Autoantibodies to cyclic citrullinated peptide 2 (CCP2) are superior to other potential diagnostic biomarkers for predicting rheumatoid arthritis in early undifferentiated arthritis

We evaluated the diagnostic value of anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies and other potential diagnostic biomarkers (IgM rheumatoid factor, anti-agalactosyl IgG antibodies, matrix metalloproteinase 3, C-reactive protein) for predicting early development of rheumatoid arthritis (RA). Patients were defined as having recent-onset undifferentiated arthritis (UA) if they had developed arthritis in two or more joints within the previous 2 years and could not be classified with a well-defined arthropathy. Baseline levels of biomarkers were measured in blood samples collected at the entry of the study and the patients were followed for 1 year to monitor development of RA. Diagnoses of RA and non-RA arthropathies were made according to individual standard diagnostic criteria. A total of 146 patients were enrolled in the study. In the follow-up year, 18 patients developed RA, 54 developed non-RA arthropathies, and 60 remained in the UA category. The sensitivity and specificity of the presence of anti-CCP2 antibodies for the diagnosis of RA were 83.3 and 93.0%, respectively. The positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of anti-CCP2 antibodies for RA (65.2, 97.2, and 91.7%, respectively) were higher than for any other biomarker. Combination of anti-CCP2 with any other biomarker only slightly improved each diagnostic value compared to the presence of anti-CCP2 alone. Among the anti-CCP2-positive patients, the average titer was significantly higher in those with RA than in non-RA or UA patients (163.7 +/- 138.4 vs 55.2 +/- 72.0 U/ml, p = 0.017). Anti-CCP2 antibodies are superior to any other single biomarker for predicting early development of RA in patients with recent-onset UA and the diagnostic value of anti-CCP2 alone is similar to that for biomarker combinations. Moreover, the anti-CCP2 antibody titer is useful to discriminate between patients at high risk for early developing RA from those at risk of developing non-RA arthropathies.     

Evaluation of third generation anti-CCP antibodies in the diagnosis of rheumatoid arthritis from undifferentiated polyarthritis after 4 years of follow-up

OBJECTIVES: Rheumatoid arthritis (RA) is a complex pathology to identify at an early stage. A large number of patients with recent onset polyarthritis (ROP) do not usually fulfil the ACR criteria for diagnosis of the disease and are classified as having undifferentiated polyarthritis. The aim of this study is to verify with certainty the diagnosis of patients whose illness has not been classified after four years of follow-up, and correlate their actual status with the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) found. METHODS: After one year of follow-up, 56 patients from a total of 322, included from January 2002 in the ROP Unit, did not meet ACR criteria for any rheumatic disease. The anti-CCP antibodies and RF levels were determined in the initial clinical assessment. RESULTS: After four years of follow-up, 12 new diagnoses were made in the 56 patients with undifferentiated polyarthritis: 3 seronegative RA, 8 seropositive RA and 1 psoriatic arthritis. The anti-CCP antibodies levels were positive for 5 of these 12 patients (median anti-CCP 228.6 U/mL), and all were RF positive. Six of the 7 anti-CCP antibodies negative patients were diagnosed of RA (3 seropositive and 3 seronegative for RF) and 1 was diagnosed of psoriatic arthritis (anti-CCP antibodies negative and RF positive). Forty-four patients still displayed undifferentiated polyarthritis and were RF negative. CONCLUSION: A positive result for RF and anti-CCP antibodies in patients who do not meet the ACR diagnostic criteria could be a useful indicator of the presence of future RA.     

The diagnostic utility of matrix metalloproteinase-3 and high-sensitivity C-reactive protein for predicting rheumatoid arthritis in anti-cyclic citrullinated peptide antibody-negative patients with recent-onset undifferentiated arthritis

Anti-cyclic citrullinated peptide (anti-CCP) antibodies are well-established serological markers that show high sensitivity and specificity in early rheumatoid arthritis (RA) and are associated with bone erosions of RA. However, some patients subsequently progress to RA even if there is no presence of anti-CCP antibodies in an early stage. The aim of this study is to evaluate the diagnostic utility of matrix metalloproteinase-3 (MMP-3), high-sensitivity C-reactive protein (hsCRP) and IgM rheumatoid factor for predicting RA in anti-CCP-negative patients with recent-onset undifferentiated arthritis (UA). Baseline levels of those markers were measured at the entry of the study. A total of 99 patients with UA were included, among them 44 patients (44.4 %) had been classified as having RA by a skilled rheumatologist at some point during 1-year follow-up. Of these 99 patients, 34 patients (34.3 %) had anti-CCP antibodies and 65 patients (65.7 %) had no anti-CCP antibodies. Eleven patients who were anti-CCP-negative developed RA. We compared sensitivity, specificity, positive predictive value and negative predictive value of serum markers of these anti-CCP-negative RA patients. The combined usage of MMP-3 with hsCRP is relatively superior to other markers as predictors of RA.     

The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis

OBJECTIVE: The shared epitope (SE)-containing HLA-DRB1 alleles represent the most significant genetic risk factor for rheumatoid arthritis (RA). Recent studies indicate that the SE alleles are associated with only RA that is characterized by the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies, and not with anti-CCP-negative disease. In this study we investigated whether the SE alleles contribute to the development of anti-CCP-positive RA, or whether they are associated solely with the presence of anti-CCP antibodies. We therefore determined the influence of the SE alleles and anti-CCP antibodies on the progression from recent-onset undifferentiated arthritis (UA) to RA. METHODS: Patients with recent-onset UA at the 2-week visit (n=570) were selected from the Leiden Early Arthritis Cohort. SE alleles, rheumatoid factor (RF) status, and anti-CCP antibody levels were determined. Progression to RA or other diagnoses was monitored. RESULTS: One hundred seventy-seven patients with UA developed RA during the 1-year followup, whereas the disease in 393 patients remained unclassified or was given other diagnoses. The SE alleles correlated with the presence of anti-CCP antibodies, but not with the presence of RF. Both in SE-positive and in SE-negative patients with UA, the presence of anti-CCP antibodies was significantly associated with the development of RA. More intriguingly, however, no apparent contribution of the SE alleles to the progression to RA was found when analyses were stratified according to the presence of anti-CCP antibodies. In patients with anti-CCP-positive disease, the presence of SE alleles was associated with significantly higher levels of anti-CCP antibodies, suggesting that the SE alleles act as classic immune response genes. CONCLUSION: The SE alleles do not independently contribute to the progression to RA from UA, but rather contribute to the development of anti-CCP antibodies.     

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.     

A case of adult periodic fever,aphthous stomatitis,pharyngitis, and cervical adenitis (PFAPA) syndrome associated with endocapillary proliferative glomerulonephritis

To examine the incorporation of anti-CCP antibodies into the American College of Rheumatology (ACR) classification criteria for rheumatoid arthritis (RA) and to evaluate the advantages of the revised anti-CCP criteria in diagnosing Chinese patients. Patients who suffered from arthritic problems during the recent 2 years were selected from the Department of Rheumatology and Immunology of Peking University People's Hospital. The patients were divided into RA group and non-RA group according to the clinical diagnosis by experienced rheumatologists. The ACR criteria were revised in three ways: (1) replacement of rheumatoid nodules and erosions as criteria with anti-CCP antibodies (RA-6 criteria); (2) replacement of rheumatoid nodules with anti-CCP antibodies as a criterion (RA-7 criteria); (3) addition of anti-CCP antibodies (RA-8 criteria). The diagnostic value of ACR criteria and anti-CCP revised criteria (RA-6, RA-7, and RA-8) were evaluated by comparing the sensitivity and specificity of all criteria, in all subjects and in subjects with arthritis symptoms within 2 years. There were 604 patients included in the study totally, among whom 312 patients were diagnosed as RA and 292 were diagnosed as other rheumatic diseases by rheumatologists. For all the RA patients, the sensitivity and specificity of anti-CCP antibodies were 76.2% and 96%, respectively. Its specificity was much higher than RF (85.2%). For the patients with a disease duration less than two years, the sensitivities were 82.0%, 91.0%, 87.0%, and 87.0%, while the specificities were 95.6%, 83.9%, 95.6%, and 95.6%, respectively, according to 1987 ACR criteria, RA-6, RA-7, and RA-8 criteria. Among all the RA patients, the corresponding sensitivities were 92.3%, 96.8%, 94.6%, and 94.6%, and the specificities were 92.8%, 83.6%, 92.8%, and 92.8%, respectively. The 1987 ACR criteria have high sensitivity and specificity in established RA, but are less sensitive in early RA. The RA-6 criteria improve the sensitivity by reducing its specificity. The RA-7 criteria with replacement of rheumatoid nodules by anti-CCP antibodies increase the sensitivity without losing specificity, which may serve as new classification criteria in routine clinical practice, especially in early RA patients.     

Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala,India

ObjectivesIn this prospective study we evaluated (i) whether the 2010 ACR/EULAR criteria would include patients who were classified as early rheumatoid arthritis (RA) according to the 1987 ACR criteria, and (ii) outcome by classification of patients who were initially classified as undifferentiated arthritis (UA).MethodsEligible cohort (all patients with at least one clinically swollen joint) consisted of 134 patients, of which 120 had clinical diagnosis of RA. All patients were classified using both 1987 and the 2010 criteria at the beginning of the study and 1 year later.ResultsOut of 134 eligible patients 102 were classified as RA based on 1987 criteria. A total of 82 (80%) out of 102 patients were seropositive for RA, i.e. positive for either rheumatoid factor (RF) or anti-citrullinated peptide antibody (ACPA). According to the 2010 criteria, 86 (84%) out of the 102 patients were classified as having RA. Among the 82 seropositive patients, only 1 (1.21%) patient was classified as not having RA whereas, among 20 patients who had seronegative (both for RF and ACPA) RA, 15 (75%) patients were not classified as RA according to the 2010 criteria. Sensitivity and specificity of the 2010 criteria was 96.67% and 92.86%, respectively, compared with 85% and 85.71% by 1987 criteria. 25% of initial UA patients were reclassified as RA by the 2010 criteria at 1 year.ConclusionsThe 2010 criteria did not identify a substantial proportion of seronegative RA classified by the 1987 criteria. Therefore due care must be taken when applying the new criteria to patients with arthritis who are seronegative.     

The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria: Is this still the same disease?

Objective

To examine the implications of using the new classification criteria for rheumatoid arthritis (RA) in clinical practice in a cohort of patients with very early arthritis.

Methods

The study group comprised 301 disease‐modifying antirheumatic drug–naive patients with early arthritis. The baseline diagnosis was assessed by applying the 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria for RA as well as established diagnostic criteria for other rheumatic diseases. Diagnostic and prognostic data were collected after 2 years of followup. Fulfillment of the 2010 ACR/EULAR criteria was evaluated in the subset of patients in whom undifferentiated arthritis (UA) was diagnosed when the 1987 ACR criteria were applied, and fulfillment of RA criteria over time was tested by applying the 2 different criteria sets.

Results

The median arthritis duration at baseline was 4 months (range 0–12 months). At baseline, 28% of the patients fulfilled the 1987 ACR criteria, and 45% fulfilled the 2010 ACR/EULAR criteria for RA. Among the patients classified as having UA at baseline according to the 1987 ACR criteria, 36% had fulfilled the 2010 ACR/EULAR criteria already at baseline. Among the patients classified as having UA at baseline but who fulfilled the 1987 ACR criteria after 2 years of followup, 85% had fulfilled the 2010 ACR/EULAR criteria at baseline. Patients with early disease who fulfilled the 2010 ACR/EULAR criteria were less likely to be autoantibody positive and more likely to have monarthritis at presentation than those fulfilling the 1987 ACR criteria.

Conclusion

Use of the 2010 ACR/EULAR criteria clearly allows earlier diagnosis of RA, although the clinical picture is slightly different on the group level, and RA may be falsely diagnosed in some patients with self‐limiting disease.

     

Comparison of long term outcome of patients with rheumatoid arthritis presenting with undifferentiated arthritis or with rheumatoid arthritis: an observational cohort study

BACKGROUND: The outcome of undifferentiated arthritis (UA) ranges from remission to rheumatoid arthritis (RA) fulfilling the American College of Rheumatology (ACR) classification criteria. OBJECTIVES: To report the outcome of UA after 1 year of follow up and compare the disease course of patients who presented with UA, but evolved into RA within 1 year (UA-RA group), with that of patients who presented with RA fulfilling the ACR criteria (RA-RA group). METHODS: The diagnosis of 330 patients who presented with UA was recorded at 1 year. The UA-RA and RA-RA groups were then followed up for 3 more years. Outcome measurements were radiographic progression, disease activity, and functional capacity. RESULTS: From 330 patients who were diagnosed UA, 91 had evolved into RA at 1 year; 62 patients had presented with RA. No significant differences were detected between the UA-RA and RA-RA groups in median Sharp/van der Heijde score at baseline, radiographic progression rates, disease activity, and functional capacity. However, significantly more disease modifying antirheumatic drugs were prescribed in the RA-RA group. CONCLUSION: The disease outcome of patients who present with UA that evolves into RA within 1 year is the same as that of patients who present with RA as measured by radiographic progression, disease activity, and functional capacity.     

以抗环瓜氨酸肽抗体改进对1987年美国风湿病学会关于类风湿关节炎分类标准的探讨

目的 改进1987年美国风湿病学会(ACR)修订的类风湿关节炎(RA)分类标准,增加抗环瓜氨酸肽(CCP)抗体和(或)保留类风湿结节或放射学改变等,探讨不同条件下的标准(分别称为RA-6、RA-7以及RA-8)对RA诊断的敏感性和特异性.方法 选取2006-2008年于北京大学人民医院风湿免疫科就诊的具有关节症状的患者604例,其中,RA患者312例,其他风湿病患者292例.在总结患者临床和实验室资料的基础上,对1987年ACR分类标准以及RA-6、RA-7和RA-8进行敏感性和特异性分析,并探讨其对于RA,尤其早期RA的诊断价值.结果 ①对于病程≤2年的早期RA患者,1987年ACR标准、RA-6、RA-7和RA-8的敏感性分别为82.0%、91.0%、87.0%和87.0%,特异性分别为95.6%、83.9%、95.6%和95.6%.②在全部RA患者中,1987年ACR标准、RA-6、RA-7和RA-8的敏感性分别为92.3%、96.8%、94.6%和94.6%,特异性分别为92.8%、83.6%、92.8%和92.8%.结论 1987年ACR的RA分类标准对早期RA诊断的敏感性较低.RA-6可以提高诊断的敏感性,但是特异性降低.RA-7和RA-8在提高敏感性的同时并不降低特异性,两者具有相同的诊断价值,但是,RA-7更简便实用,可能对RA诊断有参考意义.     

Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis

OBJECTIVE: Recent data have shown that the most prominent and longest known genetic risk factors for rheumatoid arthritis (RA), HLA-DRB1 shared epitope alleles, are only associated with RA that is characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and not with anti-CCP-negative RA. We undertook this study to investigate whether anti-CCP-negative RA is associated with other HLA-DRB1 alleles. METHODS: HLA typing was performed for 377 patients from the Leiden Early Arthritis Clinic who were diagnosed as having RA within the first year of followup (206 anti-CCP-positive patients and 171 anti-CCP-negative patients), 235 patients who, after 1 year, had undifferentiated arthritis (UA) (28 anti-CCP-positive patients and 207 anti-CCP-negative patients), and 423 healthy control subjects. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for HLA-DRB1 allele frequencies were determined for all patient groups compared with the healthy control group. RESULTS: HLA-DR3 was more frequently present in the anti-CCP-negative RA group than in the control group (OR 1.84, 95% CI 1.26-2.67). This was not the case for anti-CCP-positive RA (OR 0.92, 95% CI 0.60-1.40). HLA-DR3 was also more frequently present in anti-CCP-negative UA patients (OR 1.59, 95% CI 1.10-2.28), but not in anti-CCP-positive UA patients (OR 0.68, 95% CI 0.17-1.92). CONCLUSION: HLA-DR3 is associated with anti-CCP-negative arthritis and not with anti-CCP-positive arthritis. These data show that distinct genetic risk factors are associated with the presence of anti-CCP antibodies in RA and indicate that different pathogenetic mechanisms underlie anti-CCP-positive and anti-CCP-negative RA.     

Diagnostic performances of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis

To evaluate the rheumatoid arthritis (RA) diagnostic performances of anti-cyclic citrullinated peptide antibodies (anti-CCP). Anti-CCP was detected by an enzyme linked immunosorbent assay in 164 patients with RA and 343 controls. In addition, anti-CCP predictive value for radiological damage were investigated in 37 recent-onset RA patients followed up prospectively for 2 years. Radiological damages were assessed by Sharp method modified by van der Heijde. The sensitivity of anti-CCP was 78.7% and the specificity was 95.6%. The positive predictive value and the negative predictive value were 90.2% and 90.3%, respectively. Anti-CCP were detected in sera of 79.3% of patients with recent onset RA and 78.3% of patients with long disease duration. In univariate and multivariate analyses, anti-CCP were not predictive for radiological damage. Our study confirms the high diagnostic performances of anti-CCP in RA. They are very useful to aid the diagnostic of RA in clinical practice.     

Use of anti-citrullinated peptide and anti-RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus erythematosus and rheumatoid arthritis

OBJECTIVES: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) can both present with an erosive arthritis with the small joints of the hands affected. Therefore a serological marker would be useful to distinguish between these two diseases at onset. In this study anti-RA33 antibodies, which are found in patients with SLE and RA, and anti-citrullinated peptide antibodies (anti-CCP), which have recently been described as highly specific for RA, were assessed. METHODS: Two hundred and thirty one patients receiving long term follow up for SLE were evaluated for arthritis and classified as erosive and non-erosive disease. Sixty six patients were tested for anti-RA33 and anti-CCP antibodies. All the patients were tested for rheumatoid factor (RF) and HLA-DR4 status. RESULTS: Ten patients had erosive disease, six of whom were RF positive (60%), and six anti-RA33 positive (60%), whereas only two were anti-CCP positive (20%). Two hundred and twenty one patients had non-erosive disease, 40 of whom were RF positive (18%), 14 were anti-RA33 positive (6%), whereas only one patient was found to be anti-CCP positive (0.5%). CONCLUSION: The presence of anti-CCP antibodies may be useful in distinguishing RA from erosive SLE. Anti-RA33 antibodies and RF are unhelpful.     

Rheumatoid factor and antibodies to cyclic citrullinated Peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis

OBJECTIVE: To study the diagnostic value of IgM rheumatoid factor (RF), IgA-RF, antibodies to cyclic citrullinated peptide (anti-CCP), and combinations of these antibodies, measured at baseline, to discriminate rheumatoid arthritis (RA) from undifferentiated polyarthritis (uPA) in patients with recent onset arthritis. METHODS: Patients with early arthritis with peripheral arthritis of 2 or more joints and symptom duration less than 3 years were clinically diagnosed as having RA or uPA by an experienced rheumatologist during the first year. Patients with bacterial, psoriatic, or crystal induced arthritis or spondyloarthropathy were excluded. Optimal cutoff values for serum IgM RF, IgA RF, and anti-CCP were deduced from receiver operating characteristics curves in order to predict the diagnosis of RA in early arthritis. RESULTS: A total of 379 patients (69% female, median age 57 yrs, range 17-86 yrs) were studied; 258 patients were clinically diagnosed as RA and 121 as uPA. Both IgM-RF > 40 IU/ml and anti-CCP > 50 AU/ml showed high specificity, but the sensitivity of these tests was low. In many RA patients the occurrence of IgM-RF and anti-CCP antibodies was independent. Thus the optimal criterion proved to be the combination of IgM-RF > 40 or anti-CCP > 50, which yielded sensitivity of 55.4% and specificity of 96.7%. CONCLUSION: The criterion IgM-RF > 40 or anti-CCP > 50 is able to predict the diagnosis of RA in early arthritis patients with high specificity and acceptable sensitivity. Anti-CCP testing combined with IgM-RF testing has additional value over IgM-RF testing alone in patients with early undifferentiated oligo and polyarthritis.     

Anti-cyclic citrullinated peptide: diagnostic and prognostic values in juvenile idiopathic arthritis and rheumatoid arthritis in a Chinese population

OBJECTIVE: The incidence and clinical significance of anti-cyclic citrullinated peptide (CCP) antibodies in a cohort of Chinese patients with juvenile idiopathic arthritis (JIA) and adults with rheumatoid arthritis (RA) were studied. METHODS: Anti-CCP antibodies were determined by enzyme-linked immunosorbent assay (ELISA) in 59 patients with JIA, 129 adult RA patients, 48 children with diseases other than JIA, 68 adult patients with rheumatic diseases other than RA, and 60 normal adults. Associations between anti-CCP antibodies and clinical and laboratory parameters were determined by Fisher's exact test. RESULTS: Six of 59 (10.2%) patients with JIA and 71 of 129 (55%) patients with RA were positive for anti-CCP. Four of five RF-positive JIA patients and two of 54 RF-negative JIA patients were positive (p<0.001). One paediatric patient with allergy (0.9%) and two adult patients with rheumatic diseases other than RA (2.3%) were positive. All healthy controls were negative for anti-CCP. The specificity was 99.1% for JIA and 98.4% for RA. The sensitivity was 10.2% for JIA and 55% for RA. Positive predictive values were 85.7% for JIA and 97.3% for RA and negative predictive values were 66.9% for JIA and 68.5% for RA. CONCLUSION: The anti-CCP antibody assay is a valuable tool for the diagnosis of RA and a subset of JIA in Chinese patients. It could be a useful predictive test for joint erosion in JIA of the polyarticular RF-positive subset and may be influential in the choice of the best therapeutic strategy in patients with recent-onset arthritis.     

Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis

OBJECTIVE: To study the prognostic value of antibodies to cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF), alone and in combination, in patients with very early synovitis. METHODS: A cross-sectional study was performed in patients with established inflammatory and noninflammatory disease to validate the assay in our unit and confirm previously reported sensitivities and specificities of anti-CCP antibodies. Subsequently, patients with synovitis of 3 months' duration were followed for 72 weeks and the ability of anti-CCP antibodies and RF to predict the development of rheumatoid arthritis (RA) and persistent inflammatory arthritis was assessed. RESULTS: One hundred twenty-four patients were assessed in the initial cross-sectional study. Anti-CCP antibodies and RF were detected by ELISA in only 4% of patients with non-RA inflammatory disease and in no patient with noninflammatory disease. Ninety-six patients with very early synovitis were assessed longitudinally. In these patients with early arthritis, the combination of anti-CCP antibodies and RF had a specificity, positive predictive value (PPV), sensitivity, and negative predictive value (NPV) for a diagnosis of RA of 100%, 100%, 58%, and 88%, respectively. The specificity, PPV, sensitivity, and NPV of this antibody combination for the development of persistent disease-fulfilling classification criteria for RA were 97%, 86%, 63%, and 91%, respectively. CONCLUSION: In patients with synovitis of 3 months' duration, a combination of anti-CCP antibodies and RF has a high specificity and PPV for the development of persistent RA. This autoantibody combination can be used to identify patients with disease destined to develop RA who may be appropriate for very early intervention.     

Anti-CCP antibodies in rheumatoid arthritis and psoriatic arthritis

Our aim is to assess the prevalence and associated clinical features of anti-CCP (cyclic citrullinated peptide) antibodies for RF (rheumatoid factor)-positive and RF-negative rheumatoid arthritis (RA) and psoriatic arthritis (PsA). In a prospective, cross-sectional, multi-centre study, we determined the titres of anti-CCP antibodies in 208 RA patients (129 RF-positive, 79 RF-negative), 56 PsA patients and 39 healthy controls (HC). Clinical parameters including disease activity (disease activity score 28-DAS28), physical disability (health assessment questionnaire-HAQ), functional capacity (functional class) and radiological erosions were investigated in patients with RA. In PsA patients, clinical and radiological features were determined. Anti-CCP2 antibodies were measured using a second-generation anti-CCP enzyme-linked immunosorbent assay (Euro-Diagnostica, Netherlands). One-hundred four of 129 RF-positive RA (81%), 16 of 79 RF-negative RA (20%), seven of 56 PsA patients (12.5%) and none of the HC had anti-CCP antibodies. RA patients with anti-CCP antibodies had significantly higher disease activity, greater loss of function and more frequent erosive disease than anti-CCP antibody-negative group. In subgroup analysis, anti-CCP antibodies in RF-negative patients were also associated with erosive disease. All PsA patients with anti-CCP antibodies had symmetric arthritis with higher number of swollen joints. The prevalence of anti-CCP antibodies in RF-positive RA patients was significantly higher than in RF-negative RA and PsA patients. Anti-CCP antibodies were also associated with erosive disease in RF-negative RA patients. Both anti-CCP and RF tests were negative in 30% of the patients. Anti-CCP positivity was a frequent finding in PsA and associated with symmetrical polyarthritis.     

The additional benefit of ultrasonography to 2010 ACR/EULAR classification criteria when diagnosing rheumatoid arthritis in the absence of anti-cyclic citrullinated peptide antibodies

The aim of this study was to assess the benefit of ultrasonography (US) contributing to 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria in diagnosing rheumatoid arthritis (RA), when anti-citrullinated protein (CCP) antibody and radiographic erosions are absent. Ninety-four patients suffering from arthritis of at least one joint in hands, symptom duration of less than 2 years, normal radiographs at baseline, and negative anti-CCP had 22 joint US assessments and were followed prospectively for at least 12 months. Sensitivity and specificity for final RA diagnosis based on 1987 RA criteria were determined for ultrasound variables. Logistic regression models were then fitted to evaluate predictive ability over and above the 2010 ACR/EULAR classification criteria. Twenty-nine of them were classified as RA patients and 65 had alternative diagnoses. There were significantly more joints with synovial hypertrophy, synovitis, and bone erosion detected by US in RA patients. The gray-scale (GS) variables positively correlated with acute phase reactants. The area under curve (AUC) values of GS and power Doppler (PD) were comparable, higher than bone erosion. However, regression analysis demonstrated that only PD involvement of joints, especially wrists, provided independently predictive data, with improved AUC values from 0.738 to 0.872 combined with 2010 ACR/EULAR classification criteria. PD scanning of hand joints, especially wrists, may provide independently assistance to 2010 ACR/EULAR criteria in the early diagnosis of RA in those patients who are negative for anti-CCP antibody.     

Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity

OBJECTIVE: To measure serum levels of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and serum cartilage oligomeric matrix protein (COMP) in patients with early joint inflammation, and to study the correlation of these two tests with clinical measurements. METHODS: Adult patients with recent-onset arthritis, of <3 months' duration, were referred from primary healthcare centres to rheumatologists. Serum levels of anti-CCP antibodies and COMP at baseline were analysed by enzyme immunoassay (EIA) and compared with clinical baseline data. RESULTS: Sixty-nine patients were included. The specificity of the anti-CCP antibody test for RA was 96%, and the sensitivity was 44%. There was a significant difference between the four diagnosis groups in the anti-CCP antibody test, probability (p)<0.001, whereas no significant differences were found concerning COMP. The baseline serum COMP test correlated with age (p=0.0001), joint score for swollen joints (p=0.02), and C-reactive protein (CRP) (p=0.02). CONCLUSION: This study confirms the high diagnostic specificity of anti-CCP antibodies for rheumatoid arthritis (RA) in a prospective population-based study of very early arthritis. Raised serum COMP levels were common in all diagnosis groups in this series, indicating cartilage involvement in both self-limiting and non-erosive disease.     

Clinical features and independent predictors in the further development of rheumatoid arthritis in undifferentiated arthritis

This study aims to investigate the prognosis of undifferentiated arthritis (UA) and to estimate the putative predictors contributing to predict the development of UA into rheumatoid arthritis (RA); thus, it could improve appropriate medical intervention. A retrospective cohort study of 218 patients with an initial diagnosis of UA and 2-year follow-up monitoring was carried out. The baseline information including demographic variables, clinical features, and laboratory data was collected. A logistic regression model was used for the statistical analysis. After 2 years of follow-up, 20.18 % of UA patients evolved into RA, but 33.03 % remained undifferentiated. Meanwhile, 25.23 % went into remission, and 21.56 % developed into other connective tissue diseases. Univariate and multivariate analysis showed that the titer of antibodies to cyclic citrullinated peptide (anti-CCP), tender joint count and duration of morning stiffness were independent predictors for the development of RA. The area under the curve (AUC) of duration of morning stiffness (0.81) was largest, followed by tender joint count (0.74). The AUC of anti-CCP antibodies (0.68) was higher than that of rheumatoid factor of IgM type (IgM-RF) (0.60), and the combination of these two antibodies was significantly higher than each alone (P < 0.001). In conclusion, UA patients had variable clinical outcomes and prognosis. Only the titer of anti-CCP antibodies, tender joint count, and duration of morning stiffness, instead of IgM-RF, could predict the development of RA. Although the anti-CCP antibody was better than the IgM-RF in predicting RA, a combined detection of them still improved the diagnostic performance.