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Patient questionnaires: Standardized quantitative “scientific” data from a patient history, the primary source of rheumatology treatment decisions Theodore Pincus MD Clinical Professor of Medicine New York University [email protected] Disclosures Theodore Pincus, MD Sources of Funding for Research: Amgen Inc.; BristolMyers 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 Many, if not most, doctors have extensive information about their patients with a few mouse clicks concerning: Scheduling Billing Laboratory tests Medications BUT NOT: Is the patient better, worse, or the same? With which treatments? Why not ask the patient in a structured, “scientific” format, ie, self-report questionnaire? Why measurement? This wine is expensive – $60 or $6,000 The patient has a fever – 101º or 106ºF, 38º or 40ºC The blood pressure is high – 150/95 or 250/125 The patient is “doing well” – What is the DAS28, CDAI or RAPID3 Complexities in quantitative assessment of patients with RA and rheumatic diseases • Laboratory tests are limited in diagnosis and treatment decisions • Treat radiograph before damage • No single ‘Gold Standard’ measure, eg, blood pressure, cholesterol, glucose, for diagnosis and management in all individual patients • Therefore, need indices of 3–7 measures 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) 3. 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. Types of measures to assess patients with RA • • • • • Joint counts Radiographs Laboratory tests Patient questionnaires Global estimates 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 Widely-accepted by rheumatologists and FDA as “best” measures 28-joint count as useful as 68–70 joint count Changes in ACR Core Data Set Measures Over 12 Months: Leflunomide (LEF) vs Methotrexate (MTX) vs Placebo (PBO) Measure: LEF PBO MTX Tender Jts Swollen Jts MD Global ESR FN- HAQ FN-MHAQ Pain Pt Global -7.7 -5.7 -2.8 -6.3 -0.45 -0.29 -2.2 -2.1 -3.0 -2.9 -1.0 +2.6 +0.03 +0.07 -0.4 +0.1 -6.6 -5.4 -2.4 -6.5 -0.26 -0.15 -1.7 -1.5 Effect Relative Size Efficiency -0.59 1.00 -0.44 0.56 -0.68 1.33 -0.41 0.48 -0.80 1.84 -0.69 1.37 -0.65 1.21 -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. 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 25–49% of visits 50–74% of visits 75–99% of visits Always 32% 11% 14% 16% 14% Time to Score RA Measures - Seconds 150 114 100 50 106 94 42 9.6 4.6 0 28 Joint HAQ-DI DAS28 Count CDAI RAPID3 RAPID3 (0-10) (0-30) Pincus et al 2009; Arthritis Care Res. in press Some Limitations of Formal Joint Counts Relative efficiencies similar or lower than global and patient measures in clinical trials May improve over 5 years while joint damage and functional disability may progress Poorly reproducible Not performed at most visits in usual care The most specific measure for diagnosis is not necessarily the most significant measure for prognosis and management. 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 9- to 10-Year Survival According to Quantitative Markers in Three Chronic Diseases A Rheumatoid Arthritis – Activities of Daily Living B 100 >90% 81%–90% 80 % Active “With Ease” 60 40 71%–80% 70% 20 Survival (%) Survival (%) 100 Rheumatoid Arthritis – Formal Education Level >12 Years 80 9–12 Years 60 8 Years 40 20 (Data from Pincus et al, 1987) (Data from Pincus et al, 1987) Months 0 40 60 80 100 Hodgkin Disease – Anatomic Stage 100 0 D Stage I 80 60 Stage II All Stages, All Causes Stage III Stage IV 40 20 (Data from Kaplan, 1972) 0 2 4 6 Years 8 10 Survival (%) Survival (%) C 20 Months 20 40 60 80 100 Coronary Artery Disease – No. of Involved Vessels 100 80 1 Artery 60 2 Arteries 40 3 Arteries LCA 20 (Data from Proudfit et al, 1978) 0 2 4 6 8 Years 10 Change from baseline (Mean +/- SE) TEMPO Trial: Year 2 Radiograph: Change in Total Sharp Score from 8 Baseline to Year 2 7 6 5 MTX = 206 E = 203 MTX+E = 213 3.34 (CI 1.18, 5.50) 4 3 2 1.10* (CI 0.13, 2.07) 1 0 -1 * 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) 450 400 350 300 250 200 150 100 50 1 1.59 -0.54 ERA ETA ERA MTX TEMPO Combi 0.52 2.8 0.4 3.7 1.3 3 5.7 IFX MTX PREMIER Combi PREMIER ADA PREMIER MTX 0 TEMPO ETA TEMPO MTX IFX Combi Yazıcı Y, Yazıcı H, Arthritis Rheum 2006;54(supl) 2 Year Change in Total Sharp/van der Heijde X-ray score (0–448): TEMPO probability plot TEMPO=Trial of Etanercept and MTX with radiographic Patient Outcomes. van der Heijde, et al. Arthritis Rheum 2006;54:1063–74. 19 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 estimate Socioeconomic status Joint tenderness Age Pincus T, Sokka T: Best Pract Res Clin Rheumatol 17:753-781, 2003. 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) ARA functional class Number of comorbidities Walking time ESR mHAQ score Learned helplessness Global self-report Number of extra-articular features Duration of disease Years of education Joint count 55.1 2.2 1.1 10.8 33.8 1.98 2.41 2.6 0.2 9.1 10.8 12.8 65.5 2.6 2.1 16.8 48.3 2.32 2.55 3.0 0.5 12.7 9.4 15.9 < 0.001 < 0.001 < 0.001 < 0.001 0.004 0.005 0.007 0.01 0.02 0.03 0.03 0.04 Radiograph score RF titer Pain 1.2 2.7 5.40 1.4 2.9 5.19 0.20 0.28 0.68 Callahan LF, et al. Arthritis Care Res. 1997;10:381–394. RA Cohort #2- Cox Proportional Hazards Model Analyses Including Demographic, Functional, SelfReport, Joint Count, X-ray, Laboratory and Disease Variables in 206 patients Age Univariate RR P (95% CL) Value 1.07 <0.001 Stepwise Model RR P (95% CL) Value 1.06 <0.001 Comorbidity MHAQ ADL Score Disease duration Education ESR Joint count 1.63 2.00 1.04 0.89 1.01 1.02 <0.001 0.003 0.02 0.007 0.005 0.10 1.40 1.76 ----- Walking time X-ray 1.03 1.40 0.04 0.17 --- Arthritis Care Res 10:381,1997 0.02 0.02 ------- MRI can better identify early bone erosions than X-ray Some Problems With Radiographs in RA 1. Quantitative score tedious to perform 2. Treatment initiated prior to erosions – MRI, ultrasound more sensitive 3. Radiographic damage has poor prognostic value for work disability, death and even joint replacement 4. Treatment prior to erosions Laboratory Tests in Diagnosis and Management of Patients With RA 1. Most important measure in most clinical situations, e.g., cholesterol, hemoglobin, creatinine, glucose, etc. 2. Many tests may be of value – CBC, ESR, CRP, RF, anti-CCP 3. No work for the rheumatologist Textbook statements concerning ESR in RA "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 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 Pincus and Tugwell J Rheumatol 2006 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 Females 63% 37% Males 55% 45% Similar results have seen reported from: Nashville, TN USA Jyvaskyla, Finland Oslo, Norway Nancy, France Gronigen, the Netherlands Belfast, Ireland Mean ESR (mm/Hr) 4 Locations – 1996: Location Oslo,Norway Nancy, France Gronigen, Netherlands Belfast, N Ireland n 237 135 283 51 ESR 6 9 8 8 26 29 28 28 Smedstad LM, Moum T, Guillemin F,Kvien TK, Finch MB, Suurmeijer TPBM, Van Den Heuvel WJA Br J Rheumatol 1996; 35:746-51 ESR and CRP at 1st visit in US and Finland – 1980-2005 CRP ESR ≥28 mm/hr <28 mm/hr Jyvaskyla, Finland n=1744 Total 55% 45% <10 mg/L 11% 33% >10 mg/L 44% 12% Nashville, Tennessee, USA n=170 Total 45% 55% <10 mg/L 17% 42% >10 mg/L 28% 13% Total 100% 44% 56% 100% 59% 41% Sokka and Pincus – J Rheumatol 2009 Mean/median baseline ESR in RA patients in 23 studies, by first year of recruitment First year of recruitment Period of recruitment Median ESR (mm/h) Mean ESR (mm/h) 1954-1980 (7 studies) 1954-1995 47 50 1981-1984 (8 studies) 1981-1999 38 41 1985-1996 (8 studies) 1985-2000 36 35 Abelson B, Sokka T, Pincus T. J Rheumatol 2009 Meta-analysis: Anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) Anti-CCP Number of studies 37 Positive likelihood ratio 12.5 Odds ratio for RA 16.1 – 39.0 RF 50 4.9 1.2 – 8.7 Nishimura K et al. Annals of Internal Medicine 146:797-808, 2007 Meta-analysis: Anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) Number of studies Positive likelihood ratio Odds ratio for RA Sensitivity Specificity % of Patients with negative test result Anti-CCP 37 12.5 16.1 – 39.0 67% 95% RF 50 4.9 1.2 – 8.7 69% 85% 33% 31% Nishimura K et al. Annals of Internal Medicine 146:797-808, 2007 RA Cohort #2- Cox Proportional Hazards Model Analyses Including Demographic, Functional, SelfReport, Joint Count, X-ray, Laboratory and Disease Variables in 206 patients 1985-1990 Age Univariate RR P (95% CL) Value 1.07 <0.001 Stepwise Model RR P (95% CL) Value 1.06 <0.001 Comorbidity MHAQ ADL Score Disease duration Education ESR Joint count 1.63 2.00 1.04 0.89 1.01 1.02 <0.001 0.003 0.02 0.007 0.005 0.10 1.40 1.76 ----- Walking time X-ray 1.03 1.40 0.04 0.17 --- Arthritis Care Res 10:381,1997 0.02 0.02 ------- 5-Year Survival in 206 Patients With RA: Cohort #2 – 1985-1990 Rheumatoid Factor MHAQ Score 80 80 Survival (%) 100 Survival (%) 100 60 60 40 Absent (29) Present 20 (175) 0.00 (12) 0.01–0.99 (91) 1.00–1.99 (86) >2.00 (21) 40 20 0 0 0 12 24 36 48 Months After Baseline Arthritis Care Res 10:381,1997 60 0 12 24 36 48 Months After Baseline 60 IgM rheumatoid factor binding IgG MultiDimensional Health Assessment Questionnaire (MDHAQ) Page 1 % of RA patients with abnormal measures at presentation: evidence, not eminence-based • RF positive - 69% (1) • Anti-CCP positive - 67% (1) • ESR >28 mm/Hr - 57% (2,3) • CRP >10 - 58% (2) 1- Nishimura et al, Ann Int Med 146:797-808, 2007 2 - Wolfe and Michaud, J Rheumatol 21:1227–1237, 1994 3 - Sokka and Pincus, J Rheumatol 36:1387--1390, 2009 Some Problems With Laboratory Tests in Diagnosis and Management of RA 1. ESR & CRP - normal in 40% at presentation 2. Anti-CCP & RF - negative in 20–50% of patients 3. Treatment decisions are based primarily on clinical criteria 4. 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 Patient self-report questionnaires 1. HAQ and RAPID3 score as informative as ACR20/50/70 or DAS in clinical trials 2. Significant correlation with joint count, ESR, X-ray – individual measures and indices 3. Predict work disability, costs, TJR, and premature death more significantly than traditional measures 4. Quantitative measures to save time for patient and MD to focus on major patient matters 9-10 Year Survival According to Quantitative Markers in Three Chronic Diseases Rheumatoid Arthritis Activities of Daily Living A Rheumatoid Arthritis - B >90% 81–90% 80 % Active “With Ease” 60 40 71–80% Survival (%) Survival (%) 100 >12 Years 80 9–12 Years 60 8 Years 40 20 70% 20 Formal Education Level 100 (Data from Pincus et al, 1987) (Data from Pincus et al, 1987) 20 60 80 100 100 Stage I 80 Stage II Stage III All Stages, All Causes Stage IV 60 40 0 Months Hodgkin’s Disease Anatomic Stage C Survival (%) 40 20 D 0 2 4 6 8 10 Years 40 60 80 100 Months Coronary Artery Disease # of Involved Vessels 80 60 40 20 (Data from Kaplan, 1972) 20 100 Survival (%) 0 1 Artery 2 Arteries 3 Arteries LCA (Data from Proudfit et al, 1978) 0 2 4 6 8 10 Years 5-Year Survival in 206 Patients With RA: Cohort #2 – 1985-1990 Rheumatoid Factor MHAQ Score 80 80 Survival (%) 100 Survival (%) 100 60 60 40 Absent (29) Present 20 (175) 0.00 (12) 0.01–0.99 (91) 1.00–1.99 (86) >2.00 (21) 40 20 0 0 0 12 24 36 48 Months After Baseline Arthritis Care Res 10:381,1997 60 0 12 24 36 48 Months After Baseline 60 Significance of 8 variables as predictors of mortality in 53 RA cohorts Significant in multivariate analyses 100% 6% 4% 22% 30% Significant in univariate analyses 34% 17% 32% 23% 21% 39% 32% 46% Not Significant 50% 39% 75% 50% 50% 28% 25% 72% 0% 65% Physical Cofunction morbidities (N=18) (N=23) 45% 44% 37% 31% Rheumatoid factor (N=29) Extraarticular disease (N=18) ESR (N=19) Socioeconomic status (N=13) 22% 11% Joint count (N=18) Hand radiograph (N=18) Sokka T, Abelson B, Pincus T. Clin Exp Rheumatol 26(suppl):S35-61, 2008 Prediction of premature mortality according to blood pressure and cholesterol converted hypertension and hypercholesterolemia from optional treatments to major public health campaigns. Imagine doctors saying that they do not measure blood pressure or cholesterol because “it takes too much time” or “the staff will not cooperate,” as suggested for why they do not measure physical function. The MDHAQ in Clinical Rheumatology • In rheumatoid arthritis, the MDHAQ distinguishes MTX or LEF from placebo in a clinical trial as effectively as a joint count or the ACR 20 • In osteoarthritis, the MDHAQ distinguishes NSAID from acetaminophen as effectively as the WOMAC • In fibromyalgia, the MDHAQ distinguishes patients from those with rheumatoid arthritis as effectively as an ESR Physical function/activities of daily living (ADL) in prognosis of non-Rheumatic Diseases • In congestive heart failure, ADL predict 36month mortality as ejection fraction Konstam, Am J Cardiology 78:890, 1996 • In AIDS, ADL predict 36-month mortality as CD4/CD8 ratios, clinical AIDS prognostic staging (CAPS), severity classification for AIDS hospitalizations (SCAH) Justice, J Clin Epidemiology 49:193, 1996 • In hospitalized elder patients, ADL predict 1-year mortality beyond physiologic data and comorbidities Covinsky, J Gen Intern Med 12:203, 1997 Some limitations of patient self-report questionnaires Need for translation Cultural and linguistic issues Possibility of ‘gaming’ by patient, health professional to provide desired responses Not specific to any disease