HLA-shared Epitope Research Articles

Identification of early risk factors for anti-citrullinated-protein-antibody positive rheumatoid arthritis-a prospective cohort study.

Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression. Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥3 years or until clinical arthritis diagnosis. Blood samples from inclusion were analysed for nine ACPA reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model. Two hundred and sixty-seven individuals were included with median follow-up of 49 months (interquartile range [IQR]: 22-60); 101 (38%) developed arthritis after a median of 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (hazard ratio [HR] 8.0; 95% CI: 2.9, 22), ultrasound-detected tenosynovitis (HR 3.4; 95% CI: 2.0, 6.0), IL-6 levels (HR 1.5; 95% CI: 1.2, 1.8) and IL-15 receptor α (IL-15Rα) levels (HR 0.6; 95% CI: 0.4, 0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [s.e. 0.02], AUC 0.82 [95% CI: 0.76, 0.89], cross-validated AUC 0.70 [95% CI: 0.56, 0.85]). We propose a high RA risk phase characterized by presence of ACPA reactivity, tenosynovitis, IL-6 and IL-15Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression.

The Role of Genetics in Clinically Suspect Arthralgia and Rheumatoid Arthritis Development: A Large Cross-Sectional Study.

To investigate whether established genetic predictors for rheumatoid arthritis (RA) differentiate healthy controls, patients with clinically suspect arthralgia (CSA), and RA patients. Using analyses of variance, chi-square tests, and mean risk difference analyses, we investigated the association of an RA polygenic risk score (PRS) and HLA shared epitope (HLA-SE) with all participant groups, both unstratified and stratified for anti-citrullinated protein antibody (ACPA) status. We used 3 separate data sets sampled from the same Dutch population (1,015 healthy controls, 479 CSA patients, and 1,146 early classified RA patients). CSA patients were assessed for conversion to inflammatory arthritis over a period of 2 years, after which they were classified as either CSA converters (n=84) or CSA nonconverters (n=395). The PRS was increased in RA patients (mean ± SD PRS 1.31 ± 0.96) compared to the complete CSA group (1.07 ± 0.94) and compared to CSA converters (1.12 ± 0.94). In ACPA- strata, PRS distributions differed strongly when comparing the complete CSA group (mean ± SD PRS 1.05 ± 0.94) and CSA converters (0.97 ± 0.87) to RA patients (1.20 ± 0.94), while in the ACPA+ strata, the complete CSA group (1.25 ± 0.99) differed clearly from healthy controls (1.05 ± 0.94) and RA patients (1.41 ± 0.96). HLA-SE was more prevalent in the RA group (prevalence 0.64) than the complete CSA group (0.45), with small differences between RA patients and CSA converters (0.64 versus 0.60) and larger differences between CSA converters and CSA nonconverters (0.60 versus 0.42). HLA-SE prevalence differed more strongly within the ACPA+ strata as follows: healthy controls (prevalence 0.43), CSA nonconverters (0.48), complete CSA group (0.59), CSA converters (0.66), and RA patients (0.79). We observed that genetic predisposition increased across pre-RA participant groups. The RA PRS differed in early classified RA and inflammatory pre-disease stages, regardless of ACPA stratification. HLA-SE prevalence differed between arthritis patients, particularly ACPA+ patients, and healthy controls. Genetics seem to fulfill different etiologic roles.

Peripheral distributions of IL-4-producing CD4 + T cells and CD4 + CD25 + FoxP3 + T cells (Tregs) in rheumatoid arthritis patients with poor response to therapy are associated with HLA shared epitope alleles and ACPA status.

Specific profiling of CD4 + T cell subsets in the circulation and inflamed joints of rheumatoid arthritis (RA) patients may have therapeutic implications. This study aimed to evaluate the peripheral distributions of Th2 and Treg cells in relation to HLA-shared epitope (SE) alleles and anti-cyclic citrullinated peptide antibody (ACPAs) status in patients with good response (GR) and poor response (PR) to treatment. The frequencies of IL-4-producing CD4 + T cells (Th2) and CD4 + CD25 + Foxp3 + T cells (Tregs) were determined by flow cytometry in 167 RA patients including 114 GR and 53 PR cases. CD4 + T cell subsets were also analyzed based on HLA-SE and ACPAs statuses. One hundred nine of 167 patients were positives for HLA-SE, 63.4% for ACPAs, 43.7% for SE/ACPAs and 14.9% were negatives for SE/ACPAs. Higher frequencies of Th2 (P = 0.001) and Treg cells (P = 0.03) were found in the patients versus controls. Increased and decreased frequencies of Th2 and Tregs cells were observed in the PR versus GR patients respectively (P = 0.003 and P = 0.004). Higher proportions of Th2 cells were observed in the SE+RA versus SE-RA (P = 0.001), in ACPA+RA versus ACPA-RA (P = 0.005) and in the SE+ACPA+RA versus SE-ACPA-RA patients (P = 0.002). Treg cells frequencies decreased in the SE+RA versus SE-RA (P = 0.03) and in SE+ACPA+RA versus SE-ACPA-RA (P = 0.02). ACPA+GR and SE+PR patients showed higher proportions of Th2 cells than ACPA-GR and SE-PR patients respectively (P = 0.02 and P = 0.01). Analysis of the CD4 + T cell subsets profiles in conjunction with genetic background and autoantibodies patterns can be useful for precise therapeutic response monitoring in the RA patients.

Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis

ObjectivesThe human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert...

Circulating IFN-γ producing CD4+ T cells and IL-17A producing CD4+ T cells, HLA-shared epitope and ACPA may characterize the clinical response to therapy in rheumatoid arthritis patients

This study analyzed the association between peripheral distributions of helper T cell subsets, HLA shared-epitope (SE), anti-cyclic citrullinated peptide antibody (ACPA) and clinical response to therapy in rheumatoid arthritis (RA) patients. Frequencies of IFN-γ-producing CD4+T (Th1) and IL-17A-producing CD4+T (Th17) cells were determined by flow cytometry in 167 patients (114 cases with good-response (GR) and 53 poor-response (PR) based on DAS28). HLA-DRB1 alleles for patients and 150 healthy controls were determined by PCR-SSP. We observed that 65.2% of RA patients were SE+, 63.4%ACPA+, 43.7%SE+ACPA+ and 14.9% were SE−ACPA−. Higher significantly proportions of Th1 and Th17 cells were found in RA patients than controls (P < 0.05) as well as in the SE+ or ACPA+RA patients compared to SE− and ACPA− patients. Increased frequencies of both Th subsets were found in SE+ACPA+ versus SE−ACPA− patients (P < 0.001) and in the PR versus GR group (P < 0.001). We showed significant differences for Th cells frequencies between SE+ and SE− patients in both groups, and between ACPA+ and ACPA− cases in the PR group. Our findings suggest a close link between Th1 and Th17 cells proportions and HLA-SE/ACPA in the RA patients and remarkably in the PR group which could be indicative for the importance of immune monitoring for evaluation of response to therapy.

Genomic Influences on Susceptibility and Severity of Rheumatoid Arthritis.

Genetics in rheumatoid arthritis (RA) has moved from the finding of HLA-shared epitope decades ago toward the understanding of the role of HLA in RA and the findings of ∼100 additional genetic risk variants for disease susceptibility as well as several risk variants for severe disease. These findings increased our understanding of RA abnormality. Still, the mechanisms by which many of the variants exhibit their effect are not yet understood.

Human Leukocyte Antigen Shared Epitope and Inflammation, Cardiovascular Disease, Cancer, and Mortality Among Postmenopausal Women in the Women's Health Initiative Rheumatoid Arthritis Study.

Specific alleles of the human leukocyte antigen (HLA)-DRB1 gene (HLA-DRB1) encode a "shared epitope" (SE) associated with rheumatoid arthritis (RA), especially more severe cyclic-citrullinated peptide antibody-positive (anti-CCP+) RA. We evaluated associations of number of SE alleles (0, 1, or 2) with total and cardiovascular disease (CVD) mortality and incident coronary heart disease (CHD), CVD, and cancer over a mean8.9 (standard deviation, 3.5) years of follow-up, stratifying by baseline anti-CCP status (positive (+) vs. negative (-)). A longitudinal study, the Women's Health Initiative RA Study (1993-2010), sampled postmenopausal women who reported RA at baseline (1993-1998) or follow-up in the Women's Health Initiative, classified as anti-CCP+ RA (n=556) or anti-CCP- non-RA (n=1,070). Among anti-CCP+ RA women, SE alleles were not related to age-adjusted risks of CHD, CVD, or cancer or to total or CVD mortality. Among anti-CCP- non-RA women, age-adjusted hazard ratios for 1 and 2 SE alleles versus 0 SE alleles were 0.41 (95% confidence interval (CI): 0.34, 0.50) and 0.44 (95% CI: 0.27, 0.72), respectively, for CVD; 0.43 (95% CI: 0.37, 0.53) and 0.30 (95% CI: 0.16, 0.64), respectively, for CHD; and 0.62 (95% CI: 0.53, 0.73) and 0.52 (95% CI: 0.33, 0.83), respectively, for cancer. Associations persisted after adjustment for CVD risk factors, joint pain, rheumatoid factor positivity, and inflammatory markers (white blood cell count or cytokine level). In future studies, investigators should evaluate SE associations among anti-CCP- adults without RA and potential mechanisms.

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 Nurses' Health Studies.

Overweight/obesity and anti-citrullinated protein antibodies (ACPA) increase rheumatoid arthritis (RA) risk. We investigated the relationship between body mass index (BMI) and ACPA, tested for an interaction between BMI and ACPA for RA risk, and examined effects of BMI and ACPA on time to RA diagnosis. Within the Nurses' Health Studies, blood samples were collected before diagnosis from medical record-confirmed incident RA cases and matched controls. Multiplex assays measured 7 ACPA subtypes (biglycan, clusterin, enolase, fibrinogen, histone 2A, histone 2B, and vimentin). Logistic regression analyses tested the association of BMI and ACPA and for a multiplicative interaction between BMI groups (≥25 vs. <25kg/m2) and ACPA positivity (≥2 vs. <2 subtypes), adjusting for age, smoking, alcohol use, and HLA-shared epitope. In case-only analyses, log-rank tests compared time from blood draw to RA onset by cross-classified BMI/ACPA status. Among 255 pre-RA cases and 778 matched controls, 15.7% vs. 2.1% (p<0.001) had ≥2 ACPA and 49.4% vs. 40.2% (p<0.01) were overweight/obese. Continuous BMI was not associated with presence of ≥2 ACPA [OR per kg/m2 unit BMI: 1.03 (95% CI: 0.97-1.09)]. However, there was a multiplicative interaction between elevated BMI and the presence of ≥2 ACPA for RA risk (p = 0.027). Women with BMI≥25kg/m2 and ≥2 ACPA had OR 22.7 (95% CI: 6.64-77.72) for RA. Median time to RA differed by BMI/ACPA group (overall log-rank p<0.001) and was shortest among women with ≥2 ACPA and BMI≥25kg/m2 [45.0 months, IQR: 17.5-72.5] and longest in women with <2 ACPA and BMI<25kg/m2 [125.0 months, IQR: 72.0-161.0] (pairwise log-rank p = 0.002). Elevated BMI and presence of ACPA interacted to increase RA risk. Time to RA onset was shortest among overweight/obese women with ≥2 ACPA.

Monocyte chemotactic protein-1 elevation prior to the onset of rheumatoid arthritis among women.

To examine monocyte chemotactic protein-1 (MCP-1) concentration and future rheumatoid arthritis (RA) risk, and investigate effect modification by human leukocyte antigen-shared epitope (HLA-SE) and several lifestyle factors. We conducted a nested case-control study using stored plasma samples from the Nurses' Health Studies. Each pre-RA case was matched to three controls (N case = 220, N control = 675). Odds ratios (OR) for RA associated with MCP-1 concentration and interactions with HLA-SE, smoking, BMI and alcohol intake were estimated. MCP-1 concentration was associated with both seropositive and seronegative RA, in particular <5 years of blood draw (OR: 2.42), and among HLA-SE positive (OR: 2.05). No interactions with smoking, BMI or alcohol were detected. MCP-1 was associated with risk of RA, especially among HLA-SE positive, but did not differ by smoking status, BMI or alcohol intake.

Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis.

IntroductionIt has previously been shown that an increased number of antibodies against citrullinated peptides/proteins (ACPA) predate the onset of rheumatoid arthritis (RA). Over time antibody positivity expands, involving more specific responses when approaching the onset of symptoms. We investigated the impact of human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking on the development of ACPA, as well as in combination with ACPA during the state of quiescent autoimmunity (before the onset of symptoms), on the development of RA.MethodsBlood samples donated to the Medical Biobank of Northern Sweden from individuals prior to the onset of symptoms of RA (n = 370) and after onset (n = 203) and from population-based controls (n = 585) were used. Antibodies against 10 citrullinated peptides, fibrinogen (Fibα561-583, α580-600, ß62-81a, ß62-81b, ß36-52), vimentin (Vim2-17, 60-75), filaggrin (CCP-1/Fil307-324), α-enolase (CEP-1/Eno5-21), collagen type II (citC1359-369), and anti-cyclic citrullinated peptide (CCP)2 antibodies were analysed.ResultsHLA-SE-positive individuals were more frequently positive for ACPA compared with HLA-SE-negative individuals prior to the onset of symptoms of RA, particularly for antibodies against CEP-1 and Fibß62-81a (72). Smoking was associated with antibodies against Vim2-17 and citC1359-369. HLA-SE and smoking showed increasing association to the presence of the antibodies closer to disease onset. The highest odds ratio (OR) for development of RA was for the combination of HLA-SE alleles and ACPA positivity, especially for antibodies against Fibß62-81b, CCP-1/Fil307-324, and Fibβ36-52. A gene-environment additive interaction between smoking and HLA-SE alleles for the risk of disease development was found, with the highest OR for individuals positive for antibodies against Fibβ36-52, CEP-1, and Fibα580-600.ConclusionsThe relationships between antibodies against the different ACPA specificities, HLA-SE, and smoking showed a variable pattern in individuals prior to the onset of RA. The combination of smoking and HLA-SE alleles was significantly associated with the development of some of the antibody specificities closer to onset of symptoms, and these associations remained significant at diagnosis. An additive gene-environment interaction was found for several of the antibodies for the development of RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0638-x) contains supplementary material, which is available to authorized users.

In antisynthetase syndrome, ACPA are associated with severe and erosive arthritis: an overlapping rheumatoid arthritis and antisynthetase syndrome.

Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific for rheumatoid arthritis (RA), may be found in some patients with other systemic autoimmune diseases. The clinical significance of ACPA in patients with antisynthetase syndrome (ASS), a systemic disease characterized by the association of myositis, interstitial lung disease, polyarthralgia, and/or polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, and response to treatment. ACPA-positive ASS patients were first identified among a French multicenter registry of patients with ASS. Additionally, all French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were asked to report their observations of ASS patients with ACPA. The 17 collected patients were retrospectively studied using a standardized questionnaire and compared with 34 unselected ACPA-negative ASS patients in a case–control study. All ACPA-positive ASS patients suffered from arthritis versus 41% in the control group (P < 0.0001). The number of swollen joints was significantly higher (7.0 ± 5.0 vs 2.9 ± 3.9, P < 0.005), with a distribution resembling that of RA. Radiographic damages were also more frequent in ACPA-positive ASS patients (87% vs 11%, P < 0.0001). Aside from a significantly higher transfer factor for carbon monoxide in ACPA–ASS patients, lung, muscle, and skin involvements had similar incidences, patterns, and severity in both groups. Although Nonbiologic treatments were similarly used in both groups, ACPA-positive patients received biologics more frequently (59% vs 12%, P < 0.0008), mostly due to refractory arthritis (n = 9). Eight patients received anti-Cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) with good efficacy and tolerance, whereas 2 of the 5 patients treated with antitumor necrosis factor drugs had worsened myositis and/or interstitial lung disease. After a >7-year mean follow-up, extra-articular outcomes and survival were not different. ACPA-positive ASS patients showed an overlapping RA–ASS syndrome, were at high risk of refractory erosive arthritis, and might experience ASS flare when treated with antitumor necrosis factor drugs. In contrast, other biologics such as anti-CD20 mAb were effective in this context, without worsening systemic involvements.

OR15: SUSCEPTIBLE HLA SHARED EPITOPES IN RHEUMATOID ARTHRITIS MEDIATE BINDING OF CITRULLINATED PEPTIDES TO THE MHC

Aim Rheumatoid Arthritis (RA) is a chronic inflammatory disorder affecting 1% of the world population and results in the eventual destruction of bone and joints. A two amino acid Shared Epitope (SE) LA67,74 in HLA-DRB1 is highly associated with RA and is also positively correlated with high levels of anti-citrullinated protein antibodies. In contrast, a single amino acid SE D70 in HLA-DRB1 is associated with resistance in a resistance dominance fashion. We have previously demonstrated through assessment of peptide binding to 91 HLA class II alleles on Luminex beads that citrullinated vimentin binds significantly over native to HLA-DRB1 alleles containing the LA67,74 epitope. In this study, we assess the importance of these HLA SE in binding of citrullinated peptides to alleles containing SE mutations. Methods We measured citrullinated and native vimentin binding by flow cytometry on T2 cells transduced with either DRB1∗04:01 Wild Type (WT), DRB1∗04:02 WT, or DRB1∗04:01 containing the single mutations L67I and Q70D in addition to DRB1∗04:01 containing both mutations. Results DRB1∗04:01 WT bound citrullinated vimentin significantly over native. DRB1∗04:02 bound both citrullinated and native vimentin equally. Mutagenesis of DRB1∗04:01 L67I resulted in a modest reduction of binding of citrullinated vimentin, but excluded native vimentin binding. A Q70D mutation however allowed both citrullinated and native vimentin binding. DRB1∗04:01 containing both epitope mutations showed binding comparable to DRB1∗04:02. Conclusions As observed in our Luminex peptide binding assay, we found that LA67,74 displays a preference for citrullinated peptides. In contrast, the D70 epitope confers no preference for citrullinated peptides. Our results suggest that the presence of LA67,74 in the HLA cannot accommodate arginine in the binding pocket, whereas D70 alleles allow both arginine and citrulline binding. This provides rationale for LA67,74 associated susceptibility to RA in addition to D70 associated resistance to RA.

AB1042 Dietary Patterns, Macronutrients and Alcohol as Risk Factors for Rheumatoid Arthritis

BackgroundThere is a growing interest in the role of lifestyle factors, such as dietary habits and alcohol consumption, in development of rheumatoid arthritis (RA). The methodology in analysing dietary factors...

THU0426 Dietary Sodium Increases the Risk for Rheumatoid Arthritis among Smokers

BackgroundStudies in animal models and on human cells have suggested that sodium chloride may affect autoimmunity by the induction of pathogenic Th17 cells mediated through salt-sensing kinase-1. Since Th17 cells...

Rheumatoid arthritis in the Women's Health Initiative: methods and baseline evaluation.

Second-generation assays for anti-cyclic citrullinated peptide (anti-CCP), a highly sensitive and specific marker for rheumatoid arthritis (RA), have redefined the epidemiology of RA. In the Women's Health Initiative (WHI) RA study (2009-2011), we evaluated the prevalence of anti-CCP positivity among 15,691 (10.2% of 161,808) WHI participants aged 50-79 years who reported RA. Using stored baseline specimens, we measured serum anti-CCP, rheumatoid factor (RF), and antinuclear antibody in a defined sample of 9,988 of black, white, and Hispanic women. In a subset of women, we measured plasma cytokine levels and number of copies of the human leukocyte antigen (HLA)-DRB1 (HLA-DRB1) shared epitope in DNA by means of Luminex polymerase chain reaction typing (Luminex Corporation, Austin, Texas). We validated classification of probable clinical RA in 2 clinics as anti-CCP positivity or self-reported validated use of disease-modifying antirheumatic drugs (DMARDs). The prevalence of anti-CCP positivity was 8.1%, and the prevalence of RF positivity was approximately 16.0%. DMARD use including prednisone was reported by 1,140 (11.4%) participants (841 excluding prednisone) but by 57.5% of anti-CCP-positive women. The prevalence of 2 shared epitopes was also much higher for anti-CCP-positive women (18.2%, as opposed to only 5.5% for women with anti-CCP-negative DMARD-positive RA and 6.6% for anti-CCP-negative, RF-negative DMARD nonusers). Median cytokine levels were much higher for anti-CCP-positive/RF-positive women. Women with anti-CCP-positive RA and anti-CCP-negative RA had different characteristics with regard to HLA shared epitope, cigarette smoking, and inflammation (cytokines).

Smoking and polymorphisms of genes encoding mannose-binding lectin and surfactant protein-D in patients with rheumatoid arthritis

To investigate whether polymorphisms in genes coding for mannose-binding lectin (MBL) and surfactant protein-D (SP-D) are associated directly or by interaction with smoking with rheumatoid arthritis (RA), anti-citrullinated peptide antibody (ACPA) positive RA, and erosive RA. MBL2 genotypes, SFTPD genotype at codon 11, and HLA-shared epitope were determined in 456 patients with rheumatoid arthritis and 533 sex- and age-matched controls. Patients were grouped according to the presence of ACPA antibodies and RA-associated bone erosions and sub-stratified according to smoking status as never or ever smokers. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated using multiple logistic regression analyses controlling for shared epitope. The low-producing SFTPD genotype was not associated with risk of RA or ACPA positive RA, but with erosive disease in the RA patients (OR = 1.8; 95% CI 1.1-3.0) particularly in RA ever smokers (OR = 2.4; 95% CI 1.3-4.3). The high-producing MBL2 genotype YA/YA was associated with ACPA positive RA (OR = 1.4; 95% CI 1.0-1.9) and erosive joint disease in RA ever smokers (OR = 1.8; 95% CI 1.1-3.0). Genetic disposition for low SP-D was not associated with RA but with erosive RA by interaction with smoking. The genetic disposition for high MBL production was associated with ACPA positive RA irrespective of shared epitope. The findings need to be replicated but do as such offer further explanations for the clinical heterogeneity of RA.

THU0078 Interactions of Antibodies Against Citrullinated Peptides with HLA Shared Epitope, PTPN22 1858T Variant, and Smoking in Individuals Prior to and after the Development of Rheumatoid Arthritis

BackgroundPresence of antibodies against cyclic citrullinated peptides (ACPA) has been demonstrated to precede the development of rheumatoid arthritis (RA) by several years. The gene-environment interaction for these antibodies has not...

THU0078 Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9P21.3 region in patients with rheumatoid arthritis and cardiovascular disease

BackgroundAn increased morbidity and mortality due to cardiovascular disease in patients with rheumatoid arthritis has been identified.ObjectivesGenes related to coronary artery disease in the general population, CD40, growth differentiation factor...

SP0020 Risk Factors for RA: GENE Environment Interactions

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation in the joints involving the synovial tissue and ultimately leading to the destruction of cartilage and bone. The aetio-pathogenic...

Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study

IntroductionThe aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles.MethodsWe identified 192 women in the Nurses’ Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use. Reactivities to 18 ACPAs were measured using a custom BioPlex platform. We used conditional logistic regression to calculate the relative risk (RR) of RA for any ACPA-positive and peptide-specific ACPA-positive and examined RRs by time between blood draw and RA onset. Measures of multiplicative and additive interaction between any ACPA-positive and HLA-SE were calculated.ResultsAll ACPAs by peptide groups were significantly associated with RA risk, RRs ranged from 4.7 to 11.7. The association between ACPA and RA varied over time with the strongest association in those with blood draw less than 5 years before onset (RR 17.0 [95% CI 5.8 to 53.7]) and no association 10 or more years prior to onset (RR 1.4 [95% CI 0.5 to 4.3]). Individuals with both HLA-SE and any ACPA-positive had the highest risk of RA. HLA-SE-positive RA cases showed reactivity to more ACPA types than HLA-SE negative (χ2 test for trend, P = 0.01).ConclusionsThere is increasing ACPA reactivity up to 10 years before RA onset with the strongest association within 5 years of RA onset. The magnitude of the response to ACPAs, in combination with the presence of HLA-SE, is most important for identifying those individuals with the highest risk of RA.