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Correspondence

The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Antibodies against uncitrullinated peptides seem to occur prior to the antibodies to the corresponding citrullinated peptides 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

Table 1 Number of positive samples including the mean (SD) time and median (IQR) time when the antibodies against citrullinated and corresponding uncitrullinated (arginine) peptides were first detected positive in 717 samples from 374 presymptomatic individuals Citrullinated

Arginine

Antibody

n

Mean (SD) Median (IQR) Years Years n

CEP-1 CCP1 Fibß36-52 Fiba573 Fiba591 Fibß74 Fibß72 Vim60-75 Vim2-17

81 55 44 17 14 38 21 23 21

5.1 (4.7) 7.2 (6.5) 6.2 (5.2) 4.4 (4.3) 7.8 (6.0) 7.7 (6.6) 6.8 (6.2) 7.1 (5.6) 4.5 (3.9)

3.7 4.8 5.1 2.8 7.7 7.2 6.0 4.8 3.2

(6.3) (9.3) (10.1) (6.2) (8.3) (7.8) (8.6) (7.3) (6.1)

Mean (SD) Median (IQR) Years Years

9 11.6 (8.9) 22 12.0 (8.2) 12 9.7 (3.5) 6 7.3 (4.3) 12 8.6 (6.4) 13 7.3 (6.9) 13 7.3 (6.9) 40 7.5 (4.3) 15 10.0 (7.5)

8.7 11.1 10.5 8.1 8.3 6.5 6.5 8.5 9.3

(15.7)*† (12.3)*† (5.1)*† (8.4) (9.6) (8.3) (8.3) (7.3) (9.3)**†

The cut-off for positivity was 98% for all antibodies. †Comparisons of the pre-dating time (Mann-Whitney U test), *p