Latitude gradient influences the age of onset in rheumatoid arthritis patients

The mean age of rheumatoid arthritis (RA) onset is around 50 years as reported in several clinical trials involving Caucasian patients. However, clinical observations suggest that Mexican RA patients’ disease is initiated at a younger age. The objective of the study was to assess whether the age of onset of RA is different in Mexican and in Canadian RA patients. Certified rheumatologists from Canada and Mexico directly interviewed consecutive RA patients attending their clinics regarding the date patients first noticed a swollen joint. None of the participant rheumatologists were aware of the primary aim of this exploratory study at the time of the interviews. Data was gathered from 161 Mexican (91% women) and 130 Canadian (77% women) RA patients collected by three rheumatologists in each country. Duration since disease onset was not different within countries (mean 95% confidence interval [CI] for differences −10 to 16 years, p = 0.12 for Canadians, and −6 to 10 years, p = 0.26, for Mexicans). However, there was a significant difference between the two countries. Mexicans patients on average developed RA almost 12 years younger than Canadians (95% CI for difference 9 to 15 years, p < 0.001). Frequency distribution showed that 35.5% of Canadians but only 4% of Mexicans had the onset of the disease after the age of 55 (all p < 0.001). It appears that RA begins at a much younger age in Mexican than Canadian patients. If this were confirmed after controlling for different confounders and biases, it would have important societal, economic, and therapeutic implications.     

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 association of anti-CCP antibodies with disease activity in rheumatoid arthritis

Antibodies to citrullinated proteins have been described in patients with rheumatoid arthritis (RA) and these appear to be the most specific markers of the disease. Our objective was to determine the frequency of antibodies to cyclic citrullinated peptides (CCPs) in patients with RA and the association of anti-CCP antibodies with disease activity, radiological erosions and HLA DR genotype. Forty patients with RA and 38 patients with fibromyalgia were included in this study. Serum samples were collected from both patient groups with RA and fibromyalgia. Anti-CCP was measured by the corresponding enzyme-linked immunosorbent assay. Additionally, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), disease activity score (DAS), visual analog scala (VAS), HLA genotype and radiographic information were determined in patients with RA. The rate of sensitivity and specificity of anti-CCP reactivity for the diagnosis RA were measured (sensitivity 50%, specificity 100%). There is no significant difference between anti-CCP (+) and anti-CCP (-) RA patients for DAS28, VAS, ESR, CRP, disease duration, HLA genotype, and radiological assessment of hand. However, there was a significant difference between anti-CCP (+) and anti-CCP (-) RA patients for RF and the radiological assessment of left and right wrists (respectively, P < 0.05, P = 0.04, P = 0.01). There was no significant correlation between anti-CCP antibody and ESR, CRP, VAS, DAS 28 or radiological assessment. A small but significant correlation was found between RF and anti-CCP antibody (P = 0.02, r = 0.35).     

Differences in anti-Fab antibodies in adult and late onset rheumatoid arthritis

Summary In the present study the ratio of antigen-bound anti-IgG-Fab antibodies (hidden aFab) to free aFab was found to be significantly increased in patients with adult onset rheumatoid arthritis (AORA) as compared to late onset rheumatoid arthritis (LORA). The overall amount of aFab was similar in both groups. The difference was only seen in seropositive patients. Within the seropositive AORA group, the aFab ratio was correlated with the duration and the stage of disease but not with the patients' age at investigation. This might reflect a higher affinity of anti-Fab antibodies and/or a greater diversity of the idiotypic repertoire in adult onset disease resulting in the formation of immune complexes, the stability of which might be enhanced further by the presence of rheumatoid factors. Although a pathophysiological involvement of aFab cannot be concluded from our observations, it is conceivable that different immunoregulatory mechanisms could be operative in RA with onset at different ages.     

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.     

抗角蛋白抗体在类风湿关节炎的临床意义

目的研究抗角蛋白抗体(AKA)在类风湿关节炎(RA)的临床意义。方法98例RA患者及70例其他风湿性疾病患者测定血清抗角蛋白抗体,对两组病人AKA阳性率进行比较,并对抗角蛋白抗体与类风湿因子(RF)对RA诊断的敏感性和特异性进行比较,同时对RA患者AKA阳性组和AKA阴性组的关节肿胀指数、关节压痛指数、握力、晨僵时间、休息痛和RF、血沉、C反应蛋白、影像学检查以及关节外表现等临床指标进行比较,对资料进行统计分析。结果RA患者AKA阳性率明显高于其他风湿性疾病患者(P<0.001);AKA对于RA诊断较RF更具特异性;RA患者中AKA阳性组较AKA阴性组病情严重,除握力外各项观察指标比较均有统计学意义(P<0.05)。结论AKA检测对RA诊断、病情预测和指导治疗均有较高的临床价值。     

Clinical relevance of antikeratin antibodies in rheumatoid arthritis

Summary Antikeratin antibodies (AKA) were found in 38 out of 96 patients with rheumatoid arthritis (RA); they appeared to be quite characteristic to this disease. There was a very low incidence of AKA positivity in the control groups, i.e., 1 out of 62 healthy subjects and 4 out of 158 other patients. With regard to the sensitivity of the test as a diagnostic tool, AKA was found to be weaker than the rheumatoid factor (RF) and the antiperinuclear factor (APF), whereas the specificity was much better than APF and RF. A clear correlation was shown between the titres of AKA and APF (p<0.001) and also between AKA levels and inflammation (p<0.02).     

High prevalence of rheumatoid factor associated with clinical manifestations of rheumatic disease in Kaingang and Guarani Indians from Southern Brazil

The aim of the present study was to perform a screening for rheumatoid factor (RF) and anti-nuclear antibody in Kaingang, Guarani and Mestizos individuals from Mangueirinha Reservation, State of Paraná, Brazil, and associate it with demographic and clinical data. Serum samples from 321 aborigines (125♂ and 196♀; 4–86 years old) and 180 non-Indians healthy individuals were analysed (62♂ and 118♀; 2–81 years old). Antinuclear antibody (ANA) was tested by indirect immunofluorescence, and RF by agglutination in latex and turbidimetry. RF was higher in Kaingang when compared to Guarani (P = 0.009), Mestizos (P = 0.061) and non-Indians (P = 0.010). A significant increase of RF was observed in Kaingang women versus Kaingang men (P = 0.002) and, among the women, in Kaingang when compared to Mestizos and Guarani (P ≤ 0.008). The positivity for ANA did not show significant differences between the groups. Clinical evaluation of RF positive individuals (n = 6) confirmed rheumatoid arthritis in two Kaingang Indians. Other two individuals (RF positive) will be under medical observation, as well as two Mestizos. The differences observed among the investigated groups, suggest the influence of genetic and hormonal factors in the development of auto antibodies in these populations.     

Complement-activating properties of immune complexes are suppressed by IgM rheumatoid factor and enhanced by IgG rheumatoid factor

Summary The effect of rheumatoid factor (RF) on complement-activating capacity of aggregated IgG was investigated. The degree of complement activation induced by the addition of specific amounts of aggregated IgG to patients' sera and normal sera was demonstrated by the inhibition of hemolytic activity (%IHA). The %IHA was significantly lower in rheumatoid arthritis (RA) sera and higher in systemic lupus erythematosus (SLE) sera, compared with normal sera. There was a negative correlation between %IHA and IgMRF/IgGRF ratio in RA and SLE sera, and RA synovial fluid. The %IHA and IgGRF were positively correlated in RA sera. The IgMRF/IgGRF ratio was significantly lower in SLE sera than in RA sera and systemic sclerosis sera, and was significantly lower in RA synovial fluid than in osteoarthritis synovial fluid.Isolated RF, consisting of mostly IgMRF class, inhibited complement-activating properties of aggregated IgG, depending on the concentration of RF. Isolated RF was further purified by the fractionation using high pressure liquid chromatography, and IgGRF and IgMRF were obtained. IgMRF significantly suppressed the complement-activating capacity of aggregated IgG, whereas IgGRF promoted it. These observations suggest that IgMRF acts protectively, while IgGRF induces inflammation.Thus, the expression of the biological activity of RF with special reference to immune complex interaction mainly depends on the IgMRF/IgGRF ratio.     

Clinical significance of anti-Ro antibodies in rheumatoid arthritis

The objective of our study was to determine the frequency of anti-Ro antibodies in patients with rheumatoid arthritis (RA), their clinical significance and possible serologic and genetic associations. Consecutive patients with RA (ACR ’87) were studied. Other connective tissues diseases were excluded. Demographic characteristics, extra articular manifestations, and treatment were reviewed. Presence of leukopenia, thrombocytopenia, hypergammaglobulinemia, hypocomplementemia, and cryoglobulinemia were consigned. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anti-Ro, and anti-La were determined by ELISA in all patients; and HLA-DR was determined by PCR and oligotyping. X-rays of the hands and feet were evaluated by Larsen’s score. The study included 106 patients, 94 women and 12 men; mean age was 50.3 ± 11.4 years, mean disease duration was 11.2 ± 6.8 years. Main extra articular manifestations were subcutaneous nodules, xerophthalmia, and xerostomia; 75.5% of the patients were RF+. Anti-Ro antibodies were detected in 12.2% of the patients. When positive and negative anti-Ro patients were compared, no significant difference in any studied variable was observed. According to our results, anti-Ro antibodies lack clinical relevance in patients with RA.     

Significance of rheumatoid factor isotypes in seronegative rheumatoid arthritis

Summary In a cross-sectional study of 124 patients with definite or classical rheumatoid arthritis (RA) and negative agglutination assays, rheumatoid factor (RF) isotypes were measured using an ELISA technique. Elevated levels of IgA-RF were found in 55 patients (44%), IgG-RF in 99 (80%), and IgM-RF in 20 (16%). The levels of IgA- and IgM-RF correlated with each other (P<0.001). Elevated levels of IgM-RF were associated with a more severe disease course. Elevated levels of IgA-RF correlated with the occurrence of bone erosions. The results of this study suggest that in patients with RA and negative agglutination assays, both IgM- and IgA-RF are markers of disease severity.     

Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis

The diagnostic value of measuring rheumatoid factor (RF) by agglutination or isotype-specific enzyme-linked immunosorbent assay (ELISA) was compared. The study included 70 patients with rheumatoid arthritis (RA) and 205 patients with various other rheumatic conditions. Of the RA patients, 74% were RF-positive by agglutination and 90% had one or more RF isotypes elevated by ELISA compared to 14% and 22%, respectively, of the other patients. Strikingly, 70% of the RF-positive RA patients had an elevation of two or more RF isotypes compared to only 16% of the other RF-positive patients (P<0.0001). Furthermore, a combined elevation of IgM and IgA RF was found in 52% of the RF-positive RA patients, but only in two (4%) of the other RF-positive patients (P<0.0001). It is concluded that a combined elevation of IgM and IgA RF is highly specific for RA and is very rarely found in rheumatic diseases other than RA. Isotype-specific RF assays are therefore diagnostically superior to agglutination tests. The detection of the RA-specific RF isotype pattern may be particularly helpful early in the course of RA even before the disease is fully differentiated. Received: 10 December 1997 / Accepted: 25 June 1998     

抗环瓜氨酸肽抗体类风湿因子与类风湿关节炎活动度及骨侵蚀相关性的研究

目的探讨抗环瓜氨酸肽抗体（ACCP）及类风湿因子（RF）各亚型与类风湿关节炎（RA）疾病活动度及骨质侵蚀的相关性.方法收集110例RA患者,用SPSS10.0软件比较ACCP、RF（IgA、IgM、IgG）与病情活动指数（disease activity score,DAS）、Ritchie′s指数（Ritchie′s articular index,RAI）的相关性,以判断ACCP、RF（IgA、IgM、IgG）与疾病活动度的关系.将病程＞2年的病例分为骨质侵蚀组和非骨质侵蚀组,比较两组之间ACCP、RF（IgA、IgM、IgG）的差异.结果经Spearman相关分析,IgM-RF与RAI呈正相关,ACCP及RF其他亚型与DAS、RAI未显示明显相关性.ACCP、RF各亚型与骨质侵蚀均未表现明显相关性.结论IgM-RF与疾病活动度相关,ACCP及RF各亚型与骨质侵蚀未表现出相关性.     

Serum IgG activity against cyclic citrullinated peptide in patients evaluated for rheumatoid factor correlates with the IgM isotype

The purpose of this study was to evaluate the frequency of seric antibodies against cyclic citrullinated peptide (a-CCP) in patients tested for rheumatoid factor (RF) reactivity, and to analyze the correlation between their titers. We obtained serum from 112 consecutive patients (85 female), aged 47.2 +/- 13.4 years and from 46 clinically healthy subjects (CHS). Patients where stratified into four subgroups: rheumatoid arthritis (RA), probable RA (PRA), spondylarthropathies and other diagnosis. The a-CCP antibodies were determined by enzyme linked immunoassay (ELISA), RF by nephelometric test (IgM) and ELISA (IgG and IgM). Analysis of variance (ANOVA) showed statistically that a-CCP antibodies differs among RA versus CHS and other diagnosis; PRA versus CHS and other diagnosis. A significant Rho value of 0.84 (P < 0.05, Spearman's correlation) was identified between a-CCP antibodies and RF in PRA subgroup. When a correlation of a-CCP antibodies with RF (both isotypes) was done, the higher correlation was observed against IgM RF. The data suggests different pathways and times for each antibody generation.     

用受试者工作曲线评价抗环瓜氨酸肽抗体对诊断类风湿关节炎的价值

目的评价抗环瓜氨酸肽抗体(抗CCP抗体)在类风湿关节炎(RA)诊断中的价值。方法收集110例RA患者,与38例其他疾病患者以及36名正常人作为对照,应用受试者工作曲线(re-ceiveroperativecharacteristiccurve,ROC)分析软件评价抗CCP抗体在RA诊断中的价值,在ROC曲线上制定抗CCP抗体与类风湿因子(RF)各亚型在诊断RA中的最佳临界点。用四格表计算系列试验的特异度,进行统计学检验。用SPSS软件比较抗CCP抗体与RF各亚型之间的相关性。结果在诊断RA中,抗CCP抗体的ROC曲线下的面积(AUCROC)明显大于RF(IgA、IgM、IgG)AUCROC(P<0.01),抗CCP抗体联合任何一个RF亚型的系列试验的特异度高达100%。抗CCP抗体和RF(IgA、IgM、IgG)经Spearman相关分析,呈正相关。结论抗CCP抗体对RA有较高的诊断价值;诊断RA的系列试验中,含抗CCP抗体的系列试验的特异度高。     

Value of anti-mutated citrullinated vimentin antibodies in diagnosing rheumatoid arthritis

We assessed the diagnostic value of anti-mutated citrullinated vimentin antibodies (anti-MCV) and compared it with those of anti-cyclic citrullinated peptide antibodies (anti-CCP), IgA (ARF), IgM (MRF) and IgG (GRF) rheumatoid factors for rheumatoid arthritis (RA). Serum samples of 170 RA patients, with early and established RA, and 309 controls were tested for anti-MCV, anti-CCP, ARF, MRF and GRF using commercially available ELISA kits. Cut off of different tests was determined with ROC curves. The sensitivity and the specificity of anti-MCV were 74.1 and 79%, respectively. Sixty-five of 309 (21%) controls were anti-MCV positive. Sensitivity and specificity of anti-CCP were 72.4 and 96.1%, respectively. Only 12 of 309 (3.9%) controls were anti-CCP positive. Sensitivity of ARF, MRF and GRF were 64.1, 65.9 and 68.2%, respectively. Their specificity was 79.6, 74.4 and 68.9%, respectively. No significant association was observed between the antibodies tested and extrarticular manifestations. Anti-MCV shows comparable sensitivity but lower specificity than that of anti-CCP. They do not appear to be very useful in the diagnosis of RA.     

Diagnostic utility of anti-cyclic citrullinated peptide antibodies for rheumatoid arthritis in patients with active lung tuberculosis

This study was intended to evaluate the utility of anti-cyclic citrullinated peptide antibodies (second generation, anti-CCP2) as a diagnostic marker for rheumatoid arthritis (RA) in patients with active tuberculosis. Among 89 patients with active tuberculosis, anti-CCP2 was detected in six (6.7%), and three of these (3.4%) were strongly positive for anti-CCP2. The positive rate of anti-CCP2 in patients with newly diagnosed RA was 82.1% (87 of 106 cases), while the rate in healthy control subjects was 0.4% (one of 237 individuals). The mean level of anti-CCP2 among the RA group was 159.3 U/ml, which was significantly higher than both that among the tuberculosis group (15.4 U/ml) and that among the healthy controls (0.7 U/ml). IgM rheumatoid factor (RF) was detected in 16 patients from the tuberculosis group (18.0%) with a mean serum level of 18.6 IU/ml and in 77 patients of the RA group (72.6%) with a mean level of 164.0 IU/ml. Only two cases in the tuberculosis group were positive for both anti-CCP2 and IgM RF. These observations show that measurement of anti-CCP2 seems to be a reliable serological tool for identifying early RA in patients with active tuberculosis.     

中国汉族类风湿关节炎患者HLA-DR4基因与抗环瓜氨酸肽抗体的相关性研究

目的：探讨中国汉族类风湿关节炎（RA）患者中抗环瓜氨酸肽抗体（ACCP）与人类白细胞抗原（HLA）-DR4基因的相关性。方法：入选RA104例、正常对照122名。ACCP检测采用酶联免疫吸附法（ELISA）,类风湿因子检测采用散色比浊法,HLA-DR4基因采用序列特异性引物-聚合酶链方法（PCR-SSP）检测。结果：RA患者中HLA-DR4基因携带率为34.6%,主要亚型为HLA-DRB1＊0405,正常对照组为17.2%,差异有统计学意义（P=0.01）。RA患者的共同表位（SE）携带率为30.9%,与国内相关研究结果（33.2%,36.8%）相似,但明显低于国外相关研究（78.5%,65.4%,85%,67%）,差异有统计学意义（P〈0.01）。RA患者中ACCP阳性率为76.5%,与国内外报道相符,正常对照组为0,两者差异有统计学意义。SE（＋）患者的ACCP阳性率为84%,SE（-）患者的ACCP阳性率73.2%,两者差异无统计学意义。RA患者中ACCP的滴度与X线分期相关（r=0.233,P〈0.05）。结论：我国汉族RA患者中ACCP与HLA-DR4或SE无明显的相关性。ACCP可能与关节破坏的严重程度相关。