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Measures in RA: Joint counts, radiographs, laboratory tests, patient questionnaires - advantages and disadvantages

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Title: Measures in RA: Joint counts, radiographs, laboratory tests, patient questionnaires - advantages and disadvantages


1
Measures in RA Joint counts, radiographs,
laboratory tests, patient questionnaires -
advantages and disadvantages
tedpincus_at_gmail.com
2
Disclosures
  • Theodore Pincus, MD
  • Sources of Funding for Research Amgen Inc.
    Bristol-Myers Squibb Company
  • Consulting Agreements Abbott Laboratories Amgen
    Inc. Bristol-Myers Squibb Company UCB
  • Speakers Bureau/Honorarium Agreements Abbott
    Laboratories Wyeth Pharmaceuticals, Genentech
  • Financial Interests/Stock Ownership None
  • Discussion of Off-Label, Investigational, or
    Experimental Drug Use None

3
Its all about measurement
  • When you can measure what you are speaking
    about, and express it in numbers, you know
    something about it but when you cannot measure
    it and express it in numbers, your knowledge is
    of a meager and unsatisfactory kind.

Lord Kelvin quoted by Buchanan W, Smythe H.
J Rheumatol. 198296534.
4
Prevailing view of rheumatoid arthritis - 1984
  • Patients with rheumatoid arthritis usually
    respond to a conservative program of nonsteroidal
    anti-inflammatory drugs, rest, and physical
    therapy

Arthritis Rheumatism 271344,1984
5
  • Traditional approaches to clinical expertise
  • EMINENCE BASED MEDICINE - making the same
    mistakes with increasing confidence over an
    impressive number of years
  • ELOQUENCE BASED MEDICINE - a year-roundsuntan
    and brilliant oratory may overcome absence of
    any supporting data
  • ELEGANCE BASED MEDICINE - where the
    sartorialsplendor of a silk-suited sycophant
    substitutes for substance
  • The modern alternative?
  • EVIDENCE BASED MEDICINE - the best approach to
    clinical data - requires information from
    clinical observational data in addition to
    clinical trials
  • Pincus and Tugwell J Rheumatol 2006

6
Rheumatoid arthritis disappointing long-term
outcomes despite successful short-term clinical
trials T Pincus J Clin Epidemiol
41(11)1037-1041, 1988
7
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases J
Clin Epidemiol 411037,1988 Arthritis Rheum
48313, 2003
  1. Relatively short observation period
  2. Inclusion and exclusion criteria - most patients
    ineligible in most trials
  3. Surrogate markers - may be suboptimal for actual
    outcomes, e.g., T cell counts vs. AIDS, tender
    joints vs. surgical replacement
  4. Inflexible dosage schedules and concomitant drug
    therapies

8
Standard Composite Treatment Effect
Felson, Anderson, Meenan. Arthrit Rheum.
1990331449.
9
Estimated Continuation of Courses of 2nd Line
Therapies Over 60 Months in RA Patients
Azathioprine (56) Hydroxychloroquine
(228) Methotrexate (253) Oral gold
(84) Parenteral gold (269) Penicillamine (193)
Pincus, Marcum, Callahan. J Rheumatol.
1992191885.
10
RA Cohort 2-15 US sites 1985-90 Participating
Rheumatologists
  • A. Kennedy FL
  • R. Polk ID
  • J. Raitt CA
  • J. Reinertsen MN
  • E. Schned MN
  • J. Sergent TN
  • A. Whelton FL
  • F. Adams TN
  • J. Barber CA
  • W. Barth DC
  • M. Britton CA
  • G. Gordon PA
  • J. Huston TN
  • J.T. John TN
  • J. Johnson TN

11
Estimated Continuation of Courses of 2nd-Line
Therapy
All Courses Over 60 Months
Initial Course Over 12 Months
Methotrexate (61) Hydroxychloroquine
(130) Penicillamine (55) Parenteral gold
(207) Oral gold (5) Azathioprine (19)
Months
Pincus, Marcum, Callahan. J Rheumatol.
1992191885.
12
(No Transcript)
13
Severe functional declines, work disability, and
increased mortality rates in seventy-five
rheumatoid arthritis patients studied over nine
years T Pincus, LF Callahan, WG Sale, AL
Brooks, LE Payne, WK Vaughn Arthritis Rheum
27864-872, 1984
14
Rheumatoid Arthritis over 9 years changes in
functional status in activities of daily living
and morning stiffness 1973-1982
Morning Stiffness
Activities of daily living
1973
1982
1973
1982
0
100
30
90
60
80
90
70
120
60
150
50
180
40
210
30
240
20
270
10
300
0
Minutes
No Difficulty
Pincus et al. Arthritis Rheum. 198427864
J Rheumatol. 1992191051
15
Survival in rheumatoid arthritis 1973-1982
Pincus et al. Arthritis Rheum. 198427864. J
Rheumatol 198714240


16
Survival of Patients With Rheumatoid Arthritis
Versus Expected Survival in 10 Locales
17
Attributed Causes of Death in 2,262 RA Patients
in 13 Series from Diverse Locales Compared to
General Population
  • Attributed Cause of Death of RA Deaths
    of 1977 US DeathsCardiovascular
    disease 42.1 41.0Cancer 14.1 20.4Infection
    9.4 1.0Renal disease 7.8 1.1Pulmonary
    disease 7.2 3.9RA 5.3 lt1GI
    disease 4.2 2.4CNS disease 4.2
    9.6Accidents 1.0 5.4Miscellaneous
    6.4 15.2Unknown 0.6 lt1
  • Pincus T,
    Callahan LF. J Rheumatol. 198613841.

18
9- to 10-Year Survival According to Quantitative
Markers in Three Chronic Diseases
Rheumatoid Arthritis Activities of Daily Living
Rheumatoid Arthritis Formal Education Level
B
A
100
100
gt12 Years
gt90
80
8190
80
912 Years
Active With Ease
60
60
8 Years
Survival ()
Survival ()
40
40
7180
20
20
70
(Data from Pincus et al, 1987)
(Data from Pincus et al, 1987)
Months
Months
0
20
40
60
80
100
0
20
40
60
80
100
Hodgkin Disease Anatomic Stage
Coronary Artery Disease No. of Involved Vessels
C
D
100
100
Stage I
80
80
1 Artery
Stage II
60
60
Stage III
All Stages, All Causes
Survival ()
Survival ()
2 Arteries
Stage IV
40
40
3 Arteries
20
20
LCA
(Data from Kaplan, 1972)
(Data from Proudfit et al, 1978)
Years
Years
0
2
4
6
8
10
0
2
4
6
8
10
19
Why Include Quantitative Measurement in Care of
Patients with Rheumatic Diseases?
  • Assess Prognosis guides general approach to
    therapy
  • Treatment Decisions specific agents, changes
  • Documentation from visit to visit, compare
    patients
  • Reimbursement value of treatment by
    rheumatologist

20
Examples of measures that convey prognostic
significance
  • Blood pressure 220/140
  • Total cholesterol 528
  • Creatinine 20
  • Glucose 785
  • ESR 110
  • CCP gt100 units

21
Complexities in assessment of patients with
rheumatic diseases
  1. No single gold standard (eg, blood pressure,
    cholesterol) for clinical trials or standard
    care therefore, indices of 3-7 measures.
  2. Laboratory tests limited in both diagnosis and
    treatment - primary criteria are clinical.
  3. Patient questionnaires to assess physical
    function, pain, global status, often best
    quantitative measures.

22
American College of Rheumatology (ACR) Core Data
Set Disease Activity Score (DAS)
  • 3 Physician/Assessor measures
  • 1. Tender joint count (also in DAS)
  • 2. Swollen joint count (also in DAS)
  • Assessor Global status
  • 3 Patient self-report measures
  • 4. Physical Function - HAQ, HAQ II, MDHAQ
  • 5. Pain
  • 6. Patient Global status (also in DAS)
  • 1 Laboratory Measure
  • 7. Acute phase reactant ESR, CRPalso in DAS
  • (8. Radiograph longer than 1 year)

Felson et al, Arth Rheum 36729, 1993. van Riel,
Br J Rheumatol 31793, 1994.
23
Types of Measures to Assess RA
  • Joint count
  • Radiograph
  • Laboratory tests
  • Patient self-report questionnaires

24
Formal Joint Counts in Management of Patients
With RA
  • Most specific measure to assess RA
  • Most important measure in clinical trials 20,
    50, 70 required for ACR improvement criteria
  • 28-joint count as useful in clinical trials as
    6870 joint counts

25
Joints included in various standard joint counts
Joint 66/68 Joints Ritchie Index 44 Joints 36 Joints 28 Joints 42 Joints
Temporomandibular
Sternoclavicular
Acromioclavicular
Shoulder
Elbow
Wrist
MCP (-1)
Hand PIP
DIP
Hip
Knee
Ankle
Talocalcaneal
Tarsus
MTP
Foot DIP
26
A simplified twenty-eight-joint quantitative
articular index in rheumatoid arthritis HA
Fuchs, RH Brooks, LF Callahan, T
Pincus Arthritis Rheum 32531-537, 1989
27
Some Limitations of Formal Joint Counts
  • Joint counts have similar or lower relative
    efficiencies than global and patient measures to
    document differences between active and control
    treatments in clinical trials (Arthritis Rheum
    48625-630, 2003. Arthritis Rheum 521031-1036,
    2005. J Rheumatol 332146-2152, 2006,
    Rheumatology, in press)

28
Changes in ACR Core Data Set Measures Over 12
Months Leflunomide (LEF) vs Methotrexate (MTX)
vs Placebo (PBO)
Measure LEF PBO MTX Effect Relative Size
Efficiency Tender Jts -7.7 -3.0 -6.6 -0.59
1.00 Swollen Jts -5.7 -2.9 -5.4 -0.44
0.56 MD Global -2.8 -1.0 -2.4 -0.68
1.33 ESR -6.3 2.6 -6.5 -0.41 0.48 FN-
HAQ -0.45 0.03 -0.26 -0.80
1.84 FN-MHAQ -0.29 0.07 -0.15 -0.69
1.37 Pain -2.2 -0.4 -1.7 -0.65 1.21 Pt
Global -2.1 0.1 -1.5 -0.81 1.88
Strand V, et al. Arch Intl Med. 1999
1592542-2550 Tugwell P, et al. Arthritis
Rheum. 2000 43506-514.
29
Relative efficiencies of 7 ACR Core Data Set
measures in 4 adalimumab clinical trials a.
Arithmetic change
30
Some Limitations of Formal Joint Counts
  • Joint counts may improve over 5 years while
    progressive joint damage and functional
    disability may occur
  • (Callahan et al, Arthritis Care Res 10381-394,
    1997)

31
Changes in Measures in 100 Patients with
Rheumatoid Arthritis Over 5 Years Determined by
Effect Sizes
Tenderness
Swelling
Joint Count Measures
Pain on Motion
Deformity
Better
Limited Motion
Joint Space Narrowing
Radiographic Measures
Erosions
Worse
Malalignment
Erythrocyte Sedimentation Rate
Laboratory Measures
Rheumatoid Factor Titer
Hemoglobin
Clinical Measures
Morning Stiffness
Grip Strength
Walk Time
Button Time
Patient Questionnaire Measures
Functional Status - MHAQ
Global Status
Arthritis Care Res 10381,1997
Pain - Visual Analog Scale
Helplessness
-1.5
-1.3
-1.1
-0.9
-0.7
-0.5
-0.3
-0.1
0.1
0.3
0.5
Effect Size
32
Some Limitations of Formal Joint Counts
  • Joint counts are poorly reproducible
  • Lewis et al. Br J Rheumatol 1988 2732.
  • Hart et al. J Rheumatol 1985 12716.
  • Klinkhoff et al. J Rheumatol 1988 15492.
  • Thompson et al. J Rheumatol 1991 18661.
  • Kvien et al. Ann Rheum Dis 2005 641480.
  • Scott DL et al. 2006 15579.

33
Some Limitations of Formal Joint Counts
  • Rheumatologists perform careful non-quantitative
    joint examination, but not formal joint count, at
    most visits in usual care
  • (Pincus and Segurado, Ann Rheum Dis 65820-822,
    2006.)

34
Question for Rheumatologists
For patients with RA under your care (not
including patients in clinical trials), how often
do you perform formal tender and swollen joint
counts?
Never
13
124 of visits
32
2549 of visits
11
5074 of visits
14
7599 of visits
16
Always
14
35
Some Limitations of Formal Joint Counts
  • Relative efficiencies similar or lower than
    global and patient measures in clinical trials
  • May improve over 5 years while joint damage and
    functional disability may progress
  • Poorly reproducible
  • Not performed at most visits in usual care

36
Radiographs in Diagnosis and Management of
Patients With RA
  • Excellent quantitative scoring systems - Sharp,
    van der Heijde, Larsen, Genant
  • Erosions are closest to pathognomonic sign in RA
  • Reflect cumulative damage of disease

37
(No Transcript)
38
Radiographic and joint count findings of the hand
in rheumatoid arthritis related and unrelated
findings HA Fuchs, LF Callahan, JJ Kaye, RH
Brooks, EP Nance, T Pincus Arthritis Rheum
3144-51, 1988
39
TEMPO Trial Year 2 Radiograph Change in Total
Sharp Score from Baseline to Year 2
3.34 (CI 1.18, 5.50)
1.10 (CI 0.13, 2.07)
p lt 0.05, E vs MTX p lt 0.05, Combination vs
MTX p lt 0.05, Combination vs E
-0.56 (CI 1.05, -0.06)
40

Yazici Y, Yazici H, Arthritis Rheum 200654(supl)
41
Cross-Sectional Data in RA PatientsCohort 2-
1985 and Cohort 4-2000 Larsen X-Ray score, of
maximum 2000
1985
RF-
RF
Pincus, Sokka, Kautiainen, Arth Rheum 521009,
2005
42
Radiographs and joint counts in RA Related and
unrelated findings
Fuchs, Callahan, Kaye, Brooks, Nance, Pincus
Arthritis Rheum 3144, 1988
43
Associations of HLA-DR4 with rheumatoid factor
and radiographic severity in rheumatoid
arthritis. NJ Olsen, LF Callahan, RH Brooks,
EP Nance, JJ Kaye, P Stastny, T Pincus Am J
Med 84257-264, 1988
44
Strongly and Weakly Related Measures to Assess
RA
Radiographs ESR, CRP Shared epitope Rheumatoid
factor Joint deformity Duration of disease
Functional disability Pain Patient global Joint
swelling Joint tenderness Age
45
Predicting Mortality in RA Most Baseline
Measures Are Worse in Patients Who Will Die Over
a 5-Year Period
Mean Baseline Values
Dead
P Value
Alive
Age (years)
55.1 65.5 lt 0.001
ARA functional class
2.2 2.6 lt 0.001
1.1 2.1 lt 0.001
Number of comorbidities
10.8 16.8 lt 0.001
Walking time
33.8 48.3 0.004
ESR
1.98 2.32 0.005
mHAQ score
2.41 2.55 0.007
Learned helplessness
2.6 3.0 0.01
Global self-report
0.2 0.5 0.02
Number of extra-articular features
9.1 12.7 0.03
Duration of disease
10.8 9.4 0.03
Years of education
12.8 15.9 0.04
Joint count
1.2 1.4 0.20
Radiograph score
2.7 2.9 0.28
RF titer
5.40 5.19 0.68
Pain
Callahan LF, et al. Arthritis Care Res.
199710381394.
46
RA Cohort 2- Cox Proportional Hazards Model
Analyses Including Demographic, Functional,
Self-Report, Joint Count, X-ray, Laboratory and
Disease Variables in 206 patients
Univariate
Stepwise Model
RR (95 CL)
RR (95 CL)
P Value
P Value
1.07 lt0.001 1.06
lt0.001
Age
1.63 lt0.001 1.40
0.02
Comorbidity
2.00 0.003 1.76
0.02
MHAQ ADL Score
1.04 0.02 --
--
Disease duration
0.89 0.007 --
--
Education
1.01 0.005 --
--
ESR
1.02 0.10 --
--
Joint count
1.03 0.04 --
--
Walking time
1.40 0.17 --
--
X-ray
Arthritis Care Res 10381,1997
47
Predictors of mortality in RA n1922
  • Odds Ratio z score p value
  • HAQ 2.93 11.1 lt0.001
  • Pt Global severity 1.28 8.5 lt0.001
  • Pain 1.25 8.3 lt0.001
  • Depression 1.34 8.8 lt0.001
  • Anxiety 1.28 7.2 lt0.001
  • Grip strength 1.01 6.2 lt0.001
  • ESR 1.01 5.7 lt0.001
  • RF, titer 1.13 4.6 lt0.001
  • Hematocrit 1.06 3.8 lt0.001
  • Larsen X-ray score 1.04 4.7 0.002
  • Duration 1.01 2.1 0.036
  • Joint count 1.01 0.76 0.445
  • Age 1.09 11.9 lt0.001
  • Comorbidities 1.19 4.69 lt0.001
  • Male 2.10 5.28 lt0.001

Wolfe et al Arth Rheum 481530, 2003
48
The HAQ or MDHAQ, not a joint count, lab test or
X-ray, is Best Predictor in RA of
  • Functional status (Pincus et al. Arthritis Rheum.
    1984, Wolfe et al. J Rheumatol. 1991)
  • Work disability (Borg et al. J Rheumatol 1991,
    Callahan et al. J Clin Epidemiol. 1992, Wolfe and
    Hawley. J Rheumatol. 1998, Fex et al. J Rheumatol
    1998, Sokka et al. J Rheumatol 1999, Barrett et
    al. Rheumatology 2000, Puolakka et al. Ann Rheum
    Dis 64130-133, 2005 )
  • Costs (Lubeck et al. Arthritis Rheum. 1986)
  • Joint replacement surgery (Wolfe and Zwillich.
    Arthritis Rheum. 1998)
  • Death (Pincus et al. Arthritis Rheum. 1984, Ann
    Intern Med.1994, Wolfe et al. J Rheumatol 1988,
    LeighFries J Rheumatol 1991, Wolfe et al.
    Arthritis Rheum. 1994, Callahan et al. Arthrits
    Care Res 1996, 1997, Soderlin et al. J Rheumatol
    1998, Maiden et al. Ann Rheum Dis 1999, Sokka et
    al. Ann Rheum Dis 2004)

49
Some Problems With Radiographs in RA
  1. Quantitative score tedious to perform
  2. Treatment initiated prior to erosions MRI,
    ultrasound are more sensitive
  3. Radiographic damage has poor prognostic value for
    work disability, death and even joint replacement

50
Laboratory Tests in Diagnosis and Management of
Patients With RA
  1. Most important measure in most clinical
    situations, e.g., cholesterol, hemoglobin,
    creatinine, glucose, etc.
  2. Many tests may be of value CBC, ESR, CRP, RF,
    anti-CCP
  3. No work for the rheumatologist

51
ESR Values in Patients With RA
ESR 28 mm/h ESR lt 28 mm/h
Females 63 37
Males 55 45
Wolfe F, Michaud K, J Rheumatol.
19942112271237.
52
ESR and CRP at 1st Visit to Clinic
a. Jyvaskyla, FIN a. Jyvaskyla, FIN a. Jyvaskyla, FIN a. Jyvaskyla, FIN
CRP ESR ESR Total
28 mm/hr lt28 mm/hr
gt10 mg/L 775 (44) 202 (12) 977 (56)
lt10 mg/L 199 (11) 568 (33) 767 (44)
Total 974 (55) 770 (45) 1744 (100)
b. Nashville, TN, USA b. Nashville, TN, USA b. Nashville, TN, USA b. Nashville, TN, USA
CRP ESR ESR Total
28 mm/hr lt28 mm/hr
gt10 mg/L 48 (28) 22 (13) 70 (41)
lt10 mg/L 29 (17) 71 (42) 100 (59)
Total 77 (45) 93 (55) 170 (100)
Sokka and Pincus, EULAR 2006
53
The level of inflammation in rheumatoid arthritis
is determined early and remains stable over the
longterm course of the illness
F Wolfe, T Pincus J Rheumatol 281817-1824,
2001
54
Some Problems With Laboratory Tests in Diagnosis
and Management of RA
  1. ESR CRP - normal in 40 at presentation
  2. Anti-CCP RF - negative in 2050 of patients
  3. Treatment decisions are based primarily on
    clinical criteria
  4. Lab tests have good prognostic value for
    radiographic damage but poor prognostic value for
    work disability or death

CRP C-reactive protein CCP cyclic
citrullinated protein
55
Limitations of individual measures in RA need
for an index for patient assessment
ACR Core DAS28 CDAI
Tender joints v v v
Swollen joints v v v
MD global v - v
ESR or CRP v v --
Patient function v -- --
Patient pain v -- --
Patient global v v v
56
Disease Activity Score (DAS)in Rheumatoid
Arthritis
  • Based on score on visits with DMARD change
  • 0.56 X square root (tender joint count 28)
  • 0.28 X square root (swollen joint count 28)
  • 0.70 X log e (ESR)
  • 0.014 (patient assessment of global status or
    activity)
  • Total DAS 0-10

Van der Heijde et al, J Rheumatol
20579,1993, Prevoo et al, Arthritis Rheum 3844,
1995.
57
DAS28 Categories Activity Level Fransen and van
RielClin and Exp Rheumatol, 2005
Level Interpretation 02.6 Remission therapy
is working 2.63.19 Low maybe change
therapy 3.25.1 Moderate consider strongly
change in therapy 5.1110 High change
therapy or have a good reason not to do so
58
Some Limitations of DAS
  1. Requires complex math need calculator or
    website
  2. Requires laboratory tests often uninformative
    or unavailable
  3. Requires formal quantitative joint count often
    not done, poorly reliable

59
Clinical Disease Activity Index (CDAI)Aletaha
and Smolen Clin Exp Rheumatol 23S100, 2005.
  • No lab test or complex math
  • Can be calculated in usual care
  • Tender joint count 28 28
  • Swollen joint count 28 28
  • Patient global assessment 10
  • Patient global assessment 10
  • Total CDAI 0-76

60
CDAI Categories Activity Level Aletaha and
Smolen, 2005
Level Interpretation 02.8 Remission therapy
is working 2.8110 Low maybe change
therapy 10.122 Moderate consider strongly
change in therapy 2276 High change
therapy or have a good reason not to do so
61
CDAI Overcomes 2 of 3 Limitations of DAS
  1. No complex math
  2. No laboratory test
  3. But requires formal quantitative joint count

62
Is it possible to develop index to assess
patients with RA (and other rheumatic diseases)
that does not require a formal quantitative joint
count?
63
Limitations of individual measures in RA need
for an index for patient assessment
ACR DAS28 CDAI RAPID3
Tender joints v v v --
Swollen joints v v v --
MD global v - v --
ESR or CRP v v -- --
Patient function v -- -- v
Patient pain v -- -- v
Patient global v v v v
64
Multidimensional Health Assessment Questionnaire
Without ANY With SOME With MUCH UNABLE
Difficulty Difficulty Difficulty
To Do
AT THIS MOMENT, are you able to
Dress yourself, including tying shoelaces and doing buttons? Get in and out of bed? Lift a full cup or glass to your mouth? Walk outdoors on flat ground? Wash and dry your entire body? Bend down to pick up clothing from the floor? Turn regular faucets on and off? Get in and out of a car, bus, train or airplane? Walk two miles? Participate in sports and games as you would like? Get a good nights sleep? Deal with feelings of anxiety or being nervous? Deal with feelings of depression or feeling blue? ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ----










How much pain have you had because of your
condition IN THE PAST WEEK? Place a mark on the
line below to indicate how severe your pain has
been
PAIN AS BAD AS IT COULD BE
NO PAIN
? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? ? 0 0.5 1.0
1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
7.0 7.5 8.0 8.5 9.0 9.5 10
Considering all the ways in which your illness
and and health conditions may affect you at this
time, place a mark to show how you are doing
VERY WELL
VERY POORLY
? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? ? 0 0.5 1.0
1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
7.0 7.5 8.0 8.5 9.0 9.5 10
65
Routine Assessment of Patient Index Data (RAPID3)
Score3 Patient Core Data Set Measures on HAQ
and MDHAQ
  • Physical function 0-10
  • Pain 0-10
  • Patient global estimate 0-10
  • Total 0-30 divide by 3 0-10

66
9- to 10-Year Survival According to Quantitative
Markers in Three Chronic Diseases
Rheumatoid Arthritis Activities of Daily Living
Rheumatoid Arthritis Formal Education Level
B
A
100
100
gt12 Years
gt90
80
8190
80
912 Years
Active With Ease
60
60
8 Years
Survival ()
Survival ()
40
40
7180
20
20
70
(Data from Pincus et al, 1987)
(Data from Pincus et al, 1987)
Months
Months
0
20
40
60
80
100
0
20
40
60
80
100
Hodgkins Disease Anatomic Stage
Coronary Artery Disease of Involved Vessels
C
D
100
100
Stage I
80
80
1 Artery
Stage II
60
60
Stage III
All Stages, All Causes
Survival ()
Survival ()
2 Arteries
Stage IV
40
40
3 Arteries
20
20
LCA
(Data from Kaplan, 1972)
(Data from Proudfit et al, 1978)
Years
Years
0
2
4
6
8
10
0
2
4
6
8
10
67
Relative Risk of Death Over 12-15 Years in
rheumatoid arthritis (RA) and cardiovascular (CV)
disease according to baseline severity indicators
RA 75 pts 15 yrs Pincus et al, Ann Int Med
12026,1994 Functional status on patient
questionnaire lt vs gt 91.5 with ease 2.91
of Involved Joints gt vs lt 18 joints 3.01 CV
disease 312,000 pts 12 yrs Neaton et al,
Arch Int Med 15256,1992 Serum cholesterol gt245
vs lt182 mg/Dl 2.91 Systolic blood pressure gt142
vs lt118 mmHg 3.01 Diastolic blood pressure gt92
vs lt76 mmHg 2.91 Smoking gt26 vs 0
cigarettes/day 2.91 Data adjusted for age, sex,
education, disease duration
68
5-Year Survival in 206 Patients With RA Cohort 2
19851990
Rheumatoid Factor
MHAQ Score
100
100
80
80
60
60
Survival ()
Survival ()
0.00 (12)
Absent (29)
40
40
0.010.99 (91)
Present (175)
1.001.99 (86)
20
20
gt2.00 (21)
0
0
0
12
24
36
48
60
0
12
24
36
48
60
Months After Baseline
Months After Baseline
Callahan LF et al. Arthritis Care Res.
199710381-394.
69
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70
MDHAQPage 1
71
HAQ and Multidimensional HAQ (MDHAQ)
  • HAQ MDHAQ
  • 1st report 1980 1999
  • Patient completion 510 min 510 min
  • No. ADL 20 10
  • Pain VAS 10 cm line 21 circles
  • Pt Global VAS 10 cm line 21 circles
  • Psych, sleep No Sleep, anxiety,
    depressionRADAI self-report joint
    count No Yes
  • Fatigue No VAS
  • Review of systems No 60 symptoms
  • Medical history No Surgery, side
    effects
  • Demographic data No Yes
  • Social history No Yes
  • Scoring templates No Yes
  • Index No RAPID
  • MD scan (eyeball) 30 secs 5 secs
  • Time to score 40 secs 10 secs

72
HAQ anti-CCP 2 measures of RA
  • HAQ anti-CCP
  • 1st report 1980 1996
  • Advance Quantitate Recognize
  • physical RA in RF -
  • function patients
  • Related to
  • pathogenesis ----
  • Useful in diagnosis
  • abnormal in RA gt90 60-70
  • Monitor pt status
  • Predict work disability ?
  • Predict mortality ?
  • Cost appx 10 appx 100
  • of patients measured 20 80

73
A Practical System That (Almost) Works For
Routine Assessment of Functional Status, Fatigue
and Psychological Distress
  • 1. Patient given 2-page questionnaire by
    receptionist completed in waiting room
  • 2. Nurse (or physician) reviews and/or completes
    medication data
  • 3. Physician does as little as possible
    completes brief data (may include joint count)
  • 4. Office staff enters flow sheet with laboratory
    data

74
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75
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76
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77
Considering all the ways in which illness and
health conditions may affect you at this time,
please indicate below how you are doingVERY
? ? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? VERY WELL
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10
POORLYVERY ___________________________________
___________ VERYWELL POORLY
78
RADAI Self-Report Joint Count
Stucki G et al. Arthritis Rheum. 199538795-798.

79
Symptom Checklist From MDHAQ Please check (v)
if you have experienced any of the following over
the last month
__Lump in your throat Cough Shortness of
breath Wheezing Pain in the chest
Heart pounding (palpitations) Trouble
swallowing Heartburn or stomach gas
Stomach pain or cramps Nausea Vomiting
Constipation Diarrhea Dark or bloody
stools Problems with urination
Gynecologic (female) problems Dizziness
Loss of balance Muscle pain, aches, or
cramps Muscle weakness
__Paralysis of arms or legs Numbness or
tingling in arms/legs Fainting spells
Swelling of hands Swelling of ankles
Swelling in other joints Joint pain Back
pain Neck pain Use of drugs not sold in
stores Smoked cigarettes More than 2
alcoholic drinks/day Depression - feeling
blue Anxiety - feeling nervous Problems
with thinking Problems with memory
Problems with sleeping Sexual problems
Burning in sex organs Problems with social
activities
  • __Fever
  • Weight gain (gt10 lb)
  • Weight loss (lt10 lb)
  • Feeling sickly
  • Headaches
  • Unusual fatigue
  • Swollen glands
  • Loss of appetite
  • Skin rash or hives
  • Unusual bruising or bleeding
  • Other skin problems
  • Loss of hair
  • Dry eyes
  • Other eye problems
  • Problems with hearing
  • Ringing in the ears
  • Stuffy nose
  • Sores in the mouth
  • Dry mouth

80
Recent Medical History Self-report
  • Over the last 6 months have you had please check
    (v)
  • ?No ?Yes An operation
  • ?No ?Yes Inpatient hospitalization
  • ?No ?Yes A new illness, accident or trauma
  • ?No ?Yes An important new symptom
  • ?No ?Yes Side effect(s) of any drug
  • ?No ?Yes Cigarettes regularly
  • ?No ?Yes Change(s) of arthritis drugs or other
    drugs
  • ?No ?Yes Change of address
  • ?No ?Yes Change of marital status
  • ?No ?Yes Change of job or work duties, quit
    work, retired
  • ?No ?Yes Change of medical insurance,
    Medicare, etc.
  • ?No ?Yes Change of primary care or other
    doctor
  • Please explain any yes" answer below, or
    indicate any
  • other health matter that affects you
  • __________________________________________________
    _________

81
RA 61 yo M (9) Onset 01/1996 Visit 1
Visit Date 11/4/03
Function (0-3) 0.8
Pain (0-10) 9.6
Global (0-10) 8.9
ESR 43
Prednisone N3qd
Methotrexate N10qw
Folic Acid N1qd
Tylenol w/Codeine 30tid
Naproxen 880q6h
N new drug, C change in dose, T taper, D/C
discontinue
82
RA 61 yo M (9) Onset 01/1996 Visit 2
Visit Date 11/4/03 1/13/04
Function (0-3) 0.8 0
Pain (0-10) 9.6 0.3
Global (0-10) 8.9 0.3
ESR 43 8
Prednisone N3qd 1bid
Methotrexate N10qw C20qw
Folic Acid N1qd 1qd
Tylenol w/Codeine 30tid 30tid
Naproxen 880q6h 440bid
N new drug, C change in dose, T taper, D/C
discontinue
83
RA 61 yo M (9) Onset 01/1996 Visit 3
Visit Date 11/4/03 1/13/04 4/20/04
Function (0-3) 0.8 0 0.1
Pain (0-10) 9.6 0.3 0.2
Global (0-10) 8.9 0.3 0.3
ESR 43 8 13
Prednisone N3qd 1bid 1bid
Methotrexate N10qw C20qw 20qw
Folic Acid N1qd 1qd 1qd
Tylenol w/Codeine 30tid 30tid D/C
Naproxen 880q6h 440bid 440bid
N new drug, C change in dose, T taper, D/C
discontinue
84
RA 61 yo M (9) Onset 01/1996 Visit 4
Visit Date 11/4/03 1/13/04 4/20/04 9/28/04
Function (0-3) 0.8 0 0.1 0
Pain (0-10) 9.6 0.3 0.2 0.6
Global (0-10) 8.9 0.3 0.3 1.0
ESR 43 8 13 10
Prednisone N3qd 1bid 1bid C3bid
Methotrexate N10qw C20qw 20qw 15qw
Folic Acid N1qd 1qd 1qd 1 qd
Tylenol w/Codeine 30tid 30tid D/C
N new drug, C change in dose, T taper, D/C
discontinue
85
RA 61 yo M (9) Onset 01/1996 Visit 5
Visit Date 11/4/03 1/13/04 4/20/04 9/28/04 12/28/04
Function (0-3) 0.8 0 0.1 0 0
Pain (0-10) 9.6 0.3 0.2 0.6 6.0
Global (0-10) 8.9 0.3 0.3 1.0 5.5
ESR 43 8 13 10 14
Prednisone N3qd 1bid 1bid C3bid 3bid
Methotrexate N10qw C20qw 20qw 15qw C25qw
Folic Acid N1qd 1qd 1qd 1 qd 1qd
Tylenol w/Codeine 30tid 30tid D/C
Naproxen 880q6h 440bid 440bid 440bid 440bid
Adalimumab N40qow
N new drug, C change in dose, T taper, D/C
discontinue
86
RA 61 yo M (9) Onset 01/1996 Visit 10
Visit Date 11/4/03 1/13/04 4/20/04 9/28/04 12/28/04 12/20/05
Function (0-3) 0.8 0 0.1 0 0 0
Pain (0-10) 9.6 0.3 0.2 0.6 6.0 1
Global (0-10) 8.9 0.3 0.3 1.0 5.5 1
ESR 43 8 13 10 14 4
Prednisone N3qd 1bid 1bid C3bid 3bid T3bid
Methotrexate N10qw C20qw 20qw 15qw C25qw 15qw
Folic Acid N1qd 1qd 1qd 1 qd 1qd 1qd
Tylenol w/Codeine 30tid 30tid D/C
Naproxen 880q6h 440bid 440bid 440bid 440bid
Adalimumab N40qow 40qow
N new drug, C change in dose, T taper, D/C
discontinue
87
RAPID3 vs DAS in 285 RA Patients
  • Spearman
  • correlation
  • rho 0.657

88
RAPID3 vs CDAI in 285 RA Patients
  • Spearman
  • Correlation
  • rho 0.738

89
DAS28, CDAI and RAPID Categories
DAS Categories Fransen and van Riel,
2005 lt2.6 Remission 2.63.19 Low
Activity 3.25.1 Moderate Activity
gt5.1 High Activity CDAI Categories Aletaha
and Smolen, 2005 gt22 High
Activity 10.122.0 Moderate Activity 2.910.0
Low Activity lt2.8 Remission Proposed
RAPID Categories lt1.0 Near Remission therapy
is working 1.012 Low Severity maybe change
therapy 2.014.0 Moderate Severity consider
strongly change in therapy gt4.0 High
Severity change therapy or have a good
reason not to do so
90
DAS28 Compared to RAPID3 Scores in 285 Patients
at 3 Sites
DAS28 Activity RAPID 3 Severity RAPID 3 Severity RAPID 3 Severity RAPID 3 Severity RAPID 3 Severity
DAS28 Activity 4.110 High 2.14.0 Moderate 1.12.0Low 01.0Near Remission Total
gt5.1 High 37 (74) 11 (22) 1 (2) 1 (2) 50 (17)
3.25.1 Moderate 39 (43) 27 (30) 16 (18) 8 (9) 90 (32)
2.63.19 Low 4 (10) 15 (38) 10 (25) 11 (27) 40 (14)
02.6 Remission 10 (10) 18 (17) 24 (23) 53 (50) 105 (37)
Total 90 (31) 71 (25) 51 (18) 73 (26) 285
91
CDAI Compared to RAPID3 Scores in 285 Patients
at 3 Sites
CDAI Activity RAPID 3 Severity RAPID 3 Severity RAPID 3 Severity RAPID 3 Severity RAPID 3 Severity
CDAI Activity 4.110 High 2.14.0 Moderate 1.12.0 Low 01.0Near remission Total
gt22 High 39 (78) 9 (18) 1 (2) 1 (2) 50 (17)
10.122 Moderate 36 (40) 33 (36) 15 (17) 6 (7) 90 (32)
2.910 Low 15 (16) 28 (30) 25 (27) 25 (27) 93 (33)
02.8 Remission 0 (0) 1 (2) 10 (19) 41 (79) 52 (18)
Total 90 (31) 71 (25) 51 (18) 73 (26) 285
92
Changes in RAPID3 Scores Over 5 Years in RA
Patients in Usual Care 1996-2001
RAPID3 categories
37 33 17 13
29 25 27 18
36 25 18 21
30 30 12 28
53 30 13 3
High severity(gt4) Moderate severity(2.01-4) Low
severity(1.01-2) Near remission(?1)
Patients in Each RAPID3 Category ()
Baseline 6 mo 12 mo 24 mo 60 mo (N60)
(N60) (N55) (N56) (N43)
93
Self-report scores of all 60 new RA patients seen
between 1996-2001 6, 12, 24, and 60 months after
baseline
Mean values
? ? ? ? ? Baseline 6 mo 12 mo 24 mo
60 mo
94
Multidimensional Health Assessment Questionnaire
Without ANY With SOME With MUCH UNABLE
Difficulty Difficulty Difficulty
To Do
AT THIS MOMENT, are you able to
Dress yourself, including tying shoelaces and doing buttons? Get in and out of bed? Lift a full cup or glass to your mouth? Walk outdoors on flat ground? Wash and dry your entire body? Bend down to pick up clothing from the floor? Turn regular faucets on and off? Get in and out of a car, bus, train or airplane? Walk two miles? Participate in sports and games as you would like? Get a good nights sleep? Deal with feelings of anxiety or being nervous? Deal with feelings of depression or feeling blue? ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ----










How much pain have you had because of your
condition IN THE PAST WEEK? Place a mark on the
line below to indicate how severe your pain has
been
PAIN AS BAD AS IT COULD BE
NO PAIN
? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? ? 0 0.5 1.0
1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
7.0 7.5 8.0 8.5 9.0 9.5 10
Considering all the ways in which your illness
and and health conditions may affect you at this
time, place a mark to show how you are doing
VERY WELL
VERY POORLY
? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? ? 0 0.5 1.0
1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
7.0 7.5 8.0 8.5 9.0 9.5 10
95
RAPID (Routine Assessment of Patient Index Data)
Measures
Index RAPID 3 RAPID 4 PTJC RAPID 4 MDJC RAPID5
Physical Function v v v v
Pain v v v v
Patient Global Estimate v v v v
Patient Joint Count (RADAI) v v
MD/Assessor Joint Count v
MD/Assessor Global Estimate v
96
Spearman Correlation Coefficients in 274
Patients with RA All plt0.001() Number of
identical measures
Measure DASvs CDAI vs
CDAI 0.84 (3) ---
RAPID3 0.66 (1) 0.74 (1)
RAPID4PTJC 0.65 (1) 0.74 (1)
RAPID4MDJC 0.73 (3) 0.83 (3)
RAPID 5 0.69 (1) 0.80 (2)
All results, P lt0.001
97
DAS vs RAPID in AIM Abatacept Trial
RAPID 4-MD
RAPID 4-JC
RAPID2
RAPID3
RAPID5
DAS28
0
-10
-20
-21
Mean Change ( )
-25
-27
-30
-28
Control
-30
-32
Abatacept
-40
-43
-47
-50
-52
-54
-56
-60
-61
-70

Pincus , Maclean, Hines, Bergman, Yazici,. EULAR.
2007
98
Number of patients in remission at conclusion of
4 adalimumab trials according to DAS28, CDAI,
RAPID3, RAPID5
Pincus, Amara, Segurado, Bergman, Koch et al ACR
2007
99
Some limitations of patient self-report
questionnaires
  1. Need for translation language issues
  2. Cultural and linguistic issues
  3. Possibility of gaming by patient, health
    professional to provide desired responses
  4. Not specific to any disease

100
Can a Multi-Dimensional Health Assessment
Questionnaire (MDHAQ) and Routine Assessment of
Patient Index Data (RAPID) scores be informative
in patients with all rheumatic diseases? Pincus
T, Sokka T. Best Pract Res Clin Rheumatol.
200721733-753.
101
The MDHAQ in Clinical Rheumatology
  • In rheumatoid arthritis, the MDHAQ distinguishes
    MTX or LEF from placebo in a clinical trial as
    effectively as a joint count or the ACR 20
  • In osteoarthritis, the MDHAQ distinguishes NSAID
    from acetaminophen as effectively as the WOMAC
  • In fibromyalgia, the MDHAQ distinguishes
    patients from those with rheumatoid arthritis as
    effectively as an ESR

102
Pain/MHAQ Ratio in RA and Fibromyalgia
Callahan and Pincus. Arthritis and Rheumatism.
1990331317.
103
DNA Binding of Serums- SLE and Control Patients
100
Other Diseased controls SS Sjögrens
Syndrome SLE Unselected Patients
with SLE
90
80
70
DNA Bound
60
50
40
30
Value of 20 indicates abnormal binding activity
20
10
Pincus et al. NEJM. 1969281701.
0
Normal (84) Other (57) SS (24) SLE (44)
104
SLE 39 yo F Onset 09/2004 Education 12
Visit Date 15 Feb 05 17 May 05 19 Jul 05 20 Sep 05 23 May 06 26 Sep 06
Function (0-10) 4.3 0 0 0 0 0
Pain (0-10) 5.6 2 4 3.5 0.4 0.5
Global (0-10) 6.5 6 3 2 0.1 0.5
RAPID3 (0-30) 16.4 8 7 5.5 0.5 1
RAPID3 (0-10) 5.5 2.7 2.3 1.8 0.2 0.3
ESR 66 36 8 11 15
Ibuprofen 0-600 tid 600 tid
Prednisone N-5 qd C-10 qd T-5 qd 5 qd C-4 qd 4 qd
Solumedrol N-80
Mycophenolate mofetil N-500 bid 1000 bid 1000 bid 1000 bid 1000 bid
Hydroxychloroquine N-200 bid D-200 bid
Nnew drug Cchange in dose Ttaper
D/Cdiscontinue.
105
Quantitative Monitoring of a Patient With SLE
over 180 days ESR, anti-DNA, CH50
100
140
ESR (mm/hr)
Creat Clear(mL/min)
50
90
0
40
-
-
-
-
-
LE Prep


200
100
DNA Bound
CH50
100
50
0
0
50
Prednisone(mg/d)
0
20
40
60
80
100
120
140
160
180
Days
Pincus T et al. New Engl J Med. 1969281701-705.
106
Is it Better to Have 80 of the Information in
100 of Patients or 100 of the Information in 5
of Patients?
Pincus T, Wolfe F. J Rheumatol. 200532575-577.

107
Activities of Daily Living (ADL) in Prognosis of
Nonrheumatic Diseases
  • In congestive heart failure, ADL predicts
  • 36-mo mortality as ejection fraction
  • (Konstam. Am J Cardiol. 199678890)
  • In AIDS, ADL predict 36-month mortality as
    CD4/CD8 ratios, clinical AIDS prognostic staging
    (CAPS), severity classification for AIDS
    hospitalizations (SCAH)
  • (Justice. J Clin Epidemiol. 199649193)
  • In hospitalized elderly patients, ADL predict
    one-year mortality beyond physiologic data and
    comorbidities
  • (Covinsky. J Gen Intern Med. 199712203)

108
Requirements for clinic-based measurement tool
  • Valid
  • Reliable
  • Feasible easily completed by patient
  • Clinically useful amenable to simple review by
    MD prior to seeing patient
  • Acceptable to MD and patient
  • Amenable to charting on flow sheet
  • Saves time for patient and health professional to
    focus on major concerns of the patient
  • Recognize underappreciated disease severity and
    patient concerns

109
Patient Questionnaires in Clinical Research vs
Clinical Care
  • Clinical research Clinical care
  • Selected patients All patients
  • Long, many pages 1-page patient friendly,lt10
    min
  • Takes time for pt, staff Saves time for MD
  • Complex scoring Eyeball results
  • No scoring at visit Scoring templates for MD
  • Results unknown at visit Adds to clinical care
  • Send to data center Review with patient
  • Enter into computer Enter onto
    flowsheet document, improve care
  • Research agenda Quality improvement agenda

110
Prediction of premature mortality according to
blood pressure and cholesterol converted
hypertension and hypercholesterolemia from
optional treatments to major public health
campaigns.
111
Imagine doctors saying that they do not measure
blood pressure or cholesterol because it takes
too much time or the staff will not
cooperate, as suggested for why they do not
measure physical function.
112
Should Contemporary Rheumatology Clinical Trials
Be More Like Standard Patient Care and Vice Versa?
  • Pincus T, Sokka T.
  • Ann Rheum Dis.
  • 200463(Suppl II)ii32-ii39.

113
Should rheumatology health professionals keep
track of their patients with Gestalt impressions
or with quantitative data?
114
Patient self-report questionnaires
  1. Significant correlation with joint count, ESR,
    X-ray individual measures and indices
  2. More reproducible than jt count, lab, X-ray
  3. RAPID self-report index calculate in 10 secs vs
    90 secs for swollen/tender joint count
  4. HAQ and RAPID3 score as informative as
    ACR20/50/70 or DAS in clinical trials
  5. Predict work disability, costs, TJR, and
    premature death more significantly than
    traditional measures
  6. Saves time for patient and MD to focus on major
    patient matters including under-appreciated
    concerns
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