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

Abstract

BackgroundAntibodies 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.MethodsWe 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.ResultsWe 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.ConclusionsSmoking 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.

High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case–control study

“…These pre-RA cases were matched with controls among subjects enrolled in four EPIC cohorts: Naples, Turin and Ragusa in Italy, and Murcia in Spain. Potential RA cases were identified as previously described 24. In brief, in Murcia, RA cases were identified by linkage with primary healthcare records (International Classification of Primary Care code L88) and prescriptions of disease-modifying antirheumatic drugs, and linkage using the International Classification of Diseases (ICD) codes with hospital discharge (ICD9: 714) and mortality databases (ICD10: M05 and M06).…”

“…Identification of all RA cases was undertaken in 2011. All cases were then subsequently validated by medical record review to confirm a physician diagnosis of RA and to confirm date of diagnosis, as previously described 24. Subjects with prevalent RA at the time of the blood sample were excluded from the analyses.…”

Elevated BMI and antibodies to citrullinated proteins interact to increase rheumatoid arthritis risk and shorten time to diagnosis: A nested case–control study of women in the Nursesʼ Health Studies

“…Our analyses then included ACPA as a binary variable, <2 ACPA subtypes present vs. ≥2 subtypes present, to permit us to investigate an interaction between elevated BMI and presence of ACPA on RA risk. We chose ≥2 ACPA subtypes to define positivity since the prevalence of ACPAs in controls using this cutoff was similar to the 1-2% prevalence of ACPA observed in healthy subjects in other population-based studies [42, 43]. …”

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

“…У людей с генетическим рис-ком развития РА обнаружение антител к P. gingivalis в сы-воротке ассоциируется с гиперпродукцией АЦБ и РФ [147,148]. При РА обнаружен феномен аутоцитруллинирования ПАД P. gingivalis, ведущий к образованию антител к ПАД [149], который, однако, не характерен для «преклиниче-ской» фазы РА [150]. В то же время данные эпидемиологи-ческих исследований не подтверждают связь между пе-риодонтитом и РА [151], хотя антитела, специфичные к P. gingivalis, обнаруживаются в сыворотках АЦБ-пози-тивных пациентов с РА [152].…”