injectable therapies · 2016-09-24 · systematic review of overlapping meta-analyses hyaluronic...

GIUSEPPE FILARDO

E. KON, L. ANDRIOLO, D. REALE, S.A. ALTAMURA

and M. MARCACCI

BOLOGNA UNIVERSITY - RIZZOLI ORTHOPAEDIC INSTITUTE

NANO-BIOTECNOLOGY LAB.

Dir. E. Kon

I ORTHOPAEDIC CLINIC

BIOMECHANICS LAB.

Dir. Prof. M. Marcacci

INJECTABLE THERAPIES

DISCLOSURE

CartiHeal LTD, Israel

Finceramica, Italy

Fidia Farmaceutici, Italy

GreenBone, Italy

Cartiheal LTD, Israel

Finceramica, Italy

Fidia Farmaceutici, Italy

GreenBone, Italy

IGEA clinical biophysics, Italy

Zimmer-BIOMET, USA

DSM Biomedical, USA

Piramal/Smith & Nephew, Usa

Institutional

support

Consultant

Giuseppe Filardo

NON-PHARMACOLOGICAL

EXERCISE

PHYSICAL THERAPIES

NON-SURGICAL TREATMENTS

PHARMACOLOGICAL

ANALGESIC/ NSAIDs/

SLOW-ACTING DRUGS

Filardo G, Kon E, Longo UG, Madry H, Marchettini P, Marmotti A, Van Assche D,

Zanon G, Peretti GM. Non-surgical treatments for the management of

early osteoarthritis. KSSTA 2016

INJECTIVE TREATMENTS

CORTICOSTEROIDS

VISCOSUPPLEMENTATION

INJECTIVE BIOLOGICS

NEW TREATMENT

OPTIONS

EARLY OSTEOARTHRITIS MANAGEMENT

CORTICOSTEROIDS INJECTION

UNIVERSALLY ACCEPTED CLINICAL USE

ANTI-INFLAMMATORY AND

IMMUNOSUPPRESSIVE

ACTION

Pros

PAIN REDUCTION

Cons

TISSUE ATROPHY &

CARTILAGE DEGENERATION

REPEATED USE

SHOULD BE

AVOIDED

Law TY et al. Phys Sportmed (2015)

3 MONTHS TIME LAPSE

FROM EACH INJECTION ?


ANTI-INFLAMMATORY ACTION

FOR SYNOVITIS

(common in early OA)

TISSUE ATROPHY &

CARTILAGE DEGENERATION

EARLY OA

Fibel KH et al. WJCC (2015)

Gerwin N et al. Adv Drug Deliv Rev (2006)

INDICATION LIMITED TO EARLY

OA WITH PREVALENT SYNOVITIS

AFTER FAILURE OF COMMON

NON-SURGICAL THERAPIES


USE DURING THE INITIAL PHASE OF

POST-TRAUMATIC OA, DIMINISHING:

EARLY INFLAMMATORY RESPONSE

DIFFERENT POST-TRAUMATIC ALTERATIONS LEADING TO OA

SINGLE INJECTION OF

EXTENDED-RELEASE

FORMULATION

IN THE FUTURE…

Heard BJ et al. KSSTA (2015)

Bodick N et al. JBJSAm (2015)

NEW PARADIGM REVERSING CORTICOSTEROID REPUTATION

INHIBITS TISSUES NOCICEPTORS (ANALGESIC EFFECT)

STIMULATES ENDOGENOUS HA

SUPPRESSES THE PRODUCTION AND ACTIVITY OF

PROINFLAMMATORY MEDIATORS AND PROTEASES

INCREASE SYNOVIAL FLUID

ELASTICITY AND VISCOSITY

PREVENTS CARTILAGE

DEGRADATION AND PROMOTE ITS

REGENERATION

M Carrington Reid et al. Adv Ther (2013)

EFFECTS ON TISSUE HOMEOSTASIS

HYALURONIC ACID INJECTION

SYSTEMATIC REVIEW OF OVERLAPPING META-ANALYSES


Campbell KA et al. Arthroscopy (2015)

CLINICAL EVIDENCE

IA-HA RESULTS IN IMPROVEMENTS IN KNEE PAIN AND FUNCTION

THAT CAN PERSIST FOR UP TO 26 WEEKS.

IA-HA HAS A GOOD SAFETY PROFILE,

ITS USE SHOULD BE CONSIDERED IN EARLY KNEE OA

Rutjes AW et al. Ann Intern Med (2012)

META-ANALYSIS OF HIGH LEVEL STUDIES

BENEFIT MINIMAL OR NONEXISTENT

INCREASED RISK FOR SERIOUS ADVERSE EVENTS

ADMINISTRATION SHOULD BE DISCOURAGED


CLINICAL PRACTICE GUIDELINES

OARSI 2008 OARSI 2014

AAOS 2010 AAOS 2013

ACR 2000 ACR 2012

INDICATED

IN PATIENTS NOT RESPONDING TO NON-

PHARMACOLOGIC THERAPY AND ANALGESICS

NO RECOMMENDATION

CONSIDER IN OLDER PATIENTS WITH

CONTRAINDICATIONS TO ANALGESICS

NO

RECOMMENDATION

NOT

RECOMMENDED

INDICATED

PROLONGED DURATION OF BENEFIT

NO RECOMMENDATION

CORTICOSTEROID INJECTION: NOT INDICATED IN

EARLY OA DUE TO CHONDROTOXICITY

HYALURONIC ACID INJECTION: NOT INDICATED

RE-EVALUATE

APPROPRIATE

INDICATION?

OTHER SOLUTIONS?

IN EARLY OA

INJECTIVE OPTIONS?

PRP EFFECTS ON SYNOVIOCYTES

Enhancement of HA secretion and

increase MMP1,3 in OA

synoviocytes

PRP EFFECTS ON MENISCAL CELLS

Up-regulation of meniscal cells

viability in a dose dependent

manner

PRP EFFECTS ON CHONDROCYTES

Proliferation

ECM component deposition

Inflammation modulation

Analgesic action

PRP: INDUCTION OF POSITIVE CHANGES

IN THE WHOLE JOINT ENVIRONMENT

IN VITRO EVIDENCE

Filardo G, Kon E, Roffi, A, Marcacci M, et al. 2015

0

5

10

15

20

25

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Year

Pap

ers

Clinical studies

Preclinical studies

In Vitro studies

THE EVIDENCE FROM RCTs

PRP VS

CORTICOSTEROIDS

Forogh et al. 2015:

1 PRP INJ. > CS up to 6 m f-up

(clinical scores and

walking test, no ROM)

PRP VS

PLACEBO

Patel et al. 2013:

1 LP- PRP INJ. > saline (6M)

2 PRP INJ = 1 PRP INJ

Gormeli et al. 2015:

3 LR-PRP >> Saline (6M) even

in advanced OA grade

Smith et al. 2016:

3 LP-PRP >> Saline at any

time point up to 12 m

Cerza et al. 2012:

4 INJ. P-PRP >> 4 INJ. HA,

INDIPENDENTLY FROM OA

SEVERITY (6 M)

UNBLINDED

PRP VS

HA

Gormeli et al. 2015:

3 INJ. LR-PRP ARE

SUPERIOR TO 3 HA INJ. (6 M)

3 INJ PRP >> 1 INJ PRP

NO SUPERIORITY IN HIGH

GRADE OA

Sanchez et al. 2012:

3 INJ. PRGF vs 3 INJ. HA

PRP ONLY SUPERIOR (6M) IN

PERCENTAGE OF RESPONDERS

Vaquerizo et al. 2013:

3 INJ. PRGF >> 1 INJ. HA

(48 W) UNBLINDED

Raeissadat et al. 2015:

2 INJ. LR-PRP >>3 HA INJ. (12 M)

SIMILAR TREND IN ADVANCED OA

UNBLINDED

THE EVIDENCE FROM RCTs

INCLUSION CRITERIA

•Monolateral symptomatic knee with history of chronic pain (at least 4

months) or swelling;

•Imaging findings of degenerative changes (Kellgren Lawrence 0 to 3

at X-ray or MRI evidence of degenerative chondropathy).

EXCLUSION CRITERIA

•Age > 80 years;

•Kellgren-Lawrence score > 3;

•Major axial deviation;

•Focal chondral or osteochondral lesion;

•Presence of any concomitant knee lesion;

•Causing pain or swelling;

•Haematological diseases;

•Severe cardiovascular diseases;

•Infections.

RANDOMIZED CONTROLLED TRIAL

192 PTS, 1Y F-UP

PRP vs HA

DOUBLE - BLINDED

Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A,

Fornasari P, Marcacci M, Kon E. Am J Sports Med. 2015

“ICRS 2015 AWARD”

IKDC SUBJ IMPROVEMENT at 12M F-UP

2 MONTHS

• PRP vs HA (n.s.)

6 MONTHS


12 MONTHS


NO STATISTICAL INTER-GROUP DIFFERENCE !!!

OTHER EVALUATIONS PERFORMED

EQ-VAS FOR GENERAL HEALTH

TEGNER SCORE

KOOS SCORE

SATISFACTION RATE

ROM AND TRANSPATELLAR CIRCUMFERENCE

Filardo G, Marcacci M, Kon E, et al. 2015


ONLY ONE SIGNIFICANT

INTER-GROUP DIFFERENCE

WAS FOUND…

FAILURE RATE:

need for

reintervention

over 24 months

38.2%

HA GROUP

21.5 %

PRP GROUP

SIGNIFICANTLY LOWER

REINTERVENTION RATE IN

PRP GROUP (p=0.036)


PRP PRODUCES BETTER SUBJECTIVE

RESULTS WHEN PATIENTS ARE AWARE OF

THE TREATMENT RECEIVED, WHEREAS

LOWER OUTCOMES ARE DOCUMENTED IN

DOUBLE BLINDED TRIALS…

PRP = PRODUCT RICH IN PLACEBO (?!?!)

Filardo G and Kon E, KSSTA 2015

ANYWAY, POOR OUTCOME IN ADVANCED OA

(as seen for other treatments)

RIGHT INDICATION !!!

RIGHT TREATMENT PROTOCOL!

WHAT IS THE IDEAL NUMBER OF

INJECTIONS?

WHAT IS THE BEST TIME INTERVAL?

THAT IS STILL UNCLEAR…

MANY PROTOCOLS USED IN CLINICAL

PRACTICE

PATEL ET AL, AJSM 2013

NO CLINICAL DIFFERENCE

BETWEEN 1 OR 2 PRP INJ

3 L-PRP INJ. vs 3 HA INJ. vs 1 PRP+2 SALINE INJ. vs 3 SALINE INJ.

GORMELI ET AL, KSSTA 2015

OVERALL BETTER RESULTS WITH 3 INJECTIONS

1 LP-PRP INJECTION vs 2 PRP INJECTIONS vs 1 SALINE INJECTION

KADAVAR ET AL, J PHYS THER SCI 2015

1 PRP INJ vs 2 PRP INJs vs 3 PRP INJs

TWO WEEKS INTERVAL

3 INJECTIONS BETTER THAN 2 !

DIFFERENT PROCEDURES DIFFERENT PLATELETS

CONCENTRATES

DIFFERENT RESULTS

DIFFERENT PROPERTIES / DIFFERENT CLINICAL USE

(hemostasis, glue, scaffold, anti-inflammatory, analgesic,

antibacterial, enhancer of tissue healing potential…)

Blood volume harvested

Use of anticoagulant

Number of centrifugations

Speed of centrifugation

PRP volume obtained

Activation method

Integrity of platelets

Presence of leucocytes

Cryopreservation

PLATELET-RICH WHAT?

Pure PRP

(Cell separator PRP, Vivostat, Anitua’s PRGF)

PRP + leucocytes (Curasan,

Regen, Plateltex, SmartPReP, PCCS, Magellan,

GPS, Rizzoli’s PRP)

Platelet-rich fibrin

(Fibrinet)

Platelet-rich fibrin +

leucocytes (Choukroun’s PRF)

ACP (Arthrex)

PRPs EFFECT ON SYNOVIOCYTES

Assirelli E, Filardo G, Kon E, Marcacci M, et al. 2014

L-PRP: PROINFLAMMATORY / PRO-CATABOLIC

DOUBTFUL POSITIVE ACTION ON HA

P-PRP: WAS NOT ABLE TO EXERT A DIFFERENTIAL

PATTERN OF BIOLOGICAL EFFECT COMPARED TO PPP

PRPs EFFECT ON CHONDROCYTES

*

*

*

*

*

*

*

*

*

*

* *

*

*

*

*

Cavallo C, Filardo G, Kon E, Marcacci M, et al. 2014

PROLIFERATION: > PRP 1S

COLL GENE EXPRESSION: > PRP 1S

HYALURONAN EXPRESSION

AND SECRETION

> L-PRP (2S)

THE ROLE OF LEUKOCYTES…

38 PTS, INCLUDED IN A RCT,

UNDERWENT SYNOVIAL FLUID AND BLOOD SAMPLING

BEFORE EACH WEEKLY L-PRP or HA INJECTION (3 INJ)

PRO- AND ANTI-

INFLAMMATORY CYTOKINES

TESTED

NO DIFFERENCE IN

SYNOVIAL FLUIDS IN

INFLAMMATORY

MOLECULES

BETWEEN L-PRP AND

HA

THE LEUKOCYTE PRESENCE

DOES NOT UPREGULATE

INFLAMMATORY RESPONSE

ONE WEEK AFTER THE INJ.

Mariani E, Filardo G,

Kon E, Marcacci M, et al. 2016

ADVERSE EVENTS

PAIN SWELLING

PRP 2 STEP PRP 1 STEP PRP 2 STEP PRP 1 STEP

24 minor

34 moderate

14 severe

58 minor

9 moderate

5 severe

40 minor

21 moderate

11 severe

53 minor

16 moderate

3 severe

P = 0.0005 P = 0.03

CLINICAL

OUTCOME

IKDC SUBJ N.S.

AGE CORRELATION

COMPARATIVE STUDY

PRP 2 STEP (72 pts) vs PRP 1 STEP (72 pts)

Filardo, Kon, Pereira Ruiz, et al. KSSTA 2012

DOUBLE-BLIND, RANDOMIZED, MULTICENTRIC, CONTROLLED

PROSPECTIVE TRIAL (ITALY, BELGIUM, AUSTRIA, NORWAY)

46 PTS WITH EARLY TO MODERATE KNEE OA

SINGLE US GUIDED INJECTION: APS VS SALINE

APSS-33-00., “A Multicenter, Double-Blind, Randomized, Placebo-

Controlled Pilot Study of a Single, Intra-Articular Injection of Autologous

Protein Solution in Patients with Osteoarthritis of the Knee.” Ongoing Study.

0%

10%

20%

30%

40%

50%

60%

70%

2 4 12 26 52

Pe

rc

en

t C

ha

ng

e fro

m

Ba

se

lin

e

Weeks After Injection

APS

Saline

APS >>> Saline

ANTI-INFLAMMATORY

CYTOKINES AND

GROWTH FACTORS

FROM WHOLE BLOOD

NOVEL SOLUTIONS: EU PILOT TRIAL

PRP: THE WAY IS STILL LONG...

BIOLOGICAL EFFECTS

CHARACTERIZATION

STANDARDIZATION

COMPARISON

OPTIMIZATION OF PRP!

MESENCHYMAL STEM CELLS FOR

MUSCULOSKELETAL TISSUES REPAIR

Caplan and S.P. Bruder 2001, TRENDS in Molecular Medicine, 7(6) 259-264

Mesenchymal stem cells are pluripotent progenitor cells

capable of differentiating into different cell lineages

SECRETE MASSIVE LEVEL OF

BIOACTIVE AGENTS

POWERFUL SITE-REGULATED

“DRUG STORES”

Caplan, Tisse Engineering Part A, 2010

SEVERAL SOURCES

Sakaguchi Y et al. Arthritis Reum 2005

Shirasawa S et al. J Cell Biochem 2006

Koga H et al. Cell Tissue Res. 2008

BMSCs

ADSCs

SDSCs

GOOD DIFFERENTIATION POTENTIAL

EASY COLLECTIBLE

LIMITED MSCs FREQUENCY/VOLUME

MINIMAL HARVEST MORBIDITY

LARGE AMOUNT

HIGHER MSCs FREQUENCY/VOLUME

GREATEST CHONDROGENIC POTENTIAL

CULTURE EXPANSION IS MANDATORY

EXPANDED

CONCENTRATED

PROS:

- higher MSCs number

- selected lineage

CONS:

- contamination risk during

amplification

- regulatory aspects

PROS:

- “minimally manipulated”

- one-step

CONS:

- heterogeneous composition

MSC PROCESSING

Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the

treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics.

Knee Surg Sports Traumatol Arthrosc 2015

MECHANISM OF ACTION

EFFECTS

ON

CARTILAGE

PRE-CLINICAL EVIDENCE

EFFECTS

ON

MENISCUS

EFFECTS ON

SYNOVIAL TISSUE

IA INJECTION of MSCs

TARGETS ALL JOINT TISSUES

…DREAM

…OR REALITY?

MSCs INJECTIONS :

PRE-CLINICAL AND CLINICAL EVIDENCE

Outcome N of Papers

+ 25

- 1

PRECLINICAL STUDIES

CLINICAL STUDIES

Outcome N of Papers

+ 13

± 2

IMPROVEMENT IN:

JOINT FUNCTION

PAIN

CARTILAGE THICKNESS

QUALITY OF LIFE

HISTOLOGIC AND MRI

SCORES

NOT UNIVOCAL RESULTS:

NO IMPROVEMENT AT X-RAY

BUT… “ALL THAT GLITTERS IS NOT GOLD”

STILL MANY OPEN QUESTIONS…

WHAT DO WE WANT…??



HOPES…






AND FEARS…


CONCLUSIONS

MOST EVIDENCE ON ESTABLISHED OA

EARLY OA LESS STUDIED:

PRESERVE CARTILAGE!

CORTICOSTEROIDS AND HYALURONIC ACID

HAVE LIMITS, ESPECIALLY IN EARLY OA

SPACE FOR BIOLOGICAL TREATMENTS

NO EVIDENCE FOR REGENERATION!

HOMEOSTATIC TREATMENTS

(CYCLES?)

BUT

STILL MANY THINGS TO UNDERSTAND

(DOSAGE, SOURCE, INDICATION…)

THANK YOU

Supported by: Italian Ministry of Health Ricerca Finalizzata (RF-2011-02352638).

injectable therapies · 2016-09-24 · systematic review of overlapping meta-analyses hyaluronic...

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