Intra-articular therapies for osteoarthritis: Myth or Reality
Nancy E. Lane, MD
MACP, Fellow AAAS, FACR, ACCA, NAM
Distinguished Professor of Medicine, Rheumatology and Aging
Director, Center for Musculoskeletal Health
Dean’s Endowed Chair for Aging Research
University of California at Davis, School of Medicine
Sacramento, California
Mesenchymal Stem Cells, where do they come from and what do they do??
Paracrine Activity of Mesenchymal Stem Cells in an Osteoarthritis Articular Environment (Professional illustration by Matilde Bongio, GoArts – Istituto Ortopedico Galeazzi). MSCs:
Anatomic Sources of Mesenchymal Stem Cells
Hass R, et al Cell communication and signaling ,2011
Processing and Preparing MSCs for joint injections
What do the Studies of MSCs for treatment of knee OA find?
Oxford Center for Evidence Based Medicine 2011 Levels of Evidence for Interventions
Level 1: Systematic Reviews
Level 2: Randomized controlled clinical trials with low/moderate risk of bias or observational studies with dramatic effects
Level 3: Non-randomized controlled trials with low/moderate risk of bias or randomized controlled trials at high risk of bias
Level 4: Case series, case-control studies, historically controlled studies or non-randomized controlled trials at high risk of bias
Level 5: Mechanism-based reasoning/expert opinion.
Results for the VAS pain score between pre and post MSC treatment
in 3 RCTs with 7 data sets (n = 75).
Iijima HNPJ Regen Med 2018
Standardized Mean
Difference and 95% CI
for the self-reported
Physical Functional Outcome
between pre and post MSC
treatment.
I
Self-Reported Physical Function
Iijima et al, NPJ Reg Med 2018:3:15
Outcome SMD 95%CI
Study Design
Sample size
Downs and Black Scale
Hetero-geneity
Effect ofRehab.
Level ofEvidence
VAS Pain -1.45(-1.9 ,-1.0
7 RCTs 318 7.2 ± 2.6 84% Unclear Very Low
VAS painSensitivityanalysis
-0.67 7 RCTs 75 10.9 ± 2 68% Unclear Very Low
Self -ReportedPhysical function
1.50 (1.1-1.9)
Within Subject
528 7.2 ±2.0 86% SignificantEffect Modifier
Very Low
SRPF Sensitivity analysis
0.53(9.2,1.2)
WithinSubject
20 6.3 ±1.5 0% Unclear Low
Cartilage Volume
0.49(-0.2-1.2)
Withinsubject
20 6.3 ±1.5 0% Unclear Very Low
Cartilage Quality
-2.0(-3.5, -.50
Withinsubject
95 7.4 ±2.1 91% Unclear Very low
Iijima NPJ Regen Med 2018; 3:15
Overall Results of the Meta-analysis of the RCTs for MSCs for the treatment of knee OA
Intra-articular Mesenchymal Stem Cells in Knee OA: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair
Chul-Won et al Arthroscopy 2018 35, issue 1:277-288.
Risk of bias of included studies. Green circle, low risk; red circles, high risk.
Chul-Won et al Arthroscopy 2018 35, issue 1:277-288.
Key Messages• What are the new findings
• The available evidence supporting use of MSCs in knee osteoarthritis has a high risk of bias.
• The long-term risks of stem cells use needs further investigation.
• Methodologically sound research is needed to explore the efficacy of stem cell therapy in knee OA.
• How might it impact on clinical practice in the near future?• Presently, clinicians should refrain from using MSCs in patients with knee OA.
• If patients are treated with MSCs, they should be carefully monitored.
• International guidelines for quality control should be used and followed when working with MSCs.
Pas HI, et al Br J Sports Med 2017
How might MSCs communicate with chondrocytes or other cells in the joint?Exosome synthesis and action. A cell membrane is an inward budding and formed multivesicular body (MVB). Exosomes are released after the MVB fuses with the membrane. Exosomes can carry lipids, proteins, and nucleic acids to recipient cells; they act as intercellular communicators and play crucial roles in immune response, neurodegenerative disease, osteoarthritis, and tumor progression.
Change UH, et al Cell Transplant. 2018; 27(3):349-363.
MSC Chondrocyte
Microvesicles from Human Stem cell adipose tissue derived MSCs actively protect osteoarthritis chondrocytes. Vian et al Cell Physiology and Biochemistry 2018; 47:11-25
Characterization of MV and EX isolated from CM from AD-MSCs and effect on cell viability and after stimulation with IL-1, TNF-alpha in OA explants and OA chondrocytes
Tofino-Vian M et al Cellular and Physiology and Biochemistry 2018, 4:11-25.
Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells may protect Osteoarthritic Chondrocytes
Tofino-Vian M et al Cellular and Physiology and Biochemistry 2018, 4:11-25.
Proteome characterization of EX from AD-MSC. A: Venn diagram. The number present in the circle represents the total number of identified proteins in particular data sets. B: Most over-represented biological processes (gene ontology terms) present in EV proteomes.
Tofino-Vian M, et al Cellular and Physiology and Biochemistry 2018;4:11-25
Maybe all MSCs do not become Skeletal Stem Cells
PDPN+CD146−CD73+CD164+ marks a self-renewing, multipotent human skeletal stem cell
hSSCs can be isolated from fetal, adult, BMP2-treated human adipose stroma, and iPSCs
hSSCs undergo local expansion in response to acute skeletal injury
Comparison of mouse and human SSCs reveals evolutionary differences in skeletogenesis
Chan and Longaker, et al Cell 2018
Novel Intra-articular therapies in Phase II and III studies, are they promising?
FGF18 to stimulate cartilage growth
Wnt inhibitor
Senolytic
Pain medications- capsacin, and anti-NGF to name a few
Loss of Cartilage results in New Bone Formation with both knee and hip osteoarthritis
Osteoarthritis (OA) and the Wnt pathway
• Degenerative tissue remodeling is due to mechanical forces and inflammation1
• Overexpressed Wnt proteins and pathway mutations are associated with OA2-5
• Increased Wnt signaling drives bone formation, cartilage breakdown, and inflammation6-9
• Hypothesis: Inhibiting the Wntpathway reduces inflammation while protecting and regenerating cartilage
5. Sokolove J and Lepus CM. Ther Adv Musculoskelet Dis. 2013
6. Blom AB, et al. Arthritis Rheum. 2009
7. Monteagudo S, et al. Nat Commun. 2017
8. Rudnicki JA and Brown AM. Dev Biol. 1997
9. Thomas RS, et al. Arthritis Res Ther. 2011
1. Loeser R. Arthritis Rheum. 2006
2. Hamerman D. N Engl J Med. 1993
3. Yuasa T, et al. Lab Invest. 2008
4. Ma B and Hottiger MO. Frontiers Immun. 2016
Healthy Osteoarthritis
Mesenchymal stem cells
Synovitis
Bone marrow
Synovial membrane
Articularcartilage
• Bone remodeling
• Bone sclerosis
• Osteophyte formation
• Cartilage degradation
• Chondrocyte hypertrophy
• 29
Lorecivivint mechanism of action
33
Inflammatory gene
expression
Symptoms
Cytokines
DYRK1A
CLK2
SM04690
OsteoarthritisWnt/Mechanical stress/Metabolic/Trauma
Wnt gene expression
Chondrocyte
differentiation/function
Structural Damage
FOXO1
Altered
protein
levels
TCF7
Alt. splicing
NF-κB
Alt. splicing
STAT3: signal transducer and activator of transcription 3, SIRT1: sirtuin 1, TCF7: transcription factor 7, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, FOXO1: forkhead Box O1
Lorecivivint (LOR; SM04690) Preclinical Development
34
Protease assays
Cartilage Protection
Cytokine assays
Anti-inflammation
In vitro assays and animal models of OA
Animal modelshMSC assays
Days
SM
04
69
0 (
nM
)
0 30 60 90 120 150 180 2100
100
200
300
400
500
600
Cartilage
Bone
Plasma
Expected therapeuticlevel (~30 nM)
Chondrocyte Regeneration Sustained Local PK
Improved Joint Health(Animal models)
Protease gene expression Cytokine gene expression
Phase Ib study of Wnt Pathway inbibitor(Samumed) for the treatment of painful Knee OA
Yazici Y, et al. Osteoarthritis and Cartilage. 2017.
Percent of OMERACT-OARSI responders at Weeks 12 and 24.
Yazici Y, et al. Osteoarthritis and Cartilage2017; 1598-1606
Intention-To-TreatUnilateral Symptomatic Without
Widespread Pain
LOR (SM04690) – WOMAC Knee Pain [0-100]Actual scores (mean ± standard errors)
* * *
Comparisons of LOR vs. PBO using a baseline-adjusted ANCOVA. Data offset for visual clarity.
*SM04690 0.07 mg P<0.05 41
Intention-To-TreatUnilateral Symptomatic Without
Widespread Pain
LOR (SM04690) - WOMAC Function [0-100]Actual scores (mean ± standard errors)
* * *
42
Comparisons of LOR vs. PBO using a baseline-adjusted ANCOVA. Data offset for visual clarity.
*SM04690 0.07 mg P<0.05
Comparisons of LOR vs. PBO using a baseline-adjusted ANCOVA. Data offset for visual clarity.
*SM04690 0.07 mg P<0.05 †SM04690 0.23 mg P<0.05
Intention-To-TreatUnilateral Symptomatic Without Widespread
Pain
LOR (SM04690) - Medial Joint Space Width (mJSW)Actual scores (mean ± standard errors)
* *†
43
Lorecivivint Phase 2b clinical data
45
LOR Phase 2b: Subject Characteristics Full analysis set
46
lorecivivint
0.03 mg 0.07 mg 0.15 mg 0.23 mg Placebo
N 116 115 115 116 116
Age at Consent (years)* 57.9 (7.9) 59.9 (8.6) 58.4 (8.3) 58.5 (9.0) 60.1 (9.0)
BMI (kg/m2)* 29.2 (3.8) 29.1 (3.6) 29.4 (4.1) 28.5 (4.4) 28.6 (4.3)
Female 76 (65.5%) 66 (57.4%) 69 (60.0%) 61 (52.6%) 64 (55.2%)
Race
White 85 (73.3%) 83 (72.2%) 84 (73.0%) 89 (76.7%) 90 (77.6%)
African American 24 (20.7%) 22 (19.1%) 25 (21.7%) 21 (18.1%) 17 (14.7%)
Asian 5 (4.3%) 5 (4.3%) 6 (5.2%) 5 (4.3%) 6 (5.2%)
KL Grade 3 63 (54.3%) 74 (64.3%) 68 (59.1%) 63 (54.3%) 72 (62.1%)
Unilateral Symptomatic† 59 (50.9%) 62 (53.9%) 63 (54.8%) 63 (54.3%) 61 (52.6%)
Widespread Pain Negative†† 92 (79.3%) 93 (80.9%) 90 (78.3%) 93 (80.2%) 93 (80.2%)*Mean (SD) reported. Otherwise N (%) reported† Unilateral symptomatic vs. bilateral symptomatic stratified to 50% each†† Widespread Pain Negative (WPI ≤4 and Symptom Severity score ≤2) stratified to 80% of population
Comparisons of LOR vs. PBO using a baseline-adjusted ANCOVA. Data on x-axis is offset for visual clarity.
*SM04690 0.07 mg P<0.05 †SM04690 0.23 mg P<0.05
Pain NRS (FAS) Patient Global (FAS)
LOR (SM04690) – Pain NRS [0-10], Patient Global [0-100]Actual scores (mean ± standard errors)
†* * *
† † † †* *
† † ††*
†*
47
WOMAC Pain (FAS) WOMAC Function (FAS)
LOR (SM04690) – WOMAC Pain [0-100], Function [0-100]Actual scores (mean ± standard errors)
†* *
† † ††*
††*
† † ††*
†
48Comparisons of LOR vs. PBO using a baseline-adjusted ANCOVA. Data on x-axis is offset for visual clarity.
*SM04690 0.07 mg P<0.05 †SM04690 0.23 mg P<0.05
Studies to direct MSCs to differentiate into chondrocytes in the joint.
Kartogenin: Differentiates endogenous mesenchymal stem cells into cartilage-producing chondrocytes in vitro
NEJM 2012; 366:2522-2524
Kartogenin induced chondrocyte differentiation and promoted repair in Collagen-VII induced and surgery induced OA models.
Johnson et al, Science 2012
Treatment with Intra-articular Kartogenin for acute Post-traumatic knee OA in rats. Representative articular cartilage T1ρ and T2 maps of sham-operated control knee joint,
Mohan et al, JOR
Histologic, Imaging and Biochemical outcomes of Kartogenin treatment of rats.
Mohan et al JOR. 2012
Kartogenin is currently in a phase 1b clinical trial for the Treatment of knee OA
Senescence
Schosserer M. et al Geromtology. 2018 ·
Senescence of cells and the SASP that they release
McHugh et al JBC. 2018
Ok Hee Jeon, et al Nat Med. 2017 Jun; 23(6): 775–781.
The effects of a senolytic medication on a preclinical model of post-traumatic knee OA
INCREASED Senescent cells OBSERVED Synovium in Fibroblasts in from the Knees of OA subjects undergoing arthroscopy
Unity Biotechnology
p16INK4a+ IHC photomicrograph of a biopsy specimenRed Arrow is synoviocyte/fibroblasts a few macrophagesGreen Arrow is non senescent synoviocyte
Results of Phase Ib study of a Senolytic Agent for the Treatment of painful knee OA• Observational study , synovium from Knee OA subjects found
senescent fibroblasts in the synovium from tissue obtained at arthroscopy. ( personal communication)
• Phase Ib study of UBX0101 in knee OA subjects• First-in-human Phase 1 study of UBX0101 in patients with moderate to severe
osteoarthritis (OA) of the knee.
• UBX0101 was safe and well-tolerated.
• Improvement in several clinical measures, including pain, function, as well as modulation of certain senescence-associated secretory phenotype (SASP) factors and disease-related biomarkers was observed after a single dose of UBX0101.
Unity Biotechnology, June 18, 2019 (GLOBE NEWSWIRE) , www.gobenewswire.com
FGF18 for the treatment of knee OA through Intra- articular injections into the joint.
Recombinant human Fibroblast Growth Factor 18 (Sprifermin)
• Human version of naturally-occurring FGF-18
• Binds to FGF receptor 3 (FGFR3) on chondrocytes, leading to activation of intracellular signalling pathways and:
- stimulation of chondrocyte proliferation
-induction of anabolic phenotype
- ECM production
-Reduction of type I collagen expression
Gigout et al.
Osteoarthritis Cartilage 2017
Control Sprifermin
Porcine chondrocytes in monolayer culture, 7 days with 100 ng/mL of spriferminor in absence of compound (control)
The cell cytoskeleton (actin) was stained in green
Sprifermin 5 yr Phase II trial: FORWARD
Hochberg MC et al. EULAR 2018
Primary endpoint met: dose-dependent increase in TFTJ cartilage thickness (qMRI), with significant differences for sprifermin 100 µg q6mo and 100 µg q12mo vs placebo
Sprifermin FORWARD trial: can we define a pain and structural progression group?
Ch
ange
fro
m b
asel
ine
inW
OM
AC
pai
n s
core
“Subgroup at Risk”(N=161)
Baseline Week 26 Week 52 Week 78 Week 104 Week 156
0
0.10
-0.20
-0.30
-0.40
-0.50
Placebo
Last treatment cycle
ITT Population(N=549)
Baseline Week 26 Week 52 Week 78 Week 104 Week 156
Placebo
Last treatment cycle
Placebo
Sprifermin 30 µg q12mo
Sprifermin 30 µg q6mo
Sprifermin 100 µg q12mo
Sprifermin 100 µg q6mo
Treatment:
Adj. mean diff. to placebo: -8.75
95% CI: -22.42, 4.92
0
-0.20
-0.30
-0.40
-0.50
0.10
Guehring H et al.
EULAR 2019 [oral]
Intra-articular corticosteroids and the risk of knee osteoarthritis progression: results from the Osteoarthritis Initiative.
Zeng et al. Osteoarthritis and Cartilage 2019 vol 27, issue 6: 855-862.
Knee ROA Progression
IACs Cohort Comparison Cohort
HR**95% CI
Continuous IACs, HR
95% CI
No. Knees*
Incidence Rate
(1/100 PYs)
No. Knees*
Incidence Rate
(1/100 PYs)
KL Worsening 65 (148) 21.7 90 (536) 7.1 3.02 (2.25, 4.05)
4.67 (2.92, 7.47)
JSW Worsening
63 (104) 32.0 99 (388) 11.1 2.92 (2.19, 3.90)
3.26 (1.78, 5.96)
Association between Intra-Articular Corticosteroids (IACs)
and Risk of Knee ROA Progression
What about Platelet Rich Plasma (PRP) and PRP Injections?
• Platelet-rich plasma (PRP) therapy uses injections of a concentration of a patient’s own platelets to accelerate the healing of injured tendons, ligaments, muscles and joints.
• PRP injections are prepared by taking patient’s blood then sending it through a centrifuge to concentrate the platelets.
• Then platelets are injected directly into your injured or diseased body tissue. This releases growth factors that stimulate and increase the number of reparative cells your body produces.
• Ultrasound imaging is sometimes used to guide the injection.
Pain Medicine, Volume 20, Issue 7, July 2019, Pages 1418–1429, https://doi.org/10.1093/pm/pnz011
The content of this slide may be subject to copyright: please see the slide notes for details.
Forest plot and meta-analysis of VAS Pain Scale
Pain Medicine, Volume 20, Issue 7, July 2019, Pages 1418–1429, https://doi.org/10.1093/pm/pnz011
The content of this slide may be subject to copyright: please see the slide notes for details.
Forest plot and Meta-analysis of International Knee Documentation Committee Endpoint for Platelet Rich Plasma vs. Hyaluronic acid for Painful Knee OA.
Pain Medicine, Volume 20, Issue 7, July 2019, Pages 1418–1429, https://doi.org/10.1093/pm/pnz011
The content of this slide may be subject to copyright: please see the slide notes for details.
Forest plot and Meta-analysis of Lequesne index scores
Platelet‐Rich Plasma (PRP) From Older Males With Knee Osteoarthritis Depresses Chondrocyte Metabolism and
Upregulates Inflammation
Journal of Orthopaedic Research, Volume: 37, Issue: 8, Pages: 1760-1770, First published: 01 May 2019, DOI: (10.1002/jor.24322)
Platelet‐Rich Plasma (PRP) From Older Males With Knee Osteoarthritis Depresses Chondrocyte Metabolism and
Upregulates Inflammation
Journal of Orthopaedic Research, Volume: 37, Issue: 8, Pages: 1760-1770, First published: 01 May 2019, DOI: (10.1002/jor.24322)
Platelet Rich Plasma Summary
• Platelet-rich plasma (PRP) treatments deliver supraphysiologic amounts of growth factors and cytokines contained within platelets.
• However, evidence of its efficacy has been mixed and highly dependent on composition and on the specific indication.
• The heterogeneity of PRP preparations, both presently and historically, has made interpreting the existing literature difficult and limits our ability to make definitive treatment recommendations.
Prolotherapy is a dextrose solution that is injected into tendons and joints to reduce pain
Prolotherapy
• Basic Science• Dextrose produces a local inflammatory response in uninjured knee
ligaments.• Rabbit model of flexor tendonitis had greater strength and tissue thickness
that saline controls.
• Clinical use: treat pain in chronic conditions.• Recent work, prolotherapy for knee OA • 36 subjects case series with ACR KOA injected 1,5, and 9 weeks • Dextrose. 22% injected into periarticular tissue + intra-articularly• Average WOMAC pain improvement was 16 points• Female sex, age 46-65 yre and BMI < 25 had more improvement• Suggested “whole joint” improved.
Prolotherapy RCTs• 3 arm RCT- prolotherapy and two active control therapies: masked
saline injections and 20 week home exercise regimen. • Masked allocation was maintained among injection participants.
• Prolotherapy subjects had a 14 ± 3.2 point improvement in WOMAC through 52 weeks; saline and home program improved 7.6 ± 3.4 and 8.2 ± 3.3
• Other uses or potential indications• Tendinopathy, Lateral epicondylitis, Osgood Schlatter Disease, Rotator Cuff
Tendinopathy, Hip Adductor Tendinopathy, Achilles Tendinopathy, Plantar fasciopathy
• Appears safe
• Contraindications include skin infection
Educational and Informational Prolotherapy Resources
• Hackett-Hemwall Patterson foundation List of Prolotherapists
• Commerical Prolotherapy Physician Listing:http://www.getprolo.com
• American Association of Orthopedic Medicine: http;//www.aaomed.org
• University of Wisconsin Prolotherapy Education and Resaerch Lab (UW PEARL; http://www.farmed.wisc.edu/prolotherapy/)
Summary• MSC injections for the treatment of knee OA has short term modest
effects with reduction in structural deterioration.
• Novel agents to enhance MSC differentiation into chondrocytes are now being evaluated (including Kartogenin, FGF18, wnt inhibitor, anti-senolytic)
• Long acting anti-inflammatories medications including GCs may have deleterious effects on the joint.
• Platelet rich plasma has interesting biology but study outcomes are mixed.
• Looks like we have more work to do!!!!!!!
Any questions: [email protected]
Results of sensitivity analysis representing SMD and 95% CI for the VAS pain score between pre and post MSC treatment at final follow-up in 3 RCTs with 7 data sets (n = 75).
SMD and 95% CI for the self-reported physical functional outcome between pre and post MSC treatment at final follow-up.
Results of sensitivity analysis representing SMD and 95% CI for the self-reported physical function(WOMAC physical functional score) between pre and post MSC treatment
at final follow-up in 2 RCTs with 6 data sets (n = 60).
SMD and 95% CI for cartilage volume (a) and cartilage quality (b) between pre and post MSC treatmentat final follow-up.
MSC treatment was effective in improving cartilage quality (pooled SMD: −1.99, 95% CI: −3.51, −0.47; P < 0.001).
SMDs for cartilage quality were highly heterogeneous among studies (I2: 91%; P < 0.001)