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.     

Citrullination in extra-articular manifestations of rheumatoid arthritis

BACKGROUND: Anti-citrullinated protein antibodies have been detected with high specificity in serum of patients with rheumatoid arthritis (RA), and citrullination of proteins may play a key role in the pathogenesis of RA. We therefore investigated the presence of citrullination in two extra-articular manifestations of RA, interstitial pneumonia (IP) and rheumatoid nodules. METHODS: Open-lung biopsy specimens from patients with RA-associated IP (n = 18), idiopathic IP (n = 20) and controls (n = 10), as well as specimens of rheumatoid nodules from 26 patients, were examined. All sections were incubated with an anti-modified citrulline antibody. Masked scoring of stained sections and analysis of results by stratification according to demographic and clinical characteristics was performed. RESULTS: Presence of citrulline could be detected in eight lung specimens of patients with RA-associated IP (44%) and nine patients with idiopathic IP (46%). Conversely, lung tissue from control patients showed weak extracellular citrullination in only two cases (20%). Citrullination did not show any significant associations with demographic or clinical characteristics such as age, gender, smoking habits, disease severity, histological subtype, degree of inflammation or steroid use. Rheumatoid nodules were citrulline positive in a majority of cases (70%). CONCLUSION: Citrullination is present in extra-articular manifestations of RA such as IP and nodules. In contrast to the high specificity of anti-citrulline antibodies in RA, citrullination is not only restricted to RA but can also be observed in idiopathic IP. Whether citrullination significantly contributes to the initiation or perpetuation of autoimmunity or merely reflects ongoing inflammation remains to be clarified.     

Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study.

Serum rheumatoid factors (RF) were measured yearly in 135 women with rheumatoid arthritis by the Waaler-Rose and latex fixation tests and IgM, IgA, and IgG RF were measured by enzyme linked immunosorbent assays (ELISAs). The patients were followed up from an early phase of the disease for a mean duration of six years. Patients with a persistently positive RF test, irrespective of the type of test used, had more radiological abnormalities, more disease activity, worse functional ability, more extra-articular manifestations, and needed more treatment with second line drugs than patients with persistently negative or variably positive and negative test results during the follow up. Increased RF levels, especially a high level of IgA RF within three years of the onset of symptoms, was prognostic for a more severe disease outcome six years after the onset of symptoms.     

Extra-articular manifestations of rheumatoid arthritis: results of a university hospital of 526 patients in Turkey

OBJECTIVE: Presence of extra-articular manifestations (EAM) in rheumatoid arthritis (RA) is associated with more severe disease and increased mortality. Prevalence of EAM may vary in different geographic areas and in different ethnic populations. In this study we investigated the frequency of EAM in 526 RA patients from a single university hospital in Turkey. METHODS: The hospital records of patients who had been diagnosed as RA in Hacettepe University Department of Rheumatology between the years 1988 and 2003 were retrospectively evaluated. There were 73 males and 453 females, and mean age of the patients was 48.0 +/- 12.3 years. The mean follow-up period was 4.8 +/- 4.1 years. Three hundred and fifty-nine patients were rheumatoid factor (RF) positive (68.3%). RESULTS: The overall frequency of EAM was 38.4% (202 patients). The most common EAM was rheumatoid nodules (18.1%). Sicca symptoms, pulmonary findings, Raynaud's phenomenon, livedo reticularis, carpal tunnel syndrome, vasculitis, amyloidosis, and Felty syndrome were present in 11.4%, 4.8%, 3%, 4.8%, 2.8%, 1.3%, 1.1%, and 0.3% of the patients, respectively. Overall EAM and rheumatoid nodules were significantly more common in RF positive patients than RF negative patients. The frequency of rheumatoid nodules was significantly higher in males than in females. CONCLUSION: The prevalence of EAM in Turkey is higher than East Asia and Africa, and lower than UK and North America. Excluding secondary Sj?gren's syndrome, our results are similar to other Mediterranean populations like Italy.     

Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations

BACKGROUND: Autoantibodies such as rheumatoid factor (RF) and anticitrullinated protein antibodies can be detected in rheumatoid arthritis (RA) sera. OBJECTIVE: To determine the diagnostic values of RF, anticitrullinated protein antibodies, and the shared epitope (SE), and their associations with radiological progression rates and extra-articular manifestations. METHODS: Population 1 consisted of sera from 315 patients, consecutively sent for detection of anticitrullinated protein antibodies, of which 264 were used to determine the sensitivity and specificity of RF and of antibodies against three synthetic citrullinated peptides: peptide A (pepA), peptide B (pepB), and CCP2. Population 2 consisted of sera from 180 longstanding RA patients and was used to determine associations of RA associated antibodies and the SE with radiological progression rates and extra-articular manifestations. Antibodies to pepA and pepB were detected by line immunoassay, and antibodies to CCP2 by ELISA. HLA Class II typing was performed by LiPA. RESULTS: In population 1, we defined adapted cut offs corresponding to a specificity of >/=98.5%. This yielded the following sensitivities: RF 12.8%; anti-pepA antibodies 63.6%; anti-pepB antibodies 54.2%; and anti-CCP2 antibodies 73.7%. In population 2, significant differences in radiological progression rates were found between positive and negative patients for different RA antibodies and the SE. RF, but not anticitrullinated protein antibodies or the SE, were more frequent in patients with extra-articular manifestations. CONCLUSION: A valid comparison of RA associated antibodies shows superior sensitivity of the anticitrullinated protein antibodies compared with RF. The presence of RA associated antibodies and the SE are indicative for poorer radiological outcome, and presence of extra-articular manifestations is associated with RF but not with anticitrullinated protein antibodies.     

The occurrence of rheumatoid factor isotypes in early definite rheumatoid arthritis--no relationship with erosions or disease activity

Seventy-one patients with definite rheumatoid arthritis and disease duration less than 2 years were followed prospectively. At study entry 43 patients had IgG rheumatoid factor (RF), 59, IgA-RF and 64, IgM-RF as measured with an ELISA; 48 were Waaler-Rose positive. After 2 years, joint erosions were present in 51 patients and absent in 19. One patient has not been followed long enough. The calculated relative risks contributed by different RF to the presence of erosions were low. No significant correlations between markers of disease activity and RF levels initially were found. The clinical value of RF isotype determination seems limited.     

The temporal relationship of Raynaud's phenomenon and features of connective tissue disease in rheumatoid arthritis

OBJECTIVE: In a prospective cohort study we examined the relationship between Raynaud's phenomenon (RP) onset and other connective tissue disease (CTD) characteristics in rheumatoid arthritis (RA) to determine if RP is predictive of RA severity and associated with other CTD signs, and if late onset RP in RA has an effect on prognosis compared to other patients with RA. METHODS: Using a standardized assessment, data were collected on 328 subjects with RA [mean age 60.3 +/- 0.7; 77% women; 76% erosions, 75% positive rheumatoid factor (RF)] seen at one London, Ontario, rheumatology clinic. The data included RA disease duration; presence and duration of RP; presence of nodules, joint damage, telangiectasia, and sclerodactyly; and RF status (+/-), RF value, antinuclear antibodies, and E-nuclear antibodies. RESULTS: The mean RA disease duration was 12 +/- 0.6 years. Seventy-one (22%) had RP and the mean RP duration was 9.2 +/- 1.5 years. Patients presented with RP a mean of 3.8 +/- 1.4 years after the diagnosis of RA. RP status was positively associated with the presence of sclerodactyly (p < 0.001), but not nodules or erosions. Higher RF values were associated with longer RA disease duration (p < 0.002) and longer RP duration (p < 0.01). CONCLUSION: Idiopathic RP may have a different clinical effect on RA than secondary RP; the latter is correlated with more severe RA. Sclerodactyly is associated with erosive arthritis and RP in RA. Higher RF values were indicative of increased RA and RP duration.     

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.     

Rheumatoid factors in psoriatic arthropathy and in Waaler-Rose negative rheumatoid arthritis

Summary Serum levels of IgG, IgA and IgM rheumatoid factor (IgG RF, IgA RF and IgM RF) were determined by means of the diffusion-in-gel enzyme-linked immunosorbent assay (DIG-ELISA) in 42 Waaler-Rose negative patients with psoriatic arthropathy (PsA) type 1 (arthritis with involvement of distal interphalangeal joints) and type 3 (polyarthritis of rheumatoid type) according to the criteria of Moll and Wright as well as in 53 patients with Waaler-Rose negative rheumatoid arthritis (RA). Elevated levels of RF were found in 22% of patients with PsA type 3 and 45% of patients with Waaler-Rose negative RA. In contrast, none of the patients with PsA type 1 had detectable amounts of RF. It is suggested that the presence of IgG, IgA or IgM RF in patients having psoriasis in conjunction with inflammatory polyarthritis indicates the RA nature of the joint disease and should be considered as exclusion criterion for the diagnosis of PsA.     

Characterisation of the size and composition of circulating immune complexes in patients with rheumatoid arthritis.

The size and composition of circulating immune complexes in the sera of patients with rheumatoid arthritis (RA) were studied in relation to different manifestations of the disease. Circulating immune complexes from the sera of 94 patients (50 with extra-articular disease) and 10 matched controls were fractionated by sucrose density gradient ultracentrifugation. The composition, immunoglobulin and rheumatoid factor (RF) concentrations within each of the fractions were determined by a sensitive enzyme linked immunosorbent assay (ELISA). Intermediate size (14S-21S) IgG complexes containing RF activity and 22S IgG-IgM RF complexes were found in the sera of 40 patients with RA, while intermediate size complexes of self associated IgG RF and larger size complexes (greater than 22S) of IgG RF and IgM RF were associated with extra-articular features of RA (50% of extra-articular disease). Complexes containing IgA were found in the sera of many patients with RA, and dimeric IgA RF mainly in patients with extra-articular disease. These results support the view that whereas small size circulating immune complexes are of no primary pathogenic importance in synovitis, large size (greater than 22S) circulating immune complexes may play a role in extra-articular disease in RA. Current understanding of the formation of large complexes provides a biological explanation for their occurrence and effects.     

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.     

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.     

Predictors of extra-articular manifestations in rheumatoid arthritis

OBJECTIVE: To identify clinical and genetic risk factors for extra-articular manifestations of rheumatoid arthritis (ExRA). METHODS: ExRA patients were identified retrospectively using predefined criteria in two hospital-based cohorts of RA patients, and compared to non-extraarticular RA controls from one of the cohorts, matched for disease duration. RESULTS: Forty-nine living and thirteen deceased cases of ExRA were identified. Extra-articular disease was predicted by the demonstration of antinuclear antibodies (Odds ratio (OR) 3.6; 95% CI: 1.4-9.1) and the presence of rheumatoid nodules within two years from RA diagnosis (OR 3.4; 95%, CI: 1.1-10.9) or at any time before ExRA onset (OR 2.8; 95% CI: 1.1-7.2). Male sex and rheumatoid factor did not affect the risk of ExRA. Although present in the majority of cases as well as controls, the disease associated HLA-DRB1 subtypes were not significant predictors of ExRA. CONCLUSION: Extra-articular manifestations of rheumatoid arthritis in a hospital based population were predicted by antinuclear antibodies and rheumatoid nodules.     

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.     

Association of rheumatoid factors and anti-filaggrin antibodies with severity of erosions in rheumatoid arthritis

OBJECTIVES: To evaluate and to compare the association of two types of autoantibodies-rheumatoid factors (RF) and anti-filaggrin antibodies (AFA)-with clinical severity and joint damage progression in rheumatoid arthritis (RA) patients. METHODS: In a cross-sectional study, we determined RF and AFA titres in 199 RA patients and 65 controls. Erosions apparent on X-rays were quantified using the Larsen score in 143 patients, and the distribution of these scores was studied according to disease duration in patients who were positive and negative for RF and AFA. RESULTS: RF were detected in 72% and AFA in 47% of RA patients. AFA were highly specific for RA (100%). RF positivity was correlated with the presence of subcutaneous nodules, sicca syndrome and the severity of erosions for a given disease duration. AFA positivity was correlated only with the presence of the HLA-DRB1 shared epitope. CONCLUSIONS: Since no significant correlation was observed between joint damage progression and AFA positivity, the determination of AFA does not appear to be useful in assessing the prognosis of RA. However, AFA, which appear early in RA, could be helpful for the diagnosis of RA in patients who do not fulfil four American College of Rheumatology criteria.     

Determining rheumatologists' accuracy at assessing functional disability in rheumatoid arthritis patients using the Health Assessment Questionnaire-Disability Index

OBJECTIVE: To test rheumatologists' accuracy in determining functional disability of their patients with rheumatoid arthritis (RA). METHODS: We used the Health Assessment Questionnaire-Disability Index (HAQ-DI) as our guide at assessing functional disability in patients with RA. Included were male and female patients, 18 to 65 years of age, diagnosed with RA. Demographic data collected included the patients' age, disease duration, rheumatoid factor (RF) status, presence of rheumatoid nodules, absence or presence of erosive disease, and class and stage of their disease. The primary endpoint was the mean difference in the patients' HAQ-DI scores versus that of the physicians' (mHAQ-Diff). Secondary endpoints were the mean difference in pain assessment scale (mPAS-Diff) score; and assessing to see if the physicians' HAQ-DI was altered by the patients' age, disease duration, RF status, rheumatoid nodules, absence or presence of erosive disease, and class or stage of the patient's RA. RESULTS: A total of 223 patients (139 female, 84 male) were evaluated. The mHAQ-Diff score was statistically significant at -0.3 (p = 0.03) with the rheumatologists more often overestimating the degree of functional disability in their RA patients. The mPAS-Diff score was 0.16, but this was not significant (p = 0.53). There was no significant difference between the scores based on sex, presence or absence of RF, erosions, or rheumatoid nodules. However, the rheumatologists' estimated HAQ and PAS did seem to be more accurate in patients with lower class and stage of their RA. CONCLUSION: Our results indicate that there is a clear difference between patients' and rheumatologists' assessment of patients' functional disability in RA, with the rheumatologists significantly overestimating the degree of this disability. Although the rheumatologists' accuracy at determining the amount of their patients' functional disability was poor overall, they were somewhat more accurate in patients with RA having less severe disease.     

IgE and IgE-rheumatoid factors in circulating immune complexes in rheumatoid arthritis.

The sera of 21 patients with rheumatoid arthritis (RA), 11 patients with systemic lupus erythematosus (SLE), and 20 healthy subjects were analysed for the presence of IgE in immune complex fractions. These fractions were isolated by polyethylene glycol precipitation and gel filtration. Thirteen sera from RA patients contained IgE immune complexes (IC) and 11 of these were from patients with extra-articular manifestations. One SLE and none of the control sera contained such material. The serum IgE level did not correlate with IgE content of the IC fractions. Higher mean serum IgE levels were found in RA patients with extra-articular complications than in controls or RA patients with joint disease only, but the differences did not reach statistical significance. IgE anti-rabbit IgG (IgE rheumatoid factors) could be demonstrated in some IgE positive IC fractions. Antibodies to IgE, in 2 instances characterised as belonging to IgG class, were also found in ICs. This suggests the presence of anti IgE complexes. It is suggested that IgE, including some with rheumatoid factor activity, is contained in complexes which may be involved in some extra-articular manifestations of RA.     

Carotid ultrasound in the cardiovascular risk stratification of patients with rheumatoid arthritis: when and for whom?

Adequate stratification of cardiovascular (CV) risk is one of the major points of interest in the management of patients with rheumatoid arthritis (RA). A task force of the European League Against Rheumatism has proposed to adapt CV risk management calculated in RA patients according to the systematic coronary risk evaluation (SCORE) function by application of a multiplier factor of 1.5 in those patients with two of the following three criteria: disease duration >10 years, rheumatoid factor (RF) or anticyclic citrullinated peptide (anti-CCP) antibody positivity, and presence of severe extra-articular manifestations. However, a major concern when using the modified SCORE is to know whether the effect of chronic inflammation on the CV risk of RA patients can be fully determined using this tool. As increased carotid intima-media thickness (IMT) and carotid plaques have been proved to predict the development of CV events in RA, the authors suggest performing carotid ultrasound when SCORE does not yield results indicating high CV risk in RA patients with extra-articular manifestations, RF or anti-CCP positivity as well as in patients with 10 years disease duration or longer. The presence of abnormal carotid IMT (>0.90 mm) or carotid plaques would lead to these patients being considered as having high CV risk regardless of the results derived from the modified SCORE.     

Immunogenetic heterogeneity of rheumatoid arthritis.

Association of HLA-DR4/Dw4 with rheumatoid arthritis (RA) is well established, but conflicting data exist on a possible association with the severity of the disease, including its extra-articular manifestations. In order to investigate whether a subgroup of RA is preferentially associated with DR4, HLA typing was performed in two groups of patients with severe extra-articular manifestations (Felty's syndrome and histologically proved leucocytoclastic vasculitis), patients with severe joint destruction (seropositive and seronegative), a group with only mild joint destruction, and in healthy controls. The frequency of HLA-DR4 was significantly raised in all patient groups compared with that in healthy controls. The two groups with severe extra-articular manifestations, however, both had a DR4 frequency of 92%, which was significantly (p = 0.002) higher than the 62.7% found in the remaining patients. No significant differences were observed between severe or mild joint destruction and seropositivity or seronegativity in the groups without the above-mentioned extra-articular manifestations. From these data we concluded that DR4 is preferentially associated with severe extra-articular disease manifestations of RA. This observation provides an immunogenetic basis for the disease heterogeneity and for the immunological analogy between RA and leprosy.     

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

Published data were reviewed to evaluate the occurrence of antiphospholipid antibodies (aPL) in rheumatoid arthritis (RA) patients and to investigate their clinical relevance in this population. The mean prevalence was calculated at 28% and the median was 22%. Few studies have found a relationship between aPL antibodies and thrombosis, particularly in combination with other risk factors. Conflicting results have been reported on the association of anticardiolipin (aCL) antibody positivity and neurologic symptoms, Reynaud’s phenomenon, disease activity, radiographic erosions, extra-articular RA manifestations, rheumatoid factor, and atherosclerosis. Some studies, however, suggest that there is a correlation present between those antibodies and C-reactive protein levels, rheumatoid nodules, and antinuclear antibodies. TNF-α blocking agents may cause an induction of aCL antibodies, but it seems like they do not cause any clinical features related to the antiphospholipid syndrome. Higher 17β-estradiol levels were observed in aCL antibody-positive RA patients than in aCL antibody-negative patients and especially in premenopausal women, which may predispose to a more efficient immune response.