Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis.

Background/Purpose: In rheumatoid arthritis (RA) autoantibodies including antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF) can be predictive of incident clinical RA. However, there is limited understanding of how antibody changes over time impact prediction of the likelihood and timing of future clinical RA. Materials and Methods: We evaluated relationships between ACPA, the shared epitope (SE), RF isotypes and incident RA in a prospective cohort of 90 ACPA(+) individuals without baseline arthritis identified through health-fair testing (i.e. Healthfair). We also evaluated ACPA and RF isotypes and time-to-diagnosis of RA in a retrospective cohort of 215 individuals with RA from the Department of Defense Serum Repository (DoDSR). Results: Twenty-six of 90 (29%) of ACPA(+) Healthfair participants developed incident RA. Baseline or incident dual RF-IgA and RF-IgM positivity was associated with increased risk for incident RA (HR 3.09; 95% CI 1.15 to 8.29) although RFs were negative in ~50% of individuals with incident RA. SE was associated with increased risk of RA (HR 2.87, 95% CI 1.22-6.76). In the DoDSR cohort, triple positivity for ACPA, RF-IgA and RF-IgM was present a median of 1-2 years prior to RA diagnosis, with some sex-specific differences. Conclusion: These findings can be used to counsel individuals at-risk for future RA and to design clinical trials for RA prevention. The findings also suggest that RF could be a surrogate outcome as a success of an immunologic intervention in RA prevention. Additional studies are needed to understand the biologic of different patterns of autoantibody elevations in RA evolution.

Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity.

BACKGROUND: Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. METHODS: Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. RESULTS: Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined "seronegative" RA, associated with worse clinical outcome. CONCLUSIONS: "Seronegative" RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2-/IgM RF- patients with a high need for active treatment.

Biomarcadores genéticos de los sistemas MHC/HLA-DRB1* y PTPN22 asociados a enfermedad reumática: artritis idiopática juvenil y artritis reumatoide de instalación temprana. Un enfoque analítico en un estudio piloto / Genetics Biomarckers off the MHC/HLA-DRB1* and PTPN 22 Systems Associated to Rheumatics diseases: idiopatic juvenile arthritis and rheumatoid of early installation. A descriptive approach in a pilot study

Objetivos: Identificar biomarcadores de susceptibilidad para AIJ poliarticular y AR de instalación temprana por estudio del polimorfismos de MHC/HLA-DRB1* y PTPN22. Materiales y métodos: Se realizó un estudio de casos y controles con una relación 1:2. Todos los sujetos de investigación y los controles provinieron de una corta anidada perteneciente a un proyecto institucional; 30 pacientes con AIJ y 30 con AR de instalación temprana. Como controles se estudiaron 60 individuos sanos. El ADN se obtuvo por salting out modificado. La tipificación de los alelos MHC/DRB1* se realizó por PCR-SSP y en el polimorfismo (C1858T) del sistema PTPN22 se utilizó PCR-RTq. Resultados: Para AIJ Poliarticular, el alelo DRB1*0404 se asoció con susceptibilidad (OR=10.82; p<0.05), en el grupo con AR de instalación temprana, DRB1*0101 se mostró como marcador de susceptibilidad (OR=4.04; p<0.05). Se destaca que el alelo HLA-DRB1*0701 aparece como marcador protector para ambas patologías (OR=0,15; p<0,05). El polimorfismo del SNP (C1858T) PTPN22 no se asoció con AIJ Poliarticular. En contraste, en AR de instalación temprana, el Alelo CC se asoció con protección p<0.05. En el mismo grupo, CT/TT se mostró como un marcador de susceptibilidad <0.05. El análisis de la secuencia aminoacídica 70QRRAA74 del epítope compartido se asoció con susceptibilidad para ambas entidades (p<0.05) y la secuencia 70DRRGQ74 con protección en ambos grupos de pacientes (p<0.05). Conclusión: Se destaca que en la asociación con la secuencia del epítope compartido, la ubicación del tipo de aminoácido y posición del mismo define probable asociación como marcador molecular de susceptibilidad en ambas entidades. Los polimorfismos compartidos sugieren un origen genético común para ambas entidades.

Objectives: To identify polymorphisms of MHCIHLA-DRB1* and PTPN22 systems as a genetic biomarker of susceptibility to JIA poliarticular and early installation RA. Material and methods; This was a pilot case control study with a relation of 1:2. Patients and control individuals involved in this study were selected from a nested cohort from an institutional previous RAIJIA project. The sample was represented by thirty patients with JIA and 30 diagnosed with early installation RA. Sixty unrelated healthy individuals were involved as a control DNA Isolation was obtained by a modified salting out technique. The oligotyping of the MHCIDRB1* alleles was performed by PCR-SSP and the typing of the PTPN22 polymorphism was done by RT-PCR. Results: The DRB1*0404 allele was associated with susceptibility to JIA(OR=10.82, P<0.05). In the early installation RA group the DRB1*0101 allele was showed as a marker of susceptibility to JIA patients (OR=4.04, P<0.05). It is noteworthy that the HLA-DRB1*0701 appears as a possible protective marker for both diseases (OR=015, p<0.05). The polymorphism of (C1858T)PTPN22 was not associated with poliarticular JIA. In contrast, in the early installation RA group of patients, the CC PTPN22 polymorphism was found to be as a protective marker (p<0.05). On the other hand, the amino acid sequence 70QRRAA74 of the share epitope was a marker for susceptibility to both entities (p<0.05) By contrast, the sequence 70DRRGQ74 of the same epitope was showed as a possible marker for protection on both entities (p<0.05.). Conclusion: The model that was used for searching association between the shared epitope -region 70-74 of the DRB1* alleles and these two entities showed the importance of the location and also the type of amino acid in those positions. The polymorphisms found as molecular markers of susceptibility for both entities suggested a common origin and could suggest its probable roll as a molecular marker of susceptibility.