Out Come Of  R
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Out Come Of R

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Out Come Of  R Out Come Of R Presentation Transcript

  • RA Outcomes King’s College Hospital
  • RA Outcomes
    • Damage
    • Disability
    • Death
  • Summary Of Presentation
    • “ Disease Activity” and Outcomes
    • Clinical measures
    • Combined measures
    • Functional measures
    • Radiological assessments
    • Mortality
  • Relationships of RA Outcomes Disability Pain Damage
  • Specific Factors Related to Poor Outcome in RA
    • Severe disease
      • many involved joints
      • RF positivity
      • high ESR/CRP
      • rheumatoid nodules
    • Additional factors
      • slow onset
      • late presentation
      • old age
      • female
      • many comorbidities
      • poverty
  • Disease Activity States
    • RA symptoms come and go
      • Depending on inflammation
    • When tissues are inflamed
      • RA is active
    • When tissue inflammation subsides
      • RA is inactive (in remission)
    • High disease activity
      • More drugs needed
    • Reduced disease activity
      • Treatment successful
    • Low disease activity
      • Treatment sufficient
    • Problems
    • Physicians vary
    • Patients vary
    • Physicians and patients disagree
  • Assessing Disease Activity
    • Core Data Set
    • Swollen joints
    • Tender joints
    • Pain
    • Global Assessment
    • ESR/CRP
    • HAQ
    • X-rays
    • Combining Data
    • ACR Responders
    • DAS
  • Treatment Goals With Anti-Rheumatic Drugs Inflammation Disability Radiographs Severity (arbitrary units) Duration of Disease (years) Early 0 5 10 15 20 25 30 © ACR Intermediate Late
    • Overall Aims
    • Reduce disease severity
    • Improve disability
    • Stop joint damage
    • Avoid major adverse events
  • Clinical Measures Swollen and Tender Joint Counts 28 Joint Index 66 Joint Index
  • Joint Counts in 503 RA patients Swollen Joints Tender Joints
  • Visual Analogue Pain Scores
    • Advantages
      • Simple
      • Understandable
      • Rapidly recorded
      • Conventional
    • Limitations
      • Irrelevant
      • Variable
      • Subjective
      • Inaccurate
    None Worst Assessment
  • VAS Scores And Laboratory Measures VAS Pain VAS Patient Global ESR
    • Patient measures on VAS differ from joint counts
    • They also differ from ESR and C-reactive protein
    • “ Flatter” distribution
  • Correlations of Clinical Measures
    • Tender Swollen Patient Pain
    • Joints Joints Global
    • ESR 0.14 0.25 0.24 0.21
    • Pain 0.47 0.36 0.83
    • Patient Global 0.48 0.34
    • Swollen joints 0.51
  • Combining Measures
    • Indices
    • 1977 Smyth - A pooled index
    • 1981 Mallya - Index of disease activity
    • 1990 Davis - Stoke index
    • 1990 Van der Heijde - Disease Activity Score
    • 1995 Symmons - Overall Status (OSRA)
    • 1995 Prevoo - Modified DAS (28-joint counts )
    • Response Criteria
    • American College of Rheumatology
    • Combine joint counts, patient/physician global assessments, pain, ESR and HAQ.
    • 20%, 50% or 70% responses
  • Changes in DAS with TNF From Professor Piet Van Riel
  • Listening to Patients Self-Assessment can replace clinician assessment
    • Patient-based disease activity score (PDAS)
      • Accurate
      • Reproducible
      • Valid
    • Equivalent to clinician assessments (DAS)
  • What is functional outcome? Disability and Health Status
    • Focus on subjective assessments
      • Questionnaires rather than direct measures
    • HAQ dominates
      • Good for groups, poor for individuals
      • Rarely used in routine practice
    • Many alternative health status measures
      • SF-36, Nottingham Health Profile, EuroQol
      • Some agreement, but important differences
      • Not interchangeable
  • Measuring Disability Measuring Instruments
    • Disease specific
      • Health Assessment Questionnaire (HAQ)
      • Arthritis Impact Measurement Scale (AIMS)
    • Generic
      • Medical Outcome Study SF-36
      • Nottingham Health Profile (NHP)
  • Health Assessment Questionnaire Fries Contribution to Rheumatology
  • Components of HAQ Scores Results in 103 RA patients
  • Progression of HAQ Scores Four Key Studies in Early RA Five Key Studies in Established RA
  • Annual Change in the HAQ 25 cases followed for 5 years in London 105 cases followed for 12 years in Holland 3 2 1 0 3 6 9 12 Disease Duration in Years HAQ Score
  • Annual Increase of HAQ in Routine Practice Graphical Report of 13 studies
  • Limitations of Conventional Assessments Physician-measurement gives high placebo response
    • 1817 patients in trials
    • Physician-measurement (swollen joints)
      • high effect sizes with placebo
    • Patient-measurement (HAQ)
      • Low effect sizes with placebo
    Scott and Strand, Rheumatology, 2002
  • Comparing HAQ with EuroQol Different distributions shown in 320 RA patients
  • Health Profiles in RA Nottingham Health Profile Nottingham Health Profile
  • Health Profiles in RA Nottingham Health Profile Nottingham Health Profile
  • HAQ scores over the course of RA Changing correlations with time Welsing et al, Arthritis Rheum, 2000
    • HAQ-DAS  
    •     Baseline 0.40
    •     6 years 0.79
    •     9 years -0.02
    • HAQ-Sharp Score  
    •     Baseline 0.15
    •     6 years 0.75
    •     9 years 0.57
    Increases Over 10 Years Changing Correlations HAQ Score Months
  • HAQ and DMARDs 12 Months data from leflunomide database (US 301) LEFLUN PL MTX 0.10 0.00 -0.10 -0.20 -0.30 Improvement 1 3 6 9 12 Change in HAQ score Months
  • HAQ And DMARDs 6 month individual changes in HAQ from leflunomide trial (MN 301)
  • HAQ and DMARDs All phase III leflunomide trials (ITT analysis)
  • HAQ and DMARDs Sustained changes in HAQ during 2 years leflunomide HAQ Scores MN 305 (60 cases) MN 304 (248 cases) US 301 (97 cases)
  • Steroid/DMARD combinations in Early RA ARC (Kirwan) and Cobra studies ARC Cobra
  • Steroid/DMARD combinations in Late RA Adding IM Depomedrone to DMARDs Choy et al, Ann Rheum Dis, 2005
    • 91 RA patients on DMARDs
      • Partial responders
    • Randomised to receive
      • IM Depomedrone
      • Placebo
    • Followed for 24 months
    • HAQ scores
      • Minor short term improvements with steroids
  • DMARD Combinations Adding leflunomide to Methotrexate Kremer et al, J Rheum, 2004
    • RA patients active despite adequate MTX therapy
    • 263 randomised patients
      • 6 month RCT
      • 6 month extension
    • First 6 months
      • Methotrexate/leflunomide
      • Methotrexate/Placebo
    • Second 6 months
      • Methotrexate/leflunomide
  • DMARD combinations in Early RA FinRA-Co and MTX/SZP ( Maillefert) studies FinRA-Co MTX/SZP
  • HAQ and Anti-TNF 3-year enbrel therapy in 671 patients Baumgartner et al, J Rheum, 2004 0 6 12 18 24 30 36 0.8 1.2 1.6 0.4 HAQ Scores Months Early Established
  • Anti-TNF and HAQ Systematic Review for NICE appraisal Moreland Wadjula Weinblatt Etanercept Attract Infliximab All trials -1.0 -0.5 0 0.5 1.0 Favours treatment Favours control
  • Comparative Changes in HAQ Leflunomide versus Anti-TNF
  • Percent Changes In HAQ RCTs for registration of new DMARDs/biologics After Vibeke Strand
  • Measuring Quality of Life Improves Assessments of Anti-TNF
    • 20 RA patients
    • Treated with infliximab
    • Assessed at 3 months
    • RA QoL shows improvements
    Treatment Baseline RAQol Score 30 20 10 0
  • Aggressive DMARD regimens Aggressive/Standard DMARDs Late RA BROSG Study Early DMARDs/pyramidal NSAIDs Early RA Utrecht Arthritis Cohort Study HAQ
  • Intensive versus routine treatment TICORA trial in early RA Grigor et al, Lancet, 2004
    • Single-blind RCT
      • 111 RA patients
      • in Glasgow
    • Randomised to receive:
      • intensive management
      • routine care
    • ITT analysis
      • HAQ secondary outcome
  • Explaining Relationships of HAQ Joint damage act as “regulator” Sets disability level in which day-to-day variation occurs Synovitis Joint damage Disability
  • Measuring Damage From normality to failed joints
  • Some X-ray Scoring Systems
    • Year Authors Main features
    • 1949 Steinbrocker 0-4 grading using standardised ARA criteria
    • 1961 ERC gold study Separate erosion/joint space narrowing scores
    • 1963 Kellgren Standard reference films
    • 1969 Berens & Lin Global scale from 0 to 5
    • 1971 Sharp Erosion/oint space narrowing scores for hands
    • 1976 Trentham & Masi Carpo-metacarpal ratio
    • 1977 Amos Counting new erosions in hands and wrists
    • 1977 Larsen Global score with standard reference films
    • 1983 Genant Erosion/joint space narrowing scores with standard X-rays
    • 1983 Bluhm Erosion/joint space narrowing scores with standard X-rays
    • 1985 Scott Erosion/joint space narrowing/malalignment/total scores
    • 1987 Kaye Erosion/joint space narrowing/malalignment/total scores
    • 1989 Van der Heijde Modified Sharp index including feet
  • Changes in Larsen Score in Early RA Average of two observers
    • Correlations
    • Initial Final Change
    • Pearson 0.87 0.93 0.70
    • Spearman 0.86 0.80 0.60
  • X-ray Progression Studies using Sharp and Larsen Scores Single Centre Cross-Sectional Study Longitudinal Studies From 8 centres
  • Correlating Damage With Disability 5 studies in early RA and 8 in late RA
    • Study Year Cases Dur’n Correl Signif
    • Eberhardt 1995 63 Early 0.27 NS
    • van Leeuwen 1994 149 Early 0.31 P<0.001
    • Plant 1997 89 Early 0.32 p<0.01
    • Uhlig 2000 238 Early 0.64 p<0.001
    • Welsing 2001 131 Early 0.06 NS
    • Kaarela 1993 103 Late 0.68 p<0.001
    • Larsen 1988 200 Late NA P<0.01
    • Regan Smith 1989 54 Late NS NS
    • Pincus 1989 259 Late 0.31 p<0.001
    • Hakala 1994 103 Late 0.46 P<0.001
    • Houssein 1997 126 Late 0.38 p<0.001
    • Drossaers-Bakker 2000 105 Late 0.60 p<0.001
    • Welsing 2001 39 Late 0.57 p<0.001
  • Large Joint Damage And Disability Effect on HAQ score after 12 years RA
    • Impact on Disability
    • Multivariate analysis
    • Disease Activity 36%
    • Large Joint Damage 16%
    • Psychological status 5%
    • Small joint damage 3%
    Drossaers-Bakker et al, Rheumatology, 2000
  • Digression on Steroids: Historical Perspective Major Breakthrough in RA Over 50 Years Ago Philip Hench Edward Kendall Tadeus Reichstein “ it is still too early to judge what role cortisone may play as a remedy for cases of rheumatoid arthritis” Nobel Prize: Medicine, 1950 Presentation Speech by Prof Liljestrand ACTH Case From First Clinical Paper On Steroids in RA 45 year old female with severe RA for 5 years
  • New Role in 1990’s Combined with DMARDs In Early RA to Prevent Erosions Approaches Constant Low Dose Tapering High Dose Kirwan, NEJM, 1995 van Everdingen Ann Intern Med 2002 Boers, Lancet, 1997
  • IM Depomedrone In Established RA RCT Comparing 2-Years Monthly Depomedrone with Placebo in patients on DMARDs
  • The Popert Regimen A Strong Belief in Combination Therapy
    • Beliefs
    • Prolonged inpatient care needed
    • Seek remission at all costs
    • Approach
    • Admit >6/52 each year
    • Start chloroquine
    • If insufficient
      • add gold
      • add>20mg steroids
      • add other DMARDs
    Highfield Hospital Patients’ Lounge
  • 20 Year Results At Droitwich
  • RA Mortality An Overview
    • RA reduces the length of life
    • 14 main studies since 1980
      • 13,424 patients
      • Mean SMR 1.8 (Range 0.87-3)
      • Life expectancy shortened by 5-10 years
    • Factors predictive of premature death same as those predicting disability
    Guedes et al, Rev Rhum, 1999
  • Cause-Specific Mortality RA Deaths In 20 Year Follow-up Study 9003 Scottish RA inpatients 1981-2000 Thomas et al, J Rheumatol, 2003
  • Cause-Specific Mortality RA SMR in 20 Year Follow-up Study 9003 Scottish RA inpatients 1981-2000 Thomas et al, J Rheumatol, 2003
  • Cardiovascular Mortality in Women RA 114 342 nurses without heart disease and RA in 1976 After 20 years: 527 had RA, 2296 had MIs and 1326 strokes Solomon et al, Circulation, 2003
  • Mortality and Vascular Deaths RA, OA and No Arthritis From UK GP Database Women Men Watson et al, J Rheumatol, 2003
  • Deaths From Ischaemic Heart Disease SMR in 4 Studies of RA Patients
  • Deaths in Early Polyarthritis 1236 patients in NOAR Goodson et al, Arthritis Rheum, 2002
  • Cardiovascular Events In RA Unexplained by usual risk factors in 236 cases
    • Predictor Rel Risk 95% CI
    • RA 3.17 1.33-6.36
    • Diabetes 2.28 1.65-3.12
    • Age 2.15 1.83-2.55
    • Sex 1.99 1.50-2.66
    • Cigarettes 1.37 1.01-1.83
    • Cholesterol 1.35 1.01-1.82
    • Blood pressure 1.18 1.03-1.33
    • Body mass index 1.13 0.99-1.28
    Del Rincón et al, Arthritis Rheum 2001
  • Cardiovascular Risk Factors Comparison of OA and RA Dessein et al, Arthritis Research, 2002
  • Alternative Assessment of Risk Factors in RA
  • Joint Swelling And Cardiovascular Deaths Prospective Study of 4120 Pima Indians Jacobsson et al, Arthritis Rheum, 2001 Joint swelling predicts CVD-related death Independent of other risks including diagnosis of RA Men Women
  • Predicting Mortality in RA 20 year study of 1381 Cases ESR Rheumatoid Factor Woolf et al, Arthritis Rheum, 2003 HAQ is another strong predictor
  • Mortality With DMARDs Risks compared to no DMARDs 1240 RA patients and 191 deaths Choi et al, Lancet, 2002
  • Deaths With Methotrexate Reduced CVS Mortality Choi et al, Lancet, 2002
  • Deprivation Predicts Death in RA Long Term Results from Glasgow
  • The patient's journey with RA Carol Simpson and Chloe Franks (patients) BMJ, October 2005
  • The patient's journey with RA Carol Simpson and Chloe Franks (patients) BMJ, October 2005
    • Bad News
    Good News
  • The patient's journey with RA Carol Simpson and Chloe Franks (patients) BMJ, October 2005
    • Bad News
    • Unsuccessful drug treatments are a major concern and reality for many patients
    • High level of uncertainty for each new drug used
    Good News Emergence of the new biological drugs has given new hope to people living with RA
  • Patient’s stories: Chloe
    • “ I have tried a variety of treatments, including all the anti-TNF medications. Unfortunately I have been extremely unlucky because they have not been effective or I have had an allergic reaction to them”
    • “ I have had very little or no remittance, which is very wearing both physically and emotionally”
  • Patients Stories: Carol
    • “ My drug treatment for RA has not been at all successful... frequently the effect of the medication has worn off after 2-3 weeks.”
    • “ My anger has not been towards the doctors but with myself. In my opinion the reactions to the medication are much worse than the disease itself.”
  • Strengths and Weaknesses in Clinics Qualitative Research at Kings
    • Good Features
    • Explained treatments
    • Showed tests
    • Offered choices
    • Good Features
    • Explained treatments
    • Showed tests
    • Offered choices
    • Problems
    • Conflicting messages
    • No explanations
    • Not listened to
    Strengths and Weaknesses in Clinics Qualitative Research at Kings
  • UK Standards of Care Arthritis and Musculoskeletal Alliance
    • People have rights to:
    • Access to appropriate services
    • Timely diagnosis and treatment
    • Information
    • Services centred on users’ needs
    • Independence
    • Self-determination
  • UK Standards of Care Arthritis and Musculoskeletal Alliance
    • Information and knowledge
    • Early diagnosis and treatment
    • Ongoing treatment and support
  • Key Components of ARMA Standards
    • Information and knowledge
      • Self-management guidance
      • When to seek advice
    • Early diagnosis and treatment
      • Early access to expert advice
      • Patient involvement in service development
    • Ongoing treatment and support
      • Multi-disciplinary teams
      • Regular specialist reviews
  • Supporting People with Long Term Conditions
    • Linked NHS Programmes
    • Disease management
      • Improving pathways and protocols
    • Case management
      • Patients with complex long term conditions
    • Self Care
      • Expert patients
  • Key Issue in UK Need for Early Treatment
    • Early access to specialist advice
      • Currently 3 months
      • Want under 6 weeks
    • Rationale
      • Early diagnosis
      • Effective treatment
  • Key Points
    • RA causes damage and disability
      • both increase by about 1%/year
    • Mortality is increased in RA
      • Average SMR 1.8, but not all studies show increase
      • Mortality worse in severe seropositive RA
    • Cardiovascular mortality also increased
      • Linked to high CRP, diabetes and steroids
      • Unclear if increased risk is due to RA or ill-health?