Validation of a commercially available SARS-CoV-2 serological immunoassay.

OBJECTIVES: To validate the diagnostic accuracy of a Euroimmun SARS-CoV-2 IgG and IgA immunoassay for COVID-19. METHODS: In this unmatched (1:2) case-control validation study, we used sera of 181 laboratory-confirmed SARS-CoV-2 cases and 326 controls collected before SARS-CoV-2 emergence. Diagnostic accuracy of the immunoassay was assessed against a whole spike protein-based recombinant immunofluorescence assay (rIFA) by receiver operating characteristic (ROC) analyses. Discrepant cases between ELISA and rIFA were further tested by pseudo-neutralization assay. RESULTS: COVID-19 patients were more likely to be male and older than controls, and 50.3% were hospitalized. ROC curve analyses indicated that IgG and IgA had high diagnostic accuracies with AUCs of 0.990 (95% Confidence Interval [95%CI]: 0.983-0.996) and 0.978 (95%CI: 0.967-0.989), respectively. IgG assays outperformed IgA assays (p=0.01). Taking an assessed 15% inter-assay imprecision into account, an optimized IgG ratio cut-off > 2.5 displayed a 100% specificity (95%CI: 99-100) and a 100% positive predictive value (95%CI: 96-100). A 0.8 cut-off displayed a 94% sensitivity (95%CI: 88-97) and a 97% negative predictive value (95%CI: 95-99). Substituting the upper threshold for the manufacturer's, improved assay performance, leaving 8.9% of IgG ratios indeterminate between 0.8-2.5. CONCLUSIONS: The Euroimmun assay displays a nearly optimal diagnostic accuracy using IgG against SARS-CoV-2 in patient samples, with no obvious gains from IgA serology. The optimized cut-offs are fit for rule-in and rule-out purposes, allowing determination of whether individuals in our study population have been exposed to SARS-CoV-2 or not. IgG serology should however not be considered as a surrogate of protection at this stage.

Value of Biomarkers in the Prevention of Rheumatoid Arthritis.

Recent diagnostic advances allow to identify persons in a pre-symptomatic stage of rheumatoid arthritis (RA), opening the way for a preventive therapeutic intervention, which may potentially be curative. We review and discuss existing biomarkers predictive of future onset of RA. A responsible use of biomarkers in clinical settings will require an integration of blood-based tests, imaging techniques, clinical history, environmental risk factors, and family history.

The expression of cytokines and chemokines in the blood of patients with severe weight loss from anorexia nervosa: an exploratory study.

Anorexia nervosa (AN) is a serious, potentially life-threatening disorder characterized by severe weight loss, dysregulated eating, and often excessive exercise. While psychiatric illnesses such as depression are associated with increased levels of pro-inflammatory mediators, evidence for such disturbances in patients with AN has been less clear. In an exploratory study of possible disturbances in immune responses in AN, we assayed a panel of cytokines and chemokines in the blood of patients undergoing inpatient treatment, testing the hypothesis that metabolic disturbances in this disease would lead to a pattern of immune disturbances distinct from that of other psychiatric diseases. For this purpose, we evaluated patients by the Beck Depression Inventory-II (BDI-II) and the Eating Disorders Examination-Questionnaire and assessed cytokines and chemokines by enzyme-linked immunosorbent assays. Patients reported a moderate level of depression (mean BDI-II = 22.6) but exhibited few immunologic abnormalities of the kind associated with major depressive disorder [e.g., increased interleukin (IL)-6]; RANTES showed the most frequent elevations and was increased in 4 of the patients studied. Together, these findings suggest that features of AN such as loss of adipose tissue and excessive exercise may attenuate cytokine production and thus modulate the experience of illness that impacts on core features of disease.

Anti-apolipoprotein A-1 autoantibodies as biomarker for atherosclerosis burden in patients with periodontitis.

BACKGROUND AND OBJECTIVE: Anti-apolipoprotein A-1 (anti-apoA-1) IgG is a potential marker of atherosclerotic plaque vulnerability and cardiovascular complications. In patients with periodontitis the presence of anti-apoA-1 IgGs in serum and their association with atherosclerosis is unknown. MATERIAL AND METHODS: One-hundred and thirty subjects with periodontal disease and 46 healthy subjects, matched for age and gender, participated in this study. Anti-apoA-1 IgG, high-sensitivity C-reactive protein (hsCRP) and matrix metalloproteinase (MMP) -2, -3, -8 and -9 were measured in serum samples. An ankle-brachial index (ABI) value below 1.11 served as a surrogate marker of atherosclerosis. Predictive accuracies of biomarkers for abnormal ABI were determined using receiver-operating characteristics curves and logistic regression analyses. RESULTS: Compared with healthy controls, periodontitis patients showed lower median ABI values (1.10 vs. 1.15; p < 0.0001), a higher prevalence of anti-apoA-1 IgG positivity (23.8% vs. 6.5%; p = 0.009) and higher concentrations of hsCRP (1.62 mg/L vs. 0.85 mg/L; p = 0.02) and MMP-9 (435 µg/mL vs. 283 µg/mL; p < 0.0001). In patients younger than 50 years of age (n = 66), anti-apoA-1 IgG was found to be the best predictor for an abnormal ABI (area under the curve = 0.63; p = 0.03). Anti-apoA-1 IgG positivity increased the risk of having an abnormal ABI (odds ratio = 4.20; p = 0.04), independently of diabetes, smoking and body mass index. CONCLUSIONS: Anti-apoA-1 IgG positivity and atherosclerosis, as reflected by abnormal ABI, were more prevalent in periodontitis patients than in age- and gender-matched controls. In younger periodontitis patients, anti-apoA-1 IgG was found to be the best predictor of atherosclerosis burden.

Auto-antibodies as emergent prognostic markers and possible mediators of ischemic cardiovascular diseases.

During the last 15 years, a growing body of evidence supported the fact that auto-antibodies represent not only emergent markers but also active mediators of cardiovascular disease (CVD), clinically represented mostly by acute coronary syndrome (ACS) and stroke. There is a contrasted relationship between auto-antibodies and CVD, some being protective, while others acting as potential risk factors. Therefore, we performed a review of the literature on the respective cardiovascular prognostic value of the most relevant auto-antibodies in ACS and stroke, and their putative pathophysiological properties in atherogenesis. This review highlights auto-antibodies as active modulators of the innate immune system in atherogenesis (either toward a pro- or anti-inflammatory response), or by affecting basal heart rate regulation (anti-apoA-1 IgG). Given their apparent prognostic independency towards traditional cardiovascular risk factors, the data available in the literature indicates that some of those auto-antibodies could be of valuable help for cardiovascular risk stratification in the future, especially because their deleterious effects have been shown to be potentially abrogated in vivo and in vitro by existing therapeutic modalities. Although evidence in humans is currently lacking, these studies may open innovative therapeutic perspectives for CVD in the future.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

Anti-apolipoprotein A-1 IgG in patients with myocardial infarction promotes inflammation through TLR2/CD14 complex.

OBJECTIVES: Toll-like receptor (TLR)-mediated vascular inflammation, inducible by - amongst other factors - auto-antibodies, is increasingly recognized as a potential mediator of cardiovascular disease. We investigated whether anti-apolipoprotein (Apo)A-1 IgG was associated with a pro-inflammatory cytokine profile in myocardial infarction (MI) patients and whether anti-ApoA-1 IgG elicited a pro-inflammatory response by activating TLRs. METHODS: As surrogate markers of atherosclerotic plaque vulnerability, interleukin (IL)-6, tumour necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-9 and MMP-3 levels were assessed in 221 consecutive MI patients. Using human monocyte-derived macrophages (HMDMs) we investigated (i) the anti-ApoA-1 IgG interaction with TLRs using proximity ligation assay and (ii) anti-ApoA-1 IgG-dependent IL-6/TNF-α production. TLR involvement was further confirmed using HEK293-Blue TLR-2/-4 cells and by computational docking simulations. RESULTS: In MI patients, anti-ApoA-1 IgG positivity was associated with higher levels of IL-6, TNF-α and MMP-9, but lower MMP-3 levels. In in vitro experiments, anti-ApoA-1 antibodies bound to HDMDs in a TLR2-dependent manner, resulting in nuclear translocation of NFκB and a significant increase in TNF-α and IL-6 production. Subsequent functional studies highlighted the importance of CD14 as co-receptor in the anti-ApoA-1 IgG-TLR2-induced cytokine production. Additional bioinformatic studies identified structural homologies between TLR2 and ApoA-1, which may explain the observed cross-reactivity between antibodies against these two molecules. CONCLUSIONS: Anti-ApoA-1 IgG positivity in MI is associated with a high-risk cytokine profile. These auto-antibodies promote inflammation by stimulating the TLR2/CD14 receptor complex, probably because of molecular mimicry, which may contribute to atherosclerosis-related complications in patients.

Autoantibodies against apolipoprotein A-1 and phosphorylcholine for diagnosis of non-ST-segment elevation myocardial infarction.

OBJECTIVES: To explore the diagnostic accuracies of anti-apolipoproteinA-1 (anti-ApoA-1) IgG and anti-phosphorylcholine (anti-PC) IgM alone, expressed as a ratio (anti-ApoA-1 IgG/anti-PC IgM), and combined with the Thrombolysis In Myocardial Infarction (TIMI) score for non-ST-segment elevation myocardial infarction (NSTEMI) (NSTEMI-TIMI score) to create a new diagnostic algorithm - the Clinical Autoantibody Ratio (CABR) score - for the diagnosis of NSTEMI and subsequent cardiac troponin I (cTnI) elevation in patients with acute chest pain (ACP). METHODS: In this single-centre prospective study, 138 patients presented at the emergency department with ACP without ST-segment elevation myocardial infarction. Anti-ApoA-1 IgG and anti-PC IgM were assessed by enzyme-linked immunosorbent assay on admission. Post hoc determination of the CABR score cut-off was performed by receiver operating characteristics analyses. RESULTS: The adjudicated final diagnosis was NSTEMI in 17% (24/138) of patients. Both autoantibodies alone were found to be significant predictors of NSTEMI diagnosis, but the CABR score had the best diagnostic accuracy [area under the curve (AUC): 0.88; 95% confidence interval (CI): 0.82-0.95]. At the optimal cut-off of 3.3, the CABR score negative predictive value (NPV) was 97% (95% CI: 90-99). Logistic regression analysis showed that a CABR score >3.3 increased the risk of subsequent NSTEMI diagnosis 19-fold (odds ratio: 18.7; 95% CI: 5.2-67.3). For subsequent cTnI positivity, only anti-ApoA-1 IgG and CABR score displayed adequate predictive accuracies with AUCs of 0.80 (95% CI: 0.68-0.91) and 0.82 (95% CI: 0.70-0.94), respectively; the NPVs were 95% (95% CI: 90-98) and 99% (95% CI: 94-100), respectively. CONCLUSION: The CABR score, derived from adding the anti-ApoA-1 IgG/anti-PC IgM ratio to the NSTEMI-TIMI score, could be a useful measure to rule out NSTEMI in patients presenting with ACP at the emergency department without electrocardiographic changes.

[New tests for the diagnosis of tuberculosis]. / Nouveaux tests pour le diagnostic de la tuberculose.

Over the last decade, molecular biology techniques for identifying mycobacteria in pulmonary secretions have become more and more sensitive and rapid, even in smear negative samples. Nuclear amplification techniques also allow the rapid detection of resistance to first or second line anti-tuberculous drugs. The sensitivity of these techniques for non respiratory samples is yet to be determined. The diagnosis of latent tuberculous infection (LTBI) has also increased in sensitivity, specificity and positive predictive value through the use of interferon-γ release assays (IGRAs), which are tending to replace the tuberculin skin test, except for children aged under five. These tests, however, do have limitations which are important for the clinician; especially their inability to distinguish active from latent tuberculosis and their inability, in most circumstances, to exclude a diagnosis of active TB.

[External quality controls for allergy analysis in the Quality Control Center Switzerland from 2006 to 2008]. / Les contrôles de qualité externes pour le laboratoire d'allergologie auprès du Centre suisse de contrôle de qualité de 2006 à 2008.

External assessment of analytical performance is part of the quality assurance in medical laboratory. These external controls are mandatory in Switzerland since 2006 for IgE analysis. The Swiss Society for Immunology and Allergy and the Swiss external quality centers had launched a program for total IgE, IgE specific for cat epithelium, birch pollen and peanut, and multi-specific IgE. They have set up criteria for proficiency assessment. Analysis of data obtained from 2006 to 2008 in the Quality Control Center Switzerland shows that results are very good for all the methods used and that a large number of participants fulfill the requirements to obtain the certificate of QUALAB conformity.

Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. tuberculin skin test.

BACKGROUND: Antitumour necrosis factor (anti-TNF) treatments may reactivate latent tuberculosis infection (LTBI). For detecting LTBI, the tuberculin skin test (TST) has low sensitivity and specificity. Interferon-gamma release assays (IGRA) have been shown to be more sensitive and specific than TST. OBJECTIVE: To compare the TST and the T-SPOT.TB IGRA for identifying LTBI in patients with psoriasis before anti-TNF treatment. METHODS: A retrospective study was carried out over a 4-year period on patients with psoriasis requiring anti-TNF treatment. All were subjected to the TST, T-SPOT.TB and chest X-ray. Risk factors for LTBI and history of bacillus Calmette-Guérin (BCG) vaccination were recorded. The association of T-SPOT.TB and TST results with risk factors for LTBI was tested through univariate logistic regression models. Agreement between tests was quantified using kappa statistics. Treatment for LTBI was started 1 month before anti-TNF therapy when indicated. RESULTS: Fifty patients were included; 90% had prior BCG vaccination. A positive T-SPOT.TB was strongly associated with a presumptive diagnosis of LTBI (odds ratio 7.43; 95% confidence interval 1.38-39.9), which was not the case for the TST. Agreement between the T-SPOT.TB and TST was poor, kappa = 0.33 (SD 0.13). LTBI was detected and treated in 20% of the patients. In 20% of the cases, LTBI was not retained in spite of a positive TST but a negative T-SPOT.TB. All patients received an anti-TNF agent for a median of 56 weeks (range 20-188); among patients with a positive TST/negative T-SPOT.TB, no tuberculosis was detected with a median follow-up of 64 weeks (44-188). One case of disseminated tuberculosis occurred after 28 weeks of adalimumab treatment in a patient with LTBI in spite of treatment with rifampicin. CONCLUSION: This study is the first to underline the frequency of LTBI in patients with psoriasis (20%), and to support the use of IGRA instead of the TST for its detection. Nevertheless, there is still a risk of tuberculosis under anti-TNF therapy, even if LTBI is correctly diagnosed and treated.

Gender-based dimorphic pattern for interleukin-1 receptor antagonist in type 2 diabetes mellitus.

UNLABELLED: Adipose tissue secretes a variety of cytokines, some of which are increased in the serum of obese patients. The anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) is the most highly elevated known cytokine in human obesity, and its serum levels are strongly associated with the degree of insulin resistance in non-diabetic patients. AIM: The present study examined serum levels of IL-1Ra in type 2 diabetic patients (T2DM) and their relationships with three other adipokines (leptin, interleukin-6 [IL-6], adiponectin). Their correlation with anthropometric and biochemical variables was examined, as well as their intraindividual fluctuations. METHODS: Fifty T2DM patients, aged 58+/-13 years, were consecutively recruited among those electively hospitalized for a one-week intensive training course with our Diabetes Education Service. Anthropometric measurements and blood samples were taken after an overnight fast on admission (baseline) and after four days. RESULTS: Mean serum levels of IL-1Ra and leptin, but not of IL-6 and adiponectin, were significantly higher in women than in men (P<0.0006), and this difference persisted after correction for body mass index (BMI) (P<0.0004). In addition, IL-1Ra and leptin were strongly correlated with the BMI (P<0.0004). By contrast, no significant correlations were observed between IL-1Ra and glucose-control parameters. Finally, all four adipokines exhibited wide interindividual variability, but with limited intraindividual fluctuations over the short time period. CONCLUSION: IL-1Ra, leptin and adiponectin serum levels exhibit marked interindividual variation with high intraindividual consistency. A gender-based dimorphic pattern for IL-1Ra, independent of the degree of adiposity and glucose control, was also found.

Quantitative scoring of an interferon-gamma assay for differentiating active from latent tuberculosis.

The aim of this study was to assess the contribution of an interferon-gamma release assay (T-SPOT.TB) to the differentiation of active tuberculosis (TB) from latent TB infection by quantifying spot-forming units (sfu). The investigation was a prospective study of contacts exposed to a case of contagious TB and cases of HIV-negative culture-proven TB referred over a 16-month period. Tuberculin skin tests (TSTs) and T-SPOT.TB were performed in 310 contacts 8-12 weeks after exposure. In subjects with culture-proven TB, T-SPOT.TB was performed within 2 weeks of initiation of treatment. The analysis included all contacts with a positive T-SPOT.TB result and all subjects with TB. TB contacts (n = 127) and cases (n = 58) were included. Mean+/-sd T-SPOT.TB results were 107+/-56 (range 1-207) sfu for TB, 54+/-60 (7-239) sfu for contacts with positive T-SPOT.TB results and a TST induration diameter of >5 mm, and 19+/-27 (7-143) sfu for contacts with positive T-SPOT.TB results and a TST induration diameter of < or =5 mm. By receiver operating characteristic curve analysis, a threshold value of 49.5 sfu showed a sensitivity of 83% and specificity of 74% for distinguishing latent TB infection from TB. Although T-SPOT.TB results were significantly related to disease activity, the test cannot be recommended for the diagnosis of tuberculosis.

Synovial tissue interleukin-18 expression and the response to treatment in patients with inflammatory arthritis.

OBJECTIVE: To measure synovial tissue interleukin-18 (IL-18) expression in patients with inflammatory arthritis, and to identify associations with serum levels, disease activity, and response to treatment. METHODS: Synovial tissue biopsies and serum samples were obtained from patients with early, active, rheumatoid arthritis (RA) (n = 12), undifferentiated seronegative arthritis (SnA) (n = 9), psoriatic arthritis (PsA) (n = 5), and reactive arthritis (ReA) (n = 2) before and one year after introduction of disease modifying antirheumatic drug (DMARD) treatment. Osteoarthritis (OA) tissues were compared. Tissue IL-18 expression was determined after immunohistochemical staining using a semiquantitative scale. Serum IL-18 was measured by enzyme linked immunosorbent assay. RESULTS: Before treatment was started, tissue IL-18 expression was increased in each diagnostic group compared with OA (p<0.05). Tissue IL-18 expression was correlated with serum C reactive protein levels (r = 0.53, p = 0.003) but not with serum IL-18. After DMARD treatment, 12 patients (five RA, four SnA, three PsA) were re-evaluated. Decreases in tissue IL-18 expression were observed in eight, although the trend did not reach significance (p = 0.068). Changes in tissue IL-18 expression were correlated with changes in serum IL-18 (r = 0.62, p = 0.041) and C reactive protein (r = 0.72, p = 0.009). CONCLUSIONS: Synovial tissue IL-18 expression was correlated with disease activity in inflammatory arthritis. After treatment, tissue levels changed in parallel with changes in serum IL-18 and with changes in the acute phase response. These observations support a role for IL-18 in the pathophysiology of inflammatory arthritis.

Serum interleukin 18 and interleukin 18 binding protein in rheumatoid arthritis.

OBJECTIVE: To measure serum interleukin 18 (IL18) and IL18 binding protein (IL18BP) levels in patients with inflammatory arthropathies, and to identify associations with disease status and the response to treatment. METHODS: Serum samples were obtained before and after methotrexate treatment from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) attending an early arthritis clinic. IL18 and IL18BP were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Sixty patients with RA and 13 with PsA were evaluated. Serum IL18 levels were significantly higher in RA than in PsA (p<0.001). After six months' treatment with methotrexate, IL18 levels were reduced, but the differences were not significant (p=0.052). In cross sectional analyses, no correlations between IL18 levels and measures of disease activity or structural damage in RA were found. In longitudinal analyses, no correlations between IL18 levels and the response to treatment or the degree of progressive joint damage were found. Similarly, IL18BP levels were raised in RA, and were not associated with measures of the clinical status or the response to treatment. CONCLUSION: Raised serum levels of IL18 are consistent with a pathophysiological role in RA. However, in this study measurement of circulating IL18 and IL18BP did not correlate significantly with clinical measures of disease activity or the response to treatment in patients with early RA.

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.

Cytokines, metalloproteinases, their inhibitors and cartilage oligomeric matrix protein: relationship to radiological progression and inflammation in early rheumatoid arthritis. A prospective 5-year study.

OBJECTIVE: To assess how serum concentrations of some cytokines, proteases and their inhibitors and cartilage oligomeric matrix protein (COMP) relate to the evolution of clinical disease and joint damage in early rheumatoid arthritis (RA). METHODS: Annual assessment was performed in 24 RA patients subdivided into three groups according to disease severity as determined by the radiological progression rate. All patients were followed for 5 yr after inclusion. Functional status, Larsen's radiographic index in hands and feet (joint damage score, JDS) and C-reactive protein (CRP) were assessed annually and compared with interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1Ra), promatrix metalloproteinase 3 (proMMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1) and COMP, which were determined by specific immunological tests. RESULTS: The median JDS was initially between 4.5 and 7. During the study time the progression of JDS was 1 (median) for patients with slow progression, 33 for patients with intermediate progression and 62 for patients with rapid progression. Changes in CRP and proMMP-3 concentrations over time differed significantly between the groups, but no significant difference was observed for IL-1Ra, TIMP-1 or COMP. ProMMP-3 was closely related to CRP at each time point. IL-6 correlated significantly with CRP at the last four annual follow-up examinations. CRP and proMMP-3 correlated with JDS at the last two or three examinations and the combined levels of these markers over 5 yr correlated significantly with joint damage progression (Spearman rank correlation 0.73 and 0.74 respectively). IL-1Ra showed a weak negative correlation with JDS, and COMP tended to correlate with JDS only at the start. The initial proMMP-3 concentration was the only significant variable predicting rapidly developing joint damage, but the predictive value was low. CONCLUSIONS: ProMMP-3 correlated closely at all time points with CRP, but gave little or no additional clinical information regarding inflammation or radiographic progression. IL-1Ra and TIMP-1 showed weaker, acute-phase-like variation, which may reflect pathogenic agonist/inhibitor imbalance in the evolution of RA. COMP, in contrast, did not reflect the inflammatory CRP-related component of the disease or the destructive aspect in this study.

Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), essential components in the pathogenesis of immunoinflammatory diseases, are strongly induced in monocytes by direct contact with stimulated T lymphocytes. This study demonstrates that adult human serum (HS) but not fetal calf or cord blood serum displays inhibitory activity toward the contact-mediated activation of monocytes by stimulated T cells, decreasing the production of both TNF-alpha and IL-1beta. Fractionation of HS and N-terminal microsequencing as well as electroelution of material subjected to preparative electrophoresis revealed that apolipoprotein A-I (apo A-I), a "negative" acute-phase protein, was the inhibitory factor. Functional assays and flow cytometry analyses show that high-density lipoprotein (HDL)-associated apo A-I inhibits contact-mediated activation of monocytes by binding to stimulated T cells, thus inhibiting TNF-alpha and IL-1beta production at both protein and messenger RNA levels. Furthermore, apo A-I inhibits monocyte inflammatory functions in peripheral blood mononuclear cells activated by either specific antigens or lectins without affecting cell proliferation. These results demonstrate a new anti-inflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions. Therefore, because HDL has been shown to bind and neutralize lipopolysaccharide, HDL appears to play an important part in modulating both acute and chronic inflammation. The novel anti-inflammatory function of apo A-I reported here might lead to new therapeutic approaches in inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and atherosclerosis.

Autoantibody profiles in the sera of European patients with myositis.

OBJECTIVE: To determine the prevalence of myositis specific autoantibodies (MSAs) and several myositis associated autoantibodies (MAAs) in a large group of patients with myositis. METHODS: A total of 417 patients with myositis from 11 European countries (198 patients with polymyositis (PM), 181 with dermatomyositis (DM), and 38 with inclusion body myositis (IBM)) were serologically analysed by immunoblot, enzyme linked immunosorbent assay (ELISA) and/or immunoprecipitation. RESULTS: Autoantibodies were found in 232 sera (56%), including 157 samples (38%) which contained MSAs. The most commonly detected MSA was anti-Jo-1 (18%). Other anti-synthetase, anti-Mi-2, and anti-SRP autoantibodies were found in 3%, 14%, and 5% of the sera, respectively. A relatively high number of anti-Mi-2 positive PM sera were found (9% of PM sera). The most commonly detected MAA was anti-Ro52 (25%). Anti-PM/Scl-100, anti-PM/Scl-75, anti-Mas, anti-Ro60, anti-La, and anti-U1 snRNP autoantibodies were present in 6%, 3%, 2%, 4%, 5%, and 6% of the sera, respectively. Remarkable associations were noticed between anti-Ro52 and anti-Jo-1 autoantibodies and, in a few sera, also between anti-Jo-1 and anti-SRP or anti-Mi-2 autoantibodies. CONCLUSIONS: The incidence of most of the tested autoantibody activities in this large group of European patients is in agreement with similar studies of Japanese and American patients. The relatively high number of PM sera with anti-Mi-2 reactivity may be explained by the use of multiple recombinant fragments spanning the complete antigen. Furthermore, our data show that some sera may contain more than one type of MSA and confirm the strong association of anti-Ro52 with anti-Jo-1 reactivity.

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.