Osteoarthritis

VILNIUS, 22 SEPTEMBER 2017HANS BIJLSMAUTRECHT, NL

Clinical Case

Mrs P, 59 years

Has been running inthe past, not

possible anymoredue to painful andsometimes swollen

knee

Her GP made a plain X-ray:no signs of osteoarthritis.

KELLGREN AND LAWRENCE CLASSIFICATION

Clinical Case

Mrs P, 59 years

Her GP made a plain X-ray, noosteoarthritis signs.

She went to a private clinicMRI was made.

What do you see ?

DIAGNOSIS OATREATMENT ?

GOAL of treatment:• Reduce pain and stifness• Maintain / improve physical function

In this lady:• How do you maintain her function ? Running again ?• How do you manage her pain ?

Clinical Case

Lifestyle changes ?

Her BMI is 32She smokesHas diabetes mellitusRR 140/80

Years lived with disability due to OA

Margreet Kloppenburg, EULAR 2017

OA PATIENT POPULATION:NOT HOMOGENEOUS

PHENOTYPING OA

• In the coming years, a better definition of osteoarthritis isexpected by delineating different phenotypes of the disease.

• Treatment targeted more specifically at these phenotypesmight lead to improved outcomes.

Osteoarthritis: an update with relevance for clinical practice.Johannes WJ Bijlsma, Francis Berenbaum, Floris PJG LafeberThe Lancet 2011: 377: 2115-26

Phenotypes of osteoarthritis

Mobasheri, 2017

Phenotype-targetting therapies

Roman-Blas, Expert Opinion in Pharmacotherapy, 040716

Factors underlying metabolic alterations in OA

Mobasheri, 2017

Concept of Metaflammation

MECHAFLAMMATION vs METAFLAMMATION

local systemic

Relative contribution of overweight and MetS inknee OA and hand OA

Visser et al. ARD 2015

Knee, hip, hands, spine, …

Involvement of all 4 tissue structures“final common pathway”

OA is an Organ disease

RheumatologistRheumatologist

Orthopedic surg.Orthopedic surg.

GeneralphysicianGeneral

physicianAnalgesics

DMOADs

regenerative medicine

prosthesis

NSAIDs

joint sparing surgery

DMARDs

Treatment individualised

Placebo response

Abishek Abishek, EULAR 2017

Placebo response = contextual response

Evidence for placebo response in OA

Placebo response also in other outcomes

Placebo is a “misnomer”

In OA (and maybe other chronic pain conditions)placebo is an active treatment:• Substantial symptomatic relief• High effect size• Durable results• Effect size of placebo increases with increased

invasiviness• In many studies placebo-effect contributes to up

to 75% of pain reduction

Three treatment modalities

• Non-pharmacological

Individualise to the patient

Non-pharmacological recommendationsEducation on weight loss should incorporate individualisedstrategies that are recognised to effect successful weight lossand maintenance —for example:

• regular self-monitoring, recording monthly weight• increase physical activity• reduce fat (especially saturated) intake; reduce sugar;

limit salt; increase intake of fruit and vegetables• limit portion size;• addressing eating behaviors and triggers to eating

(eg stress)

Non-pharmacological recommendations

Walking aids, assistive technology andadaptations at home and/or at work should beconsidered—for example:

• comfortable shoes.• walking stick• increasing the height of chairs, beds and toilet seats• hand-rails for stairs• walk-in shower• car with high seat level and automatic gear

Non-pharmacological recommendations

Important principles of all exercise include:

• small amounts often• link exercise regimens to other daily activities• start with levels of exercise

within the individual’s capability,• build up over several months

Exercises

Exercises: Tai Chi versus physical therapy

Margreet Kloppenburg, EULAR 2017

Tai Chi versus physical therapy: outcomes

Three treatment modalities

• Pharmacological

Analgetic treatment

• Paracetamol first choice• Increase dosage where necessary• Not safe in long term high dosages

Analgetic treatment

• Paracetamol• Add codeine / coffeine

• Stronger analgetics only when other drugs, suchas NSAIDs, have been ineffective orcontraindicated:

• Weak opioids• Narcotic analgetics

NSAIDs

• Quite effective (E.S.>0.80)• Especially when signs of synovitis• Can be used on demand

NSAIDs and cardiovascular risk

• All NSAIDs, both non-selective and selective, should be usedwith caution, and are sometimes contra-indicated.

• Individual drug characteristics more relevant than class ofdrugs

• Naproxen “relatively safest” profile

Cardiovascular safety of celecoxib, naproxen andplacebo (PRECISION)

Margreet Kloppenburg, EULAR 2017

Cardiovascular safety of celecoxib, naproxen andplacebo (PRECISION)

NSAIDs and gastrointestinal risk

• In high risk patients (higher age, history of ulcus) prescribeeither– Selective cox-2 inhibitor– Non-selective NSAID plus PPI

Gastrointestinal safety of celecoxib andnaproxen (CONCERN)

Margreet Kloppenburg, EULAR 2017

Gastrointestinal safety of celecoxib andnaproxen (CONCERN)

Neuropathic pain in OA

Abishek Abishek, EULAR 2017

Pregabalin is more effective in hand OA painthan duloxetine or placebo: a double-blind RCT

Nidhi Sofat, ACR 2016 oral presentation

Outcome measures AUSCAN:primary pain (left), secondary function (right)

Nidhi Sofat, ACR 2016 oral presentation

HERO: a placebo-controlled RCT

Philip Conaghan, ACR 2016, oral presentation

Primary outcome: hand pain (left)Secondary outcome: radiography (right)

no effect

Philip Conaghan, ACR 2016, oral presentation

No effect either when taking inflammation intoaccount

Philip Conaghan, ACR 2016, oral presentation

Platelet Rich Plasma: popular, but does it work ?

Joel Block, ACR 2016, oral presentation

• Autologously-derived plasma sample,enriched for Platelets

• Rich source of growth factors, cytokines, andplasma components: “a biological”

• Intended to stimulate tissue healing• No standardization of preparation, platelet

enrichment, WBC content, activation or use• In vitro and animal data: suggestive

Platelet Rich Plasma: popular, but does it work ?

Joel Block, ACR 2016, oral presentation

• Evidence for a structural effect is poor• No research is done to evaluate structural effect

• In addition in OA• Patients are extraordinarily susceptible to

placebo effect (> 40% in placebo response)• Placebo-response persists often over one year

Moab blocking Nerve Growth Factor beta

TanezumabFullranumabFasinumab, all in further clinical and experimental studies

Efficacy of Anti-NGF antibodies

Safety of Anti-NGF antibodies

Peri-articular ointments

• Cremor capsaicin• NSAIDs ointments (diclofenac gel and others)

Disease Modifying OA Drugs (DMOADs)

The holy grail ?

Cartilage regeneration ?

CARTILAGE TARGETTING THERAPIES

Slowing cartilage degradation

• ADAMTS4/5 inhibitors• MMP inhibitors: TIMPs,

doxycycline

Regulating cartilage metabolism• Growth factors• Bone morphogenic protein

BONE TARGETTING THERAPIES

Anti-osteoporosis agents

• Zoledronic acid• Calcitonin• Strontium ranelate• Risedronate• Vitamin D

Bone marrow laesions• 395 knees studied; 30 months follow up• 66% changed in size; 50% regression or resolution

• BML size at baseline associated with risk of subsequent cartilage loss• Absence of BML: less risk of cartilage loss• Progression and new BML: higher risk of cartilage loss in same region

MOST-study, Roemer et al, ARD 2009; 68: 1461-5

476 mm2 → 14 mm2

528 mm2 → 26 mm2

BML and Zoledronic acid

0

20

40

60

0 3 6 12Follow-up (months)

Scor

e (%

)VA

S pa

in

placebo

Zoledronic acid

Strontium ranelate inhibits progression of spinalosteophyte formation and disc space narrowing

Bruyere, ARD 2007

Strontium ranelate (StR) is associated with a significantreduction in cartilage thinning (left) and has a moderate effect

on pain (right)Reginster Ann Rheum Dis. 2013; 72: 179-86.

Strontium ranelate (1 and 2 g/d) vs. placebo

• OA symptoms and radiography vary betweenpatients, between disease stages, and over

time• Identifying radiographic phenotypes would be

easier when using a quantitative evaluation ofseparate radiographic OA features

Plain radiography

rheumatoid arthritisosteoarthritis

• Anti-TNF antibodies• Neutralizer for IL-1• Anti-inflammatory agents

(MTX)• Lipid lowering drugs

(Statins)

Inflammation targeting therapies

Synovitis interventions: TNFα-blockers

• Erosive osteoarthritis of the interphalangeal finger joints

• Structural damage, patients with erosive hand OA

• 60 patients, 12 months adalimumba versus placebo

• At 12 months erosive progression in 40% (placebo) vs 27%(adalimumab), not significant

• Predictor palpable soft tissue swelling IP joints

Verbruggen G et al, ARD 2012; 71: 891-8

SUBCUTANEOUS ETANERCEPT IN PATIENTSWITH EROSIVE INFLAMMATORY HAND OA

RANDOMIZED, PLACEBO-CONTROLLED TRIAL TO EVALUATE CLINICAL EFFICACY AND STRUCTURE MODIFYINGPROPERTIES OF SUBCUTANEOUS ETANERCEPT (ETN) IN PATIENTS WITH EROSIVE INFLAMMATORY HANDOSTEOARTHRITIS (OA)

M. Kloppenburg et al for investigators from Gent, Leiden, Padua and ViennaF. P. Kroon et al for investigators from Gent, Leiden, Padua and Vienna

Etanercept 50mg/week Etanercept 25mg/week

Placebo

Baseline 1 year

N=45

N=45

24 weeks

N=20MRI of DIP andPIP joints

MRI

Is TNF-blockade effective in hand-OA patients with erosiveand active disease?

Pain and MRI: Proof-of-concept

MRI sub-study (N=20) Change of BML on joint-levelβ (95% CI) p-value

Treatment (etanercept) -0.22 (-0.35; -0.09) 0.001

Interaction baseline synovitis *treatment

-0.59 (-0.97; -0.20) 0.003

18% TreatmentEffect

Efficacy of diacerhein in osteoarthritis

7 studies, 1228 patients

• pain (VAS 0-100) diacerhein vs placebo-5,16 (95 % CI -9,75; -0,57)

• function (Lequesne) diacerhein vs placebohip -0,21 (95 % CI -0,82; 0,40)knee -0,95 (95 % CI -2,64; 0,74)

• diarhoe 42 %, drop-out 18 % vs 13 %

• Conclusion – diacerhein has a small, consistent benefit.

Fidelix TSA et al. The Cochrane Database of Systemic Reviews2006;Issue 1. Ar No: CD 005117

Synovitis interventions: MTX trials

• Methotrexate for pain relief in knee OA: an open label study

• US assessed effusion and synovial thickness

• 24 weeks MTX up to 20 mg/week

• At 24 weeks 43% achieved OARSI responder criteria• 23% of patients > 50% reduction in pain• 13% of patients worsening of pain

Wenham, Rheumatol (Oxford) 2013

PHENOTYPING OF OA MAY LEAD TOTARGETED TREATMENT IN OA

• Muscles and ligaments -> physical therapy

• Cartilage -> MMP inhibitors,doxycycline, growth factors, bonemorphogenic protein-7

• Bone -> bisphosphonates, strontium ranelate, calcitonin, Vit D

• Inflammation -> NSAIDs, MTX, TNFα blockers, IL-1 blockers

bone changes

cartilage damage

ligaments / muscleinvolvement

synovial inflammation

time during course of the disease

seve

rity

of d

isea

se

DMOAD

bisphosphonate

EXAMPLE POSSIBLE TREATMENT OPTIONS

bone changes

cartilage damage

ligaments / muscleinvolvement

synovial inflammation

time during course of the disease

seve

rity

of d

isea

se

physioDMOAD

DMARD

EXAMPLE POSSIBLE TREATMENT OPTIONS

NON-PHARMACEUTICALS

• Large placebo effect

• Not many comparative studies

• Effect size difficult to determine

• Publication bias

• Inadequate reporting of adverse events

“try for three months, if effective,continue, if not stop”

“ANNO 2017 THE JURY HAS A NEGATIVE VERDICT”

INTRA-ARTICULAR INJECTIONS:HYALURONIC ACID

•High molecular weight seemsimportant

•After 4-6 weeks better than placebowith regard to pain and function

•After 4-6 weeks comparable toglucocorticoid injection with regard topain and function

•Repeated injections;•New: one injection

INTRA-ARTICULAR INJECTIONS:GLUCOCORTICOIDS

•4 weeks beneficial effect, especiallywhen “flare”

•No negative effect on course of OA

•Relieve of mechanical pressure forthree days improves outcomesignificantly

PERI-ARTICULAR INJECTIONS

•Pain often outside the joint

•Local lidocain withglucocorticoid is effective

•Know your anatomy

Three treatment modalities

• Non-pharmacological• Pharmacological

• Surgical

ORTHOPAEDIC SURGEON DECIDED FOR A TKPRepresentative radiographs, photographs of cartilage macroscopy,and micrographs of synovial histochemistry

Many surgical options for knee OA

Mastbergen SC, et al. Nature Rev Rheum. 2013; 9: 277-90.

ACI: autologous chondrocyte implantation (2-steps)CCI: characterised chondrocyte implantation (2-steps)

ACI+MSC: autologous chondrons + stem cells (1-step)

Cell based therapies

THERAPEUTIC APPLICATION OF MESENCHYMALSTEM CELS IN OA

• MSCs possess functional properties that are of interest forcartilage repair

• Efficacy of MSCs to protect against cartilage degradation afterintra-articular injection in several preclinical models of OA

• MSC-based therapy has proven safety and tolerability inseveral clinical trials in patients with knee OA

• Cartilage repair or protection after MSC injection has still tobe demonstrated in large cohorts of patients with OA incontrolled, prospective studies.

Ruiz et al, Expert Opinion on Biological Therapy, online 31-8-2016

• Severe (late stage) knee OA• Age <60 yrs

• Considered for replacementsurgery

• K&L >2 / VAS pain >60%• 2 months; 5 mm distraction• 20 patients treated (open

uncontrolled)• Follow-up: 5 years

Intema F, et al. Ann Rheum Dis. 2011; 70:1441-6 (1 yrs follow-up)

Wiegant K, et al. OA&Cart. 2013; (2 yrs follow-up)

Knee joint distraction

4 years follow up knee distraction

0

20

40

60

80

100

0 1 2 3 4years

Scor

e (%

)

VAS

5

years

20

40

60

80

100

Scor

e (%

)

WOMAC

00 1 2 3 4 5

Pain

Function

1 year follow-up

baseline

2 year follow-up

REGULAR CARE

REGULAR CARE

50-plus pensioned old

disabled50-plus

Serious problemsRevisionTotal knee Prosthesis

1st total knee prosthesisJoint preserving treatment

Clinical relevance

THANK YOU FOR YOUR ATTENTION

j.w.j.bijlsma@umcutrecht.nlHANS BIJLSMAUTRECHT, NL