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Measures in RA: Joint Counts, Radiographs, Laboratory Tests, Patient Questionnaires - Advantages and Disadvantages

This article discusses the various measures used in rheumatoid arthritis, including joint counts, radiographs, laboratory tests, and patient questionnaires, and the advantages and disadvantages of each. It also highlights the importance of evidence-based medicine in clinical data analysis.

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Measures in RA: Joint Counts, Radiographs, Laboratory Tests, Patient Questionnaires - Advantages and Disadvantages

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  1. Measures in RA: Joint counts, radiographs, laboratory tests, patient questionnaires - advantages and disadvantages tedpincus@gmail.com

  2. Disclosures 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

  3. 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.

  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 & Rheumatism 27:1344,1984

  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-roundsuntan and brilliant oratory may overcome absence of any supporting data ELEGANCE BASED MEDICINE - where the sartorialsplendor 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

  6. Rheumatoid arthritis: disappointing long-term outcomes despite successful short-term clinical trials T Pincus J Clin Epidemiol 41(11):1037-1041, 1988

  7. Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic DiseasesJ Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003 • Relatively short observation period • Inclusion and exclusion criteria - most patients ineligible in most trials • Surrogate markers - may be suboptimal for actual outcomes, e.g., T cell counts vs. AIDS, tender joints vs. surgical replacement • Inflexible dosage schedules and concomitant drug therapies

  8. Effect in Standard Units 2 1.5 1 0.5 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 <.0001 <.05 *Composite of grip strength(adjust for disease duration and trial length),tender joint count (adjust for initial TJC and blinding) and ESR Standard Composite Treatment Effect* Felson, Anderson, Meenan. Arthrit Rheum. 1990;33:1449.

  9. 1.0 0.8 Estimated Continuation 0.6 0.4 0.2 0 10 20 30 40 50 60 0 Months Estimated Continuation of Courses of 2nd Line Therapies Over 60 Months in RA Patients Azathioprine (56) Hydroxychloroquine (228) Methotrexate (253) Oral gold (84) Parenteral gold (269) Penicillamine (193) Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885.

  10. F. Adams TN J. Barber CA W. Barth DC M. Britton CA G. Gordon PA J. Huston TN J.T. John TN J. Johnson TN A. Kennedy FL R. Polk ID J. Raitt CA J. Reinertsen MN E. Schned MN J. Sergent TN A. Whelton FL RA Cohort #2-15 US sites 1985-90 Participating Rheumatologists

  11. Azathioprine (56) Hydroxychloroquine (228) Methotrexate (253) Oral gold (84) Parenteral gold (269) Penicillamine (193) 100 100 80 80 60 60 Estimated Continuation (%) Estimated Continuation (%) 40 40 20 20 0 0 10 20 50 60 0 30 40 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Estimated Continuation of Courses of 2nd-Line Therapy All Courses Over 60 Months Initial Course Over 12 Months Methotrexate (61) Hydroxychloroquine (130) Penicillamine (55) Parenteral gold (207) Oral gold (5) Azathioprine (19) Months Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885.

  12. Severe functional declines, work disability, and increased mortality rates 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

  13. Survival in rheumatoid arthritis 1973-1982 Pincus et al. Arthritis Rheum. 1984;27:864. J Rheumatol 1987;14:240

  14. 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

  15. Attributed Causes of Death in 2,262 RA Patients in 13 Series from Diverse Locales Compared to General Population Attributed Cause of Death % of RA Deaths % of 1977 US DeathsCardiovascular disease 42.1 41.0Cancer 14.1 20.4Infection 9.4 1.0Renal disease 7.8 1.1Pulmonary disease 7.2 3.9RA 5.3 <1GI disease 4.2 2.4CNS disease 4.2 9.6Accidents 1.0 5.4Miscellaneous 6.4 15.2Unknown 0.6 <1 Pincus T, Callahan LF. J Rheumatol. 1986;13:841.

  16. 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 Disease – Anatomic Stage Coronary Artery Disease – No. 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

  17. Why Include Quantitative Measurement in Care of Patients with Rheumatic Diseases? Assess Prognosis – guides general approach to therapy Treatment Decisions – specific agents, changes Documentation – from visit to visit, compare patients Reimbursement –value of treatment by rheumatologist

  18. Examples of measures that convey prognostic significance Blood pressure 220/140 Total cholesterol 528 Creatinine 20 Glucose 785 ESR 110 CCP >100 units

  19. 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.

  20. 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.

  21. Types of Measures to Assess RA Joint count Radiograph Laboratory tests Patient self-report questionnaires

  22. 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 • 28-joint count as useful in clinical trials as 68–70 joint counts

  23. Some Limitations of Formal Joint Counts • Joint counts have similar or lower relative efficiencies than global and patient measures to document differences between active and control treatments in clinical trials (Arthritis Rheum 48:625-630, 2003. Arthritis Rheum 52:1031-1036, 2005. J Rheumatol 33:2146-2152, 2006, Rheumatology, in press)

  24. Some Limitations of Formal Joint Counts • Joint counts may improve over 5 years while progressive joint damage and functional disability may occur (Callahan et al, Arthritis Care Res 10:381-394, 1997)

  25. Some Limitations of Formal Joint Counts Joint counts are poorly reproducible • Lewis et al. Br J Rheumatol 1988; 27:32. • Hart et al. J Rheumatol 1985; 12:716. • Klinkhoff et al. J Rheumatol 1988; 15:492. • Thompson et al. J Rheumatol 1991; 18:661. • Kvien et al. Ann Rheum Dis 2005; 64:1480. • Scott DL et al. 2006; 15:579.

  26. Some Limitations of Formal Joint Counts • Rheumatologists perform careful non-quantitative joint examination, but not formal joint count, at most visits in usual care (Pincus and Segurado, Ann Rheum Dis 65:820-822, 2006.)

  27. 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%

  28. 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

  29. TEMPO Trial: Year 2 Radiograph:Change in Total Sharp Score from Baseline to Year 2 3.34 (CI 1.18, 5.50) 1.10* (CI 0.13, 2.07) * p < 0.05, E vs MTX † p < 0.05, Combination vs MTX ‡ p < 0.05, Combination vs E -0.56†‡(CI –1.05, -0.06)

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

  31. RF+ RF 5 RF- positive 0 0 Cross-Sectional Data in RA Patients:Cohort #2- 1985 and Cohort #4-2000: Larsen X-Ray score,% of maximum2000 1985 RF- RF+ Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005

  32. 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.

  33. 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

  34. 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

  35. 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)

  36. 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

  37. 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

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

  39. ESR and CRP at 1st Visit to Clinic Sokka and Pincus, EULAR 2006

  40. 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

  41. 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

  42. Limitations of individual measures in RA: need for an index for patient assessment

  43. Disease Activity Score (DAS)in Rheumatoid Arthritis Based on score on visits with DMARD change: 0.56 X square root (tender joint count 28) + 0.28 X square root (swollen joint count 28) + 0.70 X log e (ESR) + 0.014 (patient assessment of global status or activity) Total DAS= 0-10 Van der Heijde et al, J Rheumatol 20:579,1993, Prevoo et al, Arthritis Rheum 38:44, 1995.

  44. DAS28 Categories – Activity Level Fransen and van RielClin and Exp Rheumatol, 2005 Level Interpretation 0–2.6 = Remission – therapy is working 2.6–3.19 = Low –maybe change therapy 3.2–5.1 = Moderate – consider strongly change in therapy 5.11–10 = High – change therapy or have a good reason not to do so

  45. Some Limitations of DAS Requires complex math – need calculator or website Requires laboratory tests – often uninformative or unavailable Requires formal quantitative joint count – often not done, poorly reliable

  46. Clinical Disease Activity Index (CDAI)Aletaha and Smolen Clin Exp Rheumatol 23:S100, 2005. No lab test or complex math Can be calculated in usual care Tender joint count 28 = 28 Swollen joint count 28 = 28 Patient global assessment = 10 Patient global assessment = 10 Total CDAI = 0-76

  47. CDAI Categories – Activity Level Aletaha and Smolen, 2005 Level Interpretation 0–2.8 = Remission – therapy is working 2.81–10 = Low – maybe change therapy 10.1–22 = Moderate – consider strongly change in therapy 22–76 = High – change therapy or have a good reason not to do so

  48. CDAI Overcomes 2 of 3 Limitations of DAS No complex math No laboratory test But… requires formal quantitative joint count

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