1. Longitudinal databases and registries – why? t.pincus@vanderbilt.edu

2. Longitudinal databases and registries – why? 1.Randomized trials have many limitations, especially patient selection, short time frame 2.Document improvements in patient outcomes over 5-20 years. 3.How do we know if treatment improves outcomes, eg, survival?

3. 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 - requires information from clinical observational data in addition to clinical trials

4. Eminence-based medicine- example “ patients with rheumatoid arthritis (RA) usually respond to a conservative program of nonsteroidal anti- inflammatory drugs, rest, and physical therapy…” HE Paulus, HJ Williams, JR Ward, JC Reading, MJ Egger, ML Coleman, CO Samuelson, Jr., RF Willkens, M Guttadauria, GS Alarcon, SB Kaplan, EJ MacLaughlin, A Weinstein, RL Wilder, MA Solsky, RF Meenan. Arthritis & Rheumatism 27:721,1984.

5. 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.

6. Evidence-based medicine- example “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.

7. Longitudinal databases and registries – why? 1.Randomized trials have many limitations, especially patient selection, short time frame 2.How do we know if treatment improves outcomes, eg, survival? 3.Document improvements in patient outcomes over the years by evidence, not eminence.

8. 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 4.Inflexible dosage schedules and concomitant drug therapies

9. 0.5 1 1.5 2 0 ( n=28) Plac (n=25) AUR (n=11) AntiM (n=15) AZA (n=28) Gold (n=9) MTX (n=22) DPen (n=8) SSZ <.0001 <.05 Effect in Standard Units *Composite of grip strength (adjusted for disease duration and trial length), tender joint count (adjusted for initial TJC and blinding and ESR Standard Composite Treatment Effect* Felson, Anderson, Meenan. Arthrit Rheum. 1990;33:1449.

10. Estimated Continuation of Courses of 2nd Line Therapies Over 60 Months in RA Patients 1.0 0.8 0.6 0.4 0.2 0 0 102030405060 Months Estimated Continuation Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885. Azathioprine (56) Hydroxychloroquine (228) Methotrexate (253) Oral gold (84) Parenteral gold (269) Penicillamine (193)

11. RA Cohort #2-15 US sites 1985-90 Participating Rheumatologists F. AdamsTN J. BarberCA W. BarthDC M. BrittonCA G. GordonPA J. HustonTN J.T. JohnTN J. JohnsonTN A. KennedyFL R. PolkID J. RaittCA J. Reinertsen MN E. SchnedMN J. SergentTN A. WheltonFL

12. Azathioprine (56) Hydroxychloroquine (228) Methotrexate (253) Oral gold (84) Parenteral gold (269) Penicillamine (193) 100 80 60 40 20 0 0 1020 3040 5060 Months Estimated Continuation (%) Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885. All Courses Over 60 Months Estimated Continuation of Courses of 2nd-Line Therapy Initial Course Over 12 Months Months Estimated Continuation (%) 2020 4040 6060 8080 10 0 0 012345 6 91 78101212 Methotrexate (61) Hydroxychloroquine (130) Penicillamine (55) Parenteral gold (207) Oral gold (5) Azathioprine (19)

13. Survival in SLE Nephritis Austin, Klippel, Balow, et al, NEJ Med 314:614, 1986

14. 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 4.Inflexible dosage schedules and concomitant drug therapies

15. ATTRACT trial clinical inclusion criteria  6 tender joints and  6 swollen joints 2 of 3: Morning stiffness  45 min ESR  28 mm / hour CRP  2.0 mg / dL MTX dose  12.5 mg / week Criteria: 138 96 2177 48 15 1614 Do not meet ATTRACT criteria Meet ATTRACT criteria 74295 19 21 42 Sokka and Pincus Arthrits Rheum 48:213, 2003

16. 16 Etanercept in Early RA (ERA): ACR Responses at 52 Weeks % Patients 0 20 40 60 80 65 72 43 49 22 25 100 ACR20ACR50ACR70 Etanercept 25 mg (n = 207) MTX, mean 19 mg (n = 217) Bathon JM et al. N Engl J Med. 2000;343:1586-1593 p = NS

17. Number of patients who meet ERA clinical inclusion criteria – 1 st visit patients who did not take methotrexate  12 tender joints and  10 swollen joints Positive rheumatoid factor or erosions Morning stiffness  45 min or ESR  28 mm / hour Criteria: 19 9 2 2 0 0 0 0 Do not meet ERA criteria Meet ERA criteria 87 22 7 8 10 Sokka and Pincus Arthritis Rheum 48:213, 2003

18. % of Patients with RA who meet Criteria for Inclusion in Clinical Trials TPRecent Cliniconset RA 1998-20012001 Number of Patients 146300 1. > 6 Swollen Joints42.5%63.4% 2. > 6 Tender Joints25.3%50.4% 3. ESR > 2825.0%49.3% 4. AM Stiffness > 45 mins45.9%50.9% 1+2+3 or 422.0%34.1% 1+2+3 and 411.3%18.3% Sokka and Pincus, submitted for publication

19. 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 4.Inflexible dosage schedules and concomitant drug therapies

20. Percentage improvement Percentage deterioration Ritchie articular index Morning stiffness Radiological score VAS = 10 cm visual analogue scale Haemoglobin Pain VAS Grip strength Sedimentation rate Measures of activity and damage in patients with RA over 5 years Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268. 75 50 25 0 –25 –50 –75

21. -1.5-1.3-1.1-0.9-0.7-0.5-0.3-0.10.10.30.5 Malalignment Limited Motion Joint Space Narrowing Changes in Measures in 100 Patients with Rheumatoid Arthritis Over 5 Years Determined by Effect Sizes Tenderness Swelling Pain on Motion Radiographic Measures Joint Count Measures Laboratory Measures Clinical Measures Patient Questionnaire Measures Deformity Erosions Erythrocyte Sedimentation Rate Rheumatoid Factor Titer Hemoglobin Morning Stiffness Grip Strength Walk Time Button Time Functional Status - MHAQ Global Status Pain - Visual Analog Scale Helplessness E ffect Size Arthritis Care Res 10:381,1997 Better Better Worse

22. 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 4.Inflexible dosage schedules and concomitant drug therapies

23. Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic Diseases J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003 5. Variables other than randomization, such as education, clinical care site, etc., may affect outcome more than randomization group 6.Statistically significant results not necessarily clinically important, and vice versa 7.Rare toxicities not seen in fewer than 10,000 subjects 8.Balance of efficacy and toxicity may be unclear

26. Some Intrinsic Limitations of Controlled Clinical Trials in Chronic Diseases J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003 1.Control group does not remove bias – 1 st DMARD vs requirement to “fail” 2 DMARDs 2.Balance of efficacy and toxicity may be unclear – 90% remission with 1% renal failure Versus 50% improvement with no renal failure – which is the better therapy? 3.Results reported for groups of patients – ignore individual variation – most people prefer…is that true for all? 4.Loss of “placebo effect” when patent given “randomized” versus “best” therapy

27. 27 Infliximab + MTX (ATTRACT): ACR Responses at 30 and 54 Weeks 0 10 20 30 40 50 60 70 Week 30Week 54Week 30Week 54Week 30Week 54 ACR50ACR70ACR20 % Patients Maini R et al. Lancet. 1999;354:1932-1939. Lipsky PE et al. N Engl J Med. 2000;343:1594-1602. Placebo + MTX (n = 88) 3 mg/kg q8w* (n = 86) 3 mg/kg q4w* (n = 86) 10 mg/kg q8w* (n = 87) 10 mg/kg q4w* (n = 81) Infliximab + MTX p < 0.001* *vs placebo. ATTRACT = Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy.C

28. ACR Core Data Set Measure changes - 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

29. Longitudinal databases and registries – why? 1.Randomized trials have many limitations, especially patient selection, short time frame 2.Document improvements in patient outcomes over the years by evidence, not eminence. 3.How do we know if treatment improves outcomes, eg, survival?

30. Progression of the Larsen score in the 1970’s vs. 1980’s Disease duration (years) 12% Sokka T, Kaarela K, Mottonen T, Hannonen P. Clin Exp Rheumatol 1999 26%

31. 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 in Patients With RA: Cohort #2 in 1985 and Cohort #4 in 2000: Swollen Joint Count Scores Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005

32. 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

33. 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 in Patients With RA: Cohort #2 in 1985 and Cohort #4 in 2000: Multidimensional Health Assessment Questionnaire (MDHAQ) scores Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005

34. Cross-Sectional Data in RA Patients: Cohort #2- 1985 and Cohort #4-2000: Larsen X-Ray score,% of maximum 2000 RF+ RF- 0 5 0 RF positive RF+ RF- 1985 Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005

35. Median clinical status measures in two cohorts of patients with RA seen in 1984-86 (“1985”) and 1999-2001 (“2000”). Measure19852000p Swollen joints(0-28)12 (6,16)5 (2,10)<0.001 X-Ray (Larsen - 0-100)20 (2,36)3 (0,13)<0.001 ESR33 (16, 50)20 (9,33)0.016 Hemoglobin (g/L)129(116,138)136 (128,143)0.002 MHAQ (0-3)1.0 (0.6, 1.4)0.4 (0.1, 1.0)<0.001 Pain VAS (0-100)52 (32, 80)49 (15, 73)0.38 Gripstr,mmHg(30-300)82 (65,115)120 (91, 166)<0.001 Walk time,secs(0-20)8.6 (7.0,11.8)7.4 (6.6 8.7)0.018 Buttontest,scs(0-300)50 (39,71)40 (32, 52)<0.001 Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005

36. DMARDs used in the 1985 and 2000 TP cohorts DMARD 1985 Cohort2000 Cohort N%N% Total number of patients125100.0%150100.0% No DMARDs, no prednisone4636.8%53.3% Prednisone only3729.6%1510.0% Methotrexate + any other drug1310.4%11576.7% Prednisone + any other drug6451.2%12986.0% Methotrexate only or + prednisone or +hydroxychloroquine 1310.4%9261.3% Methotrexate + other traditional DMARDs001711.3% IM gold or hydroxychloroquine or D-pen or azathioprine or auranofin or cyclophosphamide only or + prednisone 2923.2%106.7% Leflunomide + any other drug0053.3% Infliximab + any other drug0032.0% Etanercept + any other drug0032.0% Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005

37. Mtx in RA Care - 1985-2000 Jyvaskyla, Finland & Nashville,TN

38. 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(S31):179-185, 2003

39. Is rheumatoid arthritis becoming less severe? A Silman, P Davies, HLF Currey, SJW Evans J Chronic Dis 36:891-897, 1983

40. Longitudinal databases and registries – why? 1.Randomized trials have many limitations, especially patient selection, short time frame 2.Document improvements in patient outcomes over the years by evidence, not eminence. 3.How do we know if treatment improves outcomes, eg, survival?

41. 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

43. 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

44. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis Improvement:>50%20-50%<20%D/CTotal # Patients99705235256 % Deceased21%17%52%66%34% Standard mortality 1.471.854.115.562.60 ratio Confidence(0.84-(0.97-(2.56-(3.29-(2.05- interval2.10)2.73)5.66)7.83)3.15) Krause, Schleusser, Herborn, Rau. Arth Rheum 43:14, 2000

45. 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

46. Methotrexate continuation in TP clinic standard care – 1990-2003 Yazici,Y. et al. Ann Rheum Dis 64, 207-211 (2005).

47. RA – 75 pts – 15 yrs - Pincus et al, Ann Int Med 120:26,1994 Functional status on patient questionnaire 91.5% “with ease”2.9:1 # of Involved Joints> vs < 18 joints3.0:1 CV disease – 312,000 pts – 12 yrs – Neaton et al, Arch Int Med 152:56,1992 Serum cholesterol >245 vs <182 mg/Dl2.9:1 Systolic blood pressure >142 vs <118 mmHg3.0:1 Diastolic blood pressure >92 vs <76 mmHg2.9:1 Smoking >26 vs 0 cigarettes/day2.9:1 Data adjusted for age, sex, education, disease duration Relative Risk of Death Over 12-15 Years in rheumatoid arthritis (RA) and cardiovascular (CV) disease according to baseline severity indicators

48. Longitudinal databases and registries – why? 1.Randomized trials have many limitations, especially patient selection, short time frame 2.Document improvements in patient outcomes over the years by evidence, not eminence. 3.How do we know if treatment improves outcomes, eg, survival?