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OA As A Serious Disease Sept 2018

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OA As A Serious Disease Sept 2018

  1. 1. The Burden of OA: Update on OA Epidemiology, Morbidity and Co-Morbidity Plenary Session 1: The OARSI White Paper Explained
  2. 2. Current Status: Development of Disease-Modifying Drugs for OA • Requires demonstration of an effect on ‘structural OA’ - ∆ joint space width on plain x-ray • Plain x-ray insensitive “like using stroke to diagnose hypertension”
  3. 3. Rationale for OARSI White Paper • 2014 FDA Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics outlined four programs to facilitate / expedite development & review of new drugs to address unmet need in Rx of serious or life- threatening conditions
  4. 4. Qualifying Criteria (Accelerated Approval) • The drug… • Treats a serious condition • Provides a meaningful advantage over available therapies • Demonstrates an effect on an intermediate clinical endpoint that is reasonably likely to predict clinical benefit
  5. 5. Current trials Future trials
  6. 6. A serious condition is one that is… • Associated with morbidity that has substantial impact on day-to-day functioning • Morbidity need not be irreversible if it is persistent or recurrent
  7. 7. OARSI White Paper • In-depth literature review & OA cohort analyses supporting the designation of OA as a serious disease • Submitted to the U.S. Food and Drug Administration December 1, 2016
  8. 8. Establishing that OA is a Serious Disease OARSI Plenary 2018
  9. 9. OA is Highly Prevalent Global Burden of Disease 2013 (GBD 2013) • 242 million with symptomatic hip/knee OA (3.8% population)(total burden unknown) • 2.3% men vs. 4.5% women • Higher in high income countries (4.9% men vs 9.15% women) & with increasing age
  10. 10. Prevalence of knee OA 1990 vs 2010 GBD 2010 Marita Cross et al. Ann Rheum Dis 2014;73:1323-1330 ©2014 by BMJ Publishing Group Ltd and European League Against Rheumatism Trends similar for hip OA Men Women 1990 2010
  11. 11. Prevalence of OA is Rising • Increasing prevalence of risk factors for OA
  12. 12. Obesity • GBD 2013: global all-age obesity increased by 26% from 2000 to 2013 • 2014: 39% of adults aged 18+ years overweight (> 1.9 billion adults) & 13% obese (>600 million people)
  13. 13. Physical Inactivity (muscle weakness) • Globally, insufficient physical activity in ≈23% adults aged 18+ in 2010 • 20% men & 27% women • Higher in high-income countries: 26% men & 35% women • Low physical activity increased 20% from 2000 to 2013
  14. 14. Joint Injury • Over past few decades, also an increase in participation in youth sports /recreational activity in all ages resulting in increased joint injury
  15. 15. Structural (the disease) Symptoms (the illness) Significant Burden: Disability Pain (aching, stiffness) Affect on sleep & mood Impact on function (ADLs, work & leisure activities)
  16. 16. Downstream Effects of OA Pain Fatigue Disability Depressed mood Controlling for patient age, sex, education, income, other health conditions, social support, coping; Hawker et al Arthritis Care Res 2011 pain PAIN sleep Participation restrictions Peripheral &/or central pain sensitization
  17. 17. People with OA avoid activities that exacerbate their symptoms • Qualitative studies: • Not offered other options • Desire to avoid “risky” pain killers • Other conditions prioritized as more important (patients, family, doctors) Sale JEM et al Arthritis Rheum 2006 Cheraghi-Sohi Arthritis Care & Res 2013
  18. 18. What is the contribution of hip/knee OA to reduced mobility?
  19. 19. 0 10 20 30 40 50 60 70 80 no health problems diabetes and heart disease 2 hips/knees with OA diabetes and heart disease and 2 hips/knees with OA Probability of self-reported difficulty walking (60-yr-old middle-income, normal weight woman) Lauren King et al, Arthritis Care & Res 2017
  20. 20. Potential consequences of reduced mobility due to OA
  21. 21. Osteoarthritis and comorbidity • Comorbidity (>2 conditions) is common (25% of adults in the US). • Between 59 and 87% of patients with OA have at least one other chronic condition, especially: CVD, DM and HT. • Patients with OA have on average 2.6 moderate-to-severe comorbidities1 • 31% of patients with OA have five or more other chronic conditions2 1 van Dijk GM; BMC Musculoskelet Disord 2008 2Kadam UT; Ann Rheum Dis 2004
  22. 22. • The presence of comorbidities in older adults with OA is associated with more pain, greater limitation in daily activities • Comorbidities may have significant impact on choice and tolerance of treatments for OA Osteoarthritis and comorbidity
  23. 23. Hypertension • Hypertension affects over 50% of adults over 55 in the US.1 • Hypertension is the most common comorbidity in OA: prevalence of 32 to 81% • Patients with OA have an increased risk compared to controls (75% vs 38%).2 • 24% of adults aged over 65 years in primary care have a combination of hypertension-OA • OA may limit exercise and weight loss required for treatment of hypertension. • Hypertension may limit treatment options for patients with knee OA (NSAID) 1 Mozaffarian D; circres.ahajournals.org; 2015 2 Puenpatom, R. A; Postgrad Med; 2009
  24. 24. Comorbidities: Cardiovascular Disease • CVD affects 1 in 3 American adults as the most common cause of death in the western world.1 • 61% of patients awaiting total knee replacement have CVD. • In primary care patients with hip and knee OA have twice the rate of CVD.2 • In people with established CVD, OA is associated with worse physical health and increased burden of symptoms • Several potential reasons for increased risk: common risk factors, functional limitations, medication. • Bi-directional impact on treatments 1Mozaffarian D; circres.ahajournals.org; 2015 2 Calvet J; Scand J Rheumatol; 2015
  25. 25. Diabetes Mellitus • Diabetes affects approximately 11% of adult Americans 1 • Up to 33% of patients with hip and knee OA.2 • Patients with OA have a 32% increased risk of developing diabetes over a 12 year period.3 • Shared risk factors: older age and obesity • Walking difficulty is an independent risk factor for developing diabetes.5 • OA may impair the ability to exercise and lose weight.4 1 Lipscombe, L; Lancet; 2007 2 Tuominen, U; Health Qual Life Outcomes; 2007 3 Rahman, M; Int J Rheumatol; 2014 4 Piva, S. R; Clin Geriatr Med; 2015 5 Hawker, G; Osteoarthr. Cartil; 2016
  26. 26. Obesity and metabolic syndrome • Obesity is a major contributor to other comorbidities and reduced life expectancy. • More than one third of adults in the US are obese.1 • Raised BMI (≥ 30) is present in 57% of patients with knee osteoarthritis.2 • Abdominal obesity (raised waist circumference) is present in 63% of patients with OA compared to 38% to controls.3 • Metabolic syndrome (obesity, diabetes, hypertension and dyslipidaemia) is increased in OA (59% vs 23%)4 1Choi EJ; J Korean Med Sci. 2015 2,3,4Puenpatom RA; Postgraduate medicine 2009
  27. 27. Other comorbidities • Depression affects 8% of the population ≥12 years of age in the US. • The prevalence of physician-reported depression ranges from 21% in patients awaiting total joint replacement81 to over 60% in patients with knee OA • Depression and pain commonly occur together due to a mutually reinforcing relationship. • Falls and fractures are a significant source of morbidity and mortality among older adults
  28. 28. Comorbidities: conclusion • There is an increased risk of comorbidities in patients with osteoarthritis • They effect treatment choices • May be associated with poor outcomes
  29. 29. New IPD Meta-analysis of Mortality in patients with OA Question: Are patients with OA at an increased risk of premature mortality? 1. Identify all available cohorts 2. OA defined symptomatic radiographic and symptomatic only 3. Identify and harmonise important variable 4. Agree standardised statistical analysis 5. Perform analysis in each cohort 6. Formal meta-analysis ROAD Johnston County TASOAC MOST Framingham Chingford Wuchan + Pain - Pain + ROA Pain+ ROA+ Pain- ROA+ - ROA Pain+ ROA- Pain- ROA-
  30. 30. Mortality in patients with symptomatic radiographic knee OA Kaplan-Meier plot for knee SROA in Johnston County cohort (truncated at 20 years follow up) Univariable SROA Forest Plot *The Framingham cohort was omitted from this analysis due to the very low number of subjects having the outcome of interest. [95% CI 1.52, 2.02]). The pooled estimate for the American subgroup of cohorts was HR 1.75 (95% CI 1.54, 2.03). (Figure 9). *The Framingham cohort was omitted from this analysis due to the very low number of subjects having the outcome of interest. Univariable Knee Symptomatic ROA and Mortality (Pain+/ROA+ vs Pain-/ROA-) Cohort Name Country N Follow-up Time Hazard Ratio (95% CI) % Weight Johnston County US 2361 23.7 1.75 (1.52, 2.02) 94.91 MOST US 1795 7.4 2.08 (1.12, 3.88) 5.09 Framingham* Subtotal (I-squared = 0.0%, p = 0.597) 1.77 (1.54, 2.03) 100.00 Note: Weights are from random effects analysis .2 .4 1 2 4
  31. 31. Mortality in patients with symptomatic radiographic knee OA Multivariable Knee Symptomatic ROA and Mortality (Pain+/ROA+ vs Pain-/ROA-) Cohort Name Country N Follow-up Time Hazard Ratio (95% CI) % Weight Johnston County US 2361 23.7 1.22 (1.05, 1.41) 94.91 MOST US 1795 7.4 1.53 (0.81, 2.89) 5.09 Framingham* Subtotal (I-squared = 0.0%, p = 0.491) 1.23 (1.07, 1.42) 100.00 Note: Weights are from random effects analysis .2 .4 1 2 4 *The Framingham cohort was omitted from this analysis due to the very low number of subjects having the outcome of interest. Multivariable SROA Forest Plot (adjusted for age, sex, and race)
  32. 32. Symptomatic hip OA Figure 3. Kaplan-Meier plot for hip pain in the Johnston County cohort (truncated years follow up) 3.3. Meta-analysis of Symptomatic Radiographic Knee Osteoarthritis (Pain vs Pain-/ROA-) This analysis compared subjects who had both pain and radiographic OA in the sam (Pain+/ROA+) at baseline against subjects who had no OA. It is important to note t control group contained participants who could have reported pain for up to 14 day month and therefore could have suffered from early/mild OA. The Framingham co not included in this analysis due to the very low number of subjects having the outc Johnston County Figure 9. Multivariable Hip Pain (regardless of ROA status) analysis adjusted for age, sex and race Figure 9. Multivariable Hip Pain (regardless of ROA status) analysis adjusted for age, sex and race Multivariable variable hip pain and mortality (adjusted for age, sex, and race) + Pain - Pain + ROA Pain+ ROA+ Pain- ROA+ - ROA Pain+ ROA- Pain- ROA-
  33. 33. Is SROA Knee associated with premature mortality?
  34. 34. Is Symptomatic Knee OA (ROA-ve) associated with premature mortality?
  35. 35. Mortality and Osteoarthritis Summary • Patients with knee and hip osteoarthritis have an increased risk of premature mortality. • This is not easily explained by the increase in comorbidity.
  36. 36. Progression Progression of OA knee over 48months according to Kellgren Lawrence scale Grade 3: multiple osteophytes, definite JSN, sclerosis, possible bony deformity Grade 4: large osteophytes, marked JSN, severe sclerosis and definite bony deformity In Table 10 below, incident radiographic OA is a person who was KL0/1 at baseline, and who is KL 2 or more by the 48 month follow-up. Progressive radiographic OA is anyone who was KL 2 or more at baseline, and who increased by 1 grade by the 48 month follow-up. Table 10: Progression of OA knee according to Kellgren Lawrence scale KL 0 N = 1342 KL 1 = 688 KL 2 = 1173 KL 3 = 787 KL 4= 289 Incident ROA 53 (3.7%) 112 (16.3%) - - - Progressive ROA - - 135 (11.5%) 137 (17.4%) - TKR (in first 72 months of OAI) 3 (0.2%) 5 (0.7%) 33 (2.8%) 87 (11.1%) 95 (32.9%) NB: These total numbers do not add up as data not available for all categories. Data from the OAI were also assessed to determine the proportion of people with knee OA who progress to total knee replacement (TKR) according to levels of obesity, a significant risk factor for knee OA. Tables 11 and 12 below demonstrate that progression to TKR over the 72 month period, increases with increasing BMI. With a BMI of 30+, 5.4% of males and 5.9% of females progress to TKR. Progression to TKR increases with both age and Data from the National Institutes of Health Osteoarthritis Initiative (OAI)137 has been assessed to determine rates of progression of radiographic knee OA. The Kellgren Lawrence (KL) scale is often used to classify the degree of deterioration of the joint. Kellgren-Lawrence grading scale for OA: Grade 0: normal Grade 1: doubtful joint space narrowing (JSN) and possible osteophytic lipping Grade 2: definite osteophytes and possible JSN on anteroposterior weight-bearing radiograph Grade 3: multiple osteophytes, definite JSN, sclerosis, possible bony deformity Grade 4: large osteophytes, marked JSN, severe sclerosis and definite bony deformity In Table 10 below, incident radiographic OA is a person who was KL0/1 at baseline, and who is KL 2 or more by the 48 month follow-up. Progressive radiographic OA is anyone who was KL 2 or more at baseline, and who increased by 1 grade by the 48 month follow-up. Table 10: Progression of OA knee according to Kellgren Lawrence scale
  37. 37. Predictors of progression A meta-analysis assessing patient characteristics that predict the progression of knee OA identified; • Baseline knee pain • Varus knee alignment • Heberden's nodes • Serum Hyaluronic acid and TNF-a A systematic review additionally identified: • Age • Presence of OA in multiple joints • Radiographic features • Body mass index for long-term progression (>3 years). • Moderate participation in physical activity was not associated with progression. Other variables had limited or conflicting evidence Bastick A 2015, Chapple C 2011
  38. 38. Impact of OA on Disability • OA accounts for 2.4% of all years lived with disability (YLD) • 1990 to 2013: 75% increase OA YLDs • Third most rapidly rising condition associate with disability after diabetes (135% increase) and dementia (84% increase)
  39. 39. Leading causes of global DALYs (both sexes combined) 0 5 10 15 20 25 30 35 IHD CVD COPD Back & Neck Depression Diabetes MSK (OA Knee) 1990 2005 2015 10/1/2018 Lancet 2016 Oct 8; 388(10053): 1603–1658 Rank (DALYs) 1 5 10 15 20 25 30
  40. 40. Economic Burden of OA • 2003 US: total costs attributable to arthritis/other rheumatic conditions ≈ $128 billion or 1.2% gross domestic product (GDP) • Direct costs $80.8 billion (i.e., medical expenditures) • Indirect costs $47.0 billion (i.e., lost earnings) • Arthritis accounts for ≈ 1 in 10 primary care visits; 58% of these for OA/joint pain • Compared to age/sex-matched peers, OA patients have higher out of pocket health-related expenditures
  41. 41. Economic Burden of OA Direct Costs Indirect Costs Intangible Costs Costs of surgery Hospital resources Caregiver time Pharmacological & non- pharmacological Rx Costs of side effects from treatments Research Lost productivity Premature mortality Disability payments & benefits Pain & suffering Reduced quality of life Potential depression & anxiety The Global Economic Cost of Osteoarthritis: How the UK Compares A. Chen,* C. Gupte, K. Akhtar, P. Smith, and J. Cobb Arthritis 2012
  42. 42. Impact of OA on Productivity • Costs due to lost productivity: • Absenteeism: days off work • Presenteeism: reduced self-reported productivity at work • US 2010-2012: • 3.8 million aged 18+ years with MD-diagnosed arthritis reported “unable to work now due to health condition” • 2.1 million reported “limited in kind or amount of work they can do”
  43. 43. Impact of OA on Productivity • Indirect costs due to lost productivity estimated at $3.4-$13.2 billion/year • Expected to increase
  44. 44. Economic Burden of OA Estibaliz Loza et al. Arthritis Care & Res 2009; S. Gupta et al. Rheumatology 2005 OA pain severity ≈ health care use, absenteeism & presenteeism, early retirement No cure – costs continue to accrue over time
  45. 45. Risk of TKR following clinical Knee OA diagnosis Prieto-Alhambra
  46. 46. Summary: OA is a Serious Condition • Substantial persistent morbidity (pain, fatigue, sleep disturbance, depression & disability) impacting day-to- day functioning • Major barrier to mobility (walking) & thus maintaining physical activity • No cure: joint replacement ≠ remission
  47. 47. Current treatment of Osteoarthritis • (nigel-Add newspaper article Strontium ranelate) • There is currently no cure for osteoarthritis. • There are no current licensed drugs with proven disease modifying activity.
  48. 48. Current therapies for OA • There are numerous non-pharmacologic and pharmacologic interventions for OA that reduce pain, improve function and quality of life among individuals with OA. • They have associated potential side effects and costs
  49. 49. Current therapies have limited effects • Common pharmaceutical treatments include: acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, topical NSAIDs, intra-articular corticosteroids and IA hyaluronic acid. • Most have only modest benefits on pain and function
  50. 50. Potential side effects of NSAIDs • Peptic ulcer disease is present in up to 25% of chronic NSAIDs users • Peptic ulcer bleeding and hospitalisation are increased 4.7 fold.1 • Associated with 100,000 admissions in the US annually, with 7-10,000 deaths. • NSAIDs, except naproxen, have an increased risk of cardiovascular death, rate ratios between 1.89 and 4.07.2 • Increased risk of chronic kidney disease of up to 32% depending of duration of use. 1Vos T; Lancet; 2012 2 Trelle S; BMJ 2011
  51. 51. Opioids and side effects Opioids are associated with • drowsiness, constipation, increased risk of falls. • an increased risk of all- cause mortality compared with non-steroidal.1 • Potential for abuse 1Solomon D; Arch Intern Med 2010
  52. 52. Joint replacement surgery • Up to 10% of subjects undergoing total hip replacement and 20% of total knee replacements are dissatisfied with their operation after a year. • Small risk of peri-operative mortality and complication. • Increasing risk of revision with decreasing age of surgery.
  53. 53. Summary • Osteoarthritis has now been accepted as a serious disease by the FDA. • This will allow access to the accelerated approval of drugs. White paper in production • A similar process will proceed with the EMA

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