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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
