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We have read the article by de Pablo et al1 with great interest. The authors reported higher frequencies of antibodies against the uncitrullinated form of fibrinogen and of the arginine containing α-enolase peptide-1 in patients with periodontitis compared with patients without periodontitis. As a consequence of their study the authors concluded that antibodies to uncitrullinated versions of rheumatoid arthritis (RA) associated autoantigens may occur before the development of anticitrullinated peptide/protein antibodies. This encouraged us to analyse the data for individuals identified in the Medical Biobank of Northern Sweden as having donated blood samples before the onset of the symptoms of RA with regard to the first time point when different autoantibody specificities were detectable.
The number of individuals identified and the procedure for excluding any sample have been described in detail.2 A study population of 386 presymptomatic individuals generated a total of 717 samples with a median time of 7.4 years (IQR 9.3 years) pre-dating the onset of symptoms. Samples were analysed for antibodies against nine different citrullinated and uncitrullinated antigens: fibrinogen (Fib) α573, Fibα591, Fibβ62-81a (72), Fibβ62-81b (74), Fibβ36-52, α-enolase (citrullinated α-enolase peptide (CEP)-1/Eno5-21), filaggrin (cyclic citrullinated peptide (CCP)-1/Fil307-324), vimentin (Vim) 2-17, and Vim60-75 using a microarray based ImmunoCAP ISAC system (Phadia Multiplexing Diagnostics GmbH, Vienna, Austria) as previously described by Brink et al.2 ,3 The cut-off values for all antibodies were chosen based on a specificity of 98%. The prevalence of human leucocyte antigen (HLA)-shared epitope was 64.5% and 66.5% of individuals were or had been smokers.
Numbers of patients who would eventually develop RA, positive for antibodies against citrullinated peptides varied between 20.9% for anti-CEP-1 to 3.7% for anti-Fibα591, while numbers positive for antibodies against uncitrullinated (arginine) peptides was between 10.7% for anti-Vim60-75 and 1.3% for anti-Fibα573. The frequency of ever being positive of anti-CEP-1, anti-CCP1, anti-Fibß36-52, anti-Fibα573 and anti-Fibß74 antibodies was significantly increased compared with their arginine counterparts, which was much lower except for anti-Vim 60-75 (figure 1). Considering the time point when these antibodies were first detectable before the onset of symptoms it was apparent that all uncitrullinated (arginine) antibodies except for antibodies against Fibß74 pre-dated the corresponding antibodies against citrullinated peptides. Antibodies against arginine peptides (CEP-1, CCP1, Fibß36-52 and Vim2-17) were detected significantly earlier compared with the corresponding antibodies against citrullinated peptides, (table 1). The antibodies against uncitrullinated peptides were evenly distributed throughout the pre-dating period, while antibodies to the citrullinated peptides appeared closer to the onset of symptoms.
There were also significant relationships between being seropositive for three or more antibodies against citrullinated peptides and presence of HLA-shared epitope (χ2=6.75, p=0.009) and being ever-smoker (χ2=4.45, p=0.35). No corresponding relationships were found for antibodies against the non-citrullinated peptides.
Taken together, the results from our study, albeit with a limited number of positive samples, support the concept suggested by de Pablo et al,1 and encourage further analyses.
Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. SRD had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: MB, SRD. Acquisition of data: MB, MH, SRD. Analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, final approval of the version published: MB, MH, JR, LK, SRD.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; internally peer reviewed.