| 21. |
|
|
| 22. |
|
|
| 23. |
- Lonnblom, E, et al.
(författare)
-
AUTOANTIBODIES TO JOINT PROTEINS AS NOVEL BIOMARKERS FOR THE DIAGNOSIS OF UNTREATED EARLY RHEUMATOID ARTHRITIS
- 2022
-
Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 546-546
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Autoantibodies to citrullinated protein (ACPA; measured as anti-CCP; aCCP) and rheumatoid factor (RF) appear years before clinical onset of RA and are essential tools in today’s classification criteria for RA. In animal models, antibodies to joint specific proteins (JP) can induce arthritis, and they are also present at onset of RA [1]. As there is a need for increased precision for early diagnosis of RA as well as identification of different subtypes of the disease, we aim to assess whether autoantibodies to native or modified JP can be used for early and precise diagnosis of RA.ObjectivesTo study whether antibodies to JP, alone or in combination with ACPA/RF, could increase the diagnostic sensitivity and specificity in untreated early (ue)RA patients.MethodsAntibodies to JP were analysed in serum from patients in three independent ueRA cohorts as well as from population controls without rheumatic diseases (WINGA, Gothenburg and MFM-ÅUS, Malmö n=1062). ERAp (n=66), the smallest and most recent cohort was chosen for screening, and BARFOT and TIRA-2 (n=1939) for validation. We have developed a bead-based multianalyte flow immunoassay [2] and screened approx. 350 peptides derived from JPs of interest. We included monoclonal antibodies as assay calibrators and determined limit of detection (LoD). To assess positivity for autoantibodies to JP of interest above LoD, we used 5MAD (median absolute deviation) of the control populations as the cut-off.ResultsIn the ERAp cohort, 5 autoantibodies discriminated RA patients from controls with 81% sensitivity and 100% specificity (Table 1). The same autoantibodies had 68% sensitivity and 98% specificity in the combined BARFOT and TIRA-2 cohorts. Together with RF and aCCP, only 2 of the 5 autoantibodies added statistically significant diagnostic value, increasing the sensitivity from 48% to 61% with 99% specificity. In aCCP- and RF-negative ueRA patients (n=536), the novel biomarkers identified 22.5% of the patients with 99% specificity compared to controls.Table 1.Diagnostic capacity of the joint-specific antibodiesTest panelPerformanceGroup of patientsaCCP+RF+JP+SensitivitySpecificityAUC(ROC)ERApAll patients (n=66)--X81%100%89%RF and aCCP-neg patients (n=7)1------BARFOT and TIRA-2, combined dataAll patients (N=1939)--X68%98%86%All patients (N=1939)X--58%99%78%All patients (N=1939)2XX-48%100%84%All patients (N=1939)2, 3XXX61%99%86%RF and/or aCCP-pos patients (N=1403)--X84%99%93%RF and aCCP-neg patients (N=536)--X22%99%67%RA, literature valuesAnti-CCP testXN/AN/A53–71%95–96%N/A1Not analysed due to lack of power2This patient population is both aCCP+ and RF+3Only 2 of the 5 autoantibodies added statistically significant to the diagnostic valueAUC, Area under the curve; ROC, receiver operating characteristic curve; N/A, not applicable. Controls without rheumatic diseases: N=935 for BARFOT / TIRA-2 and N=27 for ERAp.ConclusionAutoantibodies to JP discriminate ueRA patients better then aCCP and RF alone and add an increased diagnostic value in particular for seronegative patients.References[1]Holmdahl, R., V. Malmstrom, and H. Burkhardt, Autoimmune priming, tissue attack and chronic inflammation - the three stages of rheumatoid arthritis. Eur J Immunol, 2014. 44(6): p. 1593-9.[2]Viljanen, J., et al., Synthesis of an Array of Triple-Helical Peptides from Type II Collagen for Multiplex Analysis of Autoantibodies in Rheumatoid Arthritis. ACS Chem Biol, 2020. 15(9): p. 2605-2615. Correction: ACS Chem Biol, 2020. 15(11): p. 3072AcknowledgementsBARFOT study group.Disclosure of InterestsErik Lönnblom: None declared, Monica Leu Agelii: None declared, Outi Sareila Employee of: Part time employee in Vacara AB, Ingiäld Hafström: None declared, Maria Andersson: None declared, Lei Cheng: None declared, Göran Bergström: None declared, Anna-Karin H Ekwall: None declared, Anna Rudin: None declared, Alf Kastbom: None declared, Christopher Sjowall: None declared, Bingze Xu: None declared, Lennart T.H. Jacobsson: None declared, Johan Viljanen: None declared, Jan Kihlberg: None declared, Inger Gjertsson: None declared, Rikard Holmdahl Shareholder of: Rikard Holmdahl the founder of Vacara AB.
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
- Parodis, Ioannis, 1981-, et al.
(författare)
-
PREDICTORS OF DE NOVO RENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS - TIME TO REVISIT BELIMUMAB DOSE FOR EXTRA-RENAL DISEASE? : RESULTS FROM FIVE PHASE III CLINICAL TRIALS OF BELIMUMAB
- 2023
-
Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 909-910
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Each lupus nephritis (LN) flare causes nephron loss that equals a decade or more of reduction in renal function lifespan, making prompt initiation of therapy imperative and prevention of flares even more desirable. Identification of readily available signals of imminent flare is therefore expected to improve prognosis.Objectives: In light of observed cases of de novo LN during belimumab treatment (1), we evaluated predictors of de novo renal flare occurrence in patients with systemic lupus erythematosus (SLE) and no prior history of renal disease undergoing standard therapy (ST) with or without add-on belimumab in clinical trial settings.Methods: Data from five clinical trials of belimumab in SLE (BLISS-52 NCT00424476; BLISS-76 NCT00410384; BLISS-NEA NCT01345253; BLISS-SC NCT01484496; EMBRACE NCT01632241) were utilised. The study population comprised 1932 patients with a baseline renal British Isles Lupus Assessment Group (BILAG) score E. De novo renal flares were defined as a change from renal BILAG E to A or B within a 52-week follow-up. Comparisons of baseline data were made using the Mann-Whitney U test, Pearson’s chi-squared (χ2) test or Fisher’s exact test as appropriate. Predictors of renal flare occurrence were investigated using univariable and multivariable Cox regression analysis. p values <0.05 were considered statistically significant.Results: De novo renal flares were documented in 146 (7.6%) patients. Among patients who developed at least one renal flare, greater proportions were Asians (30.8% versus 20.2%; p<0.003), had positive baseline anti-dsDNA levels (74.0% versus 61.3%; p=0.003), and had low baseline levels of C3 (51.4% versus 38.2%; p=0.002) and C4 (45.2% versus 35.8%; p=0.030) compared with patients who did not flare. In univariable Cox regression analysis, azathioprine use was protective against renal flares (HR: 0.70; 95% CI: 0.49–0.99; p=0.047), while anti-Sm positivity at baseline showed a trend towards an association with imminent renal flare (HR: 1.68; 95% CI: 0.99–2.85; p=0.057). In multivariable Cox regression analysis adjusting for age, sex, ethnicity, serum creatinine, and variables that differed significantly in univariable analysis, Asian ancestry (HR: 1.60; 95% CI: 1.03–2.49; p=0.036), high mean prednisone dose from baseline until renal flare occurrence or throughout the follow-up (HR: 1.03; 95% CI: 1.02–1.05; p<0.001), and baseline serum creatinine (HR: 1.02; 95% CI: 1.01–1.03; p=0.001) were associated with imminent de novo renal flare, while extra-renal clinical SLE Disease Activity Index 2000 (cSLEDAI) showed a negative association (HR: 0.92; 95% CI: 0.86–0.98; p=0.007). Notably, use of belimumab 1 mg/kg by intravenous (IV) infusion yielded a nearly 3 times decreased hazard of renal flare (HR: 0.37; 95% CI: 0.20–0.68; p=0.001), whereas IV belimumab 10 mg/kg and belimumab 200 mg administered subcutaneously (SC) displayed no clear protection.Conclusion: Asian patients appeared particularly susceptible to new-onset renal involvement, corroborating the substantial vulnerability of Asian SLE populations to renal affliction. Add-on low-dose IV belimumab on top of ST appeared protective against renal flares in SLE patients with no prior history of nephritis, while addition of the approved 10 mg/kg IV belimumab dose and SC belimumab yielded no clear protection. Discrepant results between low and high/approved belimumab doses warrant in-depth mechanistic exploration of underlying reasons e.g., potential effects of belimumab on B cell subsets that acquire regulatory properties.Reference: [1]Parodis I, Vital EM, et al. Rheumatology (Oxford). 2021;60(9):4348-54.
|
|
