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Evidence beyond clinical trials in routine clinical care from MDHAQ and RAPID3: why and how?

Part 1 – Limitations of clinical trials Part 2 – Residual “eminence-based” medicine in 2008 despite “evidence based” medicine from clinical care Part 3 – Action plan – consecutive MDHAQ database in usual clinical care T Pincus M.D. [email protected]

Disclosures

Grants: Speaker: Advisory Board: Amgen Abbott Bristol-Meyers-Squibb Centocor UCB Abbott Centocor Bristol-Meyers-Squibb Centocor UCB

Conference on Outcome Measures in Rheumatological Clinical Trials, McMaster University, Hamilton, Ontario, Canada, December 7–8, 1981

It’s 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. 1982:9;653 –4.

Examples of advantages of quantitative measurement

  

It’s hot outside – 75 ºF or 95ºF , or 25ºC or 35ºC This wine is expensive – $60 or $6,000 The pulse is rapid –



110 or 180 per minute The RA patient is “doing well” – DAS28: 3.6 or 2.6

CDAI: 18 or 10 RAPID3: 9 or 3 (0-30), 3 or 1 (0-10)

Outcome Measures in Rheumatic Clinical trials

–

McMaster University, Hamilton, Ontario, Dec 7-8, 1981 Clinical Research Methodology Course – NYU Hospital for Joint Disease, New York Dec 11, 2008

Evidence beyond clinical trials in routine clinical care from MDHAQ and RAPID3: why and how?

Pincus and Tugwell: Editorial The Journal of Rheumatology 2007; 34 :1

Journal of Rheumatology 34:1, 2007

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 trials Pincus and Tugwell, J Rheumatol 34: 1-4, 2007

Evidence-based medicine: 1995 N Engl J Med 333:137-141, 1995

T Pincus, Y Yazici, MJ Bergman J Rheumatol. 35:1487-1488, 2008

Eminence based medicine “of a meager and unsatisfactory kind” from a clinical trial Prevailing view of RA 1984

Arthritis Rheum 27:1344-1352, 1984 “patients with rheumatoid arthritis usually respond to a conservative program of nonsteroidal anti inflammatory drugs, rest, and physical therapy…”

Eloquence-based medicine: 1983

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

Br Med J. 1983;287: 569.

Evidence-based medicine: 1984

From observational study – not clinical trial “these studies indicate severe functional declines, work disability, and excess mortality in a group of 75 RA patients, studied at 2 time points 9 years apart….” T Pincus, LF Callahan, WG Sale, AL Brooks, LE Payne, WK Vaughn

Arthritis & Rheumatism

27:864, 1984.

Rheumatoid Arthritis over 9 years – changes in functional status in activities of daily living and morning stiffness 1973-1982 Activities of daily living 100 1973 1982 90 80 70 60 50 40 30 20 10 0 % No Difficulty Morning Stiffness 1973 0 1982 30 60 90 120 150 180 210 240 270 300 Minutes Pincus et al. Arthritis Rheum. 1984;27:864; J Rheumatol. 1992;19:1051

A 100 9-10 Year Survival According to Quantitative Markers in Three Chronic Diseases Rheumatoid Arthritis Rheumatoid Arthritis Activities of Daily Living B Formal Education Level 100 >12 Years 80 >90% 81 –90% 80 9 –12 Years 60 60 % Active “With Ease”



8 Years 40 40 71 –80% 20 20



70% (Data from Pincus et al, 1987) (Data from Pincus et al, 1987) 0 20 40 60 80 100 Months C 100 0 80 20 40 60 80 100 Hodgkin’s Disease Anatomic Stage Stage I Months D 100 80 Coronary Artery Disease # of Involved Vessels 60 40 20 Stage III Stage IV Stage II All Stages, All Causes (Data from Kaplan, 1972) 60 40 20 1 Artery 2 Arteries 3 Arteries LCA (Data from Proudfit et al, 1978) Years 0 2 4 6 8 10 0 2 4 6 8 10 Years

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 120:26,1994 Functional status on patient questionnaire # of Involved Joints < vs > 91.5% “with ease” > vs < 18 joints 2.9:1 3.0:1 CV disease – 312,000 pts – 12 yrs – Neaton et al, Arch Int Med 152:56,1992 Serum cholesterol >245 vs <182 mg/Dl Systolic blood pressure >142 vs <118 mmHg Diastolic blood pressure Smoking >92 vs <76 mmHg >26 vs 0 cigarettes/day 2.9:1 3.0:1 2.9:1 2.9:1 Data adjusted for age, sex, education, disease duration

The ‘side effects’ of rheumatoid arthritis:

T Pincus, LF Callahan Br J Rheumatol 32:28-37, 1993

• • • • •

Severe functional declines Joint destruction Comorbidities Work disability Premature mortality

Evidence-based medicine: 1995 From add-on clinical trial N Engl J Med 333:137-141, 1995

Evidence-based medicine: 2005

From observational study – not clinical trial “Patients receiving standard care for RA in this setting had significantly better status for… joint counts, MHAQ, ESR, and… radiographic scores, in 2000 than in 1985, associated with aggressive treatment strategies, prior to the introduction of biologic agents.” T Pincus, T Sokka, H Kautiainen

Arthritis & Rheumatism

52: 1009 –1019, 2005

Cross-Sectional Data in all RA Patients seen by TP 1985 and 2000: Functional disability (MHAQ) scores

1985 2000 2.0

2.0

1.5

1.0

1.5

1.0

0.5

0.0

0 5 10 15 Disease Duration (Years) 20 0.0

0 5 10 15 Disease Duration (Years) 20 Pincus and Sokka, A&R 52:1009, 2005

Cross-Sectional Data in all RA Patients seen by TP 1985 and 2000: Swollen joint counts

1985 2000 20 20 16 12 8 16 12 8 4 4 0 0 5 10 15 Disease Duration (Years) 20 0 0 5 10 15 Disease Duration (Years) 20 Pincus and Sokka, A&R 52:1009, 2005

Cross-Sectional Data in all RA Patients seen by TP 1985 and 2000: Larsen X-Ray score, % of maximum

2000 30 25 1985 RF RF+ 30 25 20 20 15 RF+ 15 10 10 5 0 0 5 10 Disease duration 15 5

0 0

0 5 10 Disease duration

RF positive

RF 15 Pincus and Sokka, A&R 52:1009, 2005

Clinical status measures in two cohorts of patients with RA seen in 1984 86 (“1985”) and 1999 2001 (“2000”) Measure 1985 2000 p Swollen joints (0-28) X-Ray (Larsen: 0-100) 12 (6,16) 20 (2,36) 5 (2,10) 3 (0,13) <0.001

<0.001

ESR 33 (16, 50) 20 (9,33) 0.016

MHAQ Function (0-3) Pain VAS (0-100) 1.0 (0.6, 1.4) 0.4 (0.1, 1.0) <0.001

52 (32, 80) 49 (15, 73) Pincus and Sokka, A&R 52:1009, 2005 0.38

Evidence-based medicine – 2008 Prednisone vs placebo withdrawal clinical trial: 31 RA patients Study group Clinical trial results Prednisone Number randomized Placebo TOTAL Withdrew – lack of efficacy Completed trial Withdrew – administrative Number randomized Withdrew – lack of efficacy Completed trial Withdrew – administrative Total 15 3* 10* 2 16 11* 4* 1 31 Baseline prednisone dose 1 mg 2 mg 3 mg 4 mg 1 0 2 0 10 3 2 0 1 0 0 2 0 1 6 1 12 1 1 3 0 0 0 1 1 0 0 3 9 2 1 22 1 2 0 5 *p = 0.021 for 28 completers, p= 0.032 for all31 participants Pincus, Swearingen, Luta Ann Rheum Dis In press

Evidence beyond clinical trials in routine clinical care from MDHAQ and RAPID3: why and how?

Eminence-based and hotel-based concepts about RA – 2008

1. Clinical trials always provide best evidence for clinical care 2. RA patients are better at this time than 20 years ago primarily because of biologic agents. 3. Methotrexate does not prevent radiographic progression in most patients.

4. Methotrexate and prednisone are dangerous vs biologic therapies.

5. A DAS28 is the optimal measure to document the quality and value of rheumatology care.

Randomized Controlled Clinical Trials 1. Optimal method to analyze efficacy and safety of any therapy 2. Mimics lab experiment with control group 3.

Foundation of “evidence-based medicine” 4. Required by FDA to market new therapy 5. Nonetheless, many limitations, particularly in chronic diseases 6. Rarely informs clinician how to treat an individual patient

Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic Diseases J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 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

Evidence-based medicine- 1990: Meta-analysis of Composite DMARD Treatment Effect in RA* Effect in Standard Units 2 1.5

1 0.5

0 ( n=28) Plac (n=25) AUR <.0001

(n=11) AntiM (n=15) AZA (n=28) Gold (n=9) MTX (n=22) DPen (n=8) SSZ <.0001

<.05

*Composite of grip strength (adjusted for disease duration and trial length), tender joint count (adjusted for initial TJC and blinding and ESR Felson, Anderson, Meenan. Arthritis Rheum. 1990;33:1449.

Evidence-based medicine- 1992: Estimated Continuation of Courses of 2nd-Line Therapy All Courses Over 60 Months Initial Course Over 12 Months 100 80 60 40 20 0 0 10 Azathioprine (56) Hydroxychloroquine (228) Methotrexate (253) Oral gold (84) Parenteral gold (269) Penicillamine (193) 20 30 Months 40 50 60 10 0 8 0 6 0 4 0 2 0 0 0 1 Methotrexate (61) Hydroxychloroquine (130) Penicillamine (55) Parenteral gold (207) Oral gold (5) Azathioprine (19) 2 3 4 5 6 7 Months 8 9 10 11 12 Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885.

Evidence-based medicine – 1986

Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic Diseases J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 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

Evidence-based medicine – 2000: # of all RA patients seen by TP in 2000 who met inclusion criteria for ATTRACT trial

138

Criteria:

 

6 tender joints and 6 swollen joints

42 96

2 of 3: Morning stiffness



ESR



28 mm / hour CRP



2.0 mg / dL 45 min

MTX dose



12.5 mg / week

7 14 5 21 16 4 19 15 29 77 48 Meet ATTRACT criteria Do not meet ATTRACT criteria

Sokka and Pincus Arthritis Rheum 48:213, 2003

Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic Diseases J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 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

Evidence-based medicine – 1997: Changes (effect size) in 100 RA Patients Over 5 Years Joint Count Measures Pain Tenderness Swelling on Motion Deformity Limited Motion Joint Space Narrowing Radiographic Measures Laboratory Measures Clinical Measures Patient Questionnaire Measures Erosions Malalignment Erythrocyte Sedimentation Rate Rheumatoid Factor Titer Hemoglobin Morning Stiffness Grip Strength Walk Time Button Time Functional Status - MHAQ Global Status Pain - Visual Analog Scale Better Worse Arthritis Care Res 10:381,1997 -1.5

-1.3

-1.1

-0.9

-0.7

-0.5

Helplessness -0.3

E ffect Size -0.1

0.1

0.3

0.5

Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic Diseases J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003 4. Inflexible dosage schedules and concomitant drug therapies 5. Variables other than randomization, such as education, clinical care site, etc., may affect outcome more than randomization group 6. Rare toxicities not seen in fewer than 10,000 subjects

Intrinsic Limitations of Clinical Trials

1. The design of a clinical trial may greatly influence the results despite the inclusion of a control group.

2. Data from clinical trials are reported in groups, and individual variation is generally ignored.

3. Balance of efficacy versus adverse effects is not standardized and depends on individual assessment of risks and benefits, which may differ widely among individuals.

Intrinsic Limitations of Clinical Trials

4. Statistically significant differences between treatments, or between a treatment compared with placebo, may not necessarily indicate clinical cure or even substantial control of symptoms.

5. Clinically important differences may not be statistically significant because a clinical trial may include too few patients to provide statistical power.

6. The format of a clinical trial compromises the placebo effect by not informing patients that they may receive the “best” therapy.

Evidence-based medicine- 2008

Prednisone vs placebo withdrawal trial in RA Outcome Number randomized Withdrew – lack of efficacy Completed trial Withdrew – administrative Total Prednisone Placebo 31 14 14 3 15 3 10 2 16 11 4 1 p = 0.021 for 28 completers, p= 0.032 for all 31 patients Pincus, Swearingen, Luta Ann Rheum Dis In press

•

Clinical trials generally provide evidence-based medicine, but conclusions may not be accurate concerning actual clinical care

•

Clinical observational studies often provide eminence-based medicine, but may provide evidence that is more accurate concerning actual clinical care than clinical trials

Eminence-based and hotel-based concepts about RA – 2008

4. Methotrexate and prednisone are dangerous vs biologic therapies.

5. A DAS28 is the optimal measure to document the quality and value of rheumatology care.

Ascendancy of weekly low-dose methotrexate in usual care of rheumatoid arthritis from 1980 to 2004 at two sites in Finland and the United States.

T Sokka, T Pincus.

Rheumatology 47:1543, 2008.

Evidence-based medicine: 2005

From observational study – not clinical trial: Patients seen for standard rheumatoid arthritis care have significantly better articular, radiographic, laboratory, and functional status in 2000 than in 1985.

“Patients receiving standard care for RA in this setting had significantly better status…in 2000 than in 1985, associated with aggressive treatment strategies, prior to the introduction of biologic agents.” T Pincus, T Sokka, H Kautiainen

Arthritis & Rheumatism

52: 1009 –1019, 2005

Eminence-based and hotel-based concepts about RA – 2008

4. Methotrexate and prednisone are dangerous vs biologic therapies.

5. A DAS28 is the optimal measure to document the quality and value of rheumatology care.

4 3 2 1 0 -1

TEMPO Trial: Year 2 Radiograph:

Change in Total Sharp Score from 8 Baseline to Year 2 7 6 5 3.34

(CI 1.18, 5.50)

MTX = 206 E = 203 MTX+E = 213 1.10*

(CI 0.13, 2.07)

* p < 0.05, E vs MTX † p < 0.05, Combination vs MTX ‡ p < 0.05, Combination vs E -0.56

†‡

(CI –1.05, -0.06)

450 400 350 300 250 200 150 100 50 0 1 ERA ETA 1.59

ERA MTX -0.54

TEMPO Combi 0.52

2.8

0.4

TEMPO ETA TEMPO MTX IFX Combi 3.7

IFX MTX 1.3

PREMIER Combi 3 PREMIER ADA 5.7

PREMIER MTX

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

Change in Total Sharp/van der Heijde radiographic scores (0-448) in TEMPO trial over 2 years

Van der Heijde Arthritis Rheum 2006

Cross-Sectional Data in all RA Patients seen by TP 1985 and 2000: Larsen X-Ray score, % of maximum

2000 30 25 1985 RF RF+ 30 25 20 20 15 RF+ 15 10 10 5 0 0 5 10 Disease duration 15 5

0 0

0 5 10 Disease duration

RF positive

RF 15 Pincus and Sokka, A&R 52:1009, 2005

Eminence-based and hotel-based concepts about RA – 2008

4. Methotrexate and prednisone are dangerous vs biologic therapies.

5. A DAS28 is the optimal measure to document the quality and value of rheumatology care.

Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities

Y Yazici, T Sokka, H Kautiainen, C Swearingen, I Kulman, T Pincus Ann Rheum Dis 64:207-211, 2005

Methotrexate continuation in TP clinic standard care – 1990-2003

100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 Duration of methotrexate therapy (years)

Yazici,Y. et al. Ann Rheum Dis 64:207-211, 2005

Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis D Krause, B Schleusser, G Herborn, R Rau

Arthritis and Rheumatism 43:14, 2000

Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities

Y Yazici, T Sokka, H Kautiainen, C Swearingen, I Kulman, T Pincus Ann Rheum Dis 64:207-211, 2005

Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study H K Choi, MA Hernan, JD Seeger, JM Robins, F Wolfe The Lancet 359:1173, 2002

Is

weekly-low dose

methotrexate to treat RA (in contrast to

high dose

methotrexate to treat neoplasms) safer, better tolerated, and with a higher risk/benefit ratio than most, if not all, anti-hypertensive, statin, anti-depressant, NSAID, and antibiotic agents?

One of the safest therapies in clinical medicine?

Eminence-based and hotel-based concepts about RA – 2008

4. Methotrexate and prednisone are dangerous vs biologic therapies.

5. A DAS28 is the optimal measure to document the quality and value of rheumatology care.

Indices to assess patients with RA

# Tender joints # Swollen joints MD global ESR or CRP Patient function Patient pain Patient global ACR DAS28 CDAI √ √ √ √ √ √ √ √ √ √ - - √ √ √ √ - - - √ RAPID3 - - - - √ √ √ 64

RAPID3 vs DAS

in 285 RA Patients

Spearman correlation rho = 0.657

RAPID3 vs CDAI in 285 RA Patients Spearman Correlation rho = 0.738

DAS28 and RAPID3 Categories DAS28 Categories (0-10); Fransen and van Riel (2005) >5.1

High activity 3.21-5.1

2.6-3.2

<2.6

Moderate activity Low activity Remission Proposed RAPID3 Categories (0-30 or 0-10) >12 or 4.0

High severity-change therapy or have a good reason not to 6.01-12 or 2.01-4.0

3.01-6.0 or 1.01-2.0

≤3.0 or 1.0

Moderate severity-strongly consider changing therapy Low severity- therapy probably satisfactory Near remission- therapy working

RAPID3 & DAS28 categories are correlated significantly in 285 patients at 3 sites DAS28 (0-10) >5.1 = High Activity 3.2–5.1 = Moderate Activity 2.6–3.19 = Low Activity 0–2.6 = Remission 12.1–30= High Severity 37 (74%) 39 (43%) 4 (10%) 10 (10%) RAPID3 Scores (0-30) 6.1–12.0= Moderate Severity 3.1–6.0= Low Severity 0–3.0= Near Remission 11 (22%) 1 (2%) 1 (2%) Total 50 (17%) 27 (30%) 15 (38%) 18 (17%) 16 (18%) 10 (25%) 24 (23%) 8 (9%) 11 (27%) 90 (32%) 40 (14%) 53 (50%) 105 (37%) Total 90 (31%) 71 (25%) 51 (18%) 73 (26%) 285 Pincus, Yazici, Bergman, J Rheumatol 35:2136-47, 2008

CDAI Compared to RAPID3 Scores in 285 Patients at 3 Sites CDAI Activity >22= High 10.1

–22= Moderate 2.9

–10= Low 0 –2.8= Remission 12.1

–30= High 39 (78%) 36 (40%) 15 (16%) 0 (0%) RAPID 3 Severity (0-30) 6.1

–12.0= Moderate 3.1

–6.0= Low 0 –3.0=Near remission 9 (18%) 1 (2%) 33 (36%) 15 (17%) 28 (30%) 25 (27%) 1 (2%) 10 (19%) 1 (2%) 6 (7%) 25 (27%) 41 (79%) Total 50 (17%) 90 (32%) 93 (33%) 52 (18%) Total 90 (31%) 71 (25%) 51 (18%) 73 (26%) 285 Pincus, Yazici, Bergman, J Rheumatol 35:2136-47, 2008

Adalimumab Clinical Trial Results in Patients with Rheumatoid Arthritis (RA): DAS-EULAR vs Proposed RAPID3Improvement Categories ADA Patients

(N=695; weighted kappa =0.50; p <0.01)

PBO Patients

(N=678; weighted kappa =0.51; p <0.01)

ALL PATIENTS

(N=1,373; weighted kappa =0.54; p <0.01)

DAS28-EULAR Improvement Categories % of Patients Good Moderate 33% 44% Poor TOTAL Good 23% 100% 11% Moderate Poor TOTAL Good Moderate 36% 52% 100% 22% 40% Poor 38% TOTAL 100% RAPID3 % of Patients 34% 38% 28% 100% 12% 38% 50% 100% 23% 38% 39% 23%

Presented, ACR 2008

Eminence-based and hotel-based concepts about RA – 2008 6. The most significant prognostic measures involve structural damage.

7. Tender and swollen joint counts are excellent measures of clinical change.

8. Laboratory tests are essential in the diagnosis and monitoring of RA.

9. Patient-derived measures are “subjective,” less informative and less reliable than “objective” measures from a physician.

10.Outcomes depend primarily on health professionals –not patients.

Predicting Mortality in RA: Most Baseline Measures Are Worse in Patients Who Will Die Over a 5-Year Period Mean Baseline Values Alive Dead P Value Age (years) ARA functional class Number of comorbidities Walking time ESR mHAQ score Learned helplessness Global self-report Number of extra-articular features Duration of disease Years of education Joint count 55.1

2.2

1.1

10.8

33.8

1.98

2.41

2.6

0.2

9.1

10.8

12.8

65.5 < 0.001

2.6 < 0.001

2.1 < 0.001

16.8 < 0.001

48.3 0.004

2.32 0.005

2.55 0.007

3.0 0.01

0.5 0.02

12.7 0.03

9.4 0.03

15.9 0.04

Radiograph score RF titer Pain 1.2

2.7

5.40

1.4 0.20

2.9 0.28

5.19 0.68

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

RA Cohort #2: Cox Proportional Hazards Model Analyses Including Demographic, Functional, Self-Report, Joint Count, X-ray, Laboratory and Disease Variables in 206 Patients Age Comorbidity MHAQ ADL Score Disease duration Education ESR Joint count Walking time X-ray Univariate Stepwise Model RR (95% CL) P Value RR (95% CL) P Value 1.07 <0.001 1.06 <0.001

1.63 <0.001 1.40 0.02

2.00 0.003 1.76 0.02

1.04 0.02 - 0.89 0.007 - - - 1.01 0.005 - 1.02 0.10 - 1.03 0.04 - 1.40 0.17 - - - - - Arthritis Care Res 10:381,1997

Some Problems With Radiographs in RA

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

Eminence-based and hotel-based concepts about RA – 2008 6. The most significant prognostic measures involve structural damage.

7. Tender and swollen joint counts are excellent measures of clinical change.

8. Laboratory tests are essential in the diagnosis and monitoring of RA.

9. Patient-derived measures are “subjective,” less informative and less reliable than “objective” measures from a physician.

10.Outcomes depend primarily on health professionals –not patients.

American College of Rheumatology (ACR) Improvement Criteria

20, 50, 70% improvement in: 1. Tender joint count 2. Swollen joint count 20, 50, 70% improvement in 3 of 5: 3. Assessor Global status 4. Physical Function 5. Pain 6. Patient Global status (also in DAS) 7. Acute phase reactant –ESR, CRP Felson et al, Arthritis Rheum 1995; 38:727-35.

Changes in ACR Core Data Set Measures Over 12 Months: Leflunomide (LEF) vs Methotrexate (MTX) vs Placebo (PBO) Measure: Tender Jts Swollen Jts MD Global ESR FN- HAQ FN-MHAQ Pain Pt Global LEF -7.7

-5.7

-2.8

-6.3

-2.2

-2.1

PBO MTX -3.0

-2.9

-1.0

+2.6

-0.45 +0.03 -0.26

-0.29 +0.07 -0.15

-0.4

+0.1

-6.6

-5.4

-2.4

-6.5

-1.7

-1.5

Effect Relative Size Efficiency -0.59

-0.44

1.00

0.56

-0.68

-0.41

-0.80

1.33

0.48

1.84

-0.69

-0.65

-0.81

1.37

1.21

1.88

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

Relative efficiencies of 7 ACR Core Data Set measures in 4 adalimumab clinical trials 3.00

2.72

2.65

2.50

2.00

1.50

1.00

2.14

2.12

1.10

1.00

1.86

0.92

0.94

1.48

1.55

1.60

1.30

1.00

2.06

1.42

1.52

1.48

1.36

1.12

1.00

1.66

1.43

1.27

1.17

0.60

0.50

0.22

Tender Joint Count Swollen Joint Count Assessor Global CRP Function (HAQ) Pain Patient Global 0.00

ARMADA DE011 DE019 STAR

Pincus T, Amara I, Segurado OG, Bergman M, Koch GG J Rheumatol 35:201-205, 2008.

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% 1 –24% of visits 32% 25 –49% of visits 50 –74% of visits 75 –99% of visits 11% 14% Segurado and Pincus, 2006.

Ann Rheum Dis 65:820-822

16% Always 14%

Time Needed to Score Various RA Measures MD #1 MD #2 MD #3 MD Median 120 100 80 60 40 20 0

MD #1 MD #2 MD #3 MD Median 28 JT 84 113 71 90 HAQ-DI 41.5

42.2

*** 41.9

RAPID3 9.2

12.1

9.1

9.6

Yazici Y et al. J Rheumatol. 2008

Some Problems With Joint Counts in RA 1.

More likely to improve with placebo than patient global, patient questionnaire scores Relative efficiencies no greater than global and patient questionnaire scores to distinguish active from control treatment in clinical trials Poor reproducibility Tedious to perform – 90 seconds - interrupt visit Tender and swollen joint counts may improve over 5-10 years while damage progresses Most visits include a careful joint examination, but not formal joint count

RADAI 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 b.LEFT WRIST c.LEFT ELBOW d.LEFT SHOULDER e.LEFT HIP f.LEFT KNEE g.LEFT ANKLE h.LEFT TOES q.NECK

i.RIGHT FINGERS j.RIGHT WRIST k.RIGHT ELBOW l.RIGHT SHOULDER m.RIGHT HIP n.RIGHT KNEE o.RIGHT ANKLE p.RIGHT TOES r.BACK

RADAI vs Core Data Set measures (n=274) RADAI SJC 28 TJC 28 ESR RADAI Swollen 28 JC Tender 28 JC MDGlobal VAS ESR CRP FN MDHAQ Pt Global VAS Pain VAS -- 0.42

0.55

0.52

0.13* 0.08*** 0.68

0.69

0.71

0.42

-- 0.55

0.74

0.23

0.18** 0.47

0.36

0.39

0.55

-- 0.57

0.32

0.21

0.52

0.53

0.56

0.13* 0.23

0.32

0.26

-- 0.50

0.25

0.21

Adjusted for age, disease duration, education and center, All p<0.0001, except *p=0.035, **p=0.003, ***p>0.05

Eminence-based and hotel-based concepts about RA – 2008 6. The most significant prognostic measures involve structural damage.

7. Tender and swollen joint counts are excellent measures of clinical change.

8. Laboratory tests are essential in the diagnosis and monitoring of RA.

9. Patient-derived measures are “subjective,” less informative and less reliable than “objective” measures from a physician.

10.Outcomes depend primarily on health professionals –not patients.

ESR Values in Patients With RA

Females Males ESR ≥ 28 mm/h 63% 55% ESR < 28 mm/h 37% 45% Wolfe F, Michaud K, J Rheumatol. 1994;21:1227 –1237.

ESR and CRP at 1

Visit

a. Jyvaskyla, FIN CRP ESR ≥28 mm/hr <28 mm/hr >10 mg/L <10 mg/L 775 (44%) 199 (11%) Total 974 (55%) b. Nashville, TN, USA CRP 202 (12%) 568 (33%) 770 (45%) ESR ≥28 mm/hr <28 mm/hr >10 mg/L <10 mg/L Total 48 (28%) 29 (17%) 77 (45%) 22 (13%) 71 (42%) 93 (55%) Total 977 (56%) 767 (44%) 1744 (100%) Total 70 (41%) 100 (59%) 170 (100%)

% of RA patients with abnormal measures at presentation – Evidence- not eminence-based



ESR >28 mm/Hr



CRP >10



Rheumatoid factor positive



Anti-CCP positive 57% 58% 69% 67%

What is the meaning of 98% specificity of a lab test?

Disease Test Prevalence # with disease & + test # non-diseased & + test Odds of disease if test + Likelihood ratio RA Anti-CCP RF 1:200 1/200 1:50 1:4 50:1 SLE ANA 1:2000 1:2000 1:50 1:40 50:1

% of RA patients with abnormal measures at presentation – Evidence- not eminence-based



ESR >28 mm/Hr



CRP >10



Rheumatoid factor positive



Anti-CCP positive



Function score >2/10



Pain score >2/10



RAPID3 score 57% 58% 69% 67% 70% 89% 86%

Eminence-based and hotel-based concepts about RA – 2008 6. The most significant prognostic measures involve structural damage.

7. Tender and swollen joint counts are excellent measures of clinical change.

8. Laboratory tests are essential in the diagnosis and monitoring of RA.

9. Patient-derived measures are “subjective,” less informative and less reliable than “objective” measures from a physician.

10.Outcomes depend primarily on health professionals –not patients.

1.63 <0.001 1.40 0.02

2.00 0.003 1.76 0.02

1.04 0.02 - 0.89 0.007 - 1.01 0.005 - 1.02 0.10 - - - - - 1.03 0.04 - 1.40 0.17 - - - Arthritis Care Res 10:381,1997

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

100 80 60 40 20 0 0 Rheumatoid Factor Absent (29) Present (175) 12 24 36 48 Months After Baseline 60 100 80 60 40 20 0 0 Arthritis Care Res 10:381,1997 MHAQ Score 0.00 (12) 0.01

–0.99 (91) 1.00

–1.99 (86) >2.00 (21) 12 24 36 48 Months After Baseline 60

MDHAQ Page 1

Multi-Dimensional Health Assessment Questionnaire (R771-NP2) This questionnaire includes information not available from blood tests, X-rays, or any source other than you. Please try to answer each question, even if you do not think it is related to you at this time. Try to complete as much as you can yourself, but if you need help, please ask. There are no right or wrong answers. Please answer exactly as you think or feel. Thank you. FOR OFFICE USE ONLY 1.

Please check (√) the ONE best answer for your abilities at this time: OVER THE LAST WEEK, were you able to: a. Dress yourself, including tying shoelaces and doing buttons? b. Get in and out of bed? c. Lift a full cup or glass to your mouth? d. Walk outdoors on flat ground? e. Wash and dry your entire body? g. Turn regular faucets on and off? Without ANY Difficulty _____0 i. Walk two miles or three kilometers, if you wish? With

SOME

Difficulty _____1 With MUCH Difficulty _____2

UNABLE

To Do _____3 _____0 _____1 _____2 _____3 _____0 _____1 _____2 _____3 _____0 _____1 _____2 _____3 _____0 _____1 _____2 _____3 f. Bend down to pick up clothing from the floor? _____0 _____1 _____2 _____3 _____0 _____1 _____2 _____3 h. Get in and out of a car, bus, train, or airplane? _____0 _____1 _____2 _____3 j. Participate in recreational activities and sports as you would like, if you wish? k. Get a good night’s sleep? _____0 _____1 _____2 _____3 _____0 _____1.1 _____2.2 _____3.3 l. Deal with feelings of anxiety or being nervous? _____0 _____1.1 _____2.2 _____3.3 m.Deal with feelings of depression or feeling blue? _____0 _____1.1 _____2.2 _____3.3

2. How much pain have you had because of your condition OVER THE PAST WEEK? Please indicate below how severe your pain has been: 1.

a-j FN (0-10) 1=0.3 16=5.3 2=0.7 17=5.7 3=1.0 18=6.0 4=1.3 19=6.3 5=1.7 20=6.7 6=2.0 21=7.0 7=2.3 22=7.3 8=2.7 23=7.7 9=3.0 24=8.0 10=3.3 25=8.3 11=3.7 26=8.7 12=4.0 27=9.0 13=4.3 28=9.3 14=4.7 29=9.7 15=5.0 30=10 2.PN (0-10) 4.PTGL (0-10)

RAPID 3 (

0-30) 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 PAIN AS BAD AS IT COULD BE a-p 0-10 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:

a.LEFT FINGERS b.LEFT WRIST c.LEFT ELBOW d.LEFT SHOULDER e.LEFT HIP f.LEFT KNEE g.LEFT ANKLE h.LEFT TOES q.NECK

VERY   None    Mild Moderate Severe

time, please indicate below how you are doing:

      i.RIGHT FINGERS j.RIGHT WRIST k.RIGHT ELBOW l.RIGHT SHOULDER m.RIGHT HIP r.BACK

   n.RIGHT KNEE p.RIGHT TOES  o.RIGHT ANKLE  None   Mild Moderate Severe    2 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 POORLY For Office Use Only: RAPID 3 RAPID 3 (0-10) NR: 1=0.3, 2=0.7, 3=1.0 LS: 4=1.3, 5=1.7, 6=2.0 19=6.3, 20=6.7, 21=7.0, 22=7.3, 23=7.7, 24=8.0, RAPID 4 NR: 1=0.3, 2=0.5, 3=0.8, 4=1.0 LS: 5=1.3, 6=1.5, 7=1.8, 8=2.0 MS: 9=2.3, 10=2.5, 11=2.8, 12=3.0, 13=3.3, 14=3.5, 15=3.8, 16=4.0 RAPID 4 (0-10) RAPID 5 MS:11=2.2, 12=2.4, 13=2.6, 14=2.8, 15=3.0, 16=3.2, 17=3.4, 18=3.6, 19=3.8, 20=4.0 (0-10) HS: 21=4.2, 22=4.4, 23=4.6, 24=4.8, 25=5.0, 26=5.2, 27=5.4, 28=5.6, 29=5.8, 30=6.0, 31=6.2, 32=6.4, 33=6.6, 34=6.8, 35=7.0, 36=7.2, 37=7.4, 38=7.6, 39=7.8, 40=8.0, 41=8.2, 42=8.4, 43=8.6, 44=8.8, 45=9.0, 46=9.2, 47=9.4, 48=9.6, 49=9.8, 50=10.0 Copyright: Health Report Services, Telephone 615-936-2151, E-mail [email protected]

1=0.2 25=5.2 2=0.4 26=5.4 3=0.6 27=5.6 4=0.8 28=5.8 5=1.0 29=6.0 6=1.3 30=6.3 7=1.5 31=6.4 8=1.7 32=6.7 9=1.9 33=6.9 10=2.1 34=7.1 11=2.3 35=7.3 12=2.5 36=7.5 13=2.7 37=7.7 14=2.9 38=7.9 15=3.1 39=8.1 16=3.3 40=8.3 17=3.5 41=8.5 18=3.8 42=8.8 19=4.0 43=9.0 21=4.4 45=9.4 22=4.6 46=9.6 23=4.8 47=9.8 24=5.0 48=10

RAPID 4 (

0-40 ) \ \\ MDGLOBAL(0-10) ) RAPID 5 ( 0-50) ?

Work Status in 91 RA Patients <65

WORK STATUS 55 Disabled 54 20



0.56

1 16 36-Working MHAQ Function <1 year 0 4 Disease Duration



40.5 years 2 5 54 16 Age Callahan, Bloch, Pincus Non-professional/ Non-managerial J Clin Epidemiol 45:127, 1992.

45 6 52 11 Occupation



2.25

3 5 7 5 MHAQ Function >2.25

4 0

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, ) 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, Leigh&Fries 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)

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 (ADL) in prognosis of non-Rheumatic Diseases

•

In congestive heart failure , ADL predict 3-year mortality as effectively as ejection fraction

Konstam, Am J Cardiology 78:890, 1996

•

In AIDS , ADL predict 3-year mortality as effectively 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 comorbidities , ADL predict 1-year mortality beyond physiologic data and

Covinsky, J Gen Intern Med 12:203, 1997

Eminence-based and hotel-based concepts about RA – 2008 6. The most significant prognostic measures involve structural damage.

7. Tender and swollen joint counts are excellent measures of clinical change.

8. Laboratory tests are essential in the diagnosis and monitoring of RA.

9. Patient-derived measures are “subjective,” less informative and less reliable than “objective” measures from a physician.

10.Outcomes depend primarily on health professionals –not patients.

Formal education (socioeconomic status) and health –

Possible explanations Limited education Possible solutions More education Limited Resources Money, Medicaid Limited access to “health care” Psychosocioeco nomic problems Increase access to medical services Change how “system” works

Formal education level: a marker for the importance of behavioral variables in the pathogenesis, morbidity and mortality of most diseases? T Pincus J Rheumatology 15:1457, 1988

QUEtionnaires in STandard Care of Rheumatoid Arthritis (QUEST RA)

A Multinational Cross-Sectional Database To Assess Clinical Status Of Patients With RA T Sokka, Jyvaskyla Finland, Director Goal: 100 patients from 3 sites in standard care in each country August 2007 status: 5519 patients 63 sites 22 countries

QUEST-RA From January 2005 to August 2007: 5519 patients from 63 clinics in 22 countries Off-Europe: USA Canada Argentina Japan

Disease activity in the QUEST-RA study NL FI USA Gr DK Sp Fr Sw Ire UK Tu Ger It Est La Pol Ar Li Se Overall, patients had an active disease with the median DAS28 of 4.2. Low disease activity of DAS28 <3.2 was met by the majority of patients in 8 sites in 6 countries; in 11 sites in 7 other countries >50% of patients had high disease activity of DAS>5.1.

Sokka et al. EULAR2007 – FRI0188

QUEST-RA: Clinical status of RA was significantly associated with macro economic variables

•

GDP=gross domestic product per capita. Each country is shown as a dot or a disk; area of the disc reflects the amount of the total national health expenditure ($US) per capita r = -0.76

Sokka et al EULAR2007 – THU0477

QUEST-RA: Medications in 5,518 patients in 21 countries

Pred nisone Ever Metho trexate Ever 70.4% 82.5% Leflu nomide Ever 21.5% Biolo gical Agent Ever 22.5% Biolo gical Agent Now 16.9%

QUEST-RA: Medications in patients in selected countries Country USA Argentina Denmark Estonia Finland Germany Greece Hungary Ireland Italy Lithuania Netherlands Poland Serbia Spain Sweden Turkey UK Total Patients PrdEver 301 76.7

246 301 168 304 225 300 153 240 336 300 317 642 100 302 260 309 145 5519 82.5

43.5

75.6

73.7

54.2

89.0

58.2

71.3

72.3

96.7

30.3

78.8

88.0

68.2

68.5

75.4

53.8

70.4

MTX Ever 85.4

68.3

85.7

73.8

85.2

80.0

32.0

85.0

93.3

81.0

72.7

91.5

88.0

69.0

85.4

83.5

89.3

82.8

82.5

Biol Ever 32.6

3.3

23.3

1.2

17.4

28.9

46.0

15.7

41.7

26.8

11.0

22.4

9.5

2.0

27.2

33.1

7.1

20.0

22.5

Biol Now 27.9

2.8

20.6

0.7

12.5

22.7

16.0

19.0

32.1

12.8

9.0

19.2

6.1

0.0

15.3

25.5

5.8

14.5

16.9

Social conditions and self management are more powerful determinants of health than access to care

T Pincus, R Esther, DA DeWalt, LF Callahan Ann Intern Med 129:406-420,1998

“You observe a lot by watching.” Yogi Berra