Why is quantitative standardized measurement advantageous in usual clinical care?

1. 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 tedpincus@gmail.com

2. Why is quantitative standardized measurement advantageous in usual clinical care?

3. “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? Quantitative measurement vs descriptive impressions

4. Prevailing view of rheumatoid arthritis – 1984 “Patients with rheumatoid arthritis usually respond to a conservative program of nonsteroidal anti-inflammatory drugs, rest, and physical therapy…” Arthritis Rheum 1984;27:1344–1352.

5. 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

6. More accurate information in 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 Smith T, et al. Br Med J 1983;287:569.

7. 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

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

9. Survival in rheumatoid arthritis 1973-1982 Pincus et al. Arthritis Rheum. 1984;27:864.

10. 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

11. Monson and Hall, 1976 Massachusetts Uddin et al, 1970 Ontario Allebeck et al, 1981 Sweden Cobb et al, 1953 Massachusetts Rasker and Cosh, 1981 England 100 100 100 80 1000 80 100 80 Survival (%) 60 Survival (%) 800 Expected for women Survival (%) Expected for women 80 60 Women with OA Survival (No.) 60 Expected for men Men with OA 40 600 Expected for men Survival (%) Expected for population Women with RA Women with RA 60 Patients with “definite” RA Patients with “classic” RA Women with RA 40 20 400 Men with RA Men with RA 40 Men with RA 40 0 Patients with RA 0 200 0 5 10 5 10 15 20 25 0 5 10 15 20 25 Years Years Years 0 10 20 30 0 2 6 8 10 4 4 8 12 16 20 24 Years Years Vandenbroucke et al, 1984 Netherlands Pincus et al, 1987 Tennessee Mitchell et al, 1986 Saskatchewan Vollertsen et al, 1986 Minnesota Mutru et al, 1985 Finland 100 80 1.00 100 100 100 60 5 10 4 8 12 16 20 Survival (%) 0.80 80 Expected for men 40 80 Expected for women 0.60 80 Probability 60 60 20 Women with RA Expected for women Expected for women Expected for women Expected for men Expected for population Patients with “classic” RA Survival (%) Survival (No.) Expected for men Survival (%) Men with RA 0.40 40 Expected for men 40 0 Women with RA Women with RA 60 Women with RA 0.20 Men with RA 20 20 Men with RA Men with RA Years 0 0 0 0 Years Years Years Years 5 10 15 2 4 6 8 10 Survival of Patients With Rheumatoid Arthritis Versus Expected Survival in 10 Locales

12. 9- to 10-Year Survival According to Quantitative Markers in Three Chronic Diseases A B Rheumatoid Arthritis – Activities of Daily Living Rheumatoid Arthritis – Formal Education Level 100 100 >12 Years >90% 80 81%–90% 80 9–12 Years % Active “With Ease” 60 60 £8 Years Survival (%) Survival (%) 40 40 71%–80% 20 20 £70% (Data from Pincus et al, 1987) (Data from Pincus et al, 1987) Months Months 0 20 40 60 80 100 0 20 40 60 80 100 C D Hodgkin’s Disease – Anatomic Stage Coronary Artery Disease – # of Involved Vessels 100 100 Stage I 80 80 1 Artery Stage II 60 60 Stage III All Stages, All Causes Survival (%) Survival (%) 2 Arteries Stage IV 40 40 3 Arteries 20 20 LCA (Data from Kaplan, 1972) (Data from Proudfit et al, 1978) Years Years 0 2 4 6 8 10 0 2 4 6 8 10

13. Why are quantitative patient history data needed for clinical care of patients with rheumatoid arthritis?

14. 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”

15. Differences: hypertension, diabetes, hyperlipidemia vs rheumatoid arthritis Disease Biomarker Positive in 1. 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%

16. 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

17. RA Core Data Set – 7 or 8 measures Felson et al, Arthritis Rheum 36:729, 1993.van Riel, Br J Rheumatol 31:793, 1994.

18. Measures in clinical trials and usual care

19. Clinical Decisions Survey Please 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: hypertension diabetes mellitus rheumatoid arthritis hypercholesterolemia pulmonary fibrosis ulcerative colitis lymphoma congestive heart failure

20. Highest ranked source of clinical information 588 MDs: McCollum, Castrejon, Durusu-Tanriover, Pincus: EULAR 2010

21. 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?

22. Indices to assess patients with RA 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.

23. 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?

24. "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

25. ESR Values in Patients With RA Wolfe F, Michaud K, J Rheumatol. 1994;21:1227–1237. Wichita KS, USA Similar results have been reported from: Nashville, TN, USA Jyvaskyla, Finland Oslo, Norway Nancy, France Groningen, The Netherlands Belfast, Ireland

26. 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.

27. Meta-analysis: Anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) Nishimura K et al. Annals of Internal Medicine 146:797-808, 2007

28. Meta-analysis: Anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) Nishimura K et al. Annals of Internal Medicine 146:797-808, 2007

29. % 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

30. 5-Year Survival in 206 Patients With RA: Cohort #2 – 1985-1990 Rheumatoid Factor MHAQ Score 100 100 80 80 60 60 Survival (%) Survival (%) 0.00 (12) Absent (29) 40 40 0.01–0.99 (91) Present (175) 1.00–1.99 (86) 20 20 >2.00 (21) 0 0 0 12 24 36 48 60 0 12 24 36 48 60 Months After Baseline Months After Baseline Callahan LF et al. Arthritis Care Res 10:381,1997

32. Multi-Dimensional Health Assessment Questionnaire (MDHAQ) Page 1

33. Some Limitations of Laboratory Tests in RA • Normal in 30-50% of patients who require treatment for RA • Often not available at time of clinical decision • Add to costs needed for therapy

34. Why isn’t a joint count the best quantitative measure in RA?

35. 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

36. 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

37. RAPID3 versus DAS28 and CDAI in 285 RA patients DAS28 CDAI Spearman correlation rho = 0.657 Spearman correlation rho = 0.738 Pincus T, et al. J Rheumatol. 2008; 35: 2136-47

38. 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 Pincus T, et al. Arthritis Care Res 2011; 63:1142–1149

39. DAS28, CDAI and RAPID3 Categories Pincus T, et al. Rheum DisClin N Am. 2009;35:819-827.

40. 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 11% 50–74% of visits 14% 75–99% of visits 16% Always 14% Segurado and Pincus, 2006. Ann Rheum Dis 65:820-822.

41. Time to Score RA Measures - Seconds Pincus, Swearingen, Bergman, Colglazier, Kaell, Kunath, Siegel, YaziciArthritis Care Res. 2010; 62:181-189. HAQ-DI = Health Assessment Questionnaire-Disability Index

42. 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.

43. The DAS is the most specific measure, but a patient questionnaire is the most informative measure to assess rheumatoid arthritis. T Pincus J Rheumatol. 33:834-837, 2006

44. Some approaches to overcome limitations of joint counts in RA • All visits must include a careful joint examination, but not formal joint count • A RADAI self-report joint count may perform well to characterize joint involvement • Can a patient global score for inflammation, as well as damage, and neither (fibromyalgia/somatization), provide clinically useful quantitative data from a health professional?

45. RADAI Self-report Joint Count

46. Multi-Dimensional Health Assessment Questionnaire (MDHAQ) Page 1:Foundation for “evidence-based” visit

47. RADAI vs Core Data Set measures (n=274) Adjusted for age, disease duration, education and center, All p<0.0001, except *p=0.035, **p=0.003, ***p>0.05

48. 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?

49. Why isn’t a radiograph the best quantitative measure in RA?

50. Radiographs in RA Only pathognomonic feature of RA Permanent record of patient status Excellent quantitative scoring methods But Poorly reproducible–several readers Not scored in usual care Less sensitive than ultrasound, MRI Limited prognostic significance for work disability, mortality