| 1. |
- Hambardzumyan, Karen, et al.
(författare)
-
A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy in Early Rheumatoid Arthritis After Methotrexate Failure
- 2017
-
Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 69:5, s. 953-963
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate whether the Multi-Biomarker Disease Activity (MBDA) score predicts optimal add-on treatment in patients with early rheumatoid arthritis (RA) who were inadequate responders to MTX (MTX-IRs). Methods: We analyzed data from 157 MTX-IRs (with a Disease Activity Score using the erythrocyte sedimentation rate [DAS28-ESR] >3.2) from the Swedish Pharmacotherapy (SWEFOT) trial who were randomized to receive triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) versus MTX plus infliximab. The MBDA score as a predictor of the subsequent DAS28-based response to each second-line treatment was analyzed at randomization with the Breslow-Day test for 2 × 2 groups, using both validated categories (low [<30], moderate [30–44], and high [>44]) and dichotomized categories (lower [≤38] versus higher [>38]). Results: Among the 157 patients, 12% had a low MBDA score, 32% moderate, and 56% high. Of those with a low MBDA score, 88% responded to subsequent triple therapy, and 18% responded to MTX plus infliximab (P = 0.006); for those with a high MBDA score, the response rates were 35% and 58%, respectively (P = 0.040). When using 38 as a cutoff for the MBDA score (29% patients with lower scores versus 71% with higher scores), the differential associations with response to triple therapy versus MTX plus infliximab were 79% versus 44% and 36% versus 58%, respectively (P = 0.001). Clinical and inflammatory markers had poorer predictive capacity for response to triple therapy or MTX plus infliximab. Conclusion: In patients with RA who had an inadequate response to MTX, the MBDA score categories were differentially associated with response to subsequent therapies. Thus, patients with post-MTX biochemical improvements (lower MBDA scores) were more likely to respond to triple therapy than to MTX plus infliximab. If confirmed, these results may help to improve treatment in RA.
|
|
| 2. |
|
|
| 3. |
- Hambardzumyan, Karen
(författare)
-
Predictive biomarkers in rheumatoid arthritis
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Being a very heterogeneous disease, rheumatoid arthritis (RA) is challenging for treatment. On a group level, some therapy options might be superior compared with others, however, this does not mutually exclude the less effective option to be more suitable for some patients, if the superior therapy option does not help. In different patients the concentration of biomarkers may vary dramatically, however, translation of meaning of these variations for each patient is not feasible yet. Observations and comparisons of these biomarkers before start of therapy between patient groups with different outcome after therapy can help to understand their role and make individualised approach for the therapy choice. Low or moderate levels of a multi-biomarker disease activity (MBDA) score measured at baseline or follow-up visits could identify RA patients at very low risk of radiographic progression (RP). Moreover, in patients with high MBDA score at the start of treatment escalation, those on infliximab+methotrexate (IFX+MTX) therapy had significantly less RP than patients on non-biological triple therapy (TT) (papers I and II). In treatment-naive, early RA, patients who failed respond to MTX were randomized to IFX+MTX or non-biological TT. The categories of the MBDA score at the time of randomisation were differentially associated with treatment outcome after 1 year for these two therapies. Patients with low MBDA score benefited more from TT, while those with high MBDA score responded better to IFX (paper III). Furthermore, when the 12 component biomarkers of the MBDA score were analysed at baseline, four of those (paper IV) as well as two of 177 proteins retrieved from an affinity proteomic study (paper V) were associated with treatment outcome: low disease activity (LDA) and EULAR good response after 3 months of MTX therapy. Combination of these biomarkers within each study also showed improved prediction of treatment outcome. In patients failing on MTX monotherapy who were randomised to addition of biological TNF inhibitor IFX, very low serum IFX (sIFX) level and anti-drug antibody (ADA)-positivity were associated with poorer outcome. Among baseline parameters, female gender predicted very low sIFX level and ADA-positivity at follow-ups, with similar trend for RF-positivity (paper VI). In summary, using combination of serum biomarkers helps to predict and identify preferential therapy option for subsets of patients. Further studies of these biomarkers, if validated, will facilitate personalised therapy approach for subsets of patients.
|
|
| 4. |
|
|
| 5. |
- Hambardzumyan, Karen, et al.
(författare)
-
Serum biomarkers for prediction of response to methotrexate monotherapy in early rheumatoid arthritis : Results from the SWEFOT trial
- 2019
-
Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 46:6, s. 555-563
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate baseline levels of 12 serum biomarkers that constitute a multibiomarker disease activity test, as predictors of response to methotrexate (MTX) in patients with early rheumatoid arthritis (eRA). Methods. In 298 patients from the Swedish Pharmacotherapy (SWEFOT) clinical trial, baseline serum levels of 12 proteins were analyzed for association with disease activity based on the 28-joint count Disease Activity Score (DAS28) after 3 months of MTX monotherapy using uni-/multivariate logistic regression. Primary outcome was low disease activity (LDA; DAS28 ≤ 3.2). Results. Of 298 patients, 104 achieved LDA after 3 months on MTX. Four of the 12 biomarkers [C-reactive protein (CRP), leptin, tumor necrosis factor receptor I (TNF-RI), and vascular cell adhesion molecule 1 (VCAM-1)] significantly predicted LDA based on stepwise logistic regression analysis. Dichotomization of patients using receiver-operating characteristic curve analysis-based cutoffs for these biomarkers showed significantly higher proportions with LDA among patients with lower versus higher levels of CRP or leptin (40% vs 23%, p = 0.004, and 40% vs 25%, p = 0.011, respectively), as well as among those with higher versus lower levels of TNF-RI or VCAM-1 (43% vs 27%, p = 0.004, and 41% vs 25%, p = 0.004, respectively). Combined score based on these biomarkers, adjusted for known predictors of LDA (smoking, sex, and age), associated with decreased chance of LDA (adjusted OR 0.45, 95% CI 0.32–0.62). Conclusion. Low baseline levels of CRP and leptin, and high baseline levels of TNF-RI and VCAM-1 were associated with LDA after 3 months of MTX therapy in patients with eRA. Combination of these 4 biomarkers increased accuracy of prediction.
|
|
| 6. |
- Lourido, Lucia, et al.
(författare)
-
Association of serum anti-centromere protein F antibodies with clinical response to infliximab in patients with rheumatoid arthritis : A prospective study
- 2020
-
Ingår i: Seminars in Arthritis & Rheumatism. - : Elsevier BV. - 0049-0172 .- 1532-866X. ; 50:5, s. 1101-1108
-
Tidskriftsartikel (refereegranskat)abstract
- Background: One-third of rheumatoid arthritis (RA) patients demonstrate no clinical improvement after receiving tumor necrosis factor inhibitors (TNFi). The presence of serum autoantibodies is a hallmark in RA and may provide information on future response to treatment. The aim of this prospective study was to search for novel serum autoantibodies useful to predict clinical response to TNFi. Methods: The autoantibody repertoire was profiled on RA patients treated with TNFi as a first line of biologic therapy (N= 185), who were recruited in three independent cohorts. The presence and levels of autoantibodies in serum at baseline were analysed in association with the clinical response after 24 weeks follow-up. A multiplex bead array built using antigens selected from an initial untargeted screening was employed to identify the autoantibodies on a discovery cohort (N= 50) and to verify and validate the results on verification (N= 61) and validation (N= 74) cohorts. Non-parametric tests, meta-analysis and Receiver Operating Curves (ROC) were performed in order to assess the clinical relevance of the observed findings. Results: Novel autoantibodies were associated with the clinical response to TNFi, showing different reactivity profiles among the different TNFi. The baseline levels of IgG antibodies against Centromere protein F (CENPF), a protein related to cell proliferation, were significantly (p <0.05) increased in responders (N=111) to infliximab (IFX) compared to non-responders (N= 44). The addition of anti-CENPF antibodies to demographic and clinical variables (age, sex, DAS28-ESR) resulted in the best model to discriminate responders, showing an area under the curve (AUC) of 0.756 (95% CI [0.639-0.874], p = 0.001). A further meta-analysis demonstrated the significant association of anti-CENPF levels with the patient's subsequent response to IFX, showing a standardized mean difference (SMD) of-0.65 (95% CI [-1.02;-0.27], p = 0.018). Conclusions: Our study reveals for the first time the potential of circulating anti-CENPF antibodies to predict the clinical response to IFX before starting the treatment. This finding could be potentially useful to guide therapeutic decisions and may lead to further studies focusing on the role of CENPF on RA pathology. (C) 2020 Elsevier Inc. All rights reserved.
|
|
| 7. |
- van Vollenhoven, Ronald F, et al.
(författare)
-
Brief report: enhancement of patient recruitment in rheumatoid arthritis clinical trials using a multi-biomarker disease activity score as an inclusion criterion.
- 2015
-
Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5205 .- 2326-5191. ; 67:11, s. 2855-2860
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Rheumatoid arthritis (RA) clinical trials often exclude patients with low C-reactive protein (CRP), slowing trial enrollment. We evaluated whether RA patients with a high multi-biomarker disease activity (MBDA) score (>44) among those with low CRP (≤10 mg/L) could complement patients with CRP >10mg/L to enhance patient recruitment without affecting clinical trial outcomes. Methods We evaluated patients from the Swedish pharmacotherapy (SWEFOT) trial, which had no CRP selection criteria. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy for MTX-naïve patients (N=220) and after add-on therapy from Months 3 to 12 for MTX-inadequate responder (IR) patients (N=127). Radiographic outcomes were assessed at 1 year for all patients. Within each cohort, outcomes were compared between patients with CRP ≤10 mg/L and MBDA score >44 at the start of the respective treatment interval versus those with CRP >10 mg/L. Results Patients with baseline CRP ≤10 mg/L and MBDA score >44 at baseline had comparable clinical and radiographic outcomes to those for patients with CRP>10 mg/L. This broadened definition of inclusion criteria identified an additional 24% MTX-naïve and 47% MTX-IR patients. Conclusion Patient recruitment of RA clinical trials may be substantially enhanced by using "CRP >10 mg/L and/or MBDA score >44" as an inclusion criterion, without diminishing clinical or radiographic outcomes. This article is protected by copyright. All rights reserved.
|
|
