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. 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?

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.

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 trials Isaacs and Fitzgerald, BMJ 319:1618, 1999, per G. Eknoyan, Baylor Coll Med

6. 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?

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 Pincus et al. Arthritis Rheum. 1984;27:864; J Rheumatol. 1992;19:1051 19731982 Morning Stiffness 0 30 60 90 120 150 180 210 240 270 300 19731982 Activities of daily living 100 90 80 70 60 50 40 30 20 10 0 Minutes% No Difficulty

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

10. RAU.S. 1977U.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

11. Survival of Patients With Rheumatoid Arthritis Versus Expected Survival in 10 Locales Cobb et al, 1953 Massachusetts Years 200 400 600 800 1000 Survival (No.) 0102030 Expected for population Patients with RA Uddin et al, 1970 Ontario Years Survival (%) 0 40 60 80 100 Expected for men Women with RA Men with RA 02 4 6810 Expected for women Monson and Hall, 1976 Massachusetts Years 0 40 60 80 100 Survival (%) 5101520 Women with OA Men with OA 25 Women with RA Men with RA Allebeck et al, 1981 Sweden Years Survival (%) 0 40 60 80 100 Expected for women Expected for men Women with RA Men with RA 510 20 Rasker and Cosh, 1981 England Years 0 40 60 80 100 Survival (%) Patients with “definite” RA Patients with “classic” RA 4122024816 Vandenbroucke et al, 1984 Netherlands Years Survival (%) 40 60 80 100 Expected for women Women with RA Men with RA 510152025 20 0 Expected for men Mutru et al, 1985 Finland Years 0 60 80 100 Survival (No.) Expected for women Expected for men 246810 Women with RA Men with RA Mitchell et al, 1986 Saskatchewan Years Survival (%) 0 40 60 80 100 Expected for women Expected for men Women with RA Men with RA 20 51510 Vollertsen et al, 1986 Minnesota 0.20 0.40 0.60 0.80 1.00 Probability Expected for population Patients with “classic” RA 0 48121620 Years Pincus et al, 1987 Tennessee Survival (%) 40 60 80 100 Expected for women Expected for men Women with RA Men with RA 510 20 0 Years

12. 9- to 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) 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 – # 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

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 DiseaseBiomarker Positive in 1. HypertensionBlood pressure100% 2. Diabetes mellitusHgb A1c, glucose100% 3. HyperlipidemiaCholesterol, lipids100% 4. RheumatoidESR, 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 Source: MD exam X- ray LabPatient 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.

18. Measures in clinical trials and usual care Disease Biomarker Measures Measures in clinical trials Measures in usual care Hyper- tension Blood pressure DiabetesGlucose, HbA1c Glucose, HbA1c Glucose, HbA1c Rheumatoid arthritis RF, ACPA, ESR, CRP Core Data Set, DAS28, CDAI, RAPID3 RF, ACPA, ESR, CRP

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: 1.hypertension 2.diabetes mellitus 3.rheumatoid arthritis 4.hypercholesterolemia 5.pulmonary fibrosis 6.ulcerative colitis 7.lymphoma 8.congestive heart failure

20. Highest ranked source of clinical information 588 MDs: Source Cong Heart Failure Dia- betes Mellitus Hyper- tension Hyper- lipid- emia Lymph- oma Pulmo- nary FibrosisRA 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%:

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 Core set measure DAS28 1 CDAI 2 RAPID3 3 # Tender joints 0.56  sq rt (TJC28) 0-28-- # Swollen joints 0.28  sq rt (SJC28) 0-28-- MD global -- 0-10-- ESR or CRP 0.70  ln (ESR) -- Patient function -- 0-10 Patient pain -- 0-10 Patient global 0.014  PTGL 0-10 TOTAL 0-100-760-30 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.

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 ESR ≥ 28 mm/h ESR < 28 mm/h Females63%37% Males55%45% Similar results have been reported from: Nashville, TN, USAJyvaskyla, Finland Oslo, NorwayNancy, France Groningen, The NetherlandsBelfast, Ireland

26. Location Yr of report n % ESR<28 mm/Hr Mean Median ESR (mm/h) Wichita, KS, USA 1 1994 1556F37%,M45% 37F, 34M Oslo, Norway 2 1996237NA 26 Nancy, France 2 1996135NA29 Groningen, Netherlands 2 1996283NA28 Belfast, N Ireland 2 199651NA28 Jyvaskyla, Finland 3 2009 1892 45%30 Nashville, TN, USA 3 200973847%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.

27. 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

28. 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

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 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) 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 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

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 Spearman correlation rho = 0.657 Pincus T, et al. J Rheumatol. 2008; 35: 2136-47 Spearman correlation rho = 0.738 DAS28CDAI

38. 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

39. DAS28, CDAI and RAPID3 Categories Activity level DAS28 (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 3.2-5.110.1-226.1-12 Low – change likely not needed 2.6-3.22.9-103.1-6 Near remission  2.6  2.8  3 3 Pincus T, et al. Rheum Dis Clin N Am. 2009;35:819-827.

40. 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 Segurado and Pincus, 2006. Ann Rheum Dis 65:820-822.

41. Time to Score RA Measures - Seconds Pincus, Swearingen, Bergman, Colglazier, Kaell, Kunath, Siegel, Yazici Arthritis 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. 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.

44. Some 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?

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) RADAISJC 28TJC 28ESR RADAI ---0.420.550.13* Swollen 28 JC 0.42---0.550.23 Tender 28 JC 0.55 ---0.32 MDGlobal VAS 0.520.740.570.26 ESR 0.13*0.230.32--- CRP 0.08***0.18**0.210.50 FN MDHAQ 0.680.470.520.25 Pt Global VAS 0.690.360.530.21 Pain VAS 0.710.390.560.21 Adjusted for age, disease duration, education and center, All 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

51. 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)

52. 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

53. 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”

54. Change in Total Sharp/van der Heijde radiographic scores (0-448) in TEMPO trial over 2 years Van der Heijde Arthritis Rheum 2006

55. 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

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

57. MRI Can Better Identify Early Bone Erosions than X-ray

58. Prospective Observation of Predictors of Mortality Over 5 Years in 210 Consecutive Patients with RA -1985-1990 Mean baseline values:Dead Age 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

59. 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 -- 0.171.40 X-ray -- 0.04 1.03* Walking time -- 0.101.02 Joint 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 Model Univariable Models MHAQ=Modified Health Assessment Questionnaire, ADL=Activities of Daily Living, *= Confidence Interval does not cross 1.00

60. 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

61. Radiographs ESR, CRP Shared epitope Rheumatoid factor Joint deformity Duration of disease Functional disability Pain Patient global Joint tenderness Fatigue Age 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

62. What about patient and physician global measures as quantitative measures in RA?

63. 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

64. Relative efficiencies of 7 RA Core Data Set measures in 4 adalimumab clinical trials Pincus, Amara, Segurado, Bergman, Koch, J Rheumatol 35:201-205, 2008

65. How to collect quantitative patient history data as standardized “scientific data using the MDHAQ/RAPID3?

66. Let the patient do most of the work! Most patients are more accurate about many details of their own medical history than health professionals

67. MDHAQ helps the patient prepare for a better visit

68. MDHAQ/RAPID3 Advantages 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

69. Doctor reviews information with the patient, and interprets data for clinical decisions

70. MDHAQ/RAPID3 Advantages 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

71. MDHAQ/RAPID3: 04 Nov 2003 3 RA Core Data Set scores FN (0–10) = 2.7 PN (0–10) = 9.5 PTGL (0–10) = 9.0 RAPID3 (0–30) = 21.2 Severity: 12.1-30 = High 6.1-12 = Moderate 3.1-6 = Low 0-3 = Near remission 2.7 9.5 9.0 21.2                                 

72. 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/Codeine30tid T-Naproxen 880q6h N = new drug, C = change in dose, T = taper, D/C = discontinue

73. MDHAQ/RAPID3: 13 Jan 2004 3 RA Core Data Set scores FN (0–10) = 0 PN (0–10) = 0.5 PTGL (0–10) = 0.5 RAPID3 (0–30) = 1.0 Severity: 12.1-30 = High 6.1-12 = Moderate 3.1-6 = Low 0-3 = Near remission 0 0.5 1.0                                 

74. Visit 2 - 4 Nov 2003 N = new drug, C = change in dose, T = taper, D/C = discontinue Visit Date 4Nov0313Jan04 Q-Function (0–10) 2.70 Q-Pain (0–10) 9.50.5 Q-Global (0–10) 9.00.5 RAPID3 (0–30) 21.21.0 L-ESR 438 T-Prednisone N3qd3qd T-Methotrexate N10qwC20qw T-Folic acid N1qd1qd T-acetamnphn/codn30tid T-Naproxen 880q6h440bid

75. Visit 4 - 28 Sep 2004 N = new drug, C = change in dose, T = taper, D/C = discontinue Visit Date 4Nov0313Jan0420Apr0428Sep04 Q-Function (0–10) 2.700.30 Q-Pain (0–10) 9.50.50.00.5 Q-Global (0–10) 9.00.5 1.0 RAPID3 (0–30) 21.21.00.81.5 L-ESR 4381310 T-Prednisone N3qd3qd T-Methotrexate N10qwC20qw20qw15qw T-Folic acid N1qd1qd T-acetamnphn/codn30tid D/C T-Naproxen 880q6h440bidprn

76. 0 6.0 5.5 11.5                                  MDHAQ/RAPID3: 28 Dec 2004 3 RA Core Data Set scores FN (0–10) = 0 PN (0–10) = 6.0 PTGL (0–10) = 5.5 RAPID3 (0–30) = 11.5 Severity: 12.1-30 = High 6.1-12 = Moderate 3.1-6 = Low 0-3 = Near remission

77. Visit 5: 28 Dec 2004 N=new drug, C=change in dose, T=taper, D/C=discontinue Visit date 4Nov0313Jan0420Apr0428Sep0428Dec04 Q-Function (0–10) 2.700.300 Q-Pain (0–10) 9.50.50.00.56.0 Q-Global (0–10) 9.00.5 1.05.5 RAPID3 (0–30) 21.21.00.81.511.5 Tender Joint Count (0-28) 1420010 Swollen Joint Count (0-28) 121008 MD Global (0-10) 8.01.00.5 6.5 CDAI (0-76) 43.04.51.01.530.0 L-ESR 438131014 T-PrednisoneN3qd3qd T-MethotrexateN10qwC20qw20qw15qwC25qw T-Folic acidN1qd1qd T-acetamnphn/Codn 30tid D/C T-Naproxen880q6h440bidprn T-AdalimumabN40qow

78. 0 0 0.5                                  MDHAQ/RAPID3: 8 Feb 2005 3 RA Core Data Set scores FN (0–10) = 0 PN (0–10) = 0.0 PTGL (0–10) = 0.5 RAPID3 (0–30) = 0.5 Severity: 12.1-30 = High 6.1-12 = Moderate 3.1-6 = Low 0-3 = Near remission

79. Visit 6: 8 Feb 2005 Visit date 4No0313Ja0420Ap0428Se0428De048Fe05 Q-Function (0–10) 2.700.300 0 Q-Pain (0–10) 9.50.50.00.56.0 0.0 Q-Global (0–10) 9.00.5 1.05.5 0.5 RAPID3 (0–30) 21.21.00.81.511.5 0.5 L-ESR 438131014 T-Prednisone N3qd3qd T-Methotrexate N10qwC20qw20qw15qwC25qwC15qw T-Folic acid N1qd1qd T-acetamnphn/codn30tid D/C T-Naproxen 880q6h440bidprn D/C T-Adalimumab N40qow40qow N=new drug, C=change in dose, T=taper, D/C=discontinue

80. 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

81. 20001985 051015 Disease Duration (Years) 2.0 1.5 1.0 0.5 0.0 MHAQ Disease Duration (Years) MHAQ 2.0 1.5 1.0 0.5 0.0 2005101520 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

82. 20001985 051015 Disease Duration (Years) 20 16 12 8 4 0 Swollen Joint Count 28 Disease Duration (Years) Swollen Joint Count 28 2005101520 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

83. Cross-Sectional Data: All RA Patients seen by TP in 1985 (n=125) and in 2000 (n=150): Larsen X-Ray score,% of Maximum RF+ RF- RF+ RF- 19852000 Pincus, Sokka, Kautiainen, Arthritis Rheum 52:1009, 2005

84. Methotrexate in RA Care: 1980-2005 Jyvaskyla, Finland & Nashville, TN Sokka and Pincus. Rheumatology (Oxford). 2008:47:1543-1547

85. 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.

86. Larsen radiographic scores in 295 patients in Jyväskylä, Finland, 5 years after presentation (dx), according to the period of presentation Sokka T, Pincus T. Rheumatology (Oxford) 2008; 47:1543-7

87. 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

88. 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.

89. 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/Chapte r 26, page 690)

90. Is weekly low-dose methotrexate one of the safest medications available in clinical medicine, far safer than (almost) all antibiotics, anti-depressants, statins, etc.?

91. T Pincus, TWJ Huizinga, Y Yazici J Rheumatol. 34:250-252, 2007

92. Medication All 4,363 patients in 15 countries 301 Danish patients Prednisone Ever66%43% Methotrexate Ever83%85% Leflunomide Ever21%11% Sulfasalazine Ever43%64% Biological Agent Ever23% QUEST-RA: Medications in 4,363 patients in 15 countries Sokka, Kautiainen, Toloza, Mäkinen, Verstappen, Lund, Hetland, et al. QUEST-RA: Ann Rheum Dis 66:1491-1496, 2007.

93. Mean and median initial prednisone dose in 308 patients with rheumatoid arthritis (RA) seen from 1980 through 2004, computed in 5-year periods 1980-84 N = 37 1985-89 N = 74 1990-94 N = 77 1995-99 N = 61 2000-04 N = 59 Initial prednisone dose (mg/day)

94. Percent change (  ) over 12 and 24 months in MDHAQ-FN (0-10) in 308 patients treated with prednisone 1980-2004 (“+” indicates improvement and “-” worsening) Year First Seen N Initial dose <5 mg/d Initial dose  5 mg/d Baseline FN 12-mo  24-mo  Baseline FN 12-mo  24-mo  1980-8437None-- 4.1+33%+32% 1985-89741.4-5%-20%3.3+45%+26% 1990-94771.7+26%+46%3.2+44%+38% 1995-99612.7+33%+14%3.9+27%+28% 2000-04592.6+37%+29%4.3+25%+33% TOTAL3082.4+34%+24%3.5+40%+31%

95. 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

96. 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 groupClinical trial results1 mg2 mg3 mg4 mgTotal PrednisoneNumber randomized 1210215 Withdrew – lack of efficacy 0030 3* Completed trial 126110* Withdrew – administrative 00112 PlaceboNumber randomized 0112316 Withdrew – lack of efficacy 019111* Completed trial 0022 4* Withdrew – administrative 00101 TOTAL 1322531 *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.

97. 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 MTX B. 30 incomplete responders initiating biologic agent 63 Adequate Responders (“Controls”) 30 Incomplete Responders MTX Start Follow-up (NO Biologic) MTX Start Biologic Start ESR 24162818 MDHAQ-Function 2.31.03.23.3 Pain 4.11.45.26.8 Patient Global 4.20.95.5 RAPID3 10.63.614.916.2

98. 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.