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- Angelini, Federico, et al.
(författare)
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Osteoarthritis endotype discovery via clustering of biochemical marker data
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:5, s. 666-675
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Osteoarthritis (OA) patient stratification is an important challenge to design tailored treatments and drive drug development. Biochemical markers reflecting joint tissue turnover were measured in the IMI-APPROACH cohort at baseline and analysed using a machine learning approach in order to study OA-dominant phenotypes driven by the endotype-related clusters and discover the driving features and their disease-context meaning. Method Data quality assessment was performed to design appropriate data preprocessing techniques. The k-means clustering algorithm was used to find dominant subgroups of patients based on the biochemical markers data. Classification models were trained to predict cluster membership, and Explainable AI techniques were used to interpret these to reveal the driving factors behind each cluster and identify phenotypes. Statistical analysis was performed to compare differences between clusters with respect to other markers in the IMI-APPROACH cohort and the longitudinal disease progression. Results Three dominant endotypes were found, associated with three phenotypes: C1) low tissue turnover (low repair and articular cartilage/subchondral bone turnover), C2) structural damage (high bone formation/resorption, cartilage degradation) and C3) systemic inflammation (joint tissue degradation, inflammation, cartilage degradation). The method achieved consistent results in the FNIH/OAI cohort. C1 had the highest proportion of non-progressors. C2 was mostly linked to longitudinal structural progression, and C3 was linked to sustained or progressive pain. Conclusions This work supports the existence of differential phenotypes in OA. The biomarker approach could potentially drive stratification for OA clinical trials and contribute to precision medicine strategies for OA progression in the future. Trial registration number NCT03883568.
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| 2. |
- Dahlberg, Leif E, et al.
(författare)
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A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis
- 2016
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Ingår i: Clinical and Experimental Rheumatology. - 0392-856X. ; 34:3, s. 50-445
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate the safety of intra-articular sprifermin (primary), and to evaluate systemic exposure, biomarkers, histology, and other cartilage parameters in patients with advanced osteoarthritis (OA).METHODS: This was a first-in-human, double-blind, randomised, placebo-controlled trial of single and multiple ascending doses of sprifermin from 3-300 μg in knee OA patients scheduled for total knee replacement. Patients were randomised 3:1 to sprifermin or placebo, injected into the target knee once or once weekly for 3 weeks, and followed-up for 24 weeks.RESULTS: Fifty-five patients were treated with sprifermin, 25 with single and 30 with multiple doses, 18 received placebo. There was no clear difference between the active and placebo groups in incidence, severity, and nature of reported treatment emergent adverse events. Acute inflammatory reactions were slightly more common with sprifermin 300 μg, but none led to discontinuation. No clear difference was seen between placebo and sprifermin in physician-assessed local tolerability, pain, or swelling in the knee. No meaningful changes over time, or differences between treatment groups, were observed for safety laboratory parameters or ECG. Although individual abnormalities were observed, no patterns were evident suggesting a relation to treatment or potential safety concern. No systemic sprifermin exposure, anti-FGF18 antibodies, or clear-cut effects on systemic biomarkers were detected.CONCLUSIONS: This first clinical trial of sprifermin revealed no serious safety concerns, although larger studies are needed. The possibility of positive effects of intra-articular sprifermin on histological and other cartilage parameters in knee OA also warrant further investigation.
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| 3. |
- Hannani, Monica T., et al.
(författare)
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From biochemical markers to molecular endotypes of osteoarthritis : a review on validated biomarkers
- 2024
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Ingår i: Expert Review of Molecular Diagnostics. - 1473-7159. ; 24:1-2, s. 23-38
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Osteoarthritis (OA) affects over 500 million people worldwide. OA patients are symptomatically treated, and current therapies exhibit marginal efficacy and frequently carry safety-risks associated with chronic use. No disease-modifying therapies have been approved to date leaving surgical joint replacement as a last resort. To enable effective patient care and successful drug development there is an urgent need to uncover the pathobiological drivers of OA and how these translate into disease endotypes. Endotypes provide a more precise and mechanistic definition of disease subgroups than observable phenotypes, and a panel of tissue- and pathology-specific biochemical markers may uncover treatable endotypes of OA. Areas covered: We have searched PubMed for full-text articles written in English to provide an in-depth narrative review of a panel of validated biochemical markers utilized for endotyping of OA and their association to key OA pathologies. Expert opinion: As utilized in IMI-APPROACH and validated in OAI-FNIH, a panel of biochemical markers may uncover disease subgroups and facilitate the enrichment of treatable molecular endotypes for recruitment in therapeutic clinical trials. Understanding the link between biochemical markers and patient-reported outcomes and treatable endotypes that may respond to given therapies will pave the way for new drug development in OA.
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