Patient Reported Outcome s in Clinical Practice and Research Arthritis as an Exemplar Leigh F. Callahan, PhD Program on Health Outcomes Seminar March 4, 25 Traditionally, clinical measures of biologic functioning have been used to evaluate the effectiveness of treatments on health outcomes; however, these measures do not capture the broad aspects of human functioning affected by treatment. 1 2 Discussion Areas An increasing focus has been placed on incorporating the patient s point of view when evaluating treatment processes and health outcomes. Health-Related Quality of Life (HRQOL) s generic versus condition-specific using arthritis as an exemplar Performance of a generic HRQOL measure compared to condition-specific measures in three different rheumatic diseases in a UNC Clinic Population Examples of use of patient-reported measures in rheumatoid arthritis in clinical and research settings Rationale for completion of patient-oriented questionnaires at rheumatology clinic visits 3 4 When measured, HRQOL has been used: HRQOL is most often recognized as an individual s perception of his or her own health that can clearly and directly affect physical or mental health. To distinguish different patients or groups of patients To predict patient outcomes To evaluate therapeutic interventions 5 6 1
Generic HRQOL s Condition-specific Generic HRQOL Indicators EuroQol Quality of Well-Being Scale Nottingham Health Profile Sickness Impact Profile Medical Outcomes Study Short Form 36 (SF-36) BRFSS HRQOL 7 8 Short Form-36 Health Survey (SF-36) Validated, widely-used generic measure of HRQOL Eight domains Scored -1 Age, sex-adjusted rates Two summary scores Physical component: PCS s how decrements in physical function affect day-to-day activities Impact of physical impairment/disability on HRQOL Mental component: MCS Impact of mental effect Symptoms of pain on HRQOL Normative-based scoring (mean: 5; SD: 1) Health-related quality of life Ware JE Jr, Sherbourne CD. Med Care. 1992;3:473-483 9 Physical function SF-36 Two-Component Model Role physical Bodily pain Physical component General health Vitality Mental component Ware JE Jr, Sherbourne CD. Med Care. 1992;3:473-483. Social function Role emotion Mental health 1 Behavioral Risk Factor Surveillance System (BRFSS) Established by the Centers for Disease Control and Prevention (CDC) State-level prevalence of the major behavioral risks among adults associated with premature morbidity and mortality BRFSS Administered by each state Random-digit dialed, telephone survey Ongoing Content Standard core sections Optional modules State-added questions 11 12 2
BRFSS HRQOL Self-perceived Health Would you say that in general your health is: Excellent Very good Good Fair Poor BRFSS HRQOL Recent Physical Health Now thinking about your physical health, which includes physical illness and injury, for how many days during the past 3 days was your physical health not good? 13 14 BRFSS HRQOL Recent Mental Health Now thinking about your mental health, which includes stress, depression, and problems with emotions, for how many during the past 3 days was your mental health not good? BRFSS HRQOL Recent Activity Limitations During the past 3 days for about how many days did poor physical or mental health keep you from doing your usual activities, such as selfcare, work, or recreation? 15 16 Condition-Specific HRQOL s Arthritis as an Exemplar 17 18 3
Rheumatoid Arthritis Osteoarthritis Ankylosing Spondylitis Arthritis = Inflammation of a joint (more than 1 specific diseases) Systemic Sclerosis Gout Systemic Lupus Erythematosus Juvenile Rheumatoid Arthritis Osteoarthritis - 21 million Fibromyalgia - 3.7 million Rheumatoid Arthritis - 2.1 million 19 2 Condition-Specific HRQOL s in Rheumatology Domains Covered in Rheumatic Disease Patient-Oriented s Health Assessment Questionnaire (HAQ) and its modifications MHAQ, CLINHAQ, MDHAQ Arthritis Impact ment Scales (AIMS) and its revision AIMS2 Functional Status Index (FSI) Western Ontario and MacMaster University Osteoarthritis Index (WOMAC) Fibromyalgia Impact Questionnaire (FIQ) Rheumatology Attitudes Index (RAI) Arthritis Self-Efficacy Scales Functional Disability Pain Social Roles and Function Stiffness Symptoms Sleep/Rest Fatigue/Energy Global Health/Well Being GI Problems Emotions/Mood Depression Anxiety Helplessness/Attitude Financial Aspects Priority Areas: Self-Stated Fries, 198; Pincus, 1983; Daltroy, 199; Poole, 1991; Wolfe, 1994;Meenan, 198; Jette, 1987; Bellamy, 1992; Burckhardt, 1991; Callahan, 1988; Lorig, 1987 21 22 Health Assessment Questionnaire (HAQ) Widely accepted, validated, rheumatology-specific instrument to assess physical function in RA Gold standard of OMERACT/FDA 2 questions covering 8 activities Dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, activities of daily living HAQ Disability Index (HAQ DI) Scores the worst items within each of the 8 domains Based on use of aids and devices OMERACT = Outcome s in Rheumatoid Arthritis Clinical Trials Buchbinder R et al. Arthritis Rheum. 1995;38:1568-158. Sullivan FM et al. Ann Rheum Dis. 1987;46:598-6. 23 Clinical Importance of HAQ Scores The HAQ has proven to be more predictive of RA disease progression than any other measure of the ACR response criteria A 1-unit increase/yr in HAQ DI over the first 2 years of disease is associated with a 9% greater disability and 87% greater costs over the next 3 years HAQ scores predict Functional status Work disability Cost of treatment Joint replacement surgery Death Pincus T et al. Ann Intern Med. 1994;12:26-34. Fries JF et al. Arthritis Rheum. 1996;39:616-622. Pincus T et al. Arthritis Rheum. 1984;27:864-872. Wolfe F et al. J Rheumatol. 1991;18:1298-136. Callahan LF et al. J Clin Epidemiol. 1992; 45:127-138. Wolfe F et al. J Rheumatol. 1998;25:218-2117. Lubeck DP et al. Arthritis Rheum. 1986;29:488-493. Wolfe F et al. Arthritis Rheum. 1998;41:172-182. Wolfe F et al. Arthritis Rheum. 1994;37:481-494. 24 4
SF-36 Scores Worsen With Comorbid Conditions Both Generic and Condition- Specific s Worsen with Increased Comorbidity Better SF-36 Physical Functioning Score 1 8 6 4 2 Median 25 Worse None One Two or more n=52 (38%) n=32 (23%) n=53 (39%) Number of Comorbid Conditions Talamo J et al. Br J Rheumatol. 1997;36:463-469. 26 HAQ Scores Worsen With Comorbid Conditions Worse 3. Median 2.5 HAQ Score 2. 1.5 1..5. Better None One Two or more N = 52 (38%) N = 32 (23%) N = 53 (39%) Number of Comorbid Conditions Talamo J et al. Br J Rheumatol. 1997;36:463-469. 27 28 Patient-Oriented Clinical Assessment at UNC MSK Database Patients enrolled from musculoskeletal subspecialty clinics Patients in all clinics complete consent forms and a baseline assessment of demographics, comorbidities, and general health status (SF-12) Patients in orthopaedic clinics complete body site specific questionnaires (ie, shoulder, spine or knee forms) Patients in rheumatology clinics complete the rheumatology module 29 3 5
31 32 Findings from Comparisons of a Generic HRQOL with Condition Specific s in the UNC Clinic Population in Individuals with OA, RA, and Fibromyalgia 33 34 45 in Rheumatology Database 1759 Sent Questionnaire 456 with OA 834 with RA 469 with FM 741 Completed Questionnaire 178 with OA 391 with RA 172 with FM 619 in Analysis 133 with OA 334 with RA 152 with FM Sociodemographics for study sample overall and by diagnosis Characteristics Overall (n=619) Fibromyalgia (n=152) Rheumatoid Arthritis (n=334) Osteoarthritis (n=133) Age, years Sex, % female Race, % white t Education, years Disease duration, years ŧ Chronic Conditions 59.1 (12.7) 77.4 87. 13.7 (2.8) 1.1 (8.1) 1.45 (1.17) 52.8 (1.8) 92.3 9.3 13.8 (2.7) 9.2 (7.5) 1.64 ( 1.17) 59.8 (12.6) 71.3 85.3 13.4 (2.8) 11.6 (8.5) 1.36 (1.18) 64.6 (11.8) 75.2 87.5 14.2 (2.8) 7.7 (7.) 1.48 (1.16) Mean values are presented for all variables except when percentages are noted. Numbers in parentheses beside means are standard deviations. t N= 599, fibromyalgia n=145, rheumatoid arthritis n=326, osteoarthritis n=128 ŧ Missing values for disease duration (n=38) were imputed using the Markov Chain Monte Carlo method. 35 Currey, Rao, Winfield, and Callahan, Arthritis Care Res, 23 36 6
Condition-Specific s Modified Health Assessment Questionnaire (MHAQ) 1 cm Pain Visual Analog Scale (Pain VAS) 1 cm Fatigue Visual Analog Scale (Fatigue VAS) Rheumatology Attitudes Index (RAI) to measure helplessness Generic Health Status BRFSS Healthy Days Self-perceived health Physical health days Mental health days Limited Activity Days 37 38 Descriptive statistics on health status measures for entire sample (N=619) Adjusted means on condition-specific measures by disease diagnosis Observed Condition-specific measures MHAQ (1-4) Pain VAS (-1) Fatigue VAS (-1) RAI (1-5) BRFSS healthy days measures Self-perceived health (1-5) Mean 1.6 5.1 5.3 2.7 3.4 SD.54 2.8 3.2.94.94 range 1-4 -1-1 1-5 1-5 Fibromyalgia Rheumatoid arthritis Osteoarthritis MHAQ Pain VAS Fatigue VAS RAI 1.67 6. 6.44 2.99 1.66 4.6 4.92 2.62 1.56 5.1 4.87 2.59 Means adjusted in multiple linear regression that includes are, sex, education, disease duration, and number of chronic conditions. MHAQ = Modified Health Assessment Questionnaire; VAS = visual analog scale; RAI = helplessness subscale of the Rheumatology Attitudes Index. Physical health not good (-3) 11.8 1.8-3 Mental health not good (-3) 8.5 1.3-3 Activities limited (-3) 8.2 1.2-3 Potential ranges are presented in parentheses beside each variable. MHAQ = Modified Health Assessment Questionnaire; VAS = visual analog scale; RAI = helpless subscale of the Rheumatology Attitudes Index; BRFSS = Behavioral Risk Factor Surveillance System. 39 Currey, Rao, Winfield and Callahan, Arthritis Care Res, 23 4 Parameter estimates for differences between means by diagnosis for condition-specific measures Parameter estimates for differences between means by diagnosis for condition-specific measures FM versus RA FM versus OA ß t P ß t P MHAQ.1.21.8326 MHAQ.11 1.81.696 Pain VAS 1.4 5.22 <.1 Pain VAS.9 2.76.58 Fatigue VAS 1.52 5.36 <.1 Fatigue VAS 1.57 4.51 <.1 RAI 4.17 4.17 <.1 RAI.4 3.66.2 FM = fibromyalgia; RA = rheumatoid arthritis; MHAQ = Modified Health Assessment Questionnaire; VAS = visual analog scale; RAI = healplessness subscale of the Rheumatology Attitudes Index. FM = fibromyalgia; OA = osteoarthritis; MHAQ = Modified Health Assessment Questionnaire; VAS = visual analog scale; RAI = helplessness subscale of the Rheumatology Attitudes Index. Currey, Rao, Winfield and Callahan, Arthritis Care Res, 23 Currey, Rao, Winfield and Callahan, Arthritis Care Res, 23 41 42 7
Parameter estimates for differences between means by diagnosis for condition-specific measures Adjusted means on the BRFSS HRQOL measures by disease diagnosis Rheumatoid RA versus OA Fibromylagia Arthritis Osteoarthritis ß t P MHAQ Pain VAS Fatigue VAS RAI.1 -.49.5.3 1.95-1.76.17.32.518.777.8669.7469 FM = fibromyalgia; OA = osteoarthritis; MHAQ = Modified Health Assessment Questionnaire; VAS = visual analog scale; RAI = helplessness subscale of the Rheumatology Attitudes Index. Self-perceived health Physical health not good Mental health not good Activities limited 3.62 15.1 12.38 1.6 3.37 11.23 7.4 7.63 3.6 9.49 6.73 6.88 Means adjusted in multiple linear regression that includes age, sex, education, disease duration, and number of chronic conditions. BRFSS = Behavioral Risk Factor Surveillance System; HRQOL = health-related quality of life. Currey, Rao, Winfield and Callahan, Arthritis Care Res, 23 43 44 Parameter estimates for differences between means by diagnosis for the BRFSS HRQOL measures Parameter estimates for differences between means by diagnosis for the BRFSS HRQOL measures FM versus RA FM versus OA ß t P ß t P Self-perceived health Physical health not good Mental health not good Activities limited.25 3.78 4.99 2.97 3.8 3.73 5.28 3.1.21.2 <.1.19 BRFSS = Behavioral Risk Factor Surveillance System; HRQOL = health-related quality of life; FM = fibromyalgia; RA = rheumatoid arthritis Self-perceived health Physical health not good Mental health not good Activities limited.56 5.51 5.65 3.72 5.54 4.43 4.87 3.16 <.1 <.1 <.1.16 BRFSS = Behavioral Risk Factor Surveillance System; HRQOL = health-related quality of life; FM = fibromyalgia; OA = osteoarthritis Currey, Rao, Winfield and Callahan, Arthritis Care Res, 23 45 Currey, Rao, Winfield and Callahan, Arthritis Care Res, 23 46 Parameter estimates for differences between means by diagnosis for the BRFSS HRQOL measures Self-perceived Health in Rheumatology Patients with OA, RA, or FM RA versus OA ß t P Self-perceived health Physical health not good Mental health not good Activities limited.31 1.74.66.75 3.59 1.65.68.75.3.983.498.4531 BRFSS = Behavioral Risk Factor Surveillance System; HRQOL = health-related quality of life; FM = fibromyalgia; OA = osteoarthritis Percentage (%) 5 4 3 2 1 Poor Fair Good Very Good Excellent Fibromyalgia Rheumatoid Arthritis Osteoarthritis Currey, Rao, Winfield and Callahan, Arthritis Care Res, 23 47 Source: Musculoskeletal Outcomes Database 48 8
Healthy Days s in Rheumatology Patients with OA, RA, or FM # of poor health days 16 14 12 1 8 6 4 2 Physical Mental Limited activities Fibromyalgia Rheumatoid Arthritis Osteoarthritis Conclusions The BRFSS healthy days measures performed well in a clinic population with physiciandiagnosed rheumatic disease The measures detected interesting differences among rheumatic disease diagnoses suggesting that generic measures perform as well as condition-specific measures in discriminating poor HRQOL among individuals with OA, RA, and fibromyalgia Source: Musculoskeletal Outcomes Database 49 5 Rheumatoid Arthritis: An Overview 51 52 Stages of RA How Is Early RA Defined? Early Intermediate Late Chronologically Anatomically Functionally Radiographically Pathophysiologically Duration from start Distribution and number of involved joints HAQ or AIMS Erosions, narrowing, and alignment Synovial biopsy, cytokine levels, genetics HAQ = Health Assessment Questionnaire; AIMS = Arthritis Impact ment Scales. Courtesy of J. Cush, 22. 53 Quinn MA et al. Best Pract Res Clin Rheumatol. 21;15:49-66. 54 9
RA Progression RA Pathology and Clinical Manifestations Severity (arbitrary units) Early RA Intermediate Late ACR Inflammation Disability Radiographs Normal Synovium RA Synovium 5 1 15 2 25 3 Duration of Disease (years) ACR Graph: Adapted from Kirwan JR. J Rheumatol. 21;28:881-886. Photo: Copyright American College of Rheumatology. 55 Rosenberg A. In: Cotran RS et al, eds. Robbins Pathologic Basis of Disease. 6th ed. Philadelphia, Pa: WB Saunders; 1999:1215-1268. 56 RA: Burden of Illness Consequences of RA Prevalence 2.1 million in the United States; 165 million worldwide Estimated costs $8.74 billion in 1994.3% of the gross domestic product Direct medical costs are $5,919/case/year Indirect costs 3 to 4 times higher than direct costs $11,75 per person-year in patients with early RA Lifetime costs of RA rival those of coronary artery disease or stroke Lawrence RC et al. Arthritis Rheum. 1998;41:778-799; Yelin E. J Rheumatol Suppl. 1996;44:47-51; Yelin E, Wanke LA. Arthritis Rheum. 1999;42:129-1218; Allaire SH et al. Pharmacoeconomics. 1994;6:513-522; Merkesdal S et al. Arthritis Rheum. 21;44:528-534. 57 Premature mortality Increased morbidity Significant impact on quality of life Pain with associated functional disability Fatigue 81% of patients 42% with severe fatigue Depression Changes in family structure 3 lost days of work per year Average earnings loss of 5% Allaire SH et al. PharmacoEconomics. 1994;6:513-522; Wolfe F et al. Arthritis Rheum. 1994;37:481-494; Wolfe F et al. J Rheumatol. 1996;23:147-1417. 58 Long-term Outcomes in RA Assessment and Prediction of Functional Disability in RA Functional decline begins early Joint destruction Work disability Psychosocial dysfunction Reduced QOL and life expectancy Functional disability Treatment side effects Comorbidity 5% of patients will reach HAQ disability scores of: 1 within 2 years (moderate loss of function) 2 within 6 years (severe loss of function) 2.5 within 1 years (very severe loss of function) Kalden JR. J Rheumatol Suppl. 21;62:27-35. 59 Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-136. 6 1
Modifiable Predictors of Mortality in RA Predictors of significant mortality in >67% of studies: Patient questionnaire measures Physician s global assessment of disease status s of physical functional status Patient s global assessment of disease status Patient psychological distress Predictors of significant mortality in 5%-67% of studies: TJC ESR Predictors of significant mortality in <5%of studies: Pain score RF Pincus T, Sokka T. J Rheumatol. 21;28:1723-1734. 61 Which Patients With Early RA Stop Working Within 5 Years? Age at Onset 1.1 Female Sex 2.4 Manual Work 4.9 Semi-manual 4. Semi-sedentary 2. HAQ (.5 1.) 1.2 HAQ (1.1 1.5) 2.4 HAQ (>1.5) 3.6 ESR Raised 2.8 Erosions 1.9 1 2 3 4 5 6 Odds Ratio Young A et al. Ann Rheum Dis. 22;61:335-34. 62 RA Direct Costs: Impact of Functional Status RA Treatment Outcome s HAQ Quartile First Second Third Fourth Range of Scores in Quartiles..625.626 1.25 1.251 1.75 1.751 3. Mean Total Direct Costs/Yr $3,721 4,465 6,67 9,477 Modified Disease Activity Score (DAS28) s of radiographic progression (Sharp, Genant, Ratingen, and Larsen scores) Health Assessment Questionnaire (HAQ) HAQ Disability Index (HAQ DI) Gradient 2.55 Ratio of costs for fourth quartile/costs for first quartile. Yelin E, Wanke LA. Arthritis Rheum. 1999;42:129-1218. 63 64 Minimal Clinically Important Differences (MCID) Degree of improvement in various outcome measures Perceptible to patients Considered clinically important/meaningful Defined by patient query, delphi technique OMERACT: 33% to 36% improvement; 18% > placebo Demonstrated by statistical correlations with clinical responses in placebo-controlled, randomized clinical trials Minimal Clinically Important Differences (cont d) Score Direction Range of Scoring MCID HAQ DI -3.22 SF-36-1 + 5-1 points PCS/MCS mean 5±1 + 2.5-5 points When group median (and mean) changes exceed MCID, a majority of patients can be expected to achieve clinically meaningful improvement 65 Kosinski M et al. Arthritis Rheum. 2;43:1478-1487. Redelmeier DA, Lorig K. Arch Intern Med. 1993;153:1337-1342. Wells GA et al. J Rheumatol. 1993;2:557-56. Kosinski M et al. Arthritis Rheum. 2;43(suppl):S14. Abstract. Samsa G et al. Pharmacoeconomics. 1999;15:141-155. Thumboo J et al. J Rheumatol. 1999;26:97-12. 66 11
Etanercept in Early RA (ERA): HAQ DI at 12 Weeks Infliximab + MTX (ATTRACT): HAQ Median AUC Improvement at 12 Weeks % of Patients 7 6 5 4 3 2.5 Units Improvement 37 55 1. Units Improvement 25 29 1 -.4 -.4 -.4 -.4 -.4 MTX Etanercept MTX Etanercept p <.1 p <.1 p <.1 p <.1 p <.1 2 mg 25 mg 2 mg 25 mg -.5 (n = 169) (n = 177) (n = 169) (n = 177) p <.1 INF = infliximab; MTX = methotrexate; AUC = area under the curve; MCID = minimal clinically important difference. Genovese MC et al. Arthritis Rheum. 22;46:1443-145. 67 Lipsky P et al. Arthritis Rheum. 2;43(suppl):S269. Abstract. 68 Median AUC Improvement in HAQ -.1 -.2 -.3 Placebo + MTX (n = 64).1 INF 3 mg/kg q8w (n = 71) INF 3 mg/kg q4w (n = 71) INF 1 mg/kg q8w (n = 77) INF 1 mg/kg q4w (n = 66) -.3 All INF + MTX (n = 349) MCID Change in HAQ DI Score -.1 -.2 -.3 Anakinra Monotherapy: Change in HAQ DI at 24 Weeks Placebo (n = 114) Anakinra 3 mg/d (n = 116) -.2 p =.11 -.4 MCID = minimal clinically important difference. Bresnihan B et al. Arthritis Rheum. 1998;41:2196-224. Anakinra 75 mg/d (n = 112) -.2 p =.48 Anakinra 15 mg/d (n = 11) -.3 p =.7 MCID 69 Adalimumab + MTX: Change in HAQ DI at 2, 24, and 52 Weeks Mean Change From Baseline. -.1 -.2 -.3 -.4 -.5 -.6 -.7 -.8 -.12 Week 2 -.28 -.29 -.32 p.1 vs placebo + MTX; eow = every other week. MCID = minimal clinically important difference. Week 24 -.6 -.64 Keystone E et al. Arthritis Rheum. 22;46(suppl):S25. Abstract. -.34 Week 52 -.64 -.69 MCID Placebo + MTX Adalimumab 2 mg weekly + MTX Adalimumab 4 mg eow + MTX 7 Mean Change in HAQ DI Score Adalimumab Monotherapy: Change in HAQ Score at 26 Weeks Phase III trial with adalimumab administered alone (without DMARDs) in 544 treatment-resistant patients evaluated at 26 weeks -.2 -.4 Placebo -.7 2 mg eow -.29 2 mg weekly 4 mg eow -.39 -.38 MCID = minimal clinically important difference. eow = every other week. -.6 van de Putte LBA et al. Ann Rheum Dis. 22;61(suppl):168-169. Abstract. 4 mg weekly -.49 MCID 71 Adalimumab + MTX (ARMADA) : SF-36 Scores at 24 Weeks Better 1 SF-36 Score 9 8 7 6 5 4 3 2 1 Adalimumab 2 mg eow Adalimumab 8 mg eow (eow = every other week) Adalimumab 4 mg eow Placebo US norms (M/F 55-64 yr) Baseline Worse Physical Role Bodily General Vitality Social Role Mental Function Physical Pain Health Function Emotional Health Improvement from baseline p <.5 vs placebo. Anti-TNF Research Program of the Monoclonal Antibody D2E7 (adalimumab) in Rheumatoid Arthritis. Strand V et al. Ann Rheum Dis. 22;61(suppl 1):175. Abstract. 72 12
Rationale for completion of patient self-report questionnaires at each visit to a rheumatologist Patient self-report questionnaires address the primary concerns of patients quantitatively, including pain, physical function, fatigue, and psychological distress Questionnaire data are as effective or more effective than traditional joint counts, radiographs, and laboratory tests to predict severe outcomes of RA, including functional declines, work disability, and costs, and to predict premature mortality Questionnaire scores are highly reproducible higher than seen for 2 assessors performing a joint count or 2 radiologists scoring a radiograph T. Pincus et al, Clinical and Experimental Rheumatology, 24 73 74 Rationale Continued Questionnaire data are correlated significantly with data from traditional joint counts, radiographs, laboratory tests, and physical function measures Changes in status in clinical trials may be detected using questionnaires as effectively or more effectively than traditional measures An index of 3 self-report measures (functional disability, pain and global status) appears as sensitive as the ACR 2 in distinguishing placebo from interventions Patient questionnaires designed for use in clinical care are easily completed by patients and can save time for the physician Rationale Continued The patient questionnaire can document clinical status on a given day, which if not collected indicates data forever lost Self-report questionnaires are effective in all rheumatic diseases, including RA, OA, fibromyalgia, SLE, and scleroderma Most rheumatologists do not perform quantitative data at most visits of most patients T Pincus et al, Clinical and Experimental Rheumatology, 24 75 T Pincus et al, Clinical and Experimental Rheumatology, 24 76 77 13