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Year in review - Biochemical markers
- 1. Year in review Biochemical markers Erwin (W.E.) van Spil, MD, PhD University Medical Center Utrecht Utrecht, the Netherlands
- 2. Erwin (W.E.) Van Spil PhD, MD Univ. Med. Cent. Utrecht, Utrecht, the Netherlands Disclosure Information I have no financial relationships with commercial interests to disclose My presentation does not include discussion of off-label or investigational use.
- 3. Search and selection strategy • PubMed • Between 01-04-2018 and 01-03-2019 • Titles and abstracts – Osteoarthritis and synonyms – Biomarkers, markers and synonyms – Blood, urine, synovial fluid and synonyms • Screening by one researcher
- 4. Search and selection strategy Total 1,168 hits English 1,141 hits Original data 914 hits Human 690 hits OA 448 hits Clinical 336 hits Soluble markers in body fluids of human OA patients 116 hits English 1,141 hits Original data 914 hits
- 5. Results General overview 116 Hits • Knee 80 hits • Unspecified 9 hits • Hand 6 hits • Knee and hip 6 hits • TMJ 5 hits • Hip 4 hits • Knee and hand 2 hits • Multiple 2 hits • Ankle 1 hit • Lumbar 1 hit Intervention(s) 26 hits
- 6. Non-systematic selection of publications • Novel markers • Intervention studies • Subgrouping, phenotyping
- 7. Results Novel markers • Cathepsin K generated type X collagen neo-epitope (Col10neo) in plasma (Hu et al. 2019) • Serum adropin (Gundogdu et al. 2018) • Serum type IIB collagen NH2-propeptide (PIIBNP, hsPRO-C2) (Luo et al. 2018) • Aggrecanase degradation of type III collagen (COL3- ADAMTS) in serum (Bay-Jensen et al. 2018) • Thrombospondin-4 fragments in serum (Maly et al. 2019) • Serum CTXIII and microRNA-98 (Zheng et al. 2018) • Serum microRNA-300 (Zhou et al. 2019) • …
- 8. Conclusions Novel markers Majority • Tested for knee OA • In small cohorts • Alone or with one other marker • Case-control design • K&L grade for radiographic severity New markers can be useful, but need further characterisation • In larger and well-characterized populations • Together with other markers • Determine specificity for joint(s), OA, individual joint tissues or OA features
- 9. Non-systematic selection of publications • Novel markers • Intervention studies • Subgrouping, phenotyping
- 10. Results Intervention studies • Farmacological Systemic – Tanezumab – Lutikizimab – Celecoxib – Colchicine – Doxycycline – Diacerein Intra-articular – BIOF2 – Platelet-rich plasma – Hyaluronic acid – Polynucleotides • Supplements/diet – Boswellia serrata extract – Blueberries – Glucosamine+chondroitin – Resveratrol – Strawberries – Garlic – Low-carbohydr/low-fat diet – Vitamin D • Conservative/ non-pharmacological – Exercise – Low dose radiation – Auriculotherapy
- 11. Results Biomarkers and intervention(s) • COLKOA trial: 110 people with symptomatic knee OA • Colchicine 0.5 mg BID for 16 weeks • Primary endpoint: ≥30 improvement total WOMAC Leung et al. Osteoarthritis and Cartilage 2018;26:631-40
- 12. Results Biomarkers and intervention(s) Biomarker outcomes in per protocol analysis • Serum hsCRP and SF CTXI reduced at study end in colchicine vs. placebo arm • SF IL6, IL8, TNFα, CD14, IL18 reduced, but not statistically significantly Leung et al. Osteoarthritis and Cartilage 2018;26:631-40
- 13. Results Biomarkers and intervention(s) Leung et al. Osteoarthritis and Cartilage 2018;26:631-40 Baseline data SF CTX II Cartilage loss BML size Effusion size Infrapatellar synovitis SF IL-6 (pg/ml) 0.454** 0.525* -0.062 0.213 0.304 SF IL-8 (pg/ml) 0.273* 0.675** 0.310 0.261 0.475* SF TNF-α (pg/ml) 0.264* 0.579** 0.039 0.501* 0.536* SF CD14 (ng/ml) 0.549** 0.581** 0.094 0.609** 0.527* SF IL-18 (pg/ml) 0.409** 0.070 -0.259 0.198 0.418 SF CTXII (ng/ml) - -0.035 -0.403 0.056 0.243 urine CTXII/Cr (ng/mmol) -0.031 0.493* 0.073 0.299 0.434 serum hsCRP (mg/l) 0.026 0.321 -0.475* 0.115 0.260 Spearman’s rho correlations , * p < 0.05; ** p < 0.01 Selection of positive findings N=20 for MRI parameters
- 14. Results Biomarkers and intervention(s) • DOXY trial: 431 women with unilateral radiographic knee OA • 30 Months of doxycycline (DOXY) 100 mg or placebo BID • DOXY reduced JSW loss at 16 and 30 months • No pain reduction • Predictors, at baseline and 18 months, in plasma: – lipopolysaccharide binding protein (LBP) – soluble Toll-like receptor 4 (sTLR4) – IL6 Brandt et al. Arthritis and Rheumatism 2005;52:2015-25Huang et al. Osteoarthritis and Cartilage 2018;26:1658-65
- 15. Results Biomarkers and intervention(s) Huang et al. Osteoarthritis and Cartilage 2018;26:1658-65
- 16. Biochemical markers are used in intervention studies • As surrogate endpoints – Can be more sensitive and dynamic than structural and clinical outcomes – Are less specific for the index joint • To inform about the working mechanism of the intervention – Effect of adjusting for treatment group – Interaction with treatment group • No data on some of the major potential DMOADs so far Conclusions Biomarkers and intervention(s)
- 17. Non-systematic selection of publications • Novel markers • Intervention studies • Subgrouping, phenotyping
- 18. Results Subgroups or phenotypes • Tanezumab, NGF inhibitor • Six phase 3 clinical trials in knee and hip OA, N=7301 • 56 Adjudicated cases of type 2 rapidly progressive OA (RPOA) • Serological biochemical marker profiles Cartilage degradation, synovitis, bone signaling, inflammation, connective tissue turnover, protease burden Karsdal et al. Osteoarthritis and Cartilage 2019;27:484-92
- 19. Results Subgroups or phenotypes Limited NSAID use Time Case/contr Markers AUC Sensitivity Specificity Baseline 11/36 C2M, C3M 71 (60-83) 86 (64-100) 56 (42-70) >3 mnths 8/31 PINP/OC, CTXI, PINP 82 (72-91) 91 (73-100) 68 (51-81) ≤3 mnths 7/14 PINP/OC 78 (62-95) 60 (30-90) 96 (89-100) Karsdal et al. Osteoarthritis and Cartilage 2019;27:484-92 Time Case/contr Markers AUC Sensitivity Specificity Baseline 26/33 SOST, hsCRP, PINP/OC, MMP9 78 (69-88) 47 (32-62) 93 (84-100) >3 mnths 17/23 MMP9, COMP, SOST, OC 79 (70-89) 48 (32-68) 83 (69-94) ≤3 mnths 18/14 ICTP, CTXI/OC, COMP 84 (77-92) 58 (38-77) 100 (100-100) Chronic NSAID use
- 20. Results Subgroups or phenotypes • Exercise trial: 42 women with knee pain – K&L grade 0/1 in 32 women – K&L grade 2/3 in 10 women • 12 Weekly supervised 90-minute exercise classes – No other treatment • Outcome assessment at 12 and 24 weeks Azukizawa et al. Cartilage 2018
- 21. Results Subgroups or phenotypes Azukizawa et al. Cartilage 2018 sPIICP uCTXII uC2C sCOMP
- 22. Results Subgroups or phenotypes • Estonian cohort: 60 middle-aged people • Radiographic JSN and osteophytes – Tibiofemoral – Patellofemoral • 60 Markers in plasma (Luminex) – Chemokines – Cytokines – Growth factors Kisand et al. Osteoarthritis and Cartilage 2018;26:1045-54
- 24. Kisand et al. Osteoarthritis and Cartilage 2018;26:1045-54
- 25. Conclusions Subgroups or phenotypes • Biochemical markers could support subgroup/phenotype identification • Probably multiple markers required – Multiple markers for the same domain (e.g. cartilage turnover) – Markers for multiple domains (e.g. cartilage, bone, synovium) • Observational studies: cluster analysis, factor analysis, group- based trajectory modelling etc. • Intervention studies – Study interaction of marker vs. intervention and outcome – Include marker in the selection criteria
- 26. Final conclusions • Biochemical markers added nuance to studies and generated some interesting hypotheses • No major breakthroughs though • Particularly the lack of specificity for the index joint(s) remains a major drawback • Biomarker panels and SF assessments might be helpful in overcoming some of the challenges in this field
- 28. Last reviews 2017 (F.E. Watt) • “…Strength is seen in studies with large numbers, prospective sampling, high quality clinical and imaging data, robust biomarker measurement and considered bioinformatic/statistical approaches…” • “…Challenges which are being addressed include a perhaps excessive focus on the best-studied serum biomarkers of matrix degradation, and a lack of gold standard definition for early OA…” Osteoarthritis and Cartilage 2018;26(3):312-18
- 29. Last reviews 2018 (Saberi Hosnijeh et al.) • “…a low number of articles published about other joints other than the knee…” • “…assessment of multiple biomarkers associated with different joint tissue types like cartilage, bone, and synovium, products of pathological pathways and even genetic factors, is required for considering a personalized medication protocol for the treatment of OA…” • “…The number of investigative biomarkers has increased rapidly with expansion of proteomics. Metabolic changes of joint tissues start long before the onset of structural alterations. Therefore, identification of early OA biomarkers will help…” Osteoarthritis and Cartilage 2019;27(3):412-23
- 30. Kisand et al. Osteoarthritis and Cartilage 2018;26:1045-54
Editor's Notes
- Adropin, PIIBNP and COL3-ADAMTS have negative associations MicroRNA-98 associated with immune status. Non-coding for proteins.
- No efficacy for the primary or any of the secondary outcomes, in the intention to treat nor the per protocol analysis No efficacy in MRI effusion or infrapatellar synovitis in a subset of 20 persons
- The sample size was smaller than expected and, therefore, the study underpowered
- No associations with WOMAC pain and function
- Effect on JSW in the index knee only, not in the contralateral one Pain was low at baseline, so maybe a floor effect The first study to measure sTLR4 in knee OA patients
- Models were adjusted for the corresponding baseline measure Models did not change from adjustment for treatment group TIC=time integrated over 12 or 18 months
- N=7301 tanezumab treated Matching by propensity scores on multiple variables Chronic use is NSAID on 90 or more days during tanezumab treatment
- Remodeling markers in men, angiogenesis markers in women