Patient questionnaires: Standardized quantitative

1
Patient questionnaires Standardized quantitative
scientific data from a patient history, the
primary source of rheumatology treatment
decisions
Theodore Pincus MD Clinical Professor of
Medicine New York University 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

• Many, if not most, doctors have extensive
  information about their patients with a few mouse
  clicks concerning
• Scheduling
• Billing
• Laboratory tests
• Medications
• BUT NOT Is the patient better, worse, or the
  same? With which treatments?
• Why not ask the patient in a structured,
  scientific format, ie, self-report
  questionnaire?

4
Why measurement?

• This wine is expensive
• 60 or 6,000
• The patient has a fever
• 101º or 106ºF, 38º or 40ºC
• The blood pressure is high
• 150/95 or 250/125
• The patient is doing well
• What is the DAS28, CDAI or RAPID3

5
Complexities in quantitative assessment of
patients with RA and rheumatic diseases

• Laboratory tests are limited in diagnosis and
  treatment decisions
• Treat radiograph before damage
• No single Gold Standard measure, eg, blood
  pressure, cholesterol, glucose, for diagnosis and
  management in all individual patients
• Therefore, need indices of 37 measures

6
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.
7
Types of measures to assess patients with RA

• Joint counts
• Radiographs
• Laboratory tests
• Patient questionnaires
• Global estimates

8
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
• Widely-accepted by rheumatologists and FDA as
  best measures
• 28-joint count as useful as 6870 joint count

9
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.
10
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
11
Time to Score RA Measures - Seconds
Pincus et al 2009 Arthritis Care Res. in press
12
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

13

• The most specific measure for diagnosis is not
  necessarily the most significant measure for
  prognosis and management.

14
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

15
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
16
(No Transcript)
17
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)
18

Yazici Y, Yazici H, Arthritis Rheum 200654(supl)
19
2 Year Change in Total Sharp/van der Heijde
X-ray score (0448) TEMPO probability plot
TEMPOTrial of Etanercept and MTX with
radiographic Patient Outcomes.
van der Heijde, et al. Arthritis Rheum
200654106374.
19
20
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
estimate Socioeconomic status Joint tenderness Age
Pincus T, Sokka T Best Pract Res Clin Rheumatol
17753-781, 2003.
21
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.
22
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
23
MRI can better identify early bone erosions than
X-ray
24
Some Problems With Radiographs in RA

• Quantitative score tedious to perform
• Treatment initiated prior to erosions MRI,
  ultrasound more sensitive
• Radiographic damage has poor prognostic value for
  work disability, death and even joint replacement
• Treatment prior to erosions

25
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

26
Textbook statements concerning ESR in RA

• "the erythrocyte sedimentation rate is increased
  in nearly all patients with active RA
• Lipsky PE. Rheumatoid arthritis. In Fauci AS,
  Langford CA, eds. Harrison's Medicine. New York
  McGraw-Hill,200685.
• at least 5 of patients with clinically active
  disease may have a normal ESR
• Chatham WW, Blackburn WD, Jr. Laboratory
  findings in rheumatoid arthritis. In Koopman
  WJ, Moreland LW, editors. Arthritis and allied
  conditions a textbook of rheumatology.
  Philadelphia, PA Lippincott, Williams
  Wilkins, 20051207

27

• 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

28
ESR Values in Patients With RA Wolfe F, Michaud
K, J Rheumatol. 19942112271237. Wichita KS, USA
ESR 28 mm/h ESR lt 28 mm/h
Females 63 37
Males 55 45
Similar results have seen reported
from Nashville, TN USA Jyvaskyla, Finland Oslo,
Norway Nancy, France Gronigen, the
Netherlands Belfast, Ireland
29
Mean ESR (mm/Hr) 4 Locations 1996
Location n ESR ESR
Oslo,Norway 237 6 26
Nancy, France 135 9 29
Gronigen, Netherlands 283 8 28
Belfast, N Ireland 51 8 28
Smedstad LM, Moum T, Guillemin F,Kvien TK, Finch
MB, Suurmeijer TPBM, Van Den Heuvel WJA
Br J Rheumatol 1996 35746-51
30
ESR and CRP at 1st visit in US and Finland
1980-2005
CRP ESR ESR Total
28 mm/hr lt28 mm/hr
Jyvaskyla, Finland n1744 Jyvaskyla, Finland n1744 Jyvaskyla, Finland n1744 Jyvaskyla, Finland n1744
Total 55 45 100
lt10 mg/L 11 33 44
gt10 mg/L 44 12 56
Nashville, Tennessee, USA n170 Nashville, Tennessee, USA n170 Nashville, Tennessee, USA n170 Nashville, Tennessee, USA n170
Total 45 55 100
lt10 mg/L 17 42 59
gt10 mg/L 28 13 41
Sokka and Pincus J Rheumatol 2009
31
Mean/median baseline ESR in RA patients in 23
studies, by first year of recruitment
 First year of recruitment Period of recruitment Median ESR (mm/h) Mean ESR (mm/h)
1954-1980 (7 studies) 1954-1995 47 50
1981-1984 (8 studies) 1981-1999 38 41
1985-1996 (8 studies) 1985-2000 36 35
Abelson B, Sokka T, Pincus T. J Rheumatol 2009
32
Meta-analysis Anti-cyclic citrullinated peptide
(CCP) antibody and rheumatoid factor (RF)
Anti-CCP RF
Number of studies 37 50
Positive likelihood ratio 12.5 4.9
Odds ratio for RA 16.1 39.0 1.2 8.7
Nishimura K et al. Annals of Internal Medicine
146797-808, 2007
33
Meta-analysis Anti-cyclic citrullinated peptide
(CCP) antibody and rheumatoid factor (RF)
Anti-CCP RF
Number of studies 37 50
Positive likelihood ratio 12.5 4.9
Odds ratio for RA 16.1 39.0 1.2 8.7
Sensitivity 67 69
Specificity 95 85
of Patients with negative test result 33 31
Nishimura K et al. Annals of Internal Medicine
146797-808, 2007
34
RA Cohort 2- Cox Proportional Hazards Model
Analyses Including Demographic, Functional,
Self-Report, Joint Count, X-ray, Laboratory and
Disease Variables in 206 patients 1985-1990
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
35
5-Year Survival in 206 Patients With RA Cohort
2 1985-1990
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
Arthritis Care Res 10381,1997
36
IgM rheumatoid factor binding IgG
37
Multi-Dimensional Health Assessment Questionnaire
(MDHAQ) Page 1

38
of RA patients with abnormal measures at
presentation evidence, not eminence-based

• RF positive - 69 (1)
• Anti-CCP positive - 67 (1)
• ESR gt28 mm/Hr - 57 (2,3)
• CRP gt10 - 58 (2)

1- Nishimura et al, Ann Int Med 146797-808,
2007 2 - Wolfe and Michaud, J Rheumatol
2112271237, 1994 3 - Sokka and Pincus, J
Rheumatol 361387--1390, 2009
39
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
40
Patient self-report questionnaires

1. HAQ and RAPID3 score as informative as
   ACR20/50/70 or DAS in clinical trials
2. Significant correlation with joint count, ESR,
   X-ray individual measures and indices
3. Predict work disability, costs, TJR, and
   premature death more significantly than
   traditional measures
4. Quantitative measures to save time for patient
   and MD to focus on major patient matters

41
9-10 Year Survival According to Quantitative
Markers in Three Chronic Diseases
Rheumatoid Arthritis -
Rheumatoid Arthritis -
Active With Ease
C
Hodgkins Disease - Anatomic Stage
100
Stage I
80
Stage II
60
Survival ()
All Stages, All Causes
Stage III
40
Stage IV
20
(Data from Kaplan, 1972)
Years
0
2
4
6
8
10
42
5-Year Survival in 206 Patients With RA Cohort
2 1985-1990
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
Arthritis Care Res 10381,1997
43
Significance of 8 variables as predictors of
mortality in 53 RA cohorts
4
39
50
32
6
23
34
17
22
30
50
32
46
21
39
28
22
11
37
72
65
31
45
44
Physicalfunction (N18)
Hand radio- graph (N18)
Jointcount (N18)
Rheum-atoid factor (N29)
ESR (N19)
Extra- articular disease (N18)
Co- morbidities (N23)
Socio- economic status (N13)
Sokka T, Abelson B, Pincus T. Clin Exp Rheumatol
26(suppl)S35-61, 2008
44
Prediction of premature mortality according to
blood pressure and cholesterol converted
hypertension and hypercholesterolemia from
optional treatments to major public health
campaigns.
45
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.
46
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

47
Physical function/activities of daily living
(ADL) in prognosis of non-Rheumatic Diseases

• In congestive heart failure, ADL predict 36-month
  mortality as ejection fraction Konstam, Am J
  Cardiology 78890, 1996
• 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
  Epidemiology 49193, 1996
• In hospitalized elder patients, ADL predict
  1-year mortality beyond physiologic data and
  comorbidities Covinsky, J Gen Intern Med 12203,
  1997

48
Some limitations of patient self-report
questionnaires

• Need for translation
• Cultural and linguistic issues
• Possibility of gaming by patient, health
  professional to provide desired responses
• Not specific to any disease