Patient questionnaires: Standardized quantitative “scientific” data from a

patient history, the primary source of rheumatology

treatment decisions Theodore Pincus MD

Clinical Professor of MedicineNew York University

tedpincus@gmail.com

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

Disclosures

Many, if not most, doctors have extensive information about their patients with a few mouse clicks concerning:

SchedulingBillingLaboratory testsMedications

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?

Many, if not most, doctors have extensive information about their patients with a few mouse clicks concerning:

SchedulingBillingLaboratory testsMedications

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?

Why measurement?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

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

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 3–7 measures

American College of Rheumatology (ACR) Core Data Set & Disease Activity Score (DAS)

3 Physician/Assessor measures1. Tender joint count (also in DAS)2. Swollen joint count (also in DAS)3. Assessor Global status

3 Patient self-report measures4. Physical Function - HAQ, HAQ II, MDHAQ5. Pain 6. Patient Global status (also in DAS)

1 Laboratory Measure7. Acute phase reactant –ESR, CRP–also in DAS(8. Radiograph – longer than 1 year)

Felson et al, Arth Rheum 36:729, 1993. van Riel, Br J Rheumatol 31:793, 1994.

Types of measures to assess patients with RA

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

Formal Joint Counts in Management of Patients With RA

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 68–70 joint count

Changes in ACR Core Data Set Measures Over 12 Months: Leflunomide (LEF) vs Methotrexate (MTX) vs Placebo (PBO)Changes in ACR Core Data Set Measures Over 12 Months: Leflunomide (LEF) vs Methotrexate (MTX) vs Placebo (PBO)

Strand V, et al. Arch Intl Med. 1999; 159:2542-2550; Tugwell P, et al. Arthritis Rheum. 2000; 43:506-514.

Measure: LEF PBO MTX Effect Relative Size Efficiency

Tender Jts -7.7 -3.0 -6.6 -0.59 1.00Swollen Jts -5.7 -2.9 -5.4 -0.44 0.56MD Global -2.8 -1.0 -2.4 -0.68 1.33ESR -6.3 +2.6 -6.5 -0.41 0.48FN- HAQ -0.45 +0.03 -0.26 -0.80 1.84FN-MHAQ -0.29 +0.07 -0.15 -0.69 1.37Pain -2.2 -0.4 -1.7 -0.65 1.21Pt Global -2.1 +0.1 -1.5 -0.81 1.88

13%

32%

11%

14%

16%

14%

Never

1–24% of visits

25–49% of visits

50–74% of visits

75–99% of visits

Always

For patients with RA under your care (not including patients in clinical trials), how often do you perform

formal tender and swollen joint counts?

Question for RheumatologistsQuestion for Rheumatologists

Time to Score RA Measures - Seconds

94

42

106

9.6 4.6

114

0

50

100

150

28 JointCount

HAQ-DI DAS28 CDAI RAPID3(0-10)

RAPID3(0-30)

Pincus et al 2009; Arthritis Care Res. in press

Some Limitations of Formal Joint Counts 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

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

Radiographs in Diagnosis and Management of Patients With RA

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

9- to 10-Year Survival According to Quantitative Markers in Three Chronic Diseases

Hodgkin Disease – Anatomic Stage

Years

20

40

60

80

100

0 2 4 6 8

Su

rviv

al (

%)

10

CStage I

Stage IIAll Stages, All Causes

Stage III

Stage IV

(Data from Kaplan, 1972)

20

40

60

80

100

0 20 40 60 80 100Months

8 Years

9–12 Years

>12 Years

B

Su

rviv

al (

%)

(Data from Pincus et al, 1987)

DCoronary Artery Disease – No. of Involved Vessels

Years

1 Artery

2 Arteries

3 ArteriesLCA20

40

60

80

100

0 2 4 6 8 10

Su

rviv

al (

%)

(Data from Proudfit et al, 1978)

A100

80

60

40

20

0 20 40 60 80 100

>90%

81%–90%

71%–80%

70%

Su

rviv

al (

%)

Months(Data from Pincus et al, 1987)

% Active “With Ease”

Rheumatoid Arthritis – Activities of Daily Living Rheumatoid Arthritis – Formal Education Level

TEMPO Trial: Year 2 Radiograph: Change in Total Sharp Score from

Baseline to Year 2

* p < 0.05, E vs MTX† p < 0.05, Combination vs MTX ‡ p < 0.05, Combination vs E

-1

0

1

2

3

4

5

6

7

8

Ch

an

ge

fro

m b

as

elin

e (

Me

an

+/-

SE

)

MTX = 206

E = 203

MTX+E = 2133.34

(CI 1.18, 5.50)

1.10* (CI 0.13, 2.07)

-0.56†‡ (CI –1.05, -0.06)

1 1.59 -0.54 0.52 2.8 0.4 3.7 1.3 3 5.70

50

100

150

200

250

300

350

400

450

ERA ETA ERA MTX TEMPOCombi

TEMPO ETA TEMPO MTX IFX Combi IFX MTX PREMIERCombi

PREMIERADA

PREMIERMTX

Yazıcı Y, Yazıcı H, Arthritis Rheum 2006;54(supl)

19

2 Year Change in Total Sharp/van der Heijde X-ray score (0–448): TEMPO probability plot

van der Heijde, et al. Arthritis Rheum 2006;54:1063–74.

TEMPO=Trial of Etanercept and MTX with radiographic Patient Outcomes.

Radiographs ESR, CRP

Shared epitopeRheumatoid factor

Joint deformityDuration of disease

Functional disabilityPainPatient global estimateSocioeconomic statusJoint tendernessAge

Strongly and Weakly Related Measures to Assess RA

Pincus T, Sokka T: Best Pract Res Clin Rheumatol 17:753-781, 2003.

Predicting Mortality in RA: Most Baseline Measures Are Worse in Patients Who Will

Die Over a 5-Year Period

Predicting Mortality in RA: Most Baseline Measures Are Worse in Patients Who Will

Die Over a 5-Year Period

Callahan LF, et al. Arthritis Care Res. 1997;10:381–394.

Mean Baseline Values Dead

Age (years) 55.1 65.5 < 0.001

P Value

ARA functional class 2.2 2.6 < 0.001Number of comorbidities 1.1 2.1 < 0.001

Walking time 10.8 16.8 < 0.001

ESR 33.8 48.3 0.004

mHAQ score 1.98 2.32 0.005

Learned helplessness 2.41 2.55 0.007

Global self-report 2.6 3.0 0.01

Number of extra-articular features 0.2 0.5 0.02

Duration of disease 9.1 12.7 0.03

Years of education 10.8 9.4 0.03

Joint count 12.8 15.9 0.04

Radiograph score 1.2 1.4 0.20

RF titer 2.7 2.9 0.28

Pain 5.40 5.19 0.68

Alive

RR (95% CL)

P Value

Age 1.07 <0.001 1.06 <0.001

RA Cohort #2- Cox Proportional Hazards Model Analyses Including Demographic, Functional, Self-Report, Joint Count, X-ray, Laboratory and Disease

Variables in 206 patients

P Value

Comorbidity 1.63 <0.001 1.40 0.02

MHAQ ADL Score 2.00 0.003 1.76 0.02

Disease duration 1.04 0.02 -- --

Education 0.89 0.007 -- --

ESR 1.01 0.005 -- --

Joint count 1.02 0.10 -- --

Walking time 1.03 0.04 -- --

X-ray

Univariate Stepwise Model

Arthritis Care Res 10:381,1997

1.40 0.17 -- --

RR (95% CL)

MRI can better identify early bone erosions than X-ray

Some Problems With Radiographs in RA

Some Problems With Radiographs in RA

1. Quantitative score tedious to perform

2. Treatment initiated prior to erosions – MRI, ultrasound more sensitive

3. Radiographic damage has poor prognostic value for work disability, death and even joint replacement

4. Treatment prior to erosions

Laboratory Tests in Diagnosis and Management of Patients With RA

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

"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,2006:85.

“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, 2005:1207

Textbook statements concerning ESR in RA

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

ESR Values in Patients With RA Wolfe F, Michaud K, J Rheumatol.

1994;21:1227–1237. Wichita KS, USA

ESR Values in Patients With RA Wolfe F, Michaud K, J Rheumatol.

1994;21:1227–1237. Wichita KS, USA

ESR ≥ 28 mm/h

ESR < 28 mm/h

Females 63% 37%

Males 55% 45%

Similar results have seen reported from:Nashville, TN USA Jyvaskyla, FinlandOslo, Norway Nancy, FranceGronigen, the Netherlands Belfast, Ireland

Location n ESR

Oslo,Norway 237 6 26

Nancy, France 135 9 29

Gronigen, Netherlands 283 8 28

Belfast, N Ireland 51 8 28

Mean ESR (mm/Hr) 4 Locations – 1996:

Smedstad LM, Moum T, Guillemin F,Kvien TK, Finch MB, Suurmeijer TPBM, Van Den Heuvel WJA Br J Rheumatol 1996; 35:746-51

ESR and CRP at 1st visit in US and Finland – 1980-2005

CRP ESR Total

≥28 mm/hr <28 mm/hr

Jyvaskyla, Finland n=1744

Total 55% 45% 100%

<10 mg/L 11% 33% 44%

>10 mg/L 44% 12% 56%

Nashville, Tennessee, USA n=170

Total 45% 55% 100%

<10 mg/L 17% 42% 59%

>10 mg/L 28% 13% 41%

Sokka and Pincus – J Rheumatol 2009

 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

Mean/median baseline ESR in RA patients in 23 studies, by first year of recruitment

Abelson B, Sokka T, Pincus T. J Rheumatol 2009

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 146:797-808, 2007

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 146:797-808, 2007

RR (95% CL)

P Value

Age 1.07 <0.001 1.06 <0.001

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

P Value

Comorbidity 1.63 <0.001 1.40 0.02

MHAQ ADL Score 2.00 0.003 1.76 0.02

Disease duration 1.04 0.02 -- --

Education 0.89 0.007 -- --

ESR 1.01 0.005 -- --

Joint count 1.02 0.10 -- --

Walking time 1.03 0.04 -- --

X-ray

Univariate Stepwise Model

Arthritis Care Res 10:381,1997

1.40 0.17 -- --

RR (95% CL)

5-Year Survival in 206 Patients With RA: Cohort #2 – 1985-1990

100100

8080

6060

4040

2020

0000 1212 2424 3636 4848 6060

Su

rviv

al (

%)

Su

rviv

al (

%)

Months After BaselineMonths After Baseline

Rheumatoid FactorRheumatoid Factor

Absent (29)Absent (29)

Present Present (175)(175)

100100

8080

6060

4040

2020

0000 1212 2424 3636 4848 6060

Su

rviv

al (

%)

Su

rviv

al (

%)

Months After BaselineMonths After Baseline

MHAQ ScoreMHAQ Score

0.00 (12)0.00 (12)0.01–0.99 (91)0.01–0.99 (91)1.00–1.99 (86)1.00–1.99 (86)>2.00 (21)>2.00 (21)

Arthritis Care Res 10:381,1997

IgM rheumatoid factor binding IgG

Multi-Dimensional

Health Assessment

Questionnaire (MDHAQ) Page 1

% of RA patients with abnormal measures at presentation: evidence,

not eminence-based

• RF positive - 69% (1)

• Anti-CCP positive - 67% (1)

• ESR >28 mm/Hr - 57% (2,3)

• CRP >10 - 58% (2)1- Nishimura et al, Ann Int Med 146:797-808, 20072 - Wolfe and Michaud, J Rheumatol 21:1227–1237, 19943 - Sokka and Pincus, J Rheumatol 36:1387--1390, 2009

Some Problems With Laboratory Tests in Diagnosis and Management of RA

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 20–50% 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

Patient self-report questionnairesPatient 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

9-10 Year Survival According to Quantitative Markers in Three Chronic Diseases

Hodgkin’s Disease -Hodgkin’s Disease -Anatomic StageAnatomic Stage

YearsYears

2020

4040

6060

8080

100100

00 22 44 66 88

Su

rviv

al (

%)

Su

rviv

al (

%)

1010

CC

Stage IStage I

Stage IIStage IIAll Stages, All Stages, All CausesAll Causes

Stage IIIStage IIIStage IVStage IV

(Data from Kaplan, 1972)(Data from Kaplan, 1972)

Formal Education LevelFormal Education Level

2020

4040

6060

8080

100100

00 2020 4040 6060 8080 100100 MonthsMonths

8 Years8 Years

9–12 Years9–12 Years

>12 Years>12 YearsBB

Su

rviv

al (

%)

Su

rviv

al (

%)

(Data from Pincus et al, 1987)(Data from Pincus et al, 1987)

DD Coronary Artery Disease -Coronary Artery Disease - # of Involved Vessels# of Involved Vessels

YearsYears

1 Artery1 Artery

2 Arteries2 Arteries

3 Arteries3 ArteriesLCALCA2020

4040

6060

8080

100100

00 22 44 66 88 1010

Su

rviv

al (

%)

Su

rviv

al (

%)

(Data from Proudfit et al, 1978)(Data from Proudfit et al, 1978)

Activities of Daily LivingActivities of Daily LivingAA100

80

60

40

20

0 20 40 60 80 100

>90%81–90%

71–80%

70%

Su

rviv

al

(%)

Months

(Data from Pincus et al, 1987)(Data from Pincus et al, 1987)

% Active “With Ease”% Active “With Ease”

Rheumatoid Arthritis -Rheumatoid Arthritis - Rheumatoid Arthritis -Rheumatoid Arthritis -

5-Year Survival in 206 Patients With RA: Cohort #2 – 1985-1990

100100

8080

6060

4040

2020

0000 1212 2424 3636 4848 6060

Su

rviv

al (

%)

Su

rviv

al (

%)

Months After BaselineMonths After Baseline

Rheumatoid FactorRheumatoid Factor

Absent (29)Absent (29)

Present Present (175)(175)

100100

8080

6060

4040

2020

0000 1212 2424 3636 4848 6060

Su

rviv

al (

%)

Su

rviv

al (

%)

Months After BaselineMonths After Baseline

MHAQ ScoreMHAQ Score

0.00 (12)0.00 (12)0.01–0.99 (91)0.01–0.99 (91)1.00–1.99 (86)1.00–1.99 (86)>2.00 (21)>2.00 (21)

Arthritis Care Res 10:381,1997

0%

25%

50%

75%

100%

Physicalfunction(N=18)

Handradio-graph(N=18)

Jointcount (N=18)

Rheum-atoidfactor(N=29)

ESR(N=19)

Extra-articulardisease(N=18)

Co-morbidities

(N=23)

Socio-economic

status(N=13)

22%

11%

28%

39%

50%

50%

37%

32%

32%

72%

6%

22%

65%

4%

30%

46%

31%

23%

45%

34%

21%

44%

17%

39%

Significant in multivariate analyses Significant in univariate analyses Not Significant

Significance of 8 variables as predictors of mortality in 53 RA cohorts

Sokka T, Abelson B, Pincus T. Clin Exp Rheumatol 26(suppl):S35-61, 2008

Prediction of premature mortality according to blood

pressure and cholesterol converted hypertension and hypercholesterolemia from

optional treatments to major public health campaigns.

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.

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

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 78:890, 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 49:193, 1996

• In hospitalized elder patients, ADL predict 1-year mortality beyond physiologic data and comorbidities Covinsky, J Gen Intern Med 12:203, 1997

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