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: nelane@ucdavis.edu

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)