities, HLA-SE, and smoking showed a variable pattern in individuals prior to the onset of RA. The combination of smoking and HLA-SE alleles was significantly associated with the development of some of the antibody specificities closer to onset of symptoms, and these associations remained significant at diagnosis. An additive gene-environment interaction was found for several of the antibodies for the development of RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0638-x) contains supplementary material, which is available to authorized users.
Highlights
It has previously been shown that an increased number of antibodies against citrullinated peptides/ proteins (ACPA) predate the onset of rheumatoid arthritis (RA)
A study by Lundberg et al showed that human leukocyte antigen-shared epitope (HLA-shared epitope (SE)), protein tyrosine phosphatase non receptor type 22 (PTPN22) 1858T, and smoking were associated with specific anti-citrullinated protein antibodies (ACPA) reactivities, especially with antibodies against CEP-1 and citrullinated vimentin in patients with RA [9]
Impact of HLA-SE and smoking on the presence of different ACPA-fine specificities prior to the onset of symptoms and at diagnosis of rheumatoid arthritis The presence of HLA-SE predicted positivity of antibodies against Fibß62-81a (72) (OR = 2.52, 95% confidence intervals (CI): 1.13 to 5.61), and of CEP-1 (OR = 1.65, 95% CI: 1.003 to 2.73), including all pre-dating samples in the analyses
Summary
It has previously been shown that an increased number of antibodies against citrullinated peptides/ proteins (ACPA) predate the onset of rheumatoid arthritis (RA). We have shown that an increased number of ACPA antibody specificities predate the onset of RA [5] These ACPA antibody specificities were initially restricted and without any obvious epitope profile, but over time they expanded and involved more specific responses, especially antibodies against α-enolase (CEP-1/ Eno5-21), fibrinogen (Fib)β36-52, and filaggrin (CCP-1/ Fil307-324), when approaching the onset of symptoms [5]. A study by Lundberg et al showed that HLA-SE, PTPN22 1858T, and smoking were associated with specific ACPA reactivities, especially with antibodies against CEP-1 and citrullinated vimentin (anti-Vim 60-75) in patients with RA [9]. In a study on Spanish RA patients, those with anti-CEP-1 antibodies showed an interaction with PTPN22 1858T and HLA-SE whilst having anti-citvimentin antibodies was associated with the presence of two HLA-SE alleles [10]
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