IntroductionWe evaluated the presence of Porphyromonas gingivalis (Pg) DNA in the synovial tissue through synovial biopsy and in other compartments of rheumatoid arthritis (RA) patients in comparison with patients affected by other arthritides. Possible links with clinical, immunologic and genetic features were assessed.MethodsPeripheral blood (PB), sub-gingival dental plaque, synovial fluid (SF) and synovial tissue samples were collected from 69 patients with active knee arthritis (32 with RA and 37 with other arthritides, of which 14 had undifferentiated peripheral inflammatory arthritis - UPIA). Demographic, clinical, laboratory and immunological data were recorded. The presence of Pg DNA was evaluated through PCR. The HLA-DR haplotype was assessed for 45 patients with RA and UPIA.ResultsNo differences arose in the positivity for Pg DNA in the sub-gingival plaque, PB and SF samples between RA and the cohort of other arthritides. Full PB samples showed a higher positivity for Pg DNA than plasma samples (11.8% vs. 1.5%, P = 0.04). Patients with RA showed a higher positivity for Pg DNA in the synovial tissue compared to controls (33.3% vs. 5.9%, P <0.01). UPIA and RA patients carrying the HLA DRB1*04 allele showed a higher positivity for Pg DNA in the synovial tissue compared to patients negative for the allele (57.1% vs. 16.7%, P = 0.04). RA patients positive for Pg DNA in the sub-gingival plaque had a lower disease duration and a higher peripheral blood leucocyte and neutrophil count. The presence of Pg DNA did not influence disease activity, disease disability or positivity for autoantibodies.ConclusionsThe presence of Pg DNA in the synovial tissue of RA patients suggests a pathogenic role of the bacterium. The higher positivity of Pg DNA in full peripheral blood and synovial tissue samples compared to plasma and synovial fluid suggests a possible intracellular localization of Pg, in particular in patients positive for HLA-DR4.

ObjectiveThe PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data.MethodsA total of 396 RA cases and 477 controls, all of Italic ancestry, were genotyped for PTPN22 rs2476601 polymorphism. Patients were tested for autoantibodies positivity. The meta-analysis was performed on 23 selected studies.ResultsThe PTPN22 T1858 allele was significantly more frequent in RA patients compared to controls (5.7% vs. 3.7%, p = 0.045). No clear relationship arose with the autoantibodies tested. The 1858T allele frequency in Italian RA patients was lower than the one described in northern European populations and similar to the frequency found in Spain, Turkey, Greece, Tunisia. A clear-cut North-South gradient arose from the analysis.ConclusionsThe PTPN22 T1858 allele is associated with RA in the Italian population. A North-South gradient of the allele frequency seems to exist in Europe, with a lower prevalence of the mutation in the Mediterranean area.

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The presence of allele*2 seems to be related to a good response to BCDT with RTX in seropositive RA patients, thus highlighting the role of the HS1,2A enhancer in B cell maturation and class-switch recombination.

Background A tight control strategy is necessary for an optimal management of early rheumatoid arthritis (ERA). However, it is not sufficient because there is a huge need of biomarkers in order to predict drug responsiveness and improve assessment of both disease activity and structural damage. Objectives To identify possible biomarkers predictors of response to Methotrexate (MTX) treatment in a cohort of ERA treated according to a tight control protocol. Methods A total of 286 consecutive patients with ERA were enrolled in the study. All patients were treated with MTX for three months, then with a combination with Tumor Necrosis Factor (TNF) blockers if they had an incomplete response after 3-month treatment period. At baseline and every 3 months demographic and immunological data and the ACR/EULAR core data set [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), swollen joint count (SJC), tender joint count (TJC), physician and patient global assessment, pain, health assessment questionnaire (HAQ)] were recorded. Moreover, DNA from all patients was genotyped for the PTPN22 1858C>T by polymerase chain restriction fragment length polymorphism method. The EULAR response criteria were used as the primary outcome measure at 3- and 6-month follow-up visits. The likelihoods of achieving a good EULAR response (defined as a disease activity score (DAS) <2.4 and a fall in this score from baseline by >1.2) at the third month and a sustained remission at the sixth month follow-up visits (defined as a DAS value of <1.6 for at least two consecutive visits 3 months apart) were evaluated using univariate and multivariate logistic regression and the results were expressed as ORs with 95% CI. Results 45.7% of the patients reached a good EULAR response at the third month and 21.8% reached a sustained remission at the sixth month of follow-up. A lower percentage of ERA patients carrying the PTPN22 1858 CT/TT genotype reached a good EULAR response to MTX treatment after 3 month follow-up (22.6%) and a sustained remission at the sixth month of follow-up (6.7%) compared to subjects with the CC genotype (good EULAR response at the third month: 49.1% (OR 0.30, 95%CI 0.13-0.73); sustained remission at the sixth month 24.1% (OR 0.23, 95%CI 0.05-0.98)). The influence of each baseline parameter (demographic, genetic and immunological) on the likelihood of reaching a good EULAR response was evaluated and the PTPN22 CT/TT genotype arose as a significant predictor of good response to MTX at the third month (OR 0.30, 95%CI 0.13-0.75). When considering the sustained remission at the sixth month, the PTPN22 CT/TT genotype again proved as a “negative” predictor of this target (OR 0.19, 95%CI 0.04-0.86), together with female sex (OR 0.47, 95%CI 0.23-0.96) and “having at onset an ESR>30 mm/h” (OR 0.28, 95%CI 0.14-0.55). Conclusions The PTPN22 CT/TT genotype predicts a worse response to MTX therapy at the third month of follow-up and a lower likelihood of reaching sustained remission at the sixth month, together with female sex and h...

Objectives To evaluate the relationship between the response to therapy in early rheumatoid arthritis (ERA) and polymorphisms in the genes of molecules involved in inflammatory processes (TNF-α, TNF-RII, IL6, IL1b, IL1Ra, BAFF) or in the homeostasis of T and B cells (PTPN22, HS1,2 enhancer). Methods Two hundreds and eighty six ERA patients were enrolled in the study (females: 75.2%; mean age: 55.1±13.6 years; anti-CCP positive patients: 63.3%; IgA RF positive patients: 34.5%; IgM RF positive patients: 51.0%). All patients were treated with Methotrexate for three months, then with a combination with Tumor Necrosis Factor (TNF) blockers if they had an incomplete response after 3-month treatment period. DNA from patients was genotyped for the TNF-α (-308G>A and -238G>A), TNF-RII +196T>G, IL6 -174G>C, IL1b (-511C>T and +3953C>T), IL1Ra VNTR, BAFF -871C>T, PTPN22 +1858C>T, HS1,2A polymorphisms by polymerase chain reaction restriction fragment length polymorphism method. Clinical and laboratory data were recorded at baseline and every 3 months. The EULAR response criteria based on DAS were used to assess the disease activity after 3 and 6 months of follow-up (good response: DAS <2.4 and a fall in this score from baseline by >1.2; sustained remission: DAS value of <1.6 for at least two consecutive visits 3 months apart). Exact Hardy Weinberg Equilibrium (HWE) tests were performed for each polymorphism independently. Generalized multifactor dimensionality reduction (MDR) was used to verify interaction results. Models were evaluated on the testing balanced accuracy statistic (TBA), the cross-validation consistency (CVC) and the statistical significance of the model. Results All the polymorphisms were in Hardy-Weinberg equilibrium. According to the multi-locus GMDR approach, TNF-308G>A, TNFRII+196T>G, IL1RA VNTR, IL1b-511, IL1b+3956, IL6-174G>C and BAFF-871C>T polymorphisms predicted the EULAR good response at 3 months correctly 60.9% of the time (Sign Test p=0.001). The EULAR sustained remission at 6 months was predicted 55.9% of the time by an ensemble of 5 polymorphisms (TNF-α-308, TNF-RII+196, IL1Ra VNTR, IL1β+3953, BAFF-871; Sign Test p=0.055). Conclusions The genetic background is a possible predictor of the response to therapy of patients with early rheumatoid arthritis. The analysis of gene-gene interactions, especially in genes of molecules related to the major inflammatory cytokines, will lead to a better understanding of the biological pathways underlying the therapeutic outcome in the earliest phases of the disease. Disclosure of Interest None Declared