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Patient questionnaire responses: a standardized, quantitative, “scientific” patient history to recognize effective and incomplete responses to prednisone, methotrexate and biological agents Theodore Pincus, MD Clinical Professor of Medicine New York University School of Medicine - PowerPoint PPT Presentation
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Patient questionnaire responses: a standardized, quantitative, “scientific” patient history to
recognize effective and incomplete responses to prednisone,
methotrexate and biological agents
Theodore Pincus, MDClinical Professor of Medicine
New York University School of [email protected]
Why is quantitative standardized measurement
advantageous in usual clinical care?
Quantitative measurement vs descriptive impressions
Quantitative measurement vs descriptive impressions
“It’s cold outside” – 35ºF or 10ºF?“My child has a fever” – 100ºF or 108ºF?“This wine is expensive”– $60 or $6000?
“The RA patient is better” – –DAS28 ↓ 4.2 or 2.4?–CDAI ↓ 16 or 5? –RAPID3 ↓ 10 or 4?
“Patients with rheumatoid arthritis usually respond to a conservative program of nonsteroidal anti-inflammatory drugs, rest, and physical therapy…”
Prevailing view of rheumatoid arthritis – 1984
Arthritis Rheum 1984;27:1344–1352.
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-round suntan and brilliant oratory may overcome absence of any supporting data
ELEGANCE BASED MEDICINE - where the sartorial splendor 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 trialsIsaacs and Fitzgerald, BMJ 319:1618, 1999,per G. Eknoyan, Baylor Coll Med
Clinicians may all too easily spend years writing “doing well” in the notes of a patient who has become progressively crippled before their eyes…
–Verna Wright
Smith T, et al. Br Med J 1983;287:569.
More accurate information in 1983?
Severe functional declines, work disability, and increased
mortality in seventy-five rheumatoid arthritis patients
studied over nine years
T Pincus, LF Callahan, WG Sale, AL Brooks, LE Payne, WK Vaughn
Arthritis Rheum 27:864-872, 1984
Rheumatoid Arthritis over 9 years – changes in functional status in activities of daily living and morning stiffness 1973-1982
Pincus et al. Arthritis Rheum. 1984;27:864; J Rheumatol. 1992;19:1051
1973 1982
Morning Stiffness
0
30
60
90
120
150
180
210
240
270
300
1973 1982
Activities of daily living
100
90
80
70
60
50
40
30
20
10
0
Minutes% No Difficulty
Survival in rheumatoid arthritis 1973-1982
Pincus et al. Arthritis Rheum. 1984;27:864.
RA U.S. 1977 U.S. 2005
No. of reports (cohorts) 50 (54) -- --Total no. of patients 91,618 -- --Total no. of deaths 33,250 -- --Cardiovascular 39.6% 41.0% 38.3%Cancer 16.8% 20.4% 22.8%Renal 5.8% 1.1% 1.8%Respiratory 9.0% 3.9% 5.3%Infection 14.3% 1.0% 4.4%Gastrointestinal 5.1% 2.4% 1.1%Accidents or intoxication 4.2% 5.4% 6.9%RA/musculoskel diseases 9.4% -- --Other 16.0% 24.8% 21.4%
Causes of death: RA patients in 50 published reports 1953–2008, vs U.S. general population
Sokka T, Abelson B, Pincus T. Clin Exp Rheumatol 26(suppl):S35-61, 2008
Survival of Patients With Rheumatoid Arthritis Versus Expected Survival in 10 Locales
Cobb et al, 1953Massachusetts
Years
200400600800
1000
Su
rviv
al
(No
.)
0 10 20 30
Expected for population
Patients with RA
Uddin et al, 1970Ontario
Years
Su
rviv
al
(%)
040
60
80
100
Expected for menWomen with RAMen with RA
0 2 4 6 8 10
Expected for women
Monson and Hall, 1976Massachusetts
Years
0
40
60
80
100
Su
rviv
al
(%)5 10 15 20
Women with OAMen with OA
25
Women with RAMen with RA
Allebeck et al, 1981Sweden
Years
Su
rviv
al
(%)
0
406080
100
Expected for womenExpected for menWomen with RAMen with RA
5 10
20
Rasker and Cosh, 1981England
Years
0
40
60
80100
Su
rviv
al
(%)
Patients with “definite” RAPatients with “classic” RA
4 12 20248 16
Vandenbroucke et al, 1984Netherlands
Years
Su
rviv
al
(%)
406080
100
Expected for womenWomen with RAMen with RA
5 10 15 20 25
200
Expected for men
Mutru et al, 1985Finland
Years
0
60
80
100
Su
rviv
al
(No
.)
Expected for womenExpected for men
2 4 6 8 10
Women with RAMen with RA
Mitchell et al, 1986Saskatchewan
Years
Su
rviv
al
(%)
0
406080
100
Expected for womenExpected for menWomen with RAMen with RA20
5 1510
Vollertsen et al, 1986Minnesota
0.200.400.600.801.00
Pro
ba
bil
ity
Expected forpopulationPatients with “classic” RA
04 8 12 1620
Years
Pincus et al, 1987Tennessee
Su
rviv
al
(%)
406080
100
Expected for womenExpected for menWomen with RAMen with RA
5 10
200
Years
9- to 10-Year Survival According to Quantitative Markers in Three Chronic Diseases
Hodgkin’s Disease – Anatomic Stage
Years
20
40
60
80
100
0 2 4 6 8
Su
rviv
al (
%)
10
C
Stage 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)
D Coronary Artery Disease – # 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)
A
100
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
Why are quantitative patient history data
needed for clinical care of patients with rheumatoid
arthritis?
Treat-to-target in hypetension or diabetes
Treat-to-target in hypetension or diabetes
“Treat-to-target” in hypertension and diabetes is based on single “gold standard” measure applicable to all patients
Patient history and physical exam are largely irrelevant to “treat-to-target”
Differences: hypertension, diabetes, hyperlipidemia vs
rheumatoid arthritis
Differences: hypertension, diabetes, hyperlipidemia vs
rheumatoid arthritis
Disease Biomarker Positive in1. Hypertension Blood pressure 100%
2. Diabetes mellitus Hgb A1c, glucose 100%
3. Hyperlipidemia Cholesterol, lipids 100%
4. Rheumatoid ESR, CRP, ACPA, arthritis rheumatoid factor 60-70%
Complexities in diagnosis and assessment of patients with rheumatic diseases
Complexities in diagnosis and assessment of patients with rheumatic diseases
No single ‘gold standard’ (e.g., blood pressure, cholesterol) for clinical trials or standard care
Laboratory tests limited in both diagnosis and treatment; primary criteria are clinical
Patient history and physical examination generally are more important in clinical decisions than lab tests
Therefore, indices of 3-7 measures to assess RA quantitatively – include history (pt questionnaire), physical exam, lab tests
RA Core Data Set – 7 or 8 measuresSource: MD
examX-ray
Lab Patient self-report
Tender joint count Swollen joint count Assessor Global estimate ESR or CRP Phys Function-HAQ,MDHAQ Pain Patient Global estimate Radiographic score if >1 yr
Felson et al, Arthritis Rheum 36:729, 1993.van Riel, Br J Rheumatol 31:793, 1994.
Measures in clinical trials and usual care
DiseaseBiomarkerMeasures
Measures in clinical
trials
Measures in usual
care
Hyper-tension
Blood pressure
Blood pressure
Blood pressure
Diabetes Glucose,HbA1c
Glucose,HbA1c
Glucose,HbA1c
Rheumatoid arthritis
RF, ACPA, ESR, CRP
Core Data Set, DAS28,
CDAI, RAPID3
RF, ACPA, ESR, CRP
Clinical Decisions SurveyPlease indicate your opinion of the importance of each of 5 sources: 1) vital signs, 2) patient history, 3) physical examination, 4) laboratory tests, 5) ancillary studies, to provide 0-20%, 21-40%, 41-60%, 61-80%, or 81-100% of information for diagnosis and management of:
1.hypertension2.diabetes mellitus3.rheumatoid arthritis 4.hypercholesterolemia 5.pulmonary fibrosis6.ulcerative colitis7.lymphoma8.congestive heart failure
Highest ranked source of clinical information 588 MDs:
Source
CongHeart
Failure
Dia-betes
MellitusHyper-tension
Hyper-lipid-emia
Lymph-oma
Pulmo-nary
Fibrosis RA
Ulcer-ative
Colitis
Vital Signs
97%
Patient History
69% 50%
Physical Exam
64% 68%
Lab tests
96% 98%
Ancillary studies
52% 73% 81% 80%
McCollum, Castrejon, Durusu-Tanriover, Pincus: EULAR 2010
>50%: 20-50%: <20%:
Standardized measurement required for the scientific method in medicine
• A patient with hypertension, diabetes, osteoporosis, etc. goes to the doctor to find out how she/he is doing, based on “gold-standard” measures by the doctor.
• A patient with RA goes to the doctor to tell the doctor how she/he is doing.
• Why not record the patient history as standard, “scientific” data?
Indices to assess patients with RACore set measure DAS28 1 CDAI 2 RAPID3 3
# Tender joints 0.56 sq rt (TJC28) 0-28 --
# Swollen joints 0.28sq rt (SJC28) 0-28 --
MD global -- 0-10 --ESR or CRP 0.70
ln (ESR) -- --Patient function -- -- 0-10Patient pain -- -- 0-10Patient global 0.014
PTGL 0-10 0-10TOTAL 0-10 0-76 0-30
1. Prevoo MLL, et al. Arthritis Rheum 1995;38:44-8.2. Aletaha D, Smolen J. Clin Exp Rheumatol 2005;23:S100-8.3. Pincus T, et al. J Rheumatol. 2008;35: 2136-47.DAS = Disease Activity Score, CDAI = Clinical Disease Activity Index.
Why aren’t laboratory tests the best quantitative measures to assess,
monitor and treat-to-target patients with rheumatoid
arthritis as in patients with diabetes or hyperlipidemia?
"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
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 been reported from:Nashville, TN, USA Jyvaskyla, FinlandOslo, Norway Nancy, FranceGroningen, The Netherlands Belfast, Ireland
Location Yr of
reportn
% ESR<28 mm/Hr
Mean Median
ESR (mm/h)
Wichita, KS, USA1 1994 1556 F37%,M45% 37F, 34M
Oslo, Norway2 1996 237 NA 26
Nancy, France2 1996 135 NA 29
Groningen, Netherlands2 1996 283 NA 28
Belfast, N Ireland2 1996 51 NA 28
Jyvaskyla, Finland 3 2009 1892 45% 30
Nashville, TN, USA3 2009 738 47% 30
ESR in 7 Locations 1994-2005
1- Wolfe and Michaud, J Rheumatol. 1994;21:1227–1237.2- Smedstad, Kvein, et al. Br J Rheumatol 1996;35:746-751.3- Sokka T, Kauitinen, Pincus. J Rheumatol. 2009;36(1):1387-1390.
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
% of RA patients with abnormal measures at presentation:
% of RA patients with abnormal measures at presentation:
ESR >28 mm/Hr - 57% CRP >10 - 58% Rheumatoid factor positive - 69% Anti-CCP positive - 67% Function score >2/10 - 70% Pain score >2/10 - 89%Wolfe F, et al. J Rheumatol. 1994;21:1227-37. Sokka T, et al. J Rheumatol. 2009;36:1387-90.Nishimura K, et al. Ann Intern Med. 2007;146:797-808.Pincus T, Swearingen CJ. Arthritis Rheum 2009;60(Suppl):S160
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)
Callahan LF et al. Arthritis Care Res 10:381,1997
Multi-Dimensional
Health Assessment
Questionnaire (MDHAQ) Page 1
Some Limitations of Laboratory Tests in RA
Some Limitations of Laboratory Tests in RA
1. Normal in 30-50% of patients who require treatment for RA
2. Often not available at time of clinical decision
3. Add to costs needed for therapy
Why isn’t a joint count the best
quantitative measure in RA?
Joint counts in RA Joint exam needed for diagnosis Joint count is the most specific measure of RA
status. The most specific measure may not be the most
informative measure. Poorly reproducible by different observers - must
be done by same observer – not GP, infusion, etc. Most likely to improve with placebo Rigorous formal joint count not performed at
most visits
Relative efficiencies of 7 Core Data Set measures and 3 Indices, DAS28, CDAI, and RAPID3, to distinguish patients treated with
infliximab vs control therapies in ATTRACT and ASPIRE clinical trials
Furer, Pincus, et al, EULAR 2009
RAPID3 versus DAS28 and CDAI in 285 RA patients
Spearman correlation rho = 0.657
Pincus T, et al. J Rheumatol. 2008; 35: 2136-47
Spearman correlation rho = 0.738
DAS28 CDAI
Pincus T, et al. Arthritis Care Res 2011; 63:1142–1149
Spearman’s correlations of RAPID3 scores with DAS28–ESR scores and CDAI scores at 52 weeks in
982 patients in the RAPID1 clinical trial of CZP vs PBO
p <0.001 for both correlations
DAS28, CDAI and RAPID3 Categories
Activity levelDAS28(0-10)
CDAI(0-76)
RAPID3(0-30)
High - change therapy or have a good reason not to
> 5.1 > 22 > 12
Moderate - strongly consider change 3.2-5.1 10.1-22 6.1-12
Low – change likely not needed 2.6-3.2 2.9-10 3.1-6
Near remission 2.6 2.8 3
Pincus T, et al. Rheum Dis Clin N Am. 2009;35:819-827.
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
Segurado and Pincus, 2006. Ann Rheum Dis 65:820-822.
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, Swearingen, Bergman, Colglazier, Kaell, Kunath, Siegel, Yazici Arthritis Care Res. 2010; 62:181-189. HAQ-DI = Health Assessment Questionnaire-Disability Index
A simplified twenty-eight joint quantitative articular
index in rheumatoid arthritis
HA Fuchs, RH Brooks, LF Callahan, T Pincus.
Arthritis Rheum 1989;32:531–537.
T Pincus
J Rheumatol. 33:834-837, 2006
The DAS is the most specific measure, but a patient questionnaire is the most informative
measure to assess rheumatoid arthritis.
Some approaches to overcome limitations of joint counts in RASome approaches to overcome limitations of joint counts in RA
1. All visits must include a careful joint examination, but not formal joint count
2. A RADAI self-report joint count may perform well to characterize joint involvement
3. Can a patient global score for inflammation, as well as damage, and neither (fibromyalgia/somatization), provide clinically useful quantitative data from a health professional?
RADAI Self-report Joint CountRADAI Self-report Joint Count
3. Please place a check (√) in the appropriate spot to indicate the amount of pain you are having today in each of the joint areas listed below: None Mild Moderate Severe None Mild Moderate Severe
a.LEFT FINGERS 0 1 2 3 i.RIGHT FINGERS 0 1 2 3 b.LEFT WRIST 0 1 2 3 j.RIGHT WRIST 0 1 2 3 c.LEFT ELBOW 0 1 2 3 k.RIGHT ELBOW 0 1 2 3 d.LEFT SHOULDER 0 1 2 3 l.RIGHT SHOULDER 0 1 2 3 e.LEFT HIP 0 1 2 3 m.RIGHT HIP 0 1 2 3 f.LEFT KNEE 0 1 2 3 n.RIGHT KNEE 0 1 2 3 g.LEFT ANKLE 0 1 2 3 o.RIGHT ANKLE 0 1 2 3 h.LEFT TOES 0 1 2 3 p.RIGHT TOES 0 1 2 3
q.NECK 0 1 2 3 r.BACK 0 1 2 3
Multi-Dimensional
Health Assessment
Questionnaire (MDHAQ) Page 1:
Foundation for “evidence-
based” visit
Multi-Dimensional
Health Assessment
Questionnaire (MDHAQ) Page 1:
Foundation for “evidence-
based” visit
RADAI vs Core Data Set measures (n=274)RADAI vs Core Data Set measures (n=274)RADAI SJC 28 TJC 28 ESR
RADAI --- 0.42 0.55 0.13*
Swollen 28 JC 0.42 --- 0.55 0.23
Tender 28 JC 0.55 0.55 --- 0.32
MDGlobal VAS 0.52 0.74 0.57 0.26
ESR 0.13* 0.23 0.32 ---
CRP 0.08*** 0.18** 0.21 0.50
FN MDHAQ 0.68 0.47 0.52 0.25
Pt Global VAS 0.69 0.36 0.53 0.21
Pain VAS 0.71 0.39 0.56 0.21
Adjusted for age, disease duration, education and center, All p<0.0001, except *p=0.035, **p=0.003, ***p>0.05
Four physician global estimates: 1.Overall, 2. Inflammation,
3. Damage, 4. Neither
The expertise of a rheumatologist is to determine whether a patient’s pain, fatigue, distress, etc. results from inflammation, damage or neither. Why not record scores?
Why isn’t a radiograph the best
quantitative measure in RA?
Radiographs in RA Only pathognomonic feature of RA Permanent record of patient status Excellent quantitative scoring methodsBut Poorly reproducible–several readers Not scored in usual care Less sensitive than ultrasound, MRI Limited prognostic significance for work
disability, mortality
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)
MTX and radiographic progression“When used as monotherapy, the structure-
sparing effects of MTX is quite modest compared with that of TNF blockers, even if MTX is used in DMARD-naïve patients.”
Schett et al. Arthritis Rheum 2008
“…studies of anti-TNF therapy plus MTX, compared with the effect with MTX alone, have shown that although MTX is relatively effective at relieving clinical symptoms, it has little or no effect on underlying radiological progression.”
Emery, McInnes, van Vollenhoven, Kraan. Rheumatology 2008
T Pincus, Y Yazici, MJ Bergman J Rheumatol. 35:1487-1488, 2008
More hotel-based medicine
Another form of “making the same mistakes with increasing confidence over an impressive number of years”
Change in Total Sharp/van der Heijde radiographic scores (0-448) in TEMPO trial over 2 years
Van der Heijde Arthritis Rheum 2006
Evidence from clinical trials and long-term observational studies that
disease-modifying anti-rheumatic drugs slow radiographic progression
in rheumatoid arthritis: updating a 1983 review
T Pincus, G Ferraccioli, T Sokka, A Larsen, R Rau, I Kushner, F Wolfe
Rheumatology 41:1346-1356, 2002
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)
MRI Can Better Identify Early Bone Erosions than X-ray
Prospective Observation of Predictors of Mortality Over 5 Years in 210 Consecutive
Patients with RA -1985-1990Mean baseline values: DeadAge yrs 55.1 65.5 <0.001
p Value
ARA Functional Class 2.2 2.6 <0.001# Comorbidities 1.1 2.1 <0.001
Walking time 10.8 16.8 <0.001
ESR 33.8 48.3 0.004
ADL score 1.98 2.32 0.005
Learned helplessness 2.41 2.55 0.007
Global self-report 2.6 3.0 0.01
# 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
Rheumatoid factor titer 2.7 2.9 0.28
Pain-Visual analog scale score 5.40 5.19 0.68
Alive
Callahan et al, Arthritis Care Res 10:381,1997
Prospective analysis of predictors of mortality over 5 years in 210 consecutive patients with RA: Cox proportional hazards model including demographic, disease, patient questionnaire,
laboratory, joint count, and X-ray variables
Callahan, et al Arthritis Care Res 10:381,1997
----0.171.40X-ray
----0.04 1.03*Walking time
----0.101.02Joint count
---- 0.005 1.01*ESR
---- 0.007 0.89*Education
----0.02 1.04*Disease duration
0.021.76* 0.002 2.00*MHAQ ADL score*
0.021.40*<0.001 1.63*Comorbidity
<0.0011.06*<0.001 1.07*Age
P ValueRelative RiskP ValueRelative Risk
Stepwise ModelUnivariable Models
MHAQ=Modified Health Assessment Questionnaire, ADL=Activities of Daily Living, *= Confidence Interval does not cross 1.00
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
Radiographs ESR, CRP
Shared epitope
Rheumatoid factorJoint deformity
Duration of disease
Functional disabilityPainPatient global
Joint tendernessFatigueAge
Strongly and weakly correlated measures to assess rheumatoid arthritis
ESR=erythrocyte sedimentation rate; CRP=C-reactive protein.
Sokka & Pincus Best Pract Res Clin Rheumatol 2007;21:653-661
Joint swelling
What about patient and physician global
measures as quantitative
measures in RA?
Relative efficiencies of 7 Core Data Set measures and 3 Indices, DAS28, CDAI, and RAPID3, to distinguish patients treated with
infliximab vs control therapies in ATTRACT and ASPIRE clinical trials
Furer, Pincus, et al, EULAR 2009
Relative efficiencies of 7 RA Core Data Set measures in 4 adalimumab clinical trials
Relative efficiencies of 7 RA Core Data Set measures in 4 adalimumab clinical trials
0.00
0.50
1.00
1.50
2.00
2.50
3.00
ARMADA DE011 DE019 STAR
Tender Joint CountSwollen Joint Count
Assessor GlobalCRP
Function (HAQ)Pain
Patient Global
Pincus, Amara, Segurado, Bergman, Koch, J Rheumatol 35:201-205, 2008
How to collect quantitative patient history data as
standardized “scientific data using the
MDHAQ/RAPID3?
Let the patient do most of the work! Most patients are more accurate about many details of their own medical history than health professionals
MDHAQ helps the patient prepare for a better visit
MDHAQ/RAPID3Advantages to patient
• Prepares patient for encounter
• Simple format for patient to communicate level of pain, fatigue, function, exercise, symptoms
• Quantitative data for any doctor – not restricted to specific rheumatologist
• “Benchmark” to compare to future visits
• Assures inclusion of important patient symptoms and recent medical history
Doctor reviews information with the patient,and interprets data for clinical decisions
MDHAQ/RAPID3Advantages to doctor
• Saves time – especially recent history, symptom review, self-report joint count
• Doctor is not measurer but interprets measures
• Specific doctor not required, unlike joint count
• Familiar, standard format for patient data
• Quantitative data for “treat to target” strategy
• Clues to possible fibromyalgia/distress
• MDHAQ – all key data on one page
• “Benchmark” to document future status
• “Checklist” documentation of patient status
MDHAQ/RAPID3:04 Nov 20033 RA Core Data Set scoresFN (0–10) = 2.7 PN (0–10) = 9.5PTGL (0–10) = 9.0
RAPID3 (0–30) = 21.2
Severity:12.1-30 = High6.1-12 = Moderate3.1-6 = Low0-3 = Near remission
2.7
9.5
9.0
21.2
RA 61 yo M (#9) Onset: 01/1996 Visit 1: 11/4/03
Visit Date 11/4/03
Q-Function (0-10) 2.7
Q-Pain (0-10) 9.6
Q-Global (0-10) 8.9
RAPID3 (0-30) 21.2
L-ESR 43
Prednisone N-3qd
T-Methotrexate N10qw
T-Folic Acid N1qd
T-Tylenol w/Codeine 30tid
T-Naproxen 880q6h
N = new drug, C = change in dose, T = taper, D/C = discontinue
MDHAQ/RAPID3:13 Jan 20043 RA Core Data Set scoresFN (0–10) = 0 PN (0–10) = 0.5PTGL (0–10) = 0.5
RAPID3 (0–30) = 1.0
Severity:12.1-30 = High6.1-12 = Moderate3.1-6 = Low0-3 = Near remission
0
0.5
0.5
1.0
Visit 2 - 4 Nov 2003
N = new drug, C = change in dose, T = taper, D/C = discontinue
Visit Date 4Nov03 13Jan04
Q-Function (0–10) 2.7 0
Q-Pain (0–10) 9.5 0.5
Q-Global (0–10) 9.0 0.5
RAPID3 (0–30) 21.2 1.0
L-ESR 43 8
T-Prednisone N3qd 3qd
T-Methotrexate N10qw C20qw
T-Folic acid N1qd 1qd
T-acetamnphn/codn 30tid 30tid
T-Naproxen 880q6h 440bid
Visit 4 - 28 Sep 2004
N = new drug, C = change in dose, T = taper, D/C = discontinue
Visit Date 4Nov03 13Jan04 20Apr04 28Sep04
Q-Function (0–10) 2.7 0 0.3 0
Q-Pain (0–10) 9.5 0.5 0.0 0.5
Q-Global (0–10) 9.0 0.5 0.5 1.0
RAPID3 (0–30) 21.2 1.0 0.8 1.5
L-ESR 43 8 13 10
T-Prednisone N3qd 3qd 3qd 3qd
T-Methotrexate N10qw C20qw 20qw 15qw
T-Folic acid N1qd 1qd 1qd 1qd
T-acetamnphn/codn 30tid 30tid D/C
T-Naproxen 880q6h 440bid prn prn
0
6.0
5.5
11.5
MDHAQ/RAPID3:28 Dec 20043 RA Core Data Set scoresFN (0–10) = 0 PN (0–10) = 6.0PTGL (0–10) = 5.5
RAPID3 (0–30) = 11.5
Severity:12.1-30 = High6.1-12 = Moderate3.1-6 = Low0-3 = Near remission
Visit 5: 28 Dec 2004
N=new drug, C=change in dose, T=taper, D/C=discontinue
Visit date 4Nov03 13Jan04 20Apr04 28Sep04 28Dec04
Q-Function (0–10) 2.7 0 0.3 0 0
Q-Pain (0–10) 9.5 0.5 0.0 0.5 6.0
Q-Global (0–10) 9.0 0.5 0.5 1.0 5.5
RAPID3 (0–30) 21.2 1.0 0.8 1.5 11.5
Tender Joint Count (0-28) 14 2 0 0 10
Swollen Joint Count (0-28) 12 1 0 0 8
MD Global (0-10) 8.0 1.0 0.5 0.5 6.5
CDAI (0-76) 43.0 4.5 1.0 1.5 30.0
L-ESR 43 8 13 10 14
T-Prednisone N3qd 3qd 3qd 3qd 3qd
T-Methotrexate N10qw C20qw 20qw 15qw C25qw
T-Folic acid N1qd 1qd 1qd 1qd 1qd
T-acetamnphn/Codn 30tid 30tid D/C
T-Naproxen 880q6h 440bid prn prn prn
T-Adalimumab N40qow
0
0
0.5
0.5
MDHAQ/RAPID3:8 Feb 20053 RA Core Data Set scoresFN (0–10) = 0 PN (0–10) = 0.0PTGL (0–10) = 0.5
RAPID3 (0–30) = 0.5
Severity:12.1-30 = High6.1-12 = Moderate3.1-6 = Low0-3 = Near remission
Visit 6: 8 Feb 2005Visit date 4No03 13Ja04 20Ap04 28Se04 28De04 8Fe05
Q-Function (0–10) 2.7 0 0.3 0 0 0Q-Pain (0–10) 9.5 0.5 0.0 0.5 6.0 0.0Q-Global (0–10) 9.0 0.5 0.5 1.0 5.5 0.5RAPID3 (0–30) 21.2 1.0 0.8 1.5 11.5 0.5
L-ESR 43 8 13 10 14 14T-Prednisone N3qd 3qd 3qd 3qd 3qd 3qd
T-Methotrexate N10qw C20qw 20qw 15qw C25qw C15qw
T-Folic acid N1qd 1qd 1qd 1qd 1qd 1qd
T-acetamnphn/codn 30tid 30tid D/C
T-Naproxen 880q6h 440bid prn prn prn D/C
T-Adalimumab N40qow 40qow
N=new drug, C=change in dose, T=taper, D/C=discontinue
Patients seen for standard rheumatoid arthritis care have significantly better articular, radiographic,
laboratory, and functional status in 2000 than in 1985
T Pincus, T Sokka, H Kautiainen
Arthritis Rheum 52:1009-1019, 2005
20001985
0 5 10 15Disease Duration (Years)
2.0
1.5
1.0
0.5
0.0
MH
AQ
Disease Duration (Years)
MH
AQ
2.0
1.5
1.0
0.5
0.020 0 5 10 15 20
Cross-Sectional Data: All RA Patients seen by TP in 1985 (n=125) and in 2000 (n=150):
Pincus, Sokka, Kautiainen, Arthritis Rheum 52:1009, 2005
Multidimensional Health Assessment Questionnaire (MDHAQ) scores
20001985
0 5 10 15Disease Duration (Years)
20
16
12
8
4
0
Sw
oll
en J
oin
t C
ou
nt
28
Disease Duration (Years)
Sw
oll
en J
oin
t C
ou
nt
28
20 0 5 10 15 20
20
16
12
8
4
0
Cross-Sectional Data: All RA Patients seen by TP in 1985 (n=125) and in 2000 (n=150):
Swollen Joint Count Scores
Pincus, Sokka, Kautiainen, Arthritis Rheum 52:1009, 2005
Cross-Sectional Data: All RA Patients seen by TP in 1985 (n=125) and in 2000 (n=150):
Larsen X-Ray score,% of Maximum
0
5
10
15
20
25
30
0 5 10 15
Disease duration
La
rso
n s
co
re f
or
ha
nd
s, %
of
ma
x
RF+
RF-
0
5
10
15
20
25
30
0 5 10 15
Disease duration
La
rso
n s
co
re f
or
ha
nd
s, %
of
ma
x
RF+
RF-
1985 2000
Pincus, Sokka, Kautiainen, Arthritis Rheum 52:1009, 2005
Methotrexate in RA Care: 1980-2005Jyvaskyla, Finland & Nashville, TN
Sokka and Pincus. Rheumatology (Oxford). 2008:47:1543-1547
Quantitative target values of predictors of mortality in
rheumatoid arthritis as possible goals for therapeutic interventions:
an alternative approach to remission or ACR20 responses?
T Pincus, T Sokka
J Rheumatol 28:1723-1734, 2001.
Larsen radiographic scores in 295 patients inJyväskylä, Finland, 5 years after presentation (dx),
according to the period of presentation
Sokka T, Pincus T. Rheumatology (Oxford) 2008; 47:1543-7
Patient functional status according to (a) MHAQ physical function score and (b) pain,
in 596 patients in Nashville, TN, USA at final visit, according to the period when last visit occurred
Sokka T, Pincus T. Rheumatology (Oxford) 2008; 47:1543-7
Methotrexate as the “anchor drug” for the treatment of early rheumatoid arthritis.
T Pincus, Y Yazici, T Sokka, D Aletaha, JS Smolen
Clin Exp Rheumatol 21:S179-S185, 2003.
Goodman and Gilman Textbook of Pharmacology, 2006 edition:
"Although aspirin is regarded as the standard against which other drugs should be compared for the treatment of rheumatoid arthritis, many clinicians favor the use of other NSAIDs perceived to have better gastrointestinal tolerability, even though this perception remains unproven by convincing clinical trials.
Patients with progressive or resistant disease require therapy with more toxic, second-line drugs, such as antimalarials, glucocorticoids, methotrexate, or immunosuppressive agents.
– (Section IV/Chapter 26, page 690)
Is weekly low-dose methotrexate one of the safest medications available in clinical medicine, far safer than (almost) all antibiotics, anti-depressants, statins, etc.?
T Pincus, TWJ Huizinga, Y Yazici
J Rheumatol. 34:250-252, 2007
Medication
All 4,363 patients in
15 countries
301 Danish patients
Prednisone Ever 66% 43%
Methotrexate Ever 83% 85%
Leflunomide Ever 21% 11%
Sulfasalazine Ever 43% 64%
Biological Agent Ever 23% 23%
QUEST-RA: Medications inQUEST-RA: Medications in4,363 patients in 15 countries4,363 patients in 15 countries
Sokka, Kautiainen, Toloza, Mäkinen, Verstappen, Lund, Hetland, et al. QUEST-RA: Ann Rheum Dis 66:1491-1496, 2007.
Mean and median initial prednisone dose in 308 patients with rheumatoid arthritis (RA) seen from 1980 through 2004, computed in 5-year periods
10.3
6.5
5.14.1
3.65 5 5
3 3
0
2
4
6
8
10
12
1980-84 1985-89 1990-94 1995-99 2000-04
Mean Median
1980-84N = 37
1985-89N = 74
1990-94N = 77
1995-99N = 61
2000-04N = 59
Init
ial
pre
dn
iso
ne
do
se (
mg
/day
)
Percent change () over 12 and 24 months in MDHAQ-FN (0-10) in 308 patients treated with prednisone 1980-2004
(“+” indicates improvement and “-” worsening)
YearFirst Seen N
Initial dose <5 mg/d Initial dose 5 mg/d
Baseline FN
12-mo
24-mo
Baseline FN
12-mo
24-mo
1980-84 37 None -- -- 4.1 +33% +32%
1985-89 74 1.4 -5% -20% 3.3 +45% +26%
1990-94 77 1.7 +26% +46% 3.2 +44% +38%
1995-99 61 2.7 +33% +14% 3.9 +27% +28%
2000-04 59 2.6 +37% +29% 4.3 +25% +33%
TOTAL 308 2.4 +34% +24% 3.5 +40% +31%
Editorial:Are long-term very low doses of
prednisone for patients with rheumatoid arthritis as helpful as
high doses are harmful?
T Pincus, T Sokka, CM Stein
Ann Internal Med 136:76-78, 2002
Clinical trial results in 31 participants who were randomized to prednisone or placebo, following gradual withdrawal of
prednisone, according to baseline prednisone dose
Baseline prednisone dose
Study group Clinical trial results 1 mg 2 mg 3 mg 4 mg Total
Prednisone Number randomized 1 2 10 2 15
Withdrew – lack of efficacy 0 0 3 0 3*
Completed trial 1 2 6 1 10*
Withdrew – administrative 0 0 1 1 2
Placebo Number randomized 0 1 12 3 16
Withdrew – lack of efficacy 0 1 9 1 11*
Completed trial 0 0 2 2 4*
Withdrew – administrative 0 0 1 0 1
TOTAL 1 3 22 5 31
*For 28 participants who either completed the trial or withdrew because of lack of efficacy, p = 0.021 For all 31 randomized participants, p= 0.032 by Fisher's exact test (prednisone vs placebo).
Pincus T, Luta G, Swearingen CJ. Ann Rheum Dis. 2009 ;68(11):1715-20.
Pincus T, Swearingen CJ. [Abstract #1627] Arthritis Rheum 2009;60(Suppl):S608. Presented at ACR, 2009.
Median Levels of All Patients at Initiation of MTX 1996-2001 and Mean of 2.6 Years Later in:
A. 63 “control” adequate responders continuing MTXB. 30 incomplete responders initiating biologic agent
63 Adequate Responders (“Controls”)
30 Incomplete Responders
MTX StartFollow-up
(NO Biologic) MTX StartBiologic
Start
ESR 24 16 28 18
MDHAQ-Function 2.3 1.0 3.2 3.3
Pain 4.1 1.4 5.2 6.8
Patient Global 4.2 0.9 5.5 5.5
RAPID3 10.6 3.6 14.9 16.2
MDHAQ/RAPID3 in Clinical Rheumatology• MDHAQ – not joint count, X-ray, or lab test – best predictor
of work disability, death in RA• RAPID3 distinguishes active treatment from placebo as
efficiently as DAS28, CDAI• Useful in all rheumatic diseases –
NSAID from acetaminophen in OA vs WOMAC fibromyalgia from RA vs ESR
• Identify incomplete response to Mtx, biologic• Completed before visit - prepares patient• RAPID3, recent history and review of systems save time for
doctor – improve documentation• Flow sheets are very helpful• Does not replace history and physical exam• Does not prevent joint count imaging, etc.