Which diseases are optimal candidates for personalized health care (PHC) and what drives the need?
- Abrahamsen B.
- Eiken P.
- Eastell R.
- •Identification of patients that are in greatest need of treatment.
- •Identification of the patients whom may respond optimally, with the highest efficacy and lowest safety concerns, to a given treatment
- •Development strategy for a selected subpopulation of patients.
- •Efficient use of health care resources.
The heterogeneity of the patient population – lessons learned from rheumatoid arthritis (RA)
- Knevel R.
- Schoels M.
- Huizinga T.W.
- Aletaha D.
- Burmester G.R.
- Combe B.
- et al.
- Nam J.L.
- Winthrop K.L.
- van Vollenhoven R.F.
- Pavelka K.
- Valesini G.
- Hensor E.M.
- et al.
- Gaujoux-Viala C.
- Smolen J.S.
- Landewe R.
- Dougados M.
- Kvien T.K.
- Mola E.M.
- et al.
- Bos S.D.
- Beekman M.
- Maier A.B.
- Karsdal M.A.
- Kwok W.Y.
- Bay-Jensen A.C.
- et al.
PHC in RA: current understanding of possible technological advances
- Isaacs J.D.
- Cohen S.B.
- Emery P.
- Tak P.P.
- Wang J.
- Lei G.
- et al.
- Barascuk N.
- Veidal S.S.
- Larsen L.
- Larsen D.V.
- Larsen M.R.
- Wang J.
- et al.
- Karsdal M.A.
- Nielsen M.J.
- Sand J.M.
- Henriksen K.
- Genovese F.
- Bay-Jensen A.C.
- et al.
What does this mean for the OA field?
- Reginster J.Y.
- Badurski J.
- Bellamy N.
- Bensen W.
- Chapurlat R.
- Chevalier X.
- et al.
- •Patient phenotype 1: Traumatic OA, in the early disease course most likely involving a high level of protease activity destroying the cartilage subsequent to cartilage injury. These patients might benefit from a protease inhibitor treatment.
- •Patient phenotype 2: Generalized OA, with high turnover of bone and progression of cartilage damage characterized by an intimate relationship between bone and cartilage in the pathogenesis of OA. These patients may benefit from an anti-resorptive treatment inhibiting bone resorption and subchondral bone turnover.
- •Patient phenotype 3: Episodic subacute and acute inflammatory events precipitating worsening in stages. Macrophages play a role in this process48and likely will yield pathways to inform specific anti-inflammatory therapies for this phenotype or stage of disease.
Do different phenotypes in OA represent different pathological stages and/or different phenotypes?
|Phenotype||Quantifiable measure in synovial fluid, blood or urine||Reference|
|Low grade autoimmunity||Increase in specific autoantibodies [e.g., anti-CCP, anti-modified citrullinated vimentin (MCV) antibodies, antibodies against citrullinated type I and II collagen fragments]|
Increase in autoantigens [e.g., citrullinated and MMP degraded vimentin (VICM), citrullinated fibrinogen, Fibulin-4]
|Auto-inflammation||Local and systemic increase in matrikines from cartilage degradation and synovial turnover [e.g., Hyaluron (HA), fibronectin fragments]|
|Genetic||SNPs in genes associated with joint tissue protection (e.g., GDF5, IL-1, DIO2, IL1RN, WNT pathway)|
SNPs and dysregulation of bone specific proteins (e.g., RANK, RANK-L, Sclerostin, Cathepsin K, V-ATPase, CLC-7, MMP-9 and -2)
|Hormonal||Estrogen loss (e.g., E2, FSH, Progesterone)|
Increase in thyroid hormone (e.g., PTH)
|Metabolic||Increase in systemic levels of adipokines (e.g., leptin, resistin, adiponectin, visfatin)|
|Mechano-transduction||Above normal levels of cartilage degradation fragments (e.g., cartilage oligomeric matrix protein (COMP), dCOMP, CTX-II, C2M, C2C, AGNx1, fibronectin)|
Increased synovial fluid proteolytical activity (e.g., MMP1, MMP3)
Bone sclerosis and turnover (e.g., alpha-CTX-I, sclerostin, RANK-L, osteocalcin)
Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
Ann Rheum Dis. 2010 Dec; 69 (http://dx.doi.org/10.1136/ard.2009.122002. Epub 2010 Jun 22.): 2095-2101
|Demographic||Age, significant trauma, obesity, altered gait, altered biomechanics (varus or valgus deformity), and excessive loading on the affected joint|
|Imaging||MRI assessment of the joint including; cartilage surface, damage/lesions, synovitis, Bone morrow edema (BME), osteophytes and subchondral bone (shape and trabecular structure) in addition to other advanced technologies|
- Hashimoto J.
- Garnero P.
- van der H.D.
- Miyasaka N.
- Yamamoto K.
- Kawai S.
- et al.
- Mcpherson R.
- Felchsenhar K.
- Hellot S.
- Eckstein F.
- Valsesia A.
- Cara Di
- Berton A.
- Debaillel V.
- Wojcik J.
- Farmer P.
- et al.
- Valsesia A.
- Cara Di
- Berton A.
- Debaillel V.
- Wojcik J.
- Farmer P.
- et al.
Which technological advances may facilitate the advent of PHC for the OA field?
- 1.Identification of fast progressors
- 2.Identification of the optimal patients for a specific type of intervention
- 3.Enablement of phase II and III studies with fewer patients
- 4.Decreasing cost of trials
- 5.Minimizing drug-related adverse events
- 6.Potentially providing early confidence in mechanism of action
- 7.Surveillance for off-target effects
Conflict of interests
- Biochemical markers and the FDA critical path: how biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development.Biomarkers. 2009 May; 14: 181-202
- Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis.J Clin Endocrinol Metab. 2010 Dec; 95 (Epub 2010 Sep 15.): 5258-5265https://doi.org/10.1210/jc.2010-1571
- Efficacy and safety of oral weekly ibandronate in the treatment of postmenopausal osteoporosis.J Clin Endocrinol Metab. 2003 Oct; 88: 4609-4615
- Denosumab for prevention of fractures in postmenopausal women with osteoporosis.N Engl J Med. 2009 Aug 20; 361: 756-765
- Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study.J Clin Endocrinol Metab. 1999 Jul; 84: 2363-2368
- Chipping away at the lung cancer genome.Nat Med. 2012 Mar; 18: 349-351
- Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study.Ann Rheum Dis. 2010 Feb; 69: 345-351
- Optimal treatment of rheumatoid arthritis: EULAR recommendations for clinical practice.Pol Arch Med Wewn. 2010 Sep; 120: 347-353
- Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis.Ann Rheum Dis. 2010 Jun; 69: 987-994
- Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA.Ann Rheum Dis. 2010 Jun; 69: 976-986
- Current evidence for the management of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis.Ann Rheum Dis. 2010 Jun; 69: 1004-1009
- Evolution of treatment for rheumatoid arthritis.Rheumatology (Oxford). 2012 Dec; 51: vi28-vi36
- ACR/EULAR 2010 rheumatoid arthritis classification criteria.Rheumatology (Oxford). 2012 Dec; 51: vi5-vi9
- When is switching warranted among biologic therapies in rheumatoid arthritis?.Expert Rev Pharmacoecon Outcomes Res. 2012 Jun; 12: 319-333
- Forget personalised medicine and focus on abating disease activity.Ann Rheum Dis. 2013 Jan; 72: 3-6
- Treating rheumatoid arthritis to target: recommendations of an international task force.Ann Rheum Dis. 2010 Apr; 69: 631-637
- Pharmacogenetics: anti-TNF therapy in RA – towards personalized medicine?.Nat Rev Rheumatol. 2011 Mar; 7: 136-138
- Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs.Semin Arthritis Rheum. 2010 Jun; 39: 425-441
- Effectiveness of biologic therapies for rheumatoid arthritis: an indirect comparisons approach.Pharmacotherapy. 2011 Jan; 31: 39-51
- Osteoarthritis: an update with relevance for clinical practice.Lancet. 2011 Jun 18; 377: 2115-2126
- Role of hormones in cartilage and joint metabolism: understanding an unhealthy metabolic phenotype in osteoarthritis.Menopause. 2013 May; 20: 578-586
- Metabolic health in families enriched for longevity is associated with low prevalence of hand osteoarthritis and influences OA biomarker profiles.Ann Rheum Dis. 2013 Oct; 72 (http://dx.doi.org/10.1136/annrheumdis-2012-202013. Epub 2012 Oct 27): 1669-1674
- Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity.Arthritis Res Ther. 2008; 10: R63
- Increased interleukin-1beta gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis.Arthritis Rheum. 2011 Jul; 63: 1908-1917
- Should subchondral bone turnover be targeted when treating osteoarthritis?.Osteoarthritis Cartilage. 2008 Jun; 16: 638-646
- Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis.Ann Rheum Dis. 2013 Mar; 72 (http://dx.doi.org/10.1136/annrheumdis-2011-201117. Epub 2012 Jun 11): 329-336
- An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression.Rheumatology (Oxford). 2013 May; 52 (http://dx.doi.org/10.1093/rheumatology/kes378): 839-846
- Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisions and therapy use.Curr Med Res Opin. 2013 Jan; 29: 85-92
- Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis.J Pharm Biomed Anal. 2012 Nov; 70: 415-424
- Sustained efficacy of certolizumab pegol added to methotrexate in the treatment of rheumatoid arthritis: 2-year results from the RAPID 1 trial.Rheumatology (Oxford). 2012 Sep; 51: 1628-1638
- Predicting low disease activity and remission using early treatment response to antitumour necrosis factor therapy in patients with rheumatoid arthritis: exploratory analyses from the TEMPO trial.Ann Rheum Dis. 2012 Feb; 71: 206-212
- Biochemical markers of ongoing joint damage in rheumatoid arthritis – current and future applications, limitations and opportunities.Arthritis Res Ther. 2011 Apr 28; 13: 215
- Value of biomarkers in osteoarthritis: current status and perspectives.Ann Rheum Dis. 2013 Nov 1; 72: 1756-1763
- Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, CIIM – increased serum CIIM in subjects with severe radiographic osteoarthritis.Clin Biochem. 2011 Apr; 44: 423-429
- A novel assay for extracellular matrix remodeling associated with liver fibrosis: an enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen.Clin Biochem. 2010 Jul; 43: 899-904
- Extracellular matrix remodeling: the common denominator in connective tissue diseases possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure.Assay Drug Dev Technol. 2013 Mar; 11 (http://dx.doi.org/10.1089/adt.2012.474. Epub 2012 Oct 9): 70-92
- Procollagen type I N-terminal propeptide (PINP) is a marker for fibrogenesis in bile duct ligation-induced fibrosis in rats.Fibrogenesis Tissue Repair. 2010 Apr 1; 3: 5
- Serum concentrations of formation (PINP) and resorption (Ctx) bone turnover markers in rheumatoid arthritis.Rheumatol Int. 2009 Oct; 29: 1403-1409
- Serum CrossLaps One Step ELISA. First application of monoclonal antibodies for measurement in serum of bone-related degradation products from C-terminal telopeptides of type I collagen.Clin Chem. 1998 Nov; 44: 2281-2289
- The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation.J Bone Miner Res. 2003 May; 18: 859-867
- The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study.Osteoarthritis Cartilage. 2010 Feb; 18: 150-159
- Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173].Arthritis Res Ther. 2005; 7: R625-R633
- Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis.Climacteric. 2011 Apr; 14: 236-243
- Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial.Ann Rheum Dis. 2013 Feb; 72 (http://dx.doi.org/10.1136/annrheumdis-2012-202231. Epub 2012 Nov): 179-186
- Activated synovial macrophages as targets for osteoarthritis drug therapy.Curr Drug Targets. 2010 May; 11: 576-585
- Cartilage as a target of autoimmunity: a thin layer.Autoimmun Rev. 2013 Mar; 12: 591-598
- Systemic inflammation and antibodies to citrullinated peptides in hand osteoarthritis.Clin Exp Rheumatol. 2011 Nov; 29: 1006-1009
- Autoimmune response in cartilage-delivered peptides in a patient with osteoarthritis.Arthritis Res Ther. 2004; 6: 6-7
- Significance of immune complex deposits in osteoarthritic cartilage.J Rheumatol. 1987 May; 14 (Spec. No: 77–79)
- Genetics and epigenetics of osteoarthritis.Maturitas. 2012 Mar; 71: 200-204
- A woman's journey through the reproductive, transitional and postmenopausal periods of life: impact on cardiovascular and musculo-skeletal risk and the role of estrogen replacement.Maturitas. 2011 Oct; 70: 197-205
- Identification of progressors in osteoarthritis by combining biochemical and MRI-based markers.Arthritis Res Ther. 2009; 11: R115
- Circulating citrullinated vimentin fragments reflect disease burden in ankylosing spondylitis and have prognostic capacity for radiographic progression.Arthritis Rheum. 2013 Apr; 65: 972-980
- A rare variant in the osteoarthritis-associated locus GDF5 is functional and reveals a site that can be manipulated to modulate GDF5 expression.Eur J Hum Genet. 2013 May; 21: 517-521
- Osteoclast-derived coupling factors in bone remodeling.Calcif Tissue Int. 2013 May 23;
- Local communication on and within bone controls bone remodeling.Bone. 2009 Jun; 44 (http://dx.doi.org/10.1016/j.bone.2009.03.671. Epub 2009 Apr 5): 1026-1033
- Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations.Ann Rheum Dis. 2010 May; 69: 856-861
- The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide.Clin Orthop Relat Res. 2004 Oct; : S37-S46
- A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs.Mod Rheumatol. 2009; 19: 273-282
- Identifying phenotypes of knee osteoarthritis by separate quantitative radiographic features may improve patient selection for more targeted treatment.J Rheumatol. 2013 Jun; 40: 891-902
- Three trajectories of activity limitations in early symptomatic knee osteoarthritis: a 5-year follow-up study.Ann Rheum Dis. 2013 May 28;
- Joint injury in young adults and risk for subsequent knee and hip osteoarthritis.Ann Intern Med. 2000 Sep 5; 133: 321-328
- Body mass index in young men and the risk of subsequent knee and hip osteoarthritis.Am J Med. 1999 Dec; 107: 542-548
- A randomized, double-blind, placebo-controlled, multicenter study of rhfgf18 administered intraarticularly using single or multiple ascending doses in patients with primary knee osteoarthritis (OA), not expected to require knee surgery within 1 year.Osteoarthritis Cartilage. 1-4-2011; 19 (Ref Type: Abstract)
- Exploratory biomarker analysis reveals agenetic epistatic interaction in interleukin 1 receptor antagonist (il1rn) gene associated to cartilage volume growth measured by MRI in response to sprifermin therapy in patients with knee radiographic osteoarthritis.Osteoarthritis Cartilage. 1-4-2013; 21 (Ref Type: Abstract)
- Classification of osteoarthritis biomarkers: a proposed approach.Osteoarthritis Cartilage. 2006 Aug; 14: 723-727
- Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis.Osteoarthritis Cartilage. 2011 May; 19: 515-542
- Marking renal injury: can we move beyond serum creatinine?.Transl Res. 2012 Apr; 159: 277-289
- Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis?.Ann Rheum Dis. 2005 Oct; 64: 1443-1450
- Autoimmunity to citrullinated type II collagen in rheumatoid arthritis.Mod Rheumatol. 2006; 16: 276-281
- Fibulin-4 is a target of autoimmunity predominantly in patients with osteoarthritis.J Immunol. 2006 Mar 1; 176: 3196-3204
- Beneficial autoimmunity to proinflammatory mediators restrains the consequences of self-destructive immunity.Immunity. 2003 Nov; 19: 679-688
- Absence of autoimmunity to type II collagen in generalised nodal osteoarthritis.Ann Rheum Dis. 1991 Nov; 50: 769-771
- Anti-type II collagen antibody in naturally occurring canine joint diseases.Br J Rheumatol. 1989 Dec; 28: 480-486
- The low binding affinity of ADAMTS4 for citrullinated fibronectin may contribute to the destruction of joint cartilage in rheumatoid arthritis.Clin Exp Rheumatol. 2013 Mar; 31: 201-206
- Comparison of hyaluronan effects among normal, osteoarthritis, and rheumatoid arthritis cartilages stimulated with fibronectin fragment.Biomed Res. 2010 Feb; 31: 63-69
- Hyaluronan synthesis and degradation in cartilage and bone.Cell Mol Life Sci. 2008 Feb; 65: 395-413
- Fibronectin fragments and their role in inflammatory arthritis.Semin Arthritis Rheum. 2000 Feb; 29: 252-265
- Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcgamma receptor.Arthritis Rheum. 2011 Jan; 63: 53-62
- Immunology of articular cartilage.J Rheumatol. 1987 May; 14 (Spec. No: 73–76)
- Cartilage proteoglycan aggrecan epitopes induce proinflammatory autoreactive T-cell responses in rheumatoid arthritis and osteoarthritis.Ann Rheum Dis. 2010 Jan; 69: 255-262
- A comparative analysis of serologic parameters and oxidative stress in osteoarthritis and rheumatoid arthritis: reply to Mishra and colleagues.Rheumatol Int. 2012 May 6;
- One-year follow-up of Coll2-1, Coll2-1NO2 and myeloperoxydase serum levels in osteoarthritis patients after hip or knee replacement.Ann Rheum Dis. 2008 Feb; 67 (Epub 2007 Jul 20): 168-174
- Matrix metalloproteinase-dependent turnover of cartilage, synovial membrane, and connective tissue is elevated in rats with collagen induced arthritis.J Transl Med. 2012; 10: 195
- Post-translational aging of proteins in osteoarthritic cartilage and synovial fluid as measured by isomerized aspartate.Arthritis Res Ther. 2009; 11: R55
- Associations of the interleukin-1 gene locus polymorphisms with risk to hip and knee osteoarthritis: gender and subpopulation differences.Scand J Immunol. 2013 Feb; 77: 151-161
- Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis 1165.Hum Mol Genet. 2008 Jun 15; 17: 1867-1875
- Genetic epidemiology of hip and knee osteoarthritis.Nat Rev Rheumatol. 2011 Jan; 7: 23-32
- The response to oestrogen deprivation of the cartilage collagen degradation marker, CTX-II, is unique compared with other markers of collagen turnover.Arthritis Res Ther. 2009; 11: R9
- Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis.Arthritis Rheum. 2011 Mar; 63: 700-707
- Adipokines in the skeleton: influence on cartilage function and joint degenerative diseases.J Mol Endocrinol. 2009 Jul 1; 43: 11-18
- Osteoarthritis: a metabolic disease induced by local abnormal leptin activity?.Curr Rheumatol Rep. 2005 Apr; 7: 79-81
- Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production.Osteoarthritis Cartilage. 2006 Jul; 14: 690-695
- Increased synovial fluid visfatin is positively linked to cartilage degradation biomarkers in osteoarthritis.Rheumatol Int. 2011 Jan 19;
- Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project.Arthritis Rheum. 1999 Nov; 42: 2356-2364
- Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.Ann Rheum Dis. 2010 Dec; 69 (http://dx.doi.org/10.1136/ard.2009.122002. Epub 2010 Jun 22.): 2095-2101
- Protein modification by deamidation indicates variations in joint extracellular matrix turnover.J Biol Chem. 2012 Feb 10; 287: 4640-4651
- Novel combinations of post-translational modification (PTM) neo-epitopes provide tissue-specific biochemical markers – are they the cause or the consequence of the disease?.Clin Biochem. 2010 Jul; 43: 793-804
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