Prevalence of anti cyclic citrullinated peptide antibodies in Malaysian rheumatoid arthritis patients and its correlation with disease activity

Aim: The objectives of this study are to provide data regarding the prevalence of anti‐cyclic citrullinated peptide (CCP) antibodies in Malaysian rheumatoid arthritis (RA) patients and to correlate the levels of anti‐CCP antibody with the Disease Activity Score (DAS). Method: We studied the prevalence of anti‐CCP antibodies in 51 RA patients attending our clinic and 29 controls. We also looked for correlation between anti‐CCP antibody levels with the DAS and parameters such as duration of disease, rheumatoid factor (RF) and disease‐modifying anti rheumatic drug (DMARD) usage. Results: None of the controls demonstrated anti‐CCP antibodies. Forty‐one out of 51 patients (80.4%) were positive for anti‐CCP antibodies. Sensitivity and specificity were 80.4% and 100% respectively in this study. Anti‐CCP levels correlated significantly with rheumatoid factor, but no correlation was observed with the other parameters. Conclusions: Anti‐CCP antibody is prevalent in Malaysian RA patients at 80.4% and more sensitive than RF in our cohort of established RA patients. Even though the anti‐CCP levels correlated with RF, it did not show correlation with DAS.     

抗环瓜氨酸肽抗体检测在类风湿关节炎中的意义

目的 检测抗环瓜氨酸肽（CCP）抗体在类风湿关节炎（RA）中的阳性率,探讨抗CCP抗体检测在RA中的意义。方法 以根据已知cDNA序列人工合成的CCP为抗原建立ELISA方法检测294例RA,132例其他风湿性疾病,135例非风湿性疾病中的抗CCP抗体的分布。比较抗CCP抗体与抗核周因子（APF）、抗角蛋白抗体（AKA）、类风湿因子（RF）以及HLA－DR4的相关性。结果 294例RA病人中,抗CCP抗体的阳性率为46．6％,其他风湿性疾病的阳性率为5．3％,非风湿性疾病的阳性率为1．5％。抗CCP抗体对RA的敏感性和特异性分别为46．6％,96．6％。抗CCP抗体与APF、AKA以及HLA－DR4之间有相关性,与RF之间无相关性。结论 抗CCP抗体对RA具有良好的敏感性（46．6％）和特异性（96．6％）,能用于RA的诊断。抗CCP抗体与AFP、AKA有相关性,但不完全重叠。抗CCP抗体可视为RA新的血清学诊断指标。     

Diagnostic value of anti-modified citrullinated vimentin in rheumatoid arthritis

Background: Rheumatoid factors (RF) are currently used in the diagnosis of rheumatoid arthritis (RA). Several other autoantibodies found in RA are directed to epitopes in citrullinated proteins such as anti‐cyclic citrullinated and recently anti‐modified citrullinated vimentin (MCV). Objective: In this study we determined the sensitivity and specificity of anti‐MCV in comparison with anti‐cyclic citrullinated peptide (CCP) antibodies and RF in RA patients and in a control group using the American College of Rheumatology (ACR) criteria as the gold standard. Materials and methods: A cross sectional study was conducted from January to December 2008 on 100 patients with RA and 153 patients with arthritis or arthralgia but not fulfilling ACR criteria for RA. Serum from each subject was tested for anti‐MCV, anti‐CCP antibodies and immunoglobulin G (IgG) RF by enzyme‐linked immunosorbent assay. Sensitivity and specificity of the tests were evaluated using the ACR criteria as the gold standard. Results: The sensitivity of RF was 85% with 74.5% specificity. For anti‐CCP antibodies the sensitivity was 71% and the specificity was 94.8%. The sensitivity of anti‐MCV antibodies was 80% with 59.5% specificity. The area under the curve for RF was 0.759, for anti‐CCP antibodies was 0.866 and for anti‐MCV antibodies was 0.681, while for at least one positive test it was 0.691. Conclusion: Anti‐CCP antibodies have higher diagnostic specificity and positive predictive value than RF and anti‐MCV antibodies. RF has the highest sensitivity when compared to anti‐CCP and anti‐MCV antibodies. Thus anti‐MCV antibody is not a better marker when compared to RF or anti‐MCV antibody in the diagnosis of RA patients.     

Comparative study of anti‐CCP and RF for the diagnosis of rheumatoid arthritis

Aim: To determine the frequency of anti‐cyclic citrullinated peptide antibody (anti‐CCP) in a group of patients with rheumatoid arthritis and another group with other rheumatic diseases. Patients and methods: Anti‐CCP1 and rheumatoid factor (RF) titres were determined in 320 serum samples; 136 from RA patients, 184 from control patients (165 patients with rheumatic diseases other than RA, and 21 patients with lymphoproliferative diseases). Results: The sensitivity of Anti‐CCP was 62.5% (95% CI: 53–70%) for the diagnosis of RA with a specificity of 89.1% (95% CI: 83–93%). The sensitivity of RF was 85.3% (95% CI: 79–91%). The specificity was 64.7% (95% CI: 57–71%). Conclusions: Anti‐CCP1 has not very high specificity for RA regarding other rheumatic disease. However it is still very helpful for the diagnosis of RA.     

Role of anticyclic citrullinated peptide 2 assay in long‐standing rheumatoid arthritis

Background: The anti‐cyclic citrullinated peptide (anti‐CCP) antibody test is a new serological marker with high specificity for rheumatoid arthritis (RA). Aims: This study evaluated the frequency of anti‐CCP antibodies in comparison to rheumatoid factor (RF) in a group of patients with inflammatory polyarthritis. Methods: Samples were obtained from 106 patients with established RA and non‐RA inflammatory polyarthritis. Anti‐CCP (second generation assay – INOVA) and RF antibodies were measured by enzyme‐linked immunosorbent assay. Patient demographics, disease duration and clinical diagnosis were obtained. Results: Fifty‐five patients had established RA and the remaining 51 had non‐RA inflammatory polyarthritis. The sensitivity of the anti‐CCP2 assay for a diagnosis of RA was 73% compared with 56% for RF. In the RA group, half the RF negative patients (12/24) tested positive for anti‐CCP. The specificity of anti‐CCP was extremely high at 98% compared with RF at 94%. In the non‐RA group, only one patient with lupus tested positive for anti‐CCP compared with three who were RF positive (all of whom also had lupus). Conclusion: The second generation anti‐CCP assay was more sensitive and specific than RF for a diagnosis of RA in this population. This test may improve accuracy of diagnosis in patients with long‐standing polyarthritis.     

The prevalence of rheumatoid factor isotypes and anti-cyclic citrullinated peptides in Malaysian rheumatoid arthritis patients

Aim: The purpose of this study is to compare the prevalence of rheumatoid factor (RF) isotypes and second generation anti‐cyclic citrullinated peptides (anti‐CCP) in Malaysian rheumatoid arthritis (RA) patients. Methods: In this cross‐sectional study, 147 established RA patients from three ethnic groups were recruited from a major rheumatology clinic in Malaysia. Enzyme‐linked immunosorbent assays (ELISA) for serum RF isotypes IgA, IgG and IgM as well as second‐generation anti‐CCP were performed and the prevalence of each auto‐antibody was compared in the three ethnic groups. Results: The anti‐CCP was the most prevalent auto‐antibody in each of the ethnic groups, followed closely by RF IgM and RF IgG. Rheumatoid factor IgA was the least prevalent across all three ethnic groups. The anti‐CCP–RF IgM combination provided the best test sensitivity. Seroprevalence of anti‐CCP was strongly associated with the presence of each of the RF isotypes. The seroprevalence of RF and anti‐CCP did not increase or decrease with advancing age, age at onset and disease duration. Conclusion: When used alone, anti‐CCP provides a diagnostic advantage over RF IgM on the basis of test sensitivity. Considering the high cost of the anti‐CCP assay, step‐wise serum testing with IgM RF followed by anti‐CCP may provide a more economically sensible option to optimize test sensitivity for RA.     

A can of red herrings

Lymphomatoid granulomatosis is a rare disease. Anti‐cyclic citrullinated peptide (anti‐CCP) antibody is more commonly found in patients with rheumatoid arthritis and less frequently in some of the other rheumatic and non‐rheumatic conditions. It is not recognized to be present in lymphoproliferative disease on its own. We report the first case of anti‐CCP antibody positivity in lymphomatoid granulomatosis presenting with polyarthritis. This case illustrates the evolving nature of this disease and its characteristics at different stages leading to the challenge of an accurate diagnosis in the setting of a paraneoplastic polyarthritis.     

Association between anti–cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis

Objective

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease that may not always be related to the presence of traditional cardiovascular risk factors. The aim of this study was to determine if anti–cyclic citrullinated peptide (anti‐CCP) antibodies are associated with cardiovascular disease in patients with RA.

Methods

Anti‐CCP antibodies were determined by enzyme‐linked immunosorbent assay in the earliest serum sample available from 937 patients with a diagnosis of RA. We studied the relationship between anti‐CCP antibodies with traditional cardiovascular risk factors and cardiovascular events.

Results

We found positive anti‐CCP antibodies (>25 units/ml) in 672 patients (71.7%). There was no association between the anti‐CCP antibodies and cardiovascular risk factors such as smoking, hypertension, dyslipidemia, being overweight, or diabetes mellitus. However, patients who had positive anti‐CCP antibodies experienced more frequent ischemic heart disease (6.5% versus 2.6%; odds ratio [OR] 2.58, 95% confidence interval [95% CI] 1.17–5.65) and had higher mortality rates (11.2% versus 6.8%; OR 1.72, 95% CI 1.01–2.91). Similar results were obtained when we considered anti‐CCP titers 20‐fold higher (>500 units/ml). Multivariable analysis showed that ischemic heart disease is independently associated with positive anti‐CCP antibodies (OR 2.8, 95% CI 1.19–6.56; P = 0.009).

Conclusion

Anti‐CCP antibodies in patients with RA are independently associated with the development of ischemic heart disease.     

Isotype distribution of ANTI–CYCLIC citrullinated peptide antibodies in undifferentiated arthritis and rheumatoid arthritis reflects an ongoing immune response

Objective

The evolution of the rheumatoid arthritis (RA)–specific anti–cyclic citrullinated peptide (anti‐CCP) antibody response, as measured by the isotypes of anti‐CCP, has not been described. This study was undertaken to determine anti‐CCP isotype usage in patients with undifferentiated arthritis (UA), patients with recent‐onset RA, and patients with RA of long duration.

Methods

IgA, IgM, and IgG subclasses of anti‐CCP were measured by enzyme‐linked immunosorbent assay in serum samples that were obtained from IgG anti‐CCP antibody–positive patients with UA (n = 110) and IgG anti‐CCP antibody–positive patients with RA (n = 152) early after the onset of arthritis. Patients with UA in whom RA developed within 1 year (UA→RA) were compared with patients with UA in whom RA did not develop within 1 year (UA→UA). In addition, baseline serum samples obtained from a subset of patients with RA (n = 64) were compared with sera obtained from the same patients a median of 7 years later.

Results

IgM anti‐CCP was present in early samples from both patients with UA and patients with RA and in followup samples from patients with RA. Several IgG anti‐CCP antibody–positive patients who did not have IgM anti‐CCP early after disease onset did display IgM anti‐CCP later in the course of the arthritis. A diverse pattern of isotype usage was detected in early samples, with a trend toward lower frequencies of all isotypes of anti‐CCP in patients with UA compared with patients with RA and in UA→UA patients compared with UA→RA patients. Levels of all isotypes except IgG1 had decreased after 7 years.

Conclusion

These data indicate development of the anti‐CCP isotype repertoire into full usage early in the course of arthritis. The sustained presence of IgM anti‐CCP indicates ongoing recruitment of new B cells into the anti‐CCP response, reflecting a continuous (re)activation of the RA‐specific anti‐CCP response during the course of anti‐CCP–positive arthritis.

     

Brief Report: Anti–Carbamylated Protein Antibodies Are Present in Arthralgia Patients and Predict the Development of Rheumatoid Arthritis

Objective

Recently, we discovered a new autoantibody system in rheumatoid arthritis (RA): anti–carbamylated protein (anti‐CarP) antibodies. These antibodies have value in predicting joint destruction; however, it is not clear whether they are present before the diagnosis of RA and whether they have value as predictors of RA development. Therefore, we studied whether anti‐CarP antibodies are present in patients with arthralgia and whether their presence is associated with the development of RA.

Methods

Sera from 340 arthralgia patients who did not have clinical signs of arthritis but who were positive for IgM rheumatoid factor (IgM‐RF) and/or anti–cyclic citrullinated peptide 2 (anti–CCP‐2) and 32 healthy controls were tested for anti‐CarP IgG antibodies. Of the patients with arthralgia, 111 were IgM‐RF positive/anti–CCP‐2 antibody negative and 229 were anti–CCP‐2 antibody positive. Patients were observed for the development of RA (based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria) during a median followup period of 36 months. Cox proportional hazards regression analysis was performed to compare the risk of developing RA between arthralgia patients who were positive for anti‐CarP antibodies and those who were negative for anti‐CarP antibodies during followup.

Results

Anti‐CarP antibodies were present in the sera of 39% of the patients. One hundred twenty patients developed RA, after a median of 12 months (interquartile range [IQR] 6–24). The presence of anti‐CarP antibodies was associated with the development of RA in the entire arthralgia cohort after correction for RF and anti–CCP‐2 antibody status (hazard ratio 1.56 [95% confidence interval 1.06–2.29], P = 0.023), as well as in the anti–CCP‐2 antibody–positive subgroup (odds ratio 2.231 [95% confidence interval 1.31–3.79], P = 0.003).

Conclusion

Anti‐CarP antibodies are present in patients with arthralgia, and their presence predicts the development of RA independent of anti–CCP‐2 antibodies.

     

Benefit of early treatment in inflammatory polyarthritis patients with anti–cyclic citrullinated peptide antibodies versus those without antibodies

Objective

To compare the clinical utility of anti–cyclic citrullinated peptide (anti‐CCP) antibodies and rheumatoid factor (RF) testing in predicting both functional outcome and response to treatment in early inflammatory polyarthritis (IP) patients.

Methods

A total of 916 IP subjects from a primary care incidence registry (1990–1994) had anti‐CCP antibody and RF status determined at baseline. Mean change in Health Assessment Questionnaire (HAQ) score between baseline and 5 years was compared by antibody status. The effect of treatment with disease‐modifying antirheumatic drugs and/or steroids over 5 years, early (<6 months of symptom onset) versus late initiation, and duration of treatment were also compared by anti‐CCP antibody status. The analysis was adjusted for treatment decisions and censoring over the followup, using marginal structural models.

Results

Anti‐CCP antibody–positive patients (n = 268) had more severe disease both at presentation and 5 years of followup, and this was independent of RF. On adjustment, anti‐CCP antibody–negative patients treated early experienced a significant improvement in functional disability compared with anti‐CCP antibody–negative patients who were never treated (?0.31; 95% confidence interval [95% CI] ?0.53, ?0.08), and experienced additional benefit for each additional month of early treatment. Anti‐CCP antibody–positive patients treated early did not have a significant improvement in HAQ score compared with those not treated (?0.14; 95% CI ?0.52, 0.24).

Conclusion

In this first observational study to examine the influence of anti‐CCP antibody status on treatment response, anti‐CCP antibody–positive IP patients showed less benefit from treatment, particularly early treatment, than anti‐CCP antibody–negative patients. This provides support for the inclusion of anti‐CCP antibodies as well as RF in the classification criteria for rheumatoid arthritis and for stratification by anti‐CCP antibody status in clinical trials.

     

Associations of HLA‐DRB1 alleles with anti‐citrullinated protein antibody‐positive and anti‐citrullinated protein antibody‐negative rheumatoid arthritis in northern east part of Turkey

Aim: The aim of this study was to investigate the associations between human leukocyte antigen (HLA)‐DRB1 alleles with genetic susceptibility to rheumatoid arthritis (RA) and production of antibodies against cyclic citrullinated peptide (anti‐CCP antibody) and rheumatoid factor (RF) in Turkish RA patients. Methods: We studied 291 RA patients and 253 controls. Genotyping was performed by polymerase chain reaction with sequence‐specific oligonucleotide probes hybridization method. Serum levels of anti‐CCP antibody, IgM‐RF and high sensitive C‐reactive protein titers were measured by commercial kits using immunological methods. Results: We found that HLA‐DRB1*04 and *09 alleles were associated in anti‐CCP+ and anti‐CCP+ RA patients (P < 0.0001 and P < 0.001, respectively), while DRB1*01 and *04 were determined to be higher in RF+ RA patients (P < 0.001 and P < 0.0001, respectively). Moreover, DRB1*11 and DRB1*13 alleles were determined to be lower in RF and anti‐CCP/RF+ RA patients (P < 0.001 for both). HLA‐DRB1*04 was identified as a common responsible allele for susceptibility to the disease in anti‐CCP, RF and anti‐CCP/RF? RA patients (P = 0.0018, P = 0.0004 and P = 0.0023, respectively). HLA‐DRB1*13 allele alone was found to be protective against to anti‐CCP+ and RF? RA (P = 0.0003 and P = 0.006, respectively). On the contrary, there was no protective allele in anti‐CCP/RF? RA as well as anti‐CCP? RA patients. Conclusion: This study indicates that associate and protective HLA‐DRB1 allele distributions are different in autoantibody (anti‐CCP or RF or anti‐CCP/RF)+ RA and autoantibody? RA patients, with exceptions of DRB1*04 and DRB1*13.     

抗环瓜氨酸肽抗体联合类风湿因子检测对类风湿性关节炎诊断的临床价值

目的探讨联合检测抗环瓜氨酸肽抗体（anti-CCP）与类风湿因子（RF）对类风湿关节炎（RA）早期诊断的意义。方法选取2008年1月—2009年1月收治确诊RA患者中随机抽取100人作为RA组,以健康人50例作为对照组,采用酶联免疫吸附法（ELISA）检测抗CCP抗体,采用速率散射比浊法检测RF。结果RA组的anti-CCP阳性率为67%,RF的阳性率为78%。对比分析发现RA患者血清中的anti-CCP对RA诊断的灵敏度比RF的灵敏度低,差异具有显著性（P〈0.05）;而anti-CCP的96.0%的特异性比RF的88.0%要高,差异具有显著性（P〈0.05）。两者联合检测灵敏度可提高,特异性可达100.0%。结论RF与anti-CCP联合使用可进一步提高RA诊断的灵敏度和特异性,有利于对RA的早期检出。     

Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis

Objective

To determine whether antibodies against peptidyl arginine deiminase type 4 (PAD‐4) are present in the preclinical phase of rheumatoid arthritis (RA) and to compare the timing and extent of their appearance with those of other preclinical autoantibodies.

Methods

Prediagnosis serum samples from 83 patients with RA were evaluated for the presence of anti–PAD‐4 antibody, anti–cyclic citrullinated peptide (anti‐CCP) antibody, and rheumatoid factor. In addition, a control cohort (n = 83) matched by age, sex, race, number of serum samples, and duration of serum storage was tested for the presence of anti–PAD‐4 antibody to determine its sensitivity and specificity for the subsequent development of RA.

Results

Fifteen of 83 patients with RA (18.1%) had at least 1 prediagnosis sample positive for anti–PAD‐4. One of 83 control subjects (1.2%) had at least 1 positive sample, resulting in a sensitivity and specificity of 18.1% and 98.8%, respectively, of anti–PAD‐4 for the future development of RA. The mean duration of anti–PAD‐4 positivity prior to clinical diagnosis was 4.67 years. Anti–PAD‐4 positivity was associated with anti‐CCP positivity (odds ratio 5.13 [95% confidence interval 1.07–24.5]). In subjects with prediagnosis samples that were positive for both antibodies, anti‐CCP positivity predated anti–PAD‐4 positivity in 9 of 13 cases (69%).

Conclusion

Autoantibodies to PAD‐4 are present during the preclinical phase of RA in a subset of patients and are associated with anti‐CCP positivity. Further exploration is needed regarding the timing of appearance and disease‐related effects of PAD‐4 autoimmunity.

     

Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti–cyclic citrullinated peptide antibody

Objective

To examine the association of treatment response and disease duration with changes in rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti‐CCP) antibody levels among patients with rheumatoid arthritis (RA).

Methods

The study sample included 66 RA patients who completed double‐blind, randomized clinical protocols and for whom baseline and followup serum samples were available. Anti‐CCP and RF levels were measured using commercially available assay kits. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to describe the association of response and disease duration with declines in antibody levels.

Results

Patients had a mean ± SD age of 49.9 ± 12.0 years and were predominantly female (n = 51; 77%). The mean ± SD duration between the times at which the baseline and followup serum samples were obtained was 13.7 ± 8.6 months. Among the 64 subjects with positive antibody at baseline, 33 (52%) experienced a ≥25% reduction in the anti‐CCP antibody level during the course of treatment, and 35 patients (55%) had a ≥25% reduction in RF. After adjustment for the baseline anti‐CCP antibody level, only a shorter disease duration (≤12 months) was significantly associated with a decline in the level of anti‐CCP antibody (OR 3.0, 95% CI 1.0–8.8), and no association with treatment response was observed. Conversely, treatment response was the only significant determinant of a decrease in RF levels (OR 3.6, 95% CI 1.2–10.4).

Conclusion

Shorter disease duration predicts greater declines in anti‐CCP antibody levels with treatment in RA. Although treatment response is a robust determinant of a decrease in RF, it does not appear to be associated with declines in the anti‐CCP antibody level.

     

抗环瓜氨酸多肽抗体检测早期诊断类风湿关节炎研究

目的探讨抗环瓜氨酸多肽(CCP)抗体检测对类风湿关节炎(RA)早期诊断的意义。方法应用ELISA法检测2004—2005年中国医科大学附属盛京医院150份人血清的抗CCP抗体,包括54例RA患者,80例其它风湿病患者,16名正常人;并分析抗CCP抗体与类风湿因子(RF)、C反应蛋白(CRP)、血沉(ESR)的相关性。结果抗CCP抗体对RA的敏感性和特异性分别为70·4%和93·8%。发病2年内与2年以上的抗CCP抗体阳性率差异无显著性。抗CCP抗体阴性组与阳性组的关节畸形率差异无显著性。抗CCP抗体与RF、CRP、ESR无相关性。结论抗CCP抗体对RA具有较好的敏感性和很高的特异性,联合抗CCP抗体和RF可以提高诊断的准确性,对RA的早期诊断具有重要意义。     

Synovial fluid levels of anti–cyclic citrullinated peptide antibodies and IgA rheumatoid factor in rheumatoid arthritis,psoriatic arthritis,and osteoarthritis

Objective

To assess the levels of anti–cyclic citrullinated peptide (anti‐CCP) and IgA rheumatoid factor (IgA‐RF) in synovial fluids of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA).

Methods

Knee effusions of 29 patients with RA (23 women, 6 men; mean ± SD age 60 ± 15 years), 20 with PsA (6 women, 14 men; mean age 51 ± 12 years), and 19 with OA (9 women, 10 men; mean age 73 ± 11.8 years) were aspirated, tested for white blood cell (WBC) counts, centrifuged, and stored at ?20°. Sera of 22, 11, and 12 of these patients with RA, PsA, and OA, respectively, were similarly stored. IgG anti‐CCP and IgA‐RF were detected by enzyme‐linked immunosorbent assay. Erythrocyte sedimentation rate and C‐reactive protein levels were used as measures of disease activity.

Results

Mean levels of synovial fluid anti‐CCP and IgA‐RF were significantly increased in RA joint effusions compared with PsA and OA (anti‐CCP: 150 ± 134, 34 ± 29, and 24 ± 26 units, respectively [P < 0.003]; IgA‐RF: 76 ± 77, 15.7 ± 10, and 18 ± 20 units, respectively). No significant difference was noted between OA and PsA. A significant correlation was found between synovial fluid anti‐CCP and serum anti‐CCP and IgA‐RF. In patients with RA, a significant correlation was found between synovial fluid WBC counts and IgA‐RF (P = 0.03) and serum IgA‐RF (P = 0.008), but not between synovial fluid and serum anti‐CCP levels. In RA patients, C‐reactive protein correlated with serum IgA‐RF.

Conclusion

Anti‐CCP and IgA‐RF were significantly increased in synovial fluid of RA in comparison with PsA and OA patients.

     

Particular association of clinical and genetic features with autoimmunity to citrullinated α‐enolase in rheumatoid arthritis

Objective

To confirm that the presence of anti–citrullinated α‐enolase peptide 1 (anti–CEP‐1) antibodies identifies a subgroup of patients with rheumatoid arthritis (RA).

Methods

DNA and serum samples were obtained from 451 patients with RA and 279 healthy control subjects, all of whom were of Spanish ancestry. Antibodies to cyclic citrullinated peptide (CCP) and CEP‐1 were measured by enzyme‐linked immunosorbent assay. HLA–DRB1 and the R620W single‐nucleotide polymorphism of PTPN22 were genotyped.

Results

Anti–CEP‐1 and anti‐CCP antibodies were observed in 26.8% and 71.2% of the patients with RA, respectively. Most of the patients (86.6%) with anti–CEP‐1 antibodies also had anti‐CCP antibodies. Erosive arthritis, rheumatoid factor (RF) positivity, and the presence of the HLA shared epitope (especially the DRB1*04 alleles) were disproportionately associated with the group of patients with both antibodies. In addition, evidence of a significant interaction between the shared epitope and the risk allele of PTPN22 was observed only in these patients. In contrast, the association with these clinical and genetic features was weaker in patients with anti‐CCP antibodies but lacking anti–CEP‐1 antibodies. These results were obtained in patients in whom the prevalence of RA risk factors differed from that in other previously studied patients.

Conclusion

We observed that autoimmunity against citrullinated α‐enolase may identify a subset of patients with a higher frequency of joint erosions and RF positivity. In addition, we confirmed the disproportionately large effect of the susceptibility alleles of HLA–DRB1 and their interaction with PTPN22 in this subset of patients. These results extend, confirm, and generalize the evidence supporting the specificity of the anti–CEP‐1 antibody–positive subgroup of patients with RA among anti‐CCP antibody–positive patients with RA.

     

Low levels of anti-cyclic citrullinated peptide (CCP) 3.1 associated with diseases other than rheumatoid arthritis

Our aim was to investigate the newest generation anti-cyclic citrullinated peptide (CCP) antibody 3.1 assay in diagnosing rheumatoid arthritis (RA) compared with other autoimmune and non-autoimmune diseases. We performed a retrospective observational chart review of patients with a positive CCP level over a one-year period at a single academic institution and assessed the associated diagnoses after at least six-months of follow-up. Of the 281 CCP positive patients during that period, 48% had a diagnosis of RA. The positive predictive value of RA in patients with a high CCP 3.1 assay was 0.619 compared to 0.248 with a low positive CCP 3.1 assay (P < .0001). Overall, there was a lower than expected positive predictive value of CCP 3.1 level with an RA diagnosis, though the likelihood of having an RA diagnosis was higher with a higher CCP level.     

Association of Anti–Cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis

Objective

Anti–cyclic citrullinated peptide (anti‐CCP) antibodies are rheumatoid arthritis (RA)–specific serologic markers. RA susceptibility has been associated with HLA–DRB1 shared epitope (SE) alleles and single‐nucleotide polymorphism (SNP) haplotypes in the peptidyl arginine deiminase 4 gene (PADI4). This study was undertaken to determine whether anti‐CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean patients with RA.

Methods

Three nonsynonymous SNPs in PADI4 (padi4_89, padi4_90, and padi4_92) and SE alleles were genotyped, and serum anti‐CCP levels were measured, in 311 patients with nonerosive or erosive RA. The relationships between anti‐CCP levels and PADI4 haplotypes and/or SE alleles were analyzed statistically.

Results

Anti‐CCP levels were significantly higher in patients carrying the PADI4 RA risk haplotype than in patients who did not have the risk haplotype, among anti‐CCP–positive patients with RA with a disease duration of ≤34 months (P = 0.041), but not among patients with a longer disease duration or among those who had erosive RA versus nonerosive RA. In contrast, the levels were significantly higher in SE carriers than in noncarriers among patients with RA with a disease duration of ≥141 months (P = 0.0037) and among those who had erosive RA (P = 0.000098), but not among patients who had a shorter disease duration or those who had nonerosive RA.

Conclusion

The PADI4 RA risk haplotype is associated with increased anti‐CCP levels in RA patients with disease of short duration, and PADI4 may play a role in early RA. In contrast, SE alleles are associated with increased anti‐CCP levels in RA patients with very longstanding disease and in patients with erosive RA, suggesting that SE alleles play a role in very late RA.