Prof. Dr Margreet Kloppenburg Depart. Rheumatology, Clinical Epidemiology

1. Year in review
Clinical OA: Epidemiology and Therapy
Prof. Dr Margreet Kloppenburg
Depart. Rheumatology, Clinical Epidemiology
LEIDEN
Syst. Review
PubMed
>1400 titles
NEJM, Lancet, BMJ,
Ann Intern Med,
ARD, AR, OAC,
Rheumatology
Acknowledgement:
Prof. Francis
Berenbaum

2. Margreet Kloppenburg, MD PhD
Professor of Rheumatology
Leiden University Medical Centre, Leiden, The Netherlands
Disclosure Information
I have financial relationship(s) with:
Advisory boards (all paid to institution): Pfizer, Merck-Serono,
Levicept, Abbvie, GlazoSmithKline
Grant/ Research: Pfizer
My presentation does include discussion of off-label or
investigational use. (CNTX-4975, lutikizumab, etanercept,
galcanezumab)

3. High burden of MSK diseases, including OA
• WHO Global Health Estimates:
• Burden of MSK diseases increased significantly
between 2000-2015
• Global Burden of Disease Study (2017 update):
MSK diseases first cause of years lived with
disability (YLDs) worldwide
• Especially at middle-age
• Back pain 47.8%
• Neck pain 21.1%
• OA 7.1%
• RA & gout 2.9%
• Other MSK 21.2%
Sebbag doi:10.1136/ARD 2019-215142
Institute for Health Metrics and Evaluation (IHME). Findings from the Global Burden of Disease Study 2017. Seattle, WA: IHME, 2018
Lancet 2018;392:1789

4. Association of OA and CVD-specific mortality: role of pain or function?
• Earlier studies on association knee OA and premature mortality conflicting data: difference in phenotype?
• Johnston County OA project: analyses in 4182 participants with nearly 15 year follow-up
Cleveland OAC 2019;27:593
Corsi BMC Musculoskeletal Disorders2018;19:393; Turkiewicz OAC doi.org/10.1016/j.joca.2019.02.793
• JoCo OA project substudy (n=1709): function and decrease of function seems most important
• Danish healthcare register (including 15.901/9347 doctor-diagnosed knee/hip) increased risk of
knee/hip OA for cardiovascular death during 9-11 years of follow-up

5. Role of sensitization in pain development in OA
• Who develop pain in knee OA?
• Pain Susceptibility Phenotype (incident persistent knee pain after 2 years) in MOST
K/L grade ≥2, BMI≥30,
≥comorbidity, education,
similar across classes
74% ♀
PP=Pressure Pain
PPT= PPThreshold
TS=Temporal summation
Carlesso AR 2019;542

6. Medication for pain control
NSAIDs long term use
• Systematic review with Bayesian
random effects network meta-analysis
• Placebo/active-controlled RCTs (n=31)
in knee OA
• ≥12 months follow-up
Leopoldino Cochrane Database Syst Rev 2019;2:CD013273; Gregori JAMA 2018;320:2564
Paracetamol
• Cochrane review (n=10 RCTs, 3541
knee/hip OA pts): paracetamol
minimal not-clinical relevant
improvement of pain or function
Minimal clinical
important
difference

7. Cardiovascular risk of diclofenac
• Danish registries 1996-2016
• Cardiovascular toxicity ≤30 days of start
• Diclofenac vs. naproxen vs. ibuprofen vs. PCM vs. no-use
• Propensity matching
• THIN: UK gp (>600) database
• Myocardial infarction; nested-case control
• Diclofenac vs. naproxen vs. other NSAID ≤180 days;
reference NSAID remote use (>360 days)
Bhala Lancet 2013; 382:769, Schmidt BMJ2018;362:k3426, Dubreuil ARD 2108;77:1137
Major Adverse
Cardiovascular Event
Incidence rate
ratio (95% CI)
Diclofenac vs no use
Diclofenac vs PCM
Diclofenac vs ibuprofen
Diclofenac vs naproxen
1.5 (1.4 to 1.7)
1.2 (1.1 to 1.3)
1.2 (1.1 to 1.3)
1.3 (1.1 to 1.5)

8. Intra-articular corticosteroids: ↑ risk on knee OA progression
• Comparison of Kellgren-Lawrence worsening between knees initiated i.a. corticosteroids versus
propensity-matched knees without
• OAI, 0 to 48 months visits
• Hazard ratio:
• i.a. corticosteroids initiation 3.02 (2.19-4.16)
• i.a. corticosteroids continuous 4.67 (2.92-7.47)
Zeng OAC doi.org/10.1016/j.joca.019.01.007
McAlindon JAMA 2017;317:1967

9. Glucocorticoid i.m.: efficacy on hip pain
• RCT, double-blind, placebo-controlled
• Placebo n=54, triamcinolone acetate 40 mg n=52
Mean(SE)
Dorleijn ARD 2018;77:875

10. Zeng JAMA 2019;321:969
• THIN database
• Tramadol, vs naproxen, diclofenac, celecoxib, etoricoxib, codeine
• All-cause mortality within 1 year after initiation
• Propensity matching
Association of tramadol with all-cause mortality among patients with OA

11. CNTX-4975 (trans-capsaicin) i.a.: efficacy on knee pain
• RCT, double-blind, placebo-controlled, phase 2 in painful radiographic knee OA
• Placebo n=69; CNTX-4975 0.5/1.0 mg n=33/70
Stevens AR ePub doi:10.1002/art.40894
• Safety: ≈placebo

12. Biologicals efficacious?
• Lutikizumab (anti-interleukin 1α/β inhibitor)
• RCTs, double-blind, placebo-controlled
• Inflammatory knee OA: placebo n=85, L n=262; Erosive hand OA: placebo n=67, L n=64
• Etanercept (TNFα inhibitor)
• RCT, double-blind, placebo-controlled
• Erosive inflammatory hand OA: placebo 45, E n=45
Fleischmann AR 2019; Kloppenburg ARD 2019;78:413; Kloppenburg ARD 2018;77;1757; Jin OAC 2018;26:1609
• Galcanezumab (Calcitonin Gene-Related Peptide inhibitor)
• RCT, double-blind, placebo/celecoxib controlled
• Knee OA: placebo n=76, G n=152, c n=39
• No efficacy on WOMAC pain after 8 weeks

13. Low-dose radiation therapy: no efficacy on knee/hand pain
• RCTs, double-blind, sham-controlled
• Painful knee OA:
Sham n=28, LDRT n=28
• Painful hand OA:
Sham n=28, LDRT n=28
OMERACT-OARSI responders
OMERACT-OARSI responders
Mahler ARD 2019;78:83; Minten OAC 2018;26:1283
• Safety: ≈ sham

14. How long does a hip or knee replacement lasts?
Total Hip Total Knee Unicondylar Knee
CPRD Case
series/
cohorts
Reg. CPRD Case
series/
cohorts
Reg. CPRD Case
series/
cohorts
Reg.
15 yrs 89% 86% 89%* 91% 96% 93%* - 86% 76%
20 yrs 81% 79% 70%** 86% 95% 90%** - 82% 72%**
25 yrs 78% 58%** 82%** - 72% 70%**
CPRD = Clinical Practice Research Datalink (UK )
* Finnish & Australian registries; ** Finish registries
Bayliss Lancet 2017;389:1424;
Evans Lancet 2019;393:647; Evans Lancet 2019;393:655; Wilson BMJ;364:1352

15. Thank you for your attention