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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 (a) healthy controls versus patients with periodontitis. Using the 95th percentile of the healthy controls as a cut-off (dashed line), 48 % of patients were positive (p < 0.0001); (b) healthy and periodontitis subjects that are PCR negative for P.gingivalis in dental plaque compared to PCR positive periodontitis patients. In the latter group, 75 % were antibody positive (p < 0.0001). Solid lines represent medians
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Fig1: Antibodies to RgpB in (a) healthy controls versus patients with periodontitis. Using the 95th percentile of the healthy controls as a cut-off (dashed line), 48 % of patients were positive (p < 0.0001); (b) healthy and periodontitis subjects that are PCR negative for P.gingivalis in dental plaque compared to PCR positive periodontitis patients. In the latter group, 75 % were antibody positive (p < 0.0001). Solid lines represent medians

Mentions: We have previously found anti-RgpB antibody levels to be elevated in subjects with periodontitis [10]. The utility of anti-RgpB antibodies as a marker of infection with P.gingivalis, was further tested in a separate cohort of 30 healthy and 39 patients with periodontitis. Using the 95th percentile of the healthy, periodontitis-free controls as a cut-off, 49 % of patients with periodontitis were antibody positive (Fig. 1a). Patients with periodontitis were then divided into two groups based upon the identification of P.gingivalis 16S rRNA in subgingival plaque by PCR. Median antibody levels were higher in the PCR-positive patients and, using a higher cut-off based on the 95th percentile of PCR negative patients and controls, 75 % of PCR positive periodontitis patients were also antibody positive compared to 9 % of PCR negative patients (Fig. 1b). This data supports the use of anti-RgpB antibodies as a marker of infection with P.gingivalis.Fig. 1


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 (a) healthy controls versus patients with periodontitis. Using the 95th percentile of the healthy controls as a cut-off (dashed line), 48 % of patients were positive (p < 0.0001); (b) healthy and periodontitis subjects that are PCR negative for P.gingivalis in dental plaque compared to PCR positive periodontitis patients. In the latter group, 75 % were antibody positive (p < 0.0001). Solid lines represent medians
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Antibodies to RgpB in (a) healthy controls versus patients with periodontitis. Using the 95th percentile of the healthy controls as a cut-off (dashed line), 48 % of patients were positive (p < 0.0001); (b) healthy and periodontitis subjects that are PCR negative for P.gingivalis in dental plaque compared to PCR positive periodontitis patients. In the latter group, 75 % were antibody positive (p < 0.0001). Solid lines represent medians
Mentions: We have previously found anti-RgpB antibody levels to be elevated in subjects with periodontitis [10]. The utility of anti-RgpB antibodies as a marker of infection with P.gingivalis, was further tested in a separate cohort of 30 healthy and 39 patients with periodontitis. Using the 95th percentile of the healthy, periodontitis-free controls as a cut-off, 49 % of patients with periodontitis were antibody positive (Fig. 1a). Patients with periodontitis were then divided into two groups based upon the identification of P.gingivalis 16S rRNA in subgingival plaque by PCR. Median antibody levels were higher in the PCR-positive patients and, using a higher cut-off based on the 95th percentile of PCR negative patients and controls, 75 % of PCR positive periodontitis patients were also antibody positive compared to 9 % of PCR negative patients (Fig. 1b). This data supports the use of anti-RgpB antibodies as a marker of infection with P.gingivalis.Fig. 1

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