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Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens before the clinical onset of rheumatoid arthritis in a Southern European nested case-control study.

Fisher BA, Cartwright AJ, Quirke AM, de Pablo P, Romaguera D, Panico S, Mattiello A, Gavrila D, Navarro C, Sacerdote C, Vineis P, Tumino R, Lappin DF, Apazidou D, Culshaw S, Potempa J, Michaud DS, Riboli E, Venables PJ - BMC Musculoskelet Disord (2015)

Bottom Line: RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides.Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity.In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. b.fisher@bham.ac.uk.

ABSTRACT

Background: Antibodies to citrullinated proteins (ACPA) occur years before RA diagnosis. Porphyromonas gingivalis expresses its own peptidylarginine deiminase (PPAD), and is a proposed aetiological factor for the ACPA response. Smoking is a risk factor for both ACPA-positive RA and periodontitis. We aimed to study the relation of these factors to the risk of RA in a prospective cohort.

Methods: We performed a nested case-control study by identifying pre-RA cases in four populations from the European Prospective Investigation into Cancer and nutrition, matched with three controls. Data on smoking and other covariates were obtained from baseline questionnaires. Antibodies to CCP2 and citrullinated peptides from α-enolase, fibrinogen, vimentin and PPAD were measured. Antibodies to arginine gingipain (RgpB) were used as a marker for P.gingivalis infection and validated in a separate cohort of healthy controls and subjects with periodontitis.

Results: We studied 103 pre-RA cases. RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides. Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity. Former but not current smoking was associated with antibodies to α-enolase (OR 4.06; 95 % CI 1.02, 16.2 versus 0.54; 0.09-3.73) and fibrinogen peptides (OR 4.24; 95 % CI 1.2-14.96 versus 0.58; 0.13-2.70), and later development of RA (OR 2.48; 95 % CI 1.27-4.84 versus 1.57; 0.85-2.93), independent of smoking intensity.

Conclusions: Smoking remains a risk factor for RA well before the clinical onset of disease. In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset. Antibodies to PPAD peptides are not an early feature of ACPA ontogeny.

No MeSH data available.


Related in: MedlinePlus

Antibodies to RgpB in pre-RA subjects versus matched controls according to smoking status defined as never, former or current. * p < 0.05; *** I < 0.001; **** p < 0.0001
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Fig2: Antibodies to RgpB in pre-RA subjects versus matched controls according to smoking status defined as never, former or current. * p < 0.05; *** I < 0.001; **** p < 0.0001

Mentions: Table 4 also shows the relationship between smoking and ACPA positivity amongst the pre-RA cases. Interestingly, a positive association was only observed between former smoking and ACPA. This was confirmed by logistic regression models adjusted for age and sex with statistical significance for anti-CEP-1 and anti-cFib antibodies (data available upon request). Former pre-RA smokers were four times more likely to have anti-CEP-1 (OR 4.06, 95 % CI 1.02, 16.2) and anti-cFib (4.24; 95 % CI 1.2-14.96) antibodies than never pre-RA smokers. In comparison, no association was seen with current smoking [OR 0.54 (CI 0.09-3.73) for anti-CEP-1 and 0.58 (0.13-2.70) for anti-cFib). Interestingly, median antibody levels to both CPP5 and its control peptide, were higher in pre-RA cases who were ever smokers compared to never smokers (CPP5: 47 vs 31 u/ml; p = 0.04. RPP5: 42 vs 29 u/ml; p = 0.01). In the control group, anti-RgpB levels were highest in current smokers, intermediate in former smokers and lowest in never smokers. In the pre-RA group, antibody levels were highest in the former smoker group (Fig. 2).Fig. 2


Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens before the clinical onset of rheumatoid arthritis in a Southern European nested case-control study.

Fisher BA, Cartwright AJ, Quirke AM, de Pablo P, Romaguera D, Panico S, Mattiello A, Gavrila D, Navarro C, Sacerdote C, Vineis P, Tumino R, Lappin DF, Apazidou D, Culshaw S, Potempa J, Michaud DS, Riboli E, Venables PJ - BMC Musculoskelet Disord (2015)

Antibodies to RgpB in pre-RA subjects versus matched controls according to smoking status defined as never, former or current. * p < 0.05; *** I < 0.001; **** p < 0.0001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4634856&req=5

Fig2: Antibodies to RgpB in pre-RA subjects versus matched controls according to smoking status defined as never, former or current. * p < 0.05; *** I < 0.001; **** p < 0.0001
Mentions: Table 4 also shows the relationship between smoking and ACPA positivity amongst the pre-RA cases. Interestingly, a positive association was only observed between former smoking and ACPA. This was confirmed by logistic regression models adjusted for age and sex with statistical significance for anti-CEP-1 and anti-cFib antibodies (data available upon request). Former pre-RA smokers were four times more likely to have anti-CEP-1 (OR 4.06, 95 % CI 1.02, 16.2) and anti-cFib (4.24; 95 % CI 1.2-14.96) antibodies than never pre-RA smokers. In comparison, no association was seen with current smoking [OR 0.54 (CI 0.09-3.73) for anti-CEP-1 and 0.58 (0.13-2.70) for anti-cFib). Interestingly, median antibody levels to both CPP5 and its control peptide, were higher in pre-RA cases who were ever smokers compared to never smokers (CPP5: 47 vs 31 u/ml; p = 0.04. RPP5: 42 vs 29 u/ml; p = 0.01). In the control group, anti-RgpB levels were highest in current smokers, intermediate in former smokers and lowest in never smokers. In the pre-RA group, antibody levels were highest in the former smoker group (Fig. 2).Fig. 2

Bottom Line: RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides.Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity.In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. b.fisher@bham.ac.uk.

ABSTRACT

Background: Antibodies to citrullinated proteins (ACPA) occur years before RA diagnosis. Porphyromonas gingivalis expresses its own peptidylarginine deiminase (PPAD), and is a proposed aetiological factor for the ACPA response. Smoking is a risk factor for both ACPA-positive RA and periodontitis. We aimed to study the relation of these factors to the risk of RA in a prospective cohort.

Methods: We performed a nested case-control study by identifying pre-RA cases in four populations from the European Prospective Investigation into Cancer and nutrition, matched with three controls. Data on smoking and other covariates were obtained from baseline questionnaires. Antibodies to CCP2 and citrullinated peptides from α-enolase, fibrinogen, vimentin and PPAD were measured. Antibodies to arginine gingipain (RgpB) were used as a marker for P.gingivalis infection and validated in a separate cohort of healthy controls and subjects with periodontitis.

Results: We studied 103 pre-RA cases. RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides. Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity. Former but not current smoking was associated with antibodies to α-enolase (OR 4.06; 95 % CI 1.02, 16.2 versus 0.54; 0.09-3.73) and fibrinogen peptides (OR 4.24; 95 % CI 1.2-14.96 versus 0.58; 0.13-2.70), and later development of RA (OR 2.48; 95 % CI 1.27-4.84 versus 1.57; 0.85-2.93), independent of smoking intensity.

Conclusions: Smoking remains a risk factor for RA well before the clinical onset of disease. In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset. Antibodies to PPAD peptides are not an early feature of ACPA ontogeny.

No MeSH data available.


Related in: MedlinePlus