Sita Bierma-Zeinstra, PhD Professor of Osteoarthritis and Related Disorders Department of General Practice, Department of Orthopedics

1. EARLY OA OUTCOMES:
WHAT SHOULD THE TARGETS BE?
Sita Bierma-Zeinstra, PhD
Professor of Osteoarthritis and Related Disorders
Department of General Practice
Department of Orthopedics

2. Disclosure Information
I have financial relationship(s):
• Consultant for Infirst Healthcare.
• Associate editor for Osteoarthritis & Cartilage.
• Grants from the Dutch Arthritis Association / The Netherlands Organisation for Health
Research and Development / European Commission 7th Framework Programme /
European Institute of Innovation and Technology Health / Foundation for Research in
Rheumatology.
My presentation does not include discussion of off-label or investigational use.

3. Why early stage OA
evident symptomatic OA
with X-ray evidence
early processes of OA
               time         
early symptoms of OA

4. Prevention
Early intervention
Prevention
Early Intervention
Why early stage OA

5. Prevention & early intervention
Target population

6. Target population for prevention
High risk groups for knee OA
Overweight/obese persons
Sustained knee injury (meniscal and/or ACL injury)
Perimenopausal women
Prediction rules (gender, age, BMI, clinical, genetic, radiographic, biochemical markers):
AUC 0.8
Kerkhof et al, Ann Rheum Dis 2014

7. Target population for early intervention
Luyten F et al. Sem Arthritis Rheum 2018
To do:
Refine criteria with additonal methods
Validate in different cohorts
AUC, predictive value, sensitivity and specificity

8. Outcomes in OA
Intermediate clinical endpoint:
Less pain and better function
Clinical endpoint:
Less need for joint replacement
Surrogate endpoint:
Biochemical, biomechanical
and imaging markers, physical
signs

9. FDA requirements for DMOADS
OA as serious disease supports the
use of surrogate endpoints
for regulatory approval
- Validated surrogate outcome
OR
- Reasonably likely surrogate outcomes*
- Post marketing confirmatory studies
*Foundation for NIH OA Biomarkers Consortium Initiative
Kraus et al, OAC 2019

10. Outcomes in high risk group / early OA
Intermediate clinical endpoint:
Less pain and better function
Clinical endpoint:
Less need for joint replacement
Surrogate endpoint:
Biochemical, biomechanical
and imaging markers, physical
signs
Clinical endpoint:
Less evident symptomatic OA

11. How to define early outcomes
Predictor Long-
term
endpoint
X    outcome
AUC, PV, LR, sens/spec, etc

12. PROOF study
Females
age 50-60
BMI ≥ 27
no knee OA
- KL ≥ 2 knee
- ACR knee OA
- knee OA in medical record
- knee pain most days of last month
Predictive values of imaging in a high-risk group
Bijen C et al, Semin Arthritis Rheum 2018

13. Predictive value of signs and symptoms
Baseline ACR+ combined
at 6 yrs follow-up
OR univariable (multivariable)
Age 1.07 (1.14)
BMI 1.12 (1.13)
Mild knee symptoms 1.97
Feeling of giving way 1.14
Knee problems climbing
stairs
2.58 (2.08)
Knee problems standing
up from chair
2.46
Morning stiffness 2.50
Swollen knee 1.74
Heberden nodes 1.05
Joint line tenderness 1.37
Crepitus 0.74
Replicated in Rotterdam Study (RS 3)
5 year follow-up:
AUC 0.81
Knee problems while climbing stairs:
OR 4.7
Landsmeer et al, Arthritis Care Res (accepted); Case et al, OAC 2015
Knee problems while climbing stairs
Also a clear prodromal symptom in the
OAI for radiographic knee after 4 years.

14. How to define early outcomes
baseline Short-term
outcome
Long-term
endpoint
X1 - X0
Surrogate endpoint:
Imaging, biomechanical,
biochemical marker,
physical signs
Symtoms
  
(need for) Prothesis
Evident clinical OA
Pain, function

15. Short-term progression
“Short time interval” “Long time interval”
Runhaar et al, OAC 2014; Dam et al, Magn Res Med 2018
MOAKs compartimental progression
Automatic segmentation cartilage cavity, cartilage thickness

16. 2.5-year MRI change relevant for long-term?
0
20
40
60
80
100
pre-test
post-test
6.5 year incidence of radiographic OA (KL 2)
OR 4.9
OR 2.5 OR 2.1
OR 9.5
OR 5.3OR 6.2
OR 2.1
OR 0.7
OR 3.8
16%

17. 2.5 year MRI change relevant for long-term?
0
20
40
60
80
100
pre-test
post-test
6.5 year incidence of ACR combined knee OA
OR 2.3
OR 3.8
OR 2.0
12%

18. 1-year MRI change relevant for outcome?
KNALL cohort
- New ACL injury
- No OA (KL ≥ 2)
- N=154
Van Meer et al, Am J Sports Med 2016

19. Short-term outcomes in different target groups
Meniscal extrusion
Biochemical markers
Imaging markers
Biomechanical
Physical signs/symptoms
Landsmeer et al, OAC 2016; Van Meer et al, Am J Sports Med, 2016; Landsmeer et al, OAC 2018

20. Evident clinical knee OA (ACR)
Schiphof et al, under revision 2019
T=0
T=2
T=5
T=8
T=10
T=0
T=2
T=5
T=8
T=10

21. Pain and function in early OA as outcome
Pain and function fluctuate hugely
Frequent measurements
AUC
Sensitive scales for early stage OA
KOOS subscales
ICOAP
QuIKS
“I am considering stopping a favorite activity due to my knees”
“I participate in certain activities less often to avoid aggravating my knees”
“I am considering changing my exercise routine due to my knee problems”
Emery et al, Nat Rheum Rev (provisionally accepted) 2019; Bastick et al, Br J Gen Pract 2017

22. Outcomes in high risk group / early OA
Intermediate clinical endpoint:
Less pain and better function
Clinical endpoint:
Less need for joint replacement
Surrogate endpoint:
Biochemical, biomechanical
and imaging markers,
physical signs
Clinical endpoint:
Less evident symptomatic OA
Repeated measures?
AUC, sensitive
subscales?
Mechanism to target
Sensitive to change
Durable effect

23. • Several studies available
• Define long-term outcome of interest
• Narrow the baseline population to your
targeted population
• Assess predictive values of short–term
change for long-term outcome
• Validate in independent sets
Outcomes in early OA

24. Acknowledgements
In specific:
Jos Runhaar, PhD
Dieuwke Schiphof, PhD
Marieke Landsmeer, MSc
Claudia Bijen, PhD
Department of General Practice
Belle van Meer, PhD
Department of Orthopedics
Erasmus MC, the Netherlands
Frank Luyten, PhD, professor
Skeletal Biology & Engineering
Research Center
KU Leuven, Belgium
OA RESEARCH
DEPARTMENT OF
GENERAL PRACTICE
ERASMUS MC
ROTTERDAM