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@gmail.com

2. 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

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 3–7 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) 3. 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, 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.

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 68–70 joint count

9. 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:LEFPBOMTX 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

10. 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 Rheumatologists

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 Hodgkin Disease – Anatomic Stage Years 20 40 60 80 100 02468 Survival (%) 10 C Stage I Stage II All Stages, All Causes Stage III Stage IV (Data from Kaplan, 1972) 20 40 60 80 100 020406080100 Months  8 Years 9–12 Years >12 Years B Survival (%) (Data from Pincus et al, 1987) D Coronary Artery Disease – No. of Involved Vessels Years 1 Artery 2 Arteries 3 Arteries LCA 20 40 60 80 100 0246810 Survival (%) (Data from Proudfit et al, 1978) A 100 80 60 40 20 0 406080100 >90% 81%–90% 71%–80%  70% Survival (%) Months (Data from Pincus et al, 1987) % Active “With Ease” Rheumatoid Arthritis – Activities of Daily LivingRheumatoid Arthritis – Formal Education Level

17. 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 3.34 (CI 1.18, 5.50) 1.10* (CI 0.13, 2.07) -0.56 †‡ (CI –1.05, -0.06)

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

19. 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.

20. Radiographs ESR, CRP Shared epitope Rheumatoid factor Joint deformity Duration of disease Functional disability Pain Patient global estimate Socioeconomic status Joint tenderness Age Strongly and Weakly Related Measures to Assess RA Pincus T, Sokka T: Best Pract Res Clin Rheumatol 17:753-781, 2003.

21. 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 < 0.001 Number 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

22. 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 UnivariateStepwise Model Arthritis Care Res 10:381,1997 1.40 0.17 -- -- RR (95% CL)

23. MRI can better identify early bone erosions than X-ray

24. 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

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. "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

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-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 2006

28. 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 Females63%37% Males55%45% Similar results have seen reported from: Nashville, TN USAJyvaskyla, Finland Oslo, NorwayNancy, France Gronigen, the NetherlandsBelfast, Ireland

29. LocationnESR Oslo,Norway237626 Nancy, France135929 Gronigen, Netherlands283828 Belfast, N Ireland51828 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

30. ESR and CRP at 1 st visit in US and Finland – 1980-2005 CRPESRTotal ≥ 28 mm/hr <28 mm/hr Jyvaskyla, Finland n=1744 Total55%45%100% <10 mg/L11%33%44% >10 mg/L44%12%56% Nashville, Tennessee, USA n=170 Total45%55%100% <10 mg/L17%42%59% >10 mg/L28%13%41% Sokka and Pincus – J Rheumatol 2009

31. First year of recruitment Period of recruitment Median ESR (mm/h) Mean ESR (mm/h) 1954-1980 (7 studies) 1954-1995 4750 1981-1984 (8 studies) 1981-1999 3841 1985-1996 (8 studies) 1985-2000 3635 Mean/median baseline ESR in RA patients in 23 studies, by first year of recruitment Abelson B, Sokka T, Pincus T. J Rheumatol 2009

32. Meta-analysis: Anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) Anti-CCPRF Number of studies 3750 Positive likelihood ratio 12.54.9 Odds ratio for RA 16.1 – 39.01.2 – 8.7 Nishimura K et al. Annals of Internal Medicine 146:797-808, 2007

33. Meta-analysis: Anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) Anti-CCPRF Number of studies 3750 Positive likelihood ratio 12.54.9 Odds ratio for RA 16.1 – 39.01.2 – 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

34. 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 UnivariateStepwise Model Arthritis Care Res 10:381,1997 1.40 0.17 -- -- RR (95% CL)

35. 5-Year Survival in 206 Patients With RA: Cohort #2 – 1985-1990 100 80 60 40 20 0 01224364860 Survival (%) Months After Baseline Rheumatoid Factor Absent (29) Present (175) 100 80 60 40 20 0 01224364860 Survival (%) Months After Baseline MHAQ Score 0.00 (12) 0.01–0.99 (91) 1.00–1.99 (86) >2.00 (21) Arthritis Care Res 10:381,1997

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 >28 mm/Hr - 57% (2,3) CRP >10 -58% (2) 1- Nishimura et al, Ann Int Med 146:797-808, 2007 2 - Wolfe and Michaud, J Rheumatol 21:1227–1237, 1994 3 - Sokka and Pincus, J Rheumatol 36:1387--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 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

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 Hodgkin’s Disease - Anatomic Stage Years 20 40 60 80 100 02468 Survival (%) 10 C Stage I Stage II All Stages, All Causes Stage III Stage IV (Data from Kaplan, 1972) (Data from Kaplan, 1972) Formal Education Level Formal Education Level 20 40 60 80 100 020406080100 Months  8 Years 9–12 Years >12 Years B Survival (%) (Data from Pincus et al, 1987) D Coronary Artery Disease - Coronary Artery Disease - # of Involved Vessels # of Involved Vessels Years 1 Artery 2 Arteries 3 Arteries LCA 20 40 60 80 100 0246810 Survival (%) (Data from Proudfit et al, 1978) (Data from Proudfit et al, 1978) Activities of Daily Living Activities of Daily LivingA 100 80 60 40 20 0 406080100 >90% 81–90% 71–80%  70% Survival (%) Months (Data from Pincus et al, 1987) % Active “With Ease” Rheumatoid Arthritis -

42. 5-Year Survival in 206 Patients With RA: Cohort #2 – 1985-1990 100 80 60 40 20 0 01224364860 Survival (%) Months After Baseline Rheumatoid Factor Absent (29) Present (175) 100 80 60 40 20 0 01224364860 Survival (%) Months After Baseline MHAQ Score 0.00 (12) 0.01–0.99 (91) 1.00–1.99 (86) >2.00 (21) Arthritis Care Res 10:381,1997

43. Physical function (N=18) Hand radio- graph (N=18) Joint count (N=18) Rheum- atoid factor (N=29) ESR (N=19) Extra- articular disease (N=18) Co- morbidities (N=23) Socio- economic status (N=13) 22%11% 28% 39%50% 37% 32% 72% 6% 22% 65% 4% 30% 46% 31% 23% 45% 34% 21% 44% 17% 39% Significant in multivariate analysesSignificant in univariate analysesNot 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

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 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

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