Measures in RA: Joint counts, radiographs, laboratory tests, patient questionnaires - advantages and disadvantages

1. Measures in RA: Joint counts, radiographs, laboratory tests, patient questionnaires - advantages and disadvantages t.pincus@vanderbilt.edu

2. 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.

3. Complexities in assessment of patients with rheumatic diseases: No single “gold standard” (eg, blood pressure, cholesterol) for clinical trials or standard care: therefore, indices of 3-7 measures. Laboratory tests limited in both diagnosis and treatment - primary criteria are clinical. Patient questionnaires to assess physical function, pain, global status, often best quantitative measures.

4. 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) • 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.

5. Clinical researchClinical care Joint count 68/70 joints -tender, 28 joints – tender, swollen swollen, limited motion, pain on motion, deformed X-ray Detailed Larsen, Sharpe/ ?Erosions van der Heijde scores ?Joint space narrowing Lab ESR, CRP, anti-CCP, RF ESR, CRP, anti-CCP, RF Patient questionnaires Complete, long Patient friendly,<10 min Takes time Saves time for MD Complex scoring “Eyeball” results Results to data center Results on clinical flowsheet Results unknown in care Adds to clinical care RA Measures for clinical research vs clinical care

6. Formal Joint Counts in Management of Patients With RA • Most specific measure to assess RA • Most important measure in clinical trials • 28-joint count as useful in clinical trials as 68–70 joint counts

7. Joints included in various standard joint counts

8. A simplified twenty-eight-joint quantitative articular index in rheumatoid arthritis HA Fuchs, RH Brooks, LF Callahan, T Pincus Arthritis Rheum 32:531-537, 1989

9. 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%

10. Median number of seconds to score various RA measures

11. Relative efficiencies of 7 ACR Core Data Set measures in 4 adalimumab clinical trials a. Arithmetic change

12. Some Problems With Joint Counts in RA • Joint counts have lower relative efficiencies than MD global and patient measures • Formal studies indicate poor reproducibility • Tedious to perform – interrupt visit • Most visits to a rheumatologist include a careful joint examination, but do not include a formal joint count

14. Should contemporary rheumatoid arthritis clinical trials be more like standard patient care and vice versa? T Pincus, T Sokka Ann Rheum Dis 63(Suppl II):ii32-ii39, 2004

15. 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

17. Radiographic and joint count findings of the hand in rheumatoid arthritis: related and unrelated findings HA Fuchs, LF Callahan, JJ Kaye, RH Brooks, EP Nance, T Pincus Arthritis Rheum 31:44-51, 1988

18. Radiographs and joint counts in RA: Related and unrelated findings Fuchs, Callahan, Kaye, Brooks, Nance, Pincus Arthritis Rheum 31:44, 1988

19. Associations of HLA-DR4 with rheumatoid factor and radiographic severity in rheumatoid arthritis. NJ Olsen, LF Callahan, RH Brooks, EP Nance, JJ Kaye, P Stastny, T Pincus Am J Med 84:257-264, 1988

20. Strongly and Weakly Related Measures to Assess RA Radiographs ESR, CRP Shared epitope Rheumatoid factor Joint deformity Duration of disease Functional disability Pain Patient global Joint swelling Joint tenderness Age

21. Predicting Mortality in RA: Most Baseline Measures Are Worse in Patients Who Will Die Over a 5-Year Period Mean Baseline Values P Value Alive Dead Age (years) 55.1 65.5 < 0.001 ARA functional class 2.2 2.6 < 0.001 1.1 2.1 < 0.001 Number of comorbidities 10.8 16.8 < 0.001 Walking time 33.8 48.3 0.004 ESR 1.98 2.32 0.005 mHAQ score 2.41 2.55 0.007 Learned helplessness 2.6 3.0 0.01 Global self-report 0.2 0.5 0.02 Number of extra-articular features 9.1 12.7 0.03 Duration of disease 10.8 9.4 0.03 Years of education 12.8 15.9 0.04 Joint count 1.2 1.4 0.20 Radiograph score 2.7 2.9 0.28 RF titer 5.40 5.19 0.68 Pain Callahan LF, et al. Arthritis Care Res. 1997;10:381–394.

22. RA Cohort #2-Cox Proportional Hazards Model Analyses Including Demographic, Functional, Self-Report, Joint Count, X-ray, Laboratory and Disease Variables in 206 patients Univariate Stepwise Model RR (95% CL) RR (95% CL) P Value P Value 1.07 <0.001 1.06 <0.001 Age 1.63 <0.001 1.40 0.02 Comorbidity 2.00 0.003 1.76 0.02 MHAQ ADL Score 1.04 0.02 -- -- Disease duration 0.89 0.007 -- -- Education 1.01 0.005 -- -- ESR 1.02 0.10 -- -- Joint count 1.03 0.04 -- -- Walking time 1.40 0.17 -- -- X-ray Arthritis Care Res 10:381,1997

23. 5-Year Survival in 206 Patients with RA: 1985-1990 Rheumatoid Factor MHAQ Score 100 100 80 80 60 60 Survival (%) Survival (%) 1.00 (12) Absent (29) 40 40 1.01–1.99 (91) Present (175) 2.00–2.99 (86) 20 20 3.00 (21) 0 0 0 12 24 36 48 60 0 12 24 36 48 60 Months After Baseline Months After Baseline Arthritis Care Res. 1997;10:381.

24. Predictors of mortality in RA n=1922 Odds Ratio z score p value HAQ 2.93 11.1 <0.001 Pt Global severity 1.28 8.5 <0.001 Pain 1.25 8.3 <0.001 Depression 1.34 8.8 <0.001 Anxiety 1.28 7.2 <0.001 Grip strength 1.01 6.2 <0.001 ESR 1.01 5.7 <0.001 RF, titer 1.13 4.6 <0.001 Hematocrit 1.06 3.8 <0.001 Larsen X-ray score 1.04 4.7 0.002 Duration 1.01 2.1 0.036 Joint count 1.01 0.76 0.445 Age 1.09 11.9 <0.001 Comorbidities 1.19 4.69 <0.001 Male 2.10 5.28 <0.001 Wolfe et al Arth Rheum 48:1530, 2003

25. 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, Puolakka et al. Ann Rheum Dis 64:130-133, 2005 ) • 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)

26. Some Problems With Radiographs in RA • Quantitative score tedious to perform • Treatment initiated prior to erosions – MRI, ultrasound are more sensitive • Radiographic damage has poor prognostic value for work disability, death and even joint replacement

27. Laboratory Tests in Diagnosis and Management of Patients With RA • Most important measure in most clinical situations, e.g., cholesterol, hemoglobin, creatinine, glucose, etc. • Many tests may be of value – CBC, ESR, CRP, RF, anti-CCP • No work for the rheumatologist

28. ESR Values in Patients With RA Wolfe F, Michaud K, J Rheumatol. 1994;21:1227–1237.

29. ESR and CRP at 1st Visit

30. The level of inflammation in rheumatoid arthritis is determined early and remains stable over the longterm course of the illness F Wolfe, T Pincus J Rheumatol 28:1817-1824, 2001

31. Some Problems With Laboratory Tests in Diagnosis and Management of RA • ESR & CRP - normal in 40% at presentation • Anti-CCP & RF - negative in 20–50% of patients • Treatment decisions are based primarily on clinical criteria • 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

32. Why should rheumatologists collect patient self-report data in routine clinical care? • Significant correlation with joint counts, ESR, X-ray • More reproducible than joint counts, lab, X-ray score • As informative as ACR20/50/70 or DAS in clinical trials • Predict work disability, costs, TJR, and premature death more significantly than traditional measures • Data most relevant to patient and family • Saves time for patient and MD to focus on major patient matters including under-appreciated concerns • Record quantitative data to document status from one visit to the next, particularly over long periods • Doctor does not measure but interprets measures • MDHAQ- all key data and indices one side of one page • Adds to the rheumatologist to be a better doctor

33. ACR Core Data Set Measure changes - 12 Months: Leflunomide (LEF) vs Methotrexate (MTX)vs Placebo (PBO) Measure: LEF PBO MTX 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 Strand V, et al. Arch Intl Med. 1999; 159:2542-2550; Tugwell P, et al. Arthritis Rheum. 2000; 43:506-514.

34. 9- to 10-Year Survival According to Quantitative Markers in Three Chronic Diseases Rheumatoid Arthritis – Activities of Daily Living Rheumatoid Arthritis – Formal Education Level A B 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 Hodgkin’s Disease – Anatomic Stage Coronary Artery Disease – # of Involved Vessels C D 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

35. 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 < vs > 91.5% “with ease” 2.9:1 # of Involved Joints > vs < 18 joints 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 2.9:1 Systolic blood pressure >142 vs <118 mmHg 3.0:1 Diastolic blood pressure >92 vs <76 mmHg 2.9:1 Smoking >26 vs 0 cigarettes/day 2.9:1 Data adjusted for age, sex, education, disease duration

36. Treatment with TNF blockers is associated with reduced premature mortality in patients with rheumatoid arthritis LTH Jacobsson, C Turesson, JA Nilsson, IF Petersson, E Lindqvist, T Saxne, P Geborek Arthritis Rheumatism 54:S330, 2006

37. A Practical System That (Almost) Works For Routine Assessment of Functional Status, Fatigue and Psychological Distress 1. Patient given 2-page questionnaire by receptionist: completed in waiting room 2. Nurse (or physician) reviews and/or completes medication data 3. Physician does as little as possible: completes brief data (may include joint count) 4. Office staff enters flow sheet with laboratory data

41. Clinical researchClinical care Complete, long Patient friendly,<10 min Takes time Saves time for MD Complex scoring “Eyeball” results No scoring at visit Scoring templates for MD Results unknown in care Adds to clinical care Send to data center Review with patient Enter into computer Enter unto flowsheet add to care, documentation Patient questionnaires in clinical research vs clinical care

42. HAQ & multidimensional HAQ (MDHAQ) HAQ MDHAQ 1st report 1980 1999 Patient completion 5-10 min 5-10 min # ADL 20 10 Pain VAS 10 cm line 21 circles Pt Global VAS 10 cm line 21 circles Psych, sleep No Sleep, anxiety RADAI self-report depression joint count No Yes Fatigue No VAS Review of Systems No 60 Symptoms Medical history No Surgery, side effects Demographic data No Yes Social history No Yes Scoring templates No Yes Index No RAPID MD scan (“eyeball”) 30 secs 5 secs Time to score 41.8 secs 7.5 secs

43. MDHAQPage 1

44. KeepItSimpleStupid

45. Considering all the ways in which illness and health conditions may affect you at this time, please indicate below how you are doing:VERY              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 POORLYVERY ______________________________________________ VERYWELL POORLY

46. 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

47. RA 35 yo F (#13) Onset: 02/2003 Visit 1 N = new drug, C = change in dose, T = taper, D/C = discontinue

48. RA 35 yo F (#13) Onset: 02/2003 Visit 2 N = new drug, C = change in dose, T = taper, D/C = discontinue

49. RA 35 yo F (#13) Onset: 02/2003 Visit 3 N = new drug, C = change in dose, T = taper, D/C = discontinue

50. RA 35 yo F (#13) Onset: 02/2003 Visit 4 N = new drug, C = change in dose, T = taper, D/C = discontinue