Diagnostic tests for rheumatoid arthritis: comparison of anti-cyclic citrullinated peptide antibodies,anti-keratin antibodies and IgM rheumatoid factors

OBJECTIVES: To examine the value of anti-cyclic citrullinated peptide (anti-CCP) antibodies, anti-keratin antibodies (AKA) and immunoglobulin M rheumatoid factors (IgM RF) in discriminating between rheumatoid arthritis (RA) and other rheumatic diseases, and to determine whether the clinical manifestations or severity of erosions in RA are associated with anti-CCP positivity. METHODS: In a cross-sectional study, we determined the concentrations or titres of these three markers in 179 RA patients and 50 controls. Erosions were quantified using the Larsen score in 129 patients. RESULTS: Sensitivity was highest for IgM RF (75%), followed by anti-CCP antibodies (68%) and AKA (46%). Specificity was highest for anti-CCP antibodies (96%), followed by AKA (94%) and IgM RF (74%). A correlation with clinical manifestations and severity of erosions was observed mainly for IgM RF positivity. CONCLUSIONS: With their excellent specificity, anti-CCP antibodies can be useful in establishing the diagnosis of RA, but IgM RF is a better predictor of disease severity.     

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.     

Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis

OBJECTIVE: To evaluate a contribution of selected laboratory parameters for a prediction of progressive and erosive development in patients with early rheumatoid arthritis (RA). METHODS: In a prospective study baseline levels of antibodies to cyclic citrullinated peptide (anti-CCP), IgM, IgA, and IgG rheumatoid factors (RFs) were measured by enzyme linked immunosorbent assay (ELISA) in 104 patients with RA with disease duration <2 years. Antikeratin antibodies (AKA) and antiperinuclear factor (APF) were detected by indirect immunofluorescence. Patients were divided into two groups based either on the presence or absence of erosions or according to progression of Larsen score at the end of the 24 months' follow up. RESULTS: Sixty seven (64%) patients developed radiographic erosions, 49 (47%) had progression in Larsen score, and 36 (35%) progressed by more than 10 Larsen units. Significant differences in erosions and progression between the two groups were detected for anti-CCP, AKA, APF, IgM RF, IgA RF, and IgG RF. Baseline Larsen score correlated significantly with anti-CCP, IgM RF, and IgA RF levels, and all measured antibodies correlated with the progression >10 units. The combination of anti-CCP and IgM RF increased the ability to predict erosive and progressive disease. CONCLUSION: The data confirmed that measurement of anti-CCP, AKA, APF, and individual isotypes of RFs was useful for prediction of structural damage early in the disease course. Combined analysis of anti-CCP and IgM RF provides the most accurate prediction.     

Autoantibodies in rheumatoid arthritis: association with severity of disease in established RA

Introduction: Autoantibodies in rheumatoid arthritis (RA) are useful both for diagnosis and prognosis. Antibodies directed against citrullinated antigens have recently been shown to predict development of RA as well as poor outcome in early arthritis. Data on their role in established RA is limited. We studied the association of various autoantibodies in RA with its severity. Materials and methods: A total of one hundred and twenty nine-patients with established RA was enrolled and sera were collected and stored at −70°C. Data regarding erosions, deformities, and extra-articular features were collected. IgM rheumatoid factor (RF) was measured using nephelometry and value above 20 U was considered positive. IgA RF was measured by enzyme-linked immunosorbent assay (ELISA) and value above the mean±2 SD of normal healthy control was taken as positive. Anti-keratin antibody (AKA) was detected by indirect immunofluorescence assay using rat esophagus as substrate. Anti-cyclic citrullinated peptide (CCP) antibodies were measured by commercial ELISA and a value above 5 U was considered as positive. Results: The prevalence of various autoantibodies was: IgM RF 82.2%, anti-CCP antibodies 82.2%, AKA 51.9%, and anti IgA RF 45%. The concordance rate of anti-CCP antibodies with IgM RF was 83%, with AKA 68%, and with IgA RF 60.5%. All but one patient positive for AKA were positive for anti-CCP antibodies. The presence of IgM RF, AKA, and anti-CCP antibody was associated with joint erosions and deformities. None of the antibodies had any association with presence of extra-articular features. No association of IgA RF was seen with erosions, deformities, or extra-articular features. Among 23 seronegative RA patients, 11 were positive for anti-CCP antibodies and 6 were AKA positive. The presence of anti-CCP antibodies was associated with presence of deformities (p<0.05). Conclusion: Anti-CCP antibodies are present in majority of patients with established RA including seronegative patients. Both anti-CCP and AKA, in addition to conventional marker like IgM RF, are associated with severe erosive disease.     

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     

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.     

High IgA rheumatoid factor levels are associated with poor clinical response to tumour necrosis factor alpha inhibitors in rheumatoid arthritis

OBJECTIVE: To investigate whether rheumatoid factor isotypes and anti-cyclic citrullinated peptide (anti-CCP) antibodies are related to clinical response in patients with rheumatoid arthritis treated with tumour necrosis factor alpha (TNFalpha) inhibitors. METHODS: The study was carried out on 132 patients with advanced rheumatoid arthritis refractory to disease-modifying antirheumatic drugs. Patients were treated with infliximab (n = 63), etanercept (n = 35) or adalimumab (n = 34). All patients completed 1 year of follow-up, and 126 were evaluable for clinical response according to the disease activity score (DAS) criteria. IgM, IgA and IgG rheumatoid factors and anti-CCP antibodies were assessed by ELISA both before anti-TNFalpha treatment and 1 year later. RESULTS: The DAS response was reached in 66% of evaluable patients (61% infliximab, 65% etanercept and 76% adalimumab; p = 0.354). A significant reduction in the rheumatoid factor level was reported by all treatment groups after 1 year. The frequency of positive tests for the different antibodies did not differ between responders and non-responders at baseline; however, significantly higher IgA rheumatoid factor levels were reported by the non-responder group (130.4 U/ml (interquartile range 13.8-276.7) v 24.8 U/ml (10.2-90.8); p = 0.003). A significant decrease (p<0.001) in the levels of all rheumatoid factor isotypes in the responder group was reported after 1 year of treatment, whereas anti-CCP antibody levels were not significantly affected. CONCLUSIONS: According to the clinical response, anti-TNFalpha agents seem to reduce IgM, IgG and IgA rheumatoid factor levels. More interestingly, high pretreatment levels of IgA rheumatoid factor are associated with a poor clinical response to TNFalpha inhibitors.     

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.     

Prevalence and clinical significance of antikeratin antibodies and other serological markers in Lithuanian patients with rheumatoid arthritis

OBJECTIVES: To assess the clinical value of several serological markers in Lithuanian patients with rheumatoid arthritis (RA) compared with control patients with rheumatic disease and age matched healthy controls. METHODS: Serum samples from 96 patients with RA of approximately 8 years' duration, 90 rheumatic disease controls, and 37 healthy subjects were tested. Antikeratin antibody (AKA), antineutrophil cytoplasmic antibody (ANCA), and antinuclear antibody (ANA) titres were estimated by indirect immunofluorescence (IIF) and serum samples positive for ANA and ANCA were further studied by enzyme linked immunosorbent assay (ELISA). IgA and IgM rheumatoid factors (RF) were measured by ELISA. RESULTS: A positive AKA test was highly specific for RA (diagnostic specificity 97%), being found in 44% of the patients. Although both RF tests had a higher sensitivity, they were less specific for RA. ANCA was detected in 33% of patients with RA but lacked diagnostic specificity. AKA and ANCA were associated with more erosive disease and the presence of extra-articular manifestations. Positivity for AKA, IgA RF, and ANCA was significantly associated with disease activity and worse functional capacity. However, in multiple regression analysis only positivity for AKA was significantly correlated with functional disability (p=0.0001), evaluated by the Steinbrocker functional classification, and no single marker had any relation with radiological damage. CONCLUSION: Although AKA showed the highest disease specificity, all serological markers studied except ANA exhibited interesting associations with important clinical and paraclinical parameters of RA.     

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.     

Measurement of biomarkers in juvenile idiopathic arthritis patients and their significant association with disease severity: a comparative study

OBJECTIVE: To evaluate in juvenile idiopathic arthritis (JIA) patients a biomarker panel of anti-cyclic citrullinated peptide (anti-CCP) antibodies, cartilage oligomeric matrix protein (COMP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IgM rheumatoid factor (RF), IgG RF, and IgA RF and compare to the presence of joint erosions (JE), joint space narrowing (JSN), and synovitis in order to evaluate aggressive disease. METHODS: Sixty-eight JIA patients (19 RF positive polyarthritis, 23 RF negative polyarthritis, 17 persistent oligoarthritis, and 9 systemic-onset) were evaluated using the biomarker panel and compared to 18 healthy controls. All RF isotypes, anti-CCP antibodies, and COMP were measured by enzyme-linked immunosorbent assays (ELISA). Statistically significant differences and associations were assessed for each biomarker in relation to JE, JSN, and synovitis. Multiple regression analysis was used to find the variables associated with joint damage and synovitis. RESULTS: Patients with JE and JSN had significantly elevated levels of IgA RF, IgM RF, and anti-CCP antibodies. COMP levels were higher in early disease, but also later in disease in patients with no JE or JSN. ESR, CRP, and IgA RF were significantly elevated in patients with active synovitis. Regression analysis showed IgM RF and disease duration to be associated with JE and JSN. Anti-CCP antibodies and COMP were also associated with JSN. CRP and IgA RF were associated with synovitis. CONCLUSION: Our findings demonstrate the importance of measuring IgM RF and IgA RF by ELISA and anti-CCP antibodies by ELISA, in addition to COMP in the assessment of JIA patients to determine severity of disease.     

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.     

Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis

OBJECTIVE: To compare the diagnostic utility of anti-cyclic citrullinated peptide (anti-CCP) antibodies with other serological markers including rheumatoid factor (RF), anti-agalactosyl immunoglobulin G (IgG) antibody, and matrix metalloproteinase (MMP)-3 in very early rheumatoid arthritis (RA). METHODS: Serum concentrations of anti-CCP antibodies, RF, anti-agalactosyl IgG antibody, and MMP-3 were measured in 262 patients with RA ("total RA") including 55 patients with disease duration of less than 6 months who had not been treated before entry ("very early RA") and 116 patients with rheumatic diseases other than RA. RESULTS: The diagnostic sensitivity of anti-CCP antibodies was 82.4% in total RA and 67.3% in very early RA and was lower than that of RF (84.0% total RA, 83.6% very early RA) and anti-agalactosyl IgG antibody (90.5%, 90.9%), whereas specificity, positive predictive value, and diagnostic accuracy were the best among markers tested both in total RA and in very early RA. The presence of either anti-CCP antibodies or RF increased the sensitivity, but any combination of serological markers was not significantly better in diagnostic accuracy than anti-CCP antibodies alone. The rates of RF-positive subjects in anti-CCP antibody-negative patients both in total RA (43.5%) and in very early RA (61.1%) were higher than those of anti-CCP antibody-positive subjects in RF-negative patients (38.1% and 22.2%, for total RA and early RA, respectively). CONCLUSION: Measurement of anti-CCP antibodies, by itself, is useful for the diagnosis of RA; however, combined use of anti-CCP antibodies with RF may be more useful than either method alone for the diagnosis of very early RA.     

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.     

Rheumatoid factors and anticyclic citrullinated peptide antibodies in pediatric rheumatology

Juvenile idiopathic arthritis (JIA) is a heterogenous childhood disease without reliable biomarkers for monitoring disease progression. Immunoglobulin (Ig) M rheumatoid factor (RF) is used to define a subset of JIA patients, but its significance in JIA is dependent on the method of measurement. In addition to IgM RF, IgA RF has been implicated in determining disease severity in JIA, including functional disability and joint damage. Anticyclic citrullinated peptide (anti-CCP) antibodies have been a valuable diagnostic tool in rheumatoid arthritis, with varied results in their significance in JIA patients. Recent studies have demonstrated the possible usefulness of isotypes of anti-CCP antibodies in monitoring JIA patients to determine disease outcome. Overall, RF isotypes and anti-CCP isotypic antibodies have demonstrated increasing importance in the evaluation of JIA patients to determine which patients may have more aggressive or severe disease and to aid in possible treatment plans to prevent joint damage and disability.     

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.     

Elevated levels of IgM and IgA antibodies to Proteus mirabilis and IgM antibodies to Escherichia coli are associated with early rheumatoid factor (RF)-positive rheumatoid arthritis

OBJECTIVE: Antibodies to Proteus mirabilis were previously detected in patients with established rheumatoid arthritis (RA). We examined the prevalence of antibodies to P. mirabilis and their associations with RA in early synovitis patients. METHODS: Two hundred and forty-six patients with inflammatory arthritis for less than 1 yr were prospectively evaluated for 1 yr. Of these patients, 30% had rheumatoid factor (RF)-positive RA, 16% RF-negative RA, 17% a spondyloarthropathy and 37% undifferentiated arthritis. Serum antibodies to P. mirabilis, Escherichia coli and other potentially arthritogenic organisms (Chlamydia, Salmonella, Shigella, Campylobacter, Yersinia and parvovirus B19) and for antibodies specific for immunoglobulin (Ig) G damaged with advanced glycation end-products (anti-IgG-AGE) were measured. RESULTS: IgM and IgA anti-Proteus antibodies were significantly higher in patients with RF-positive RA compared with all other patient groups (P < 0.0005 and P < 0.005). Anti-P. mirabilis IgG, and IgG, IgA, and IgM antibodies to other potentially arthritogenic pathogens did not differ in the patient groups. IgM antibodies to E. coli were elevated in RF-positive RA patients. Anti-P. mirabilis IgM and IgA results were not explained by false-positive reactions, because after absorption of RF there was no decrease in antibodies to Proteus in 10 of 12 patients. Proteus and E. coli antibodies were highest in patients positive for both RF and anti-IgG-AGE antibodies (P<0.001). Patients with erosions tended to have higher IgA anti-Proteus titres, but no association with the shared HLA epitope or treatment was detected. CONCLUSION: Anti-P. mirabilis IgM and IgA and anti-E. coli IgM antibody elevations are associated with early seropositive RA and the presence of anti-IgG-AGE antibodies. The role that P. mirabilis or E. coli plays in early RF-positive RA requires further investigation.     

Prevalence of IgM, IgA and IgG rheumatoid factors in juvenile rheumatoid arthritis

Using an enzyme immunoassay, sera from 50 children with juvenile rheumatoid arthritis (JRA) and 39 controls were tested for IgM, IgA and IgG rheumatoid factors (RF). RF of the IgM and IgA isotypes were present in 11 (22%) patients, but in only one control (p = 0.008). IgG RF was present in the sera of 2 (4%) patients and in none of the controls (p = 0.21). Of the 22 patients with IgM RF or IgA RF, only 3 sera (14%) contained RF of both isotypes. IgM RF was more common in patients with polyarticular disease, while IgA RF was more common in patients with pauciarticular disease. These results indicate that IgM and IgA RF are present in a significant minority of JRA patients and suggest that there is independent expression of the respective RF isotypes.     

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.     

Anti-cyclic citrullinated peptide antibodies,IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis

OBJECTIVES: To evaluate the association of anti-cyclic citrullinated peptide (anti-CCP) antibodies with immunoglobulin (Ig) M and IgA rheumatoid factors (RF) in discriminating between rheumatoid arthritis (RA) and other rheumatic diseases, and to determine, in a longitudinal study, whether clinical signs of disease severity are associated with the presence of these autoantibodies at the time of patient inclusion. METHODS: The presence of these three markers was determined in 196 patients with established RA, 239 non-RA controls with various rheumatic diseases (cross-sectional study) and in 27 patients with arthritis of less than 1 yr disease duration who were subsequently followed during about 8 yr (longitudinal study). At the time of follow-up, 21 of these 27 patients had RA. They were further evaluated and several clinical variables were recorded. RESULTS: The specificity was significantly increased (from 82-90% to 98% in the cross-sectional study) when the combination of anti-CCP antibodies with IgA RF or the combination of the three serological markers was used. An association was observed between the presence of the three autoantibodies and clinical signs of disease severity (functional disability, presence of erosions and absence of clinical remission). CONCLUSIONS: The presence either of anti-CCP antibodies and IgA RF or of the three markers appears to be useful in the diagnosis of RA. Their association with clinical signs of disease severity at the time of patient inclusion suggests their potential usefulness as markers for prognosis.