Background:
First-degree relatives of rheumatoid arthritis (RA) patients (FDR-RA) have a 3 - 5-fold increased prevalence of the disease 1. RA development is triggered by an interaction between ...genetic and environmental factors.
As the field is moving towards prevention in pre-clinical stages of RA, it is key to identify individuals with imminent RA, prior to onset of symptoms, which will presumably rely on both the measurement of autoantibodies and genetic risk markers.
Objectives:
Assemble a pattern of serologic biomarkers in combination with genetics to improve the identification of individuals at high risk to develop RA.
Methods:
The cohort included 827 serum samples from 601 individuals, followed within the Swiss multicenter cohort study SCREEN-RA of FDR 2. FDR-RA were categorized into four groups according to the presence of symptoms and systemic autoimmunity associated with RA; 1: asymptomatic FDR-RA without anti-CCP or symptoms, 416 (69%); 2: FDR-RA with clinically suspect arthralgia (CSA) 3 or with signs of arthritis, without anti-CCP, 72 (12%); 3: FDR-RAs with no signs of arthritis, positive anti-CCP test, 55 (9%); 4: FDR with signs of arthritis or CSA, positive anti-CCP-test, 58 (10%).
Serum samples were analyzed for the presence of anti-CCP (IgG, IgA), RF (IgM, IgA) and anti-RA33 (IgM, IgA, IgG) using the EliA
TM
instrument platform (Phadia AB, Uppsala, Sweden).
Genetic measurements were performed using the AmpliSeq
TM
technology on the Ion GeneStudio
TM
instruments (Thermo Fisher Scientific, Carlsbad, USA), covered variants were analyzed using an algorithm focusing on the identification of RA patients.
Results:
The overall prevalence of biomarkers, considering results above cutoff values, was 1% for anti-CCP IgG and IgA, 10% and 2% for RF IgM and RF IgA, respectively, and 6-15% for all three anti-RA33 isotypes. Several individuals had multiple positive serology tests (Fig 1): 3.6% (22) were positive for 2 tests and 1% (6) were positive for 3 or more tests. Among the 28 individuals positive for ≥2 tests, 17 (61%) were symptomatic.
Figure 1.
Distribution of positive serology within the different groups. No positivity (none), positive for one (1), equal or more than 2 (2-5) of the serologic tests.
Nine of 604 FDR-RA subsequently developed classifiable RA and were positive for serologic biomarkers before date of RA diagnosis (Table 1). The RA converters had a mean age of 39 years (24-75 yrs) and an average follow-up time within the study of 3.6 years (1-7 yrs).
Table 1.
Biomarker status of subsequent RA converters before date of diagnosis.
RA converters
CCP IgG
CCP IgA
RF IgM
RF IgA
RA33 total
1
+
+
+
+
+
2
+
−
+
+
−
3
−
−
+
−
+
4
−
−
+
−
−
5
−
−
+
−
−
6
−
−
−
−
+
7
−
−
−
−
+
8
−
−
−
−
−
9
−
−
−
−
−
Using an algorithm to analyze the RA-associated genetic SNPs, we could highlight 48 FDR-RA (8%) with an increased genetic risk to develop RA. 15 out of 48 individuals (31%) at high genetic risk reported CSA, and 12 out of 48 individuals (25%) displayed signs of systemic autoimmunity associated with RA.
Conclusion:
When looking at FDR it could help to not only include anti-CCP autoantibody testing but also additional biomarkers like RF and anti-RA33. Furthermore, looking at the genetic risk factors could give additional information. The combination with the multi-variate profile could even improve the early diagnosis of these patients.
References:
1Kuo et al. Rheumatology 2017; 56:928933
2Finckh et al. Ann Rheum Dis 2011; 70: S3–282
3van Steenbergen HW, et al. Ann Rheum Dis 2017; 76:491–496
Disclosure of Interests:
Maresa Grundhuber Grant/research support from: Thermo Fisher Scientific, Employee of: Thermo Fisher Scientific, Isabel Gehring Grant/research support from: Thermo Fisher Scientific, Employee of: Thermo Fisher Scientific, Céline Lamacchia Grant/research support from: Thermo Fisher Scientific partially supported this study, Pascale Roux-Lombard: None declared, Michael Nissen Grant/research support from: Abbvie, Consultant of: Novartis, Lilly, Abbvie, Celgene and Pfizer, Speakers bureau: Novartis, Lilly, Abbvie, Celgene and Pfizer, Ulrich Walker Grant/research support from: Ulrich Walker has received an unrestricted research grant from Abbvie, Consultant of: Ulrich Walker has act as a consultant for Abbvie, Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, Sanofi, and ThermoFisher, Paid instructor for: Abbvie, Novartis, and Roche, Speakers bureau: Abbvie, Actelion, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, and ThermoFisher, Burkhard Moeller: None declared, Diego Kyburz Grant/research support from: Abbvie, Roche, Consultant of: Abbvie, BMS, Novartis, Pfizer, Roche, UCB, Gilead, Sanofi, Speakers bureau: Pfizer, BMS, Novartis, Abbvie, Adrian Ciurea Consultant of: Consulting and/or speaking fees from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer., Maryam Poorafshar Grant/research support from: Thermo Fisher Scientific, Employee of: Thermo Fisher Scientific, Axel Finckh Grant/research support from: Pfizer: Unrestricted research grant, Eli-Lilly: Unrestricted research grant, Consultant of: Sanofi, AB2BIO, Abbvie, Pfizer, MSD, Speakers bureau: Sanofi, Pfizer, Roche, Thermo Fisher Scientific
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.
Aims To assess the prognostic value of anti-apolipoprotein A-1 (anti-apoA-1) IgG after myocardial infarction (MI) and its association with major cardiovascular events (MACEs) at 12 months and to ...determine their association with resting heart rate (RHR), a well-established prognostic feature after MI. Anti-apoA-1 IgG have been reported in MI without autoimmune disease, but their clinical significance remains undetermined. Methods and results A total of 221 consecutive patients with MI were prospectively included, and all completed a 12-month follow-up. Major cardiovascular events consisted in death, MI, stroke, or hospitalization either for an acute coronary syndrome or heart failure. Resting heart rate was obtained on Holter the day before discharge under the same medical treatment. Neonate rat ventricular cardiomyocytes (NRVC) were used in vitro to assess the direct anti-apoA-1 IgG effect on RHR. During follow-up, 13% of patients presented a MACE. Anti-apoA-1 IgG positivity was 9% and was associated with a higher RHR (P = 0.0005) and higher MACE rate (adjusted OR, 4.3; 95% CI, 1.46–12.6; P = 0.007). Survival models confirmed the significant nature of this association. Patients with MACE had higher median anti-apoA-1 IgG values at admission than patients without (P = 0.007). On NRVC, plasma from MI patients and monoclonal anti-apoA-1 IgG induced an aldosterone and dose-dependent positive chronotropic effect, abrogated by apoA-1 and therapeutic immunoglobulin (IVIG) pre-incubation. Conclusions In MI patients, anti-apoA-1 IgG is independently associated with MACE at 1-year, interfering with a currently unknown aldosterone-dependent RHR determinant. Knowing whether anti-apoA-1 IgG assessment could be of interest to identify an MI patient subset susceptible to benefit from apoA-1/IVIG therapy remains to be demonstrated.
Background. End stage renal disease increases the risk of reactivating latent tuberculosis (LTBI). Interferon-γ release assays (IGRA) are an alternative to the tuberculin skin test (TST) for ...detecting LTBI. Methods. Sixty-two hemodialysis patients (46 male, 16 female, aged 65 ± 15 years) from 3 hemodialysis facilities in the Geneva area were submitted to a TST, 2 IGRA (T-SPOT.TB and QuantiFERON Gold in tube: QFT), a chest radiography, and a questionnaire to record social status, country of birth, history of prior TST, tuberculosis (TB), BCG (Bacillus of Calmette-Guérin vaccine), and any cause of immuno-suppression. LTBI was defined as prior “at risk” contact with a case of contagious TB and/or a chest X-ray suggestive of prior TB infection. Results. Positivity rate was 19% for TST, 21% for QFT and 29% for T-SPOT-TB; 8% of QFT and 11% of T-SPOT-TB were indeterminate. Agreement between IGRA was fair (κ = 0.60). After adjusting for age and BCG, OR (Odds Ratio) of having a positive QFT was 4.6-fold (p = 0.029) higher in patients with LTBI vs. those without LTBI. In contrast, no association was found between LTBI and having a positive T-SPOT.TB or a positive TST. As expected, there was a strong association between prior BCG vaccination and having a positive TST (OR 5.3, p = 0.017). QFT was the only test with a significant OR of having LTBI (adjusted OR: 4.4; 95%CI: 1.1 − 17.6; p = 0.034). Among 5 patients with definite prior TB, TST and T-SPOT.TB were positive in 1 and QFT, in 2. Conclusions. In this population, QFT was superior to TST for detecting LTBI, but both IGRAs and TST have important limitations, and are unreliable for screening for LTBI.
BACKGROUNDRenal transplant recipients (RTRs), as all immunosuppressed patients, are at increased risk of reactivating latent tuberculosis infection (LTBI). Detecting LTBI in this population is ...therefore important to prevent active TB. The tuberculin skin test (TST) has a poor sensitivity in this setting.
METHODSThe aim of this prospective study was to compare the diagnostic performance of the TST and two interferon-γ release assays (IGRAs)T-SPOT.TB (Oxford Immunotec, Oxford, UK) and QuantiFERON Gold In-Tube (QGIT; Cellestis, Australia), performed simultaneously, for the detection of patients with risk factors for LTBI or a definite history of TB among RTRs under stable immunosuppression.
RESULTSTwo hundred five patients (ages 59±13 years, tested 10.4±7.1 years after transplantation) were studied. Positivity rate was 4.5% for TST, 20.5% for T-SPOT.TB, and 23.5% for QGIT. Agreement between IGRAs was fair (κ=0.71). Sensitivity of T-SPOT.TB and QGIT for detection of prior active TB was 55.6% (95% confidence interval CI, 21.2–86.3) and 44.4 (95% CI, 13.7–78.8), respectively. Sensitivity of both IGRAs for detection of risk factors for LTBI was 33.3% (95% CI, 19.6–49.5). Specificity was 85.5% (95% CI, 78.9–90.7) for T-SPOT.TB and 80.1% (95% CI, 72.9–86.2) for QGIT. Combining IGRAs did not significantly improve sensitivity.
CONCLUSIONSBecause their sensitivity for detecting prior active TB and probable LTBI in RTRs is very low, IGRAs cannot be used to exclude LTBI. These results emphasize the limitations of IGRAs in the setting of chronic immunosuppressive therapy.
IntroductionRheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are important serological marker in the diagnosis of rheumatoid arthritis (RA) and are part of the classification ...criteria. ACPA are generally detected using anti-cyclic citrullinated peptide (CCP) antibody assays. The first generation of the CCP test uses a peptide derived from the filaggrin protein as the antigen, whereas, the second and third generation CCP (CCP2, CCP3) are based on peptides specifically designed and optimised (mimotypes) to detect ACPA, thereby enhancing the immunoreactivity of the citrulline-containing epitope.ObjectivesThe goal was to compare the performance of CCP2 and CCP3 assays.Methods1655 samples including 968 RA patients and 687 controls (450 ankylosing spondylitis (AS) and 237 psoriatic arthritis (PsA) patients), all derived from the Swiss Clinical Quality Management in Rheumatic Diseases Foundation (SCQM) were included. ACPA were determined by CCP2 ELISA (Eurodiagnostica, Sweden), CCP3 ELISA (QUANTA Lite CCP3 IgG) and CCP3 CIA (QUANTA Flash CCP3 IgG) (both Inova Diagnostics, US). RF IgM was measured by ELISA (QUANTA Lite RF IgM, Inova Diagnostics, US).ResultsThe CCP2 ELISA showed a high sensitivity (71.1%) and a moderately high specificity (86.9%) with a corresponding Odds ratio (OR) of 16.3 (95% CI: 12.5 to 21.1). The two CCP3 assays showed lower sensitivities (61.8% for the ELISA and 61.4% for the CIA), but significantly higher specificities (98.4% and 98.5% respectively), resulting in much higher predictive values, with OR of 99.3 (95% CI: 54.4 to 181.2) and 107.5 (95% CI: 57.4 to 201.5), respectively. When compared at the same specificity (95%), the sensitivities were 61.3% for the CCP2 ELISA, 68.1% for the CCP3 ELISA and 66.1% for the CCP3 CIA. When multi-parametric analyses were performed by combining ACPA with RF IgM, combining different markers resulted in higher OR than the individual markers. The combination of CCP3 and RF IgM resulted in a higher OR (OR=187.0, 510/1655) than the combination of CCP2 with RF IgM (OR=36.7, 565/1655). The addition of CCP2 to the combination of CCP3 and RF IgM resulted in a lower OR (OR=175.0, 494/1655).ConclusionsCCP3 showed a better overall performance than CCP2 in this cohort of RA and controls, when analysed individually as well as in combination with RF IgM.Disclosure of interestNone declared
Abstract 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.
Objectives To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biological therapy for rheumatoid arthritis (RA). Methods ...Patients with active RA entered a randomised study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 μg/kg twice a week. Arthroscopic synovial tissue biopsies were obtained at baseline and two further time points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis. Selected mediators were also measured in the serum. Results Twenty-two patients were randomly assigned: 11 received monotherapy and 11 combination therapy. American College of Rheumatology 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy and 36%, 9% and 0% with monotherapy, respectively. In synovial tissue, T-cell infiltration, vascularity and transforming growth factor beta (TGFβ) expression demonstrated significant utility as biomarkers of disease activity and therapeutic response. In serum, interleukin 6 (IL-6), matrix metalloproteinase (MMP) 1, MMP-3 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pretreatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor/TGFβ, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor types I and II and IL-18 correlated with radiographic progression. Conclusions Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.
The extracellular domain of tumour necrosis factor-alpha (TNF- alpha ) receptors have inhibitory properties against TNF- alpha . The relative ratio between ligand and ligand inhibitors may influence ...the outcome of meningococcaemia. To test this hypothesis, levels of TNF- alpha and of each of the soluble inhibitory fragments originating from two distinct TNF- alpha -receptors (sTNF-RI and sTNF-RII) were measured in sera of children with severe meningococcaemia.
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