Value of laboratory tests in early prediction of rheumatoid arthritis

OBJECTIVE: To determine which laboratory test or tests at presentation best predicted a diagnosis of rheumatoid arthritis (RA) 2 years later. METHODS: Two hundred seventy patients with early arthritis seen in 7 hospitals underwent comprehensive evaluations at 6-month intervals for 2 years, when the diagnosis of RA was assessed by 5 rheumatologists. The sensitivity and specificity of each test at the first visit for discriminating between RA (38%, n = 98) and non-RA patients were determined. Optimal cutoffs for continuous tests were derived from receiver operating characteristic curves. Sensitivity and specificity of test combinations selected by multiple logistic regression were determined. RESULTS: IgM rheumatoid factor (RF) by enzyme-linked immunosorbent assay, IgG-antikeratin antibody (AKA), and latex test had the strongest associations with RA. These 3 tests formed the most powerful combination for distinguishing RA from non-RA. CONCLUSION: IgM-RF, IgG-AKA, and the latex test are the best laboratory tests for discriminating between patients with and without RA. Combining these tests slightly improves diagnostic value.     

Elevation of only one rheumatoid factor isotype is not associated with increased prevalence of rheumatoid arthritis--a population based study

OBJECTIVE: To analyse the relationship between different rheumatoid factor (RF) isotype patterns and the prevalence of RA. METHODS: Serum samples, collected between 1973 and 1983 from nearly 14,000 randomly selected individuals, were screened for elevation of RF. In 1987, 173 RF positive and 156 matched RF negative participants were evaluated clinically. RESULTS: Participants with elevation of only one RF isotype, most commonly IgM, did not have significantly higher prevalence of RA than the RF negative controls. Of the 17 RF positive individuals who were diagnosed with RA, 14 (82%) had a combined elevation of IgM and IgA RF. CONCLUSION: In contrast to a combined elevation of IgM and IgA RF, elevation of only one RF isotype may not be a significant risk factor for the development of RA.     

Diagnostic and prognostic characteristics of the enzyme linked immunosorbent rheumatoid factor assays in rheumatoid arthritis.

OBJECTIVE: To determine the diagnostic and prognostic test qualities of the enzyme linked immunosorbent assays (ELISA) for rheumatoid factor isotypes in rheumatoid arthritis (RA), and to compare them with the latex fixation test. METHODS: Rheumatoid factor tests were performed in 1988 consecutive new rheumatology outpatients within two months after their first visit to the outpatient clinic of the Department of Rheumatology of Leiden University hospital. The sensitivity, specificity, accuracy, and predictive values of the tests in discriminating RA from non-rheumatoid arthritis and erosive from non-erosive disease after two years of follow up were determined and presented as receiver operating characteristic curves and post-test probability curves. RESULTS: The sensitivity of the ELISA for IgG, IgA, and IgM rheumatoid factor for RA versus all controls at optimal cut off titres was 72%, 44%, and 69%, respectively; the specificity was 52%, 84%, and 86%. For the latex fixation test the sensitivity was 66% and the specificity 91%. The post-test probability of RA, at a clinical prevalence rate of 12%, given a positive test result in the ELISAs for IgG, IgA, and IgM rheumatoid factor and the latex fixation test, was 17%, 27%, 40%, and 49%, respectively; with negative test results the probability was 7%, 8%, 5%, and 5%, respectively. The specificity of all tests in discriminating erosive from non-erosive RA at two years was low: 41%, 44%, 47%, and 58% for the ELISAs for IgG, IgA, and IgM rheumatoid factor and the latex fixation test, respectively. CONCLUSION: The ELISAs for IgG and IgA rheumatoid factor are of no significance in diagnosing RA and in the prediction of erosive disease. The ELISA for IgM rheumatoid factor is a reasonable alternative for the latex fixation test when age and gender are taken in to consideration. The specificity of all rheumatoid factor tests in discriminating erosive from non-erosive RA is low.     

Population study of the importance of rheumatoid factor isotypes in adults.

Blood samples collected from 13,858 randomly selected subjects participating in a health survey in Iceland from 1974 to 1983 were tested for rheumatoid factor. Samples that were positive in a sensitive RF screening test were analysed further by the Rose-Waaler technique and an isotype specific enzyme linked immunosorbent assay (ELISA). In 1987 the 173 available participants who were RF positive and 156 matched RF negative controls were evaluated clinically for rheumatoid diseases. RF levels and isotype patterns were more persistent in the patients with rheumatoid arthritis (RA) than in RF positive subjects who did not have overt RA. The prevalence of RA was only 19% in the participants who were RF positive in 1987. Forty per cent of the participants who had a persistent (four to 13 years) increase of IgA RF combined with either IgM or IgG RF were diagnosed as having RA. A positive correlation was found between RF levels and various manifestations of RA. This association was stronger for the IgA and IgG RF isotypes than for IgM RF. Excluding RF positivity as a diagnostic parameter, RA was diagnosed in 33 of the participants and 20 (61%) of these patients had increased levels of IgM and IgA RF. Patients with RA with bone erosions in their hands had higher levels of IgA RF than patients without erosions, but an association was not found between bone erosions and other RF isotypes. None of the RF negative participants who were symptom free when the original blood sample was taken developed RA during the four to 13 year follow up period. In contrast, five symptom free RF positive participants developed RA during this period. These five patients had all had increased levels of at least two RF isotypes before the onset of their symptoms. It is concluded that the IgA and IgG RF isotypes have a closer association with the clinical parameters of RA than IgM RF. Furthermore, increases in RF can precede clinical manifestations of RA and this applies in particular to the IgA and IgG RF isotypes.     

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     

Isotypes of rheumatoid factors in rheumatoid arthritis and chronic liver diseases

We studied isotype-specific rheumatoid factors (RFs) to clarify their significance in rheumatoid arthritis (RA) and to verify the difference in RF isotypes between RA and chronic liver diseases (CLD). Isotype-specific RFs in RA and in CLD were measured by enzyme-linked immunosorbent assay (ELISA). Most sera (n = 51, 94.1%) from RA patients contained some kind of RF isotypes (92.1% for IgM RF, 76.4% for IgG RF, and 43.1% for IgA RF), and seronegative RA by ELISA was seen in only 11.8% (n = 6). The most characteristic combination of RF isotypes in active RA was IgG, IgA, and IgM. This combination of RF isotypes changed to IgG plus IgM, according to the diminution of RA activity; then, we found only IgM RF in inactive RA. The titers of each RF isotype also decreased in parallel with the activity of RA. IgA RF seemed to be the most sensitive factor for evaluating the activity of RA. In CLD, almost the same high frequency (n = 49, 89.8% for IgM RF, 59.2% for IgG RF), with the same titer levels seen in RA, was observed. On the other hand, IgA RF was significantly lower in frequency (n = 9, 18.4%) and in titer, compared with the finding in RA. Surprisingly, even in CLD, true seronegativity by ELISA was also found in very few patients (n = 4, 8.1%). In CLD, positive RFs detected by agglutination assay were seen more often in chronic hepatitis than in liver cirrhosis. In RA patients, significant associations of IgA RF and the serum concentration of IgA, and IgG RF and the serum concentration of IgG, were observed. On the other hand, in CLD patients, significant associations of IgG RF and the serum IgG concentration, and of IgM RF and the serum IgM concentration, were observed. These results indicated that IgA RF in active RA is the most characteristic RF isotype distinguishing it from other nonrheumatic diseases, as well as from inactive RA. RF isotypes reflected the background polyclonal B-cell activation in different manners in both diseases. In CLD, RF isotypes seemed to be disease-related immunological disorders reflecting disease progression. Received: February 17, 2000 / Accepted: July 5, 2001     

Rheumatoid factor isotypes and circulating immune complexes in rheumatoid arthritis

Solid phase enzyme immunoassays were here used to quantify rheumatoid factors (RF) of the IgM, IgG and IgA classes and the immune complexes (IK) by their ability to bind to C1q or conglutinin in both the serum and synovial fluid of patients with rheumatoid arthritis (RA). Elevated serum levels of any RF isotype could be found in all patients with seropositive RA (IgM: 63%, IgG: 87%, IgA: 90%). Seronegative patients with RA presented to a significantly lesser extent with elevated levels of all the RF isotypes tested (IgM: 0%, IgG: 40%, IgA: 32%). Synovial fluid RF levels were significantly higher in SPRA patients than in SNRA patients with the exception of IgG-RF. All of the RF classes in both RA groups, however, were elevated when compared to RF in the synovial fluid of patients with osteoarthrosis. Both C1q binding and conglutinin binding immune complexes were significantly higher in the synovial fluid than in the serum of RA patients. The erythrocyte sedimentation rate and plasma iron levels were correlated with the levels of C1q binding immune complexes (IC) in the synovial fluid; total iron binding capacity showed an inverse relationship to synovial fluid IgG-RF levels. A radiographic index was also correlated with IgG-RF levels in the synovial fluid. Extraarticular manifestations were significantly more frequent in patients with elevated serum levels of IgM-RF or conglutinin binding IC. These findings indicate that IgG-RF in the synovial fluid and the formation of IC determined by their ability to bind C1q seem to be closely related to clinical features of local disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-cyclic citrullinated peptide antibody isotypes in rheumatoid arthritis: association with disease duration, rheumatoid factor production and the presence of shared epitope

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies of IgG isotype are specific diagnostic markers of rheumatoid arthritis (RA). Recent evidence also points to their direct involvement in the pathophysiology. Little information is available, however, regarding the isotype distribution of anti-CCP antibodies and the characteristics of IgA and IgM anti-CCP. METHODS: IgG, IgA and IgM anti-CCP2 and rheumatoid factor (RF) levels were measured in the sera of 119 RA patients and 118 controls, including patients with other rheumatic diseases and healthy subjects. We analyzed the diagnostic performance of IgA and IgM anti-CCP2 antibodies and their relationship with IgG anti-CCP2, RFs, disease duration and the presence of HLA-DRB1 shared epitope (SE) alleles. RESULTS: Patients with RA had significantly higher serum IgA and IgM anti-CCP2 antibody levels than healthy subjects and patients with other rheumatic diseases (p<0.0001). IgG, IgA and IgM anti-CCP2 antibodies were present in 74.8%, 52.9% and 44.5% of RA patients, and their diagnostic specificity was 95.8%, 95.8% and 91.6%, respectively. The presence of anti-CCP2 antibodies was significantly associated with SE alleles (p=0.03). The frequency of IgM anti-CCP2 positivity was lower in longstanding disease compared to early RA (p=0.03). CONCLUSION: IgA and IgM anti-CCP2 antibodies are present in RA patients, and they are similarly specific for RA as IgG anti-CCP2. The higher frequency of IgM anti-CCP2 antibodies in early RA suggests that they are mostly generated during the first phase of immune response; nonetheless, their production seems to be sustained in some patients. Further analysis of IgM and IgA anti-CCP2 antibodies may provide insights into the pathogenesis of RA.     

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。     

IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF detected by ELISA in rheumatoid arthritis.

One hundred patients with rheumatoid arthritis (RA), of whom 73 were seropositive by latex or Waaler-Rose (WR) assays, or both, 100 healthy subjects, and 102 diseased controls (22 patients with systemic lupus erythematosus (SLE) and 80 with bronchial asthma) were evaluated for the presence of IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF by an enzyme linked immunosorbent assay (ELISA). Ninety two per cent, 65%, 68%, and 66% of the patients with RA were found to be positive for IgM, IgA, IgE, and IgG respectively. A positive correlation existed between the levels of IgM RF and IgA RF on the one hand and disease activity on the other, and the levels of IgM RF and IgA RF correlated with the levels of circulating immune complexes as measured by a C1q binding assay. The presence of extra-articular features also correlated positively with the levels of IgA RF and IgE RF. Five out of six patients with Sjögren''s syndrome had very high levels of IgA RF. Of 47 patients typed for HLA-DR, DR1 and DR2 were significantly more frequent in those with the highest levels of IgM RF. Conversely, DR3 was associated with low levels or absence of IgA RF and IgE RF. These results suggest that immune response genes may regulate the level of different RF isotypes. The frequencies of IgM, IgA, IgE, and IgG RF were 59%, 36%, 9%, and 27% respectively in SLE and 25%, 2.5%, 70%, and 59% in bronchial asthma.     

Determination of anti-cyclic citrullinated peptide antibodies in the sera of patients with juvenile idiopathic arthritis

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been found in sera of 76% of patients with rheumatoid arthritis (RA), mainly in rheumatoid factor (RF) positive patients, with a specificity of 96%. We evaluated the presence of anti-CCP antibodies in patients with juvenile idiopathic arthritis (JIA) and assessed the possibility of synthetic citrullinated peptides as antigenic determinants in JIA. METHODS: The presence of anti-CCP antibodies was determined using 3 synthetic citrullinated peptide variants and 2 commercial kits (Inova Diagnostics and Axis-Shield Diagnostics) optimized for detecting JIA-specific antibodies in serum by an ELISA based assay. We evaluated 66 patients with JIA (16 RF positive polyarthritis, 18 RF negative polyarthritis, 19 oligoarthritis, and 13 systemic arthritis). We also tested 9 adult RA patients, 34 patients with systemic lupus erythematosus (SLE), and 25 healthy persons as controls. RESULTS: Significant concentrations of anti-CCP antibodies were detected in the majority of RF positive JIA patients with polyarthritis. Using the 2 synthetic linear peptides, 12/16 (75%) were positive; 9/12 (75%) were positive with the Inova kit and 9/10 (90%) were positive with the Axis-Shield kit. However, utilizing the synthetic linear peptides, significant concentrations of anti-CCP antibodies were detected in 51/66 (77%) JIA patients, including 15/18 (83%) RF negative polyarthritis, 16/19 (84%) oligoarthritis, and 8/13 (62%) systemic arthritis patients. No healthy control showed elevated antibody levels. In contrast, 4/9 (44%) patients with adult RA and 2/6 (33%) with SLE had elevated anti-CCP levels. The synthetic cyclic variant cfc-1-cyc yielded significant anti-CCP levels for 13/14 (93%) patients with RF negative polyarthritis, 6/10 (60%) with oligoarthritis, and 3/7 (43%) with systemic arthritis, and 8/9 (88%) RF positive patients. No healthy control had increased anti-CCP levels. However, 4/9 (44%) adult RA and 9/34 (26%) SLE patients were found to have elevated anti-CCP levels. Using the Inova and Axis-Shield kits, much smaller percentages were found in the RF negative patients, with only 4/16 (25%) in the oligoarthritis and RF negative polyarthritis patients with the Inova kits and 0/25 (0%) by the Axis-Shield kits. The Inova kit revealed elevated anti-CCP antibodies in 5/9 (56%) adult RA patients and in 8/34 (24%) SLE patients. No healthy control had elevated anti-CCP antibodies. However, the Axis-Shield kits did not detect anti-CCP antibodies in adult RA (0/9) or SLE (0/34) patients. Moreover, 0/25 (0%) healthy individuals exhibited anti-CCP levels. The presence of anti-CCP antibodies correlated more frequently with the presence of RF. CONCLUSION: This study confirms the presence of anti-CCP antibodies in patients with JIA, especially those with RF positive polyarthritis, by all ELISA based methods. Use of synthetic peptides also revealed anti-CCP antibodies in a percentage of RF negative patients with polyarthritis, oligoarthritis, and systemic arthritis; there was a loss in specificity, but an increase in sensitivity. These results suggest that antibodies to these antigenic peptides may be markers for JIA, and indicate a possible role of citrulline-containing epitopes in the pathogenesis of JIA.     

Comparison of the second and third generation anti-cyclic citrullinated peptide antibody assays in the diagnosis of Japanese patients with rheumatoid arthritis

The anti-cyclic citrullinated peptide (CCP) antibody has become increasingly important in the diagnosis of rheumatoid arthritis (RA), especially for early diagnosis. The purpose of this study is to compare the diagnostic usefulness of the second and third generation anti-CCP antibody kits among Japanese patients with RA. Anti-CCP antibody titers were measured with the second generation (MESACUP CCP test, Medical and biological laboratories) and third generation (QUANTA Lite CCP3 IgG ELISA, Inova Diagnostics) kits using serum samples from 106 rheumatoid arthritis (RA) patients and 57 non-RA patients. Sensitivities and specificities were compared. The sensitivity and specificity of the second generation anti-CCP (anti-CCP2) kit were 88.7 and 89.5%, and those of the third generation anti-CCP (anti-CCP3) kit were 91.5 and 87.7%. Area under the receiver operating curve showed that anti-CCP2 and anti-CCP3 had similar diagnostic performances. Diagnostic performance of the anti-CCP3 assay was comparable with the anti-CCP2 assay in Japanese patients with RA.     

Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives. METHODS: The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease. RESULTS: ACPA positivity was observed in 19% of the healthy relatives and approximately 91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs. CONCLUSION: The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.     

QUANTITATIVE DETECTION OF CLASS-SPECIFIC RHEUMATOID FACTORS USING MOUSE MONOCLONAL ANTIBODIES AND THE BIOTIN/STREPTAVIDIN ENHANCEMENT SYSTEM

An enzyme-linked immunosorbent assay (ELISA) for the quantitativedetection of rheumatoid factors (RF) was developed using mousemonoclonal antibodies against human IgG, IgA and IgM togetherwith the biotin/streptavidin enhancement system. One hundredand eight patients with rheumatoid arthritis (RA) of whom 47had a positive serum latex agglutination assay, 100 healthycontrols and 95 diseased controls (25 systemic lupus erythematosus(SLE), 25 ankylosing spondylitis, 20 osteoarthritis and 25 bronchialasthma) were evaluated for the presence of IgG-, IgA- and IgM-RFby ELISA. Elevated levels of IgG-, IgA-, and IgM-RF could bedemonstrated in respectively 94%, 91% and 98% of serum samplesfrom RA patients with a positive latex test and in 72%, 69%and 8% of serum samples from RA patients with a negative latextest. In the latter patient group, increased levels of one ormore RF isotypes could be detected m 82% of the patients. Exceptfor the presence of IgG-RF in serum of 20% of the SLE patients,increased levels of RF isotypes were present in less than 5%of the diseased controls. Highly significant correlations werefound between serum IgM-RF levels as detected by ELISA and thoseof the latex and the Rose-Waaler agglutination assays. Positivecorrelations were also found between the serum levels of thethree RF isotypes investigated and between the levels of RFisotypes as measured in serum and synovial fluid of the samepatient. Compared to agglutination assays, the ELISA for thequantitative detection of RF isotypes is a more reproducibleand sensitive test which avoids some of the problems encounteredin earlier ELISA methods. KEY WORDS: Rheumatoid factor, ELISA, Rheumatoid arthritis     

Clinical significance of rheumatoid factor isotypes in seropositive arthritis

Summary In this cross-sectional study a comparison was made of rheumatoid factor (RF) isotypes in 203 RF positive patients with arthritis. Of these, 129 had rheumatoid arthritis (RA) and 74 a milder disease that would formerly have been classified as probable RA. The majority (74%) of the RA patients had elevations of two or three RF isotypes compared with only 34% of the patients with the milder form of arthritis. A striking feature was that combined elevation of IgM RF and IgA RF was found in 67% of the RA patients compared to only 20% of the patients with milder arthritis who most frequently had an isolated elevation of IgM RF (41%). RA patients with an isolated elevation of IgA RF were younger and had a shorter disease history than RA patients with an isolated elevation in IgM RF or a combined elevation of IgA RF and IgM RF. The prevalence of raised IgM RF was, furthermore, found to increase with age and disease duration. We concluded that a raised level of IgA RF is an adverse phenomenon in patients with seropositive arthritis while patients with an isolated increase in IgM RF may be expected to experience a relatively mild disease course.     

The latex test revisited. Rheumatoid factor testing in 8,287 rheumatic disease patients.

Rheumatoid factor (RF) testing by latex fixation in 8,287 outpatients yielded a sensitivity of 81.6% and 78.0% at titers of 1:20 and 1:80, respectively, and a specificity against noninflammatory rheumatic disorders (NIRD) of 96.6% and 97.9% and against NIRD plus inflammatory disorders of 95.2% and 96.8%, respectively. The predictive value of a positive test result at the clinic prevalence rate for rheumatoid arthritis (RA) (16.4%) was approximately 80%, and was 70% at 10% prevalence and 10% at 1% prevalence. No associations of RF with age or sex were found in non-RA patients. RF titers increased minimally with age in RA patients and were higher in men than in women. This study suggests that latex testing is far more specific than has been believed and that the titer is not spuriously increased with age.     

Disease manifestations in patients with isolated elevation of IgA rheumatoid factor.

In this retrospective study a comparison was made between the disease manifestations in patients with isolated elevation of IgA rheumatoid factor (RF) and patients with elevation of IgM RF. Of the 28 patients with isolated elevation of IgA RF, 14 (50%) had rheumatoid arthritis (RA) and 9 (32%) miscellaneous other inflammatory rheumatic disorders. It was found that 61% of these 23 rheumatic patients had disease manifestations from mucous membranes or secretory organs compared to 18% in the IgM RF positive group (p = 0.020). Patients with RA and an isolated elevation of IgA RF had more often mucosal or secretory symptoms than RA patients with elevation of IgM RF. We suggest that IgA RF may be a marker for activation of the mucosal or secretory immune system. The relationship between IgA RF and non-articular symptoms is discussed.     

Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis

OBJECTIVE: To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and anti-cyclic citrullinated peptides (anti-CCP) to discriminate between patients with and without rheumatoid arthritis (RA) and to determine the diagnostic value of anti-CCP used alone or with other tests. METHODS: Two hundred and seventy patients with early arthritis underwent standardized investigations in 1995-1997. The clinical utility of APF, AKA, and anti-CCP in first-visit sera was evaluated using receiver-operating characteristic curves. Combinations of anti-CCP with other laboratory tests were assessed by multiple logistic regression. RESULTS: Anti-CCP, APF, and AKA were not perfectly correlated with one another. Anti-CCP with 53 UI as the cutoff was 47% sensitive and 93% specific, versus 52% and 79%, and 47% and 94%, for APF and AKA, respectively. Multiple logistic regression selected anti-CCP, AKA, IgM-rheumatoid factor (RF) ELISA, and the latex test. CONCLUSION: Rheumatologists can routinely use 2 or 3 tests for diagnosing RA (latex and/or IgM RF ELISA, and either AKA or anti-CCP ELISA) and can add a third or fourth test when the diagnosis remains in doubt.     

ELISA determined IgM, IgG and IgA rheumatoid factors in rheumatoid arthritis and in other connective tissue diseases

We used an adaptation of an enzyme-linked immunoadsorbent assay (ELISA) to determine serum levels of IgM, IgG and IgA rheumatoid factors (RF) in 50 patients with classic or definite rheumatoid arthritis (RA) according to the ARA criteria, balanced for positive or negative-routine Latex-RF reaction. A control group of 50 young normal subjects and a reference group of 44 patients with other connective tissue diseases (OCTD) were also studied. We confirmed the high sensibility of the method, together with its good specificity and reproducibility. For the IgM RF a very significant correlation was found between ELISA results and Latex-RF titration (p less than 0.001). Many Latex-RF negative RA patients had high ELISA levels of IgM RF, suggesting that this assay reveals, at least in part, hidden or non-agglutinating IgM RF. Among the OCTD group only some SLE cases, mainly Latex-RF positive, had enhanced IgM RF on ELISA. Considered quantitatively, IgG RF did not play a significant diagnostic role for RA (p greater than 0.05), because they were also found, with widely dispersed values, in normal subjects, and because the mean increase in RA patients was relatively small. Interestingly, IgA RF were above the normal range in many RA patients, both Latex-RF positive or negative. The mean values differed significantly from those of controls (p less than 0.005), and a correlation was observed between IgA RF levels and IgA containing immune-complexes. Normal IgA RF values were observed in SLE patients, even if Latex-RF positive, suggesting that their increase in RA patients is not the mere expression of a polyclonal B cell activation.     

The predictive value of rheumatoid factor isotypes, anti-cyclic citrullinated peptide antibodies, and antineutrophil cytoplasmic antibodies for mortality in patients with rheumatoid arthritis

OBJECTIVE: To evaluate the significance of rheumatoid factor (RF) and its isotypes (IgA RF, IgG RF, and IgM RF), anti-cyclic citrullinated peptide antibodies (anti-CCP), and antineutrophil cytoplasmic antibodies (ANCA) in predicting mortality in patients with rheumatoid arthritis (RA). METHODS: The study population comprised 604 patients with RA participating in a cross-sectional study in 1987. Presence of RF (n = 604), RF isotypes (n = 206), anti-CCP (n = 184), and ANCA (n = 200) were determined in these patients from available baseline sera. Vital status was assessed in 1999 and multivariate Cox regression analysis used to compare mortality in RA patients with or without different antibodies. RESULTS: Of the 604 patients with RA, 55% were positive for RF, 66% for anti-CCP, and 14.5% for perinuclear ANCA. Twelve patients (19%) with RF were anti-CCP-negative and 34 (40%) without RF were anti-CCP-positive. Of the total 604 patients, 160 had died by 1999. Positive RF and high IgA and IgM RF levels predicted increased mortality, while positive anti-CCP or ANCA did not. However, high anti-CCP levels were related to an increased mortality risk. CONCLUSION: Patients with RA with positive RF, especially IgA and IgM isotypes, carry a risk of dying earlier than patients without these serological findings.