Derivation of an Appropriate Outcome Measure in Lupus

156 Pages·2012·1.58 MB·English

Derivation of an Appropriate Outcome Measure in
Lupus
by

Zahi Touma
A thesis submitted in conformity with the requirements
for the degree of PhD
Institute of Medical Science
University of Toronto
© Copyright by Zahi Touma 2012
Derivation of an Appropriate Outcome Measure in Lupus
Zahi Touma
PhD
Institute of Medical Science
University of Toronto
2012
Abstract
Aim: To develop an outcome measure to identify “responders” for patients who had a clinically
important improvement in lupus disease activity with treatment.

Methods: The outcome measure derived was based on the commonly used disease activity
measure SLEDAI-2K which documents findings over the previous 10 days. Since patients in
drug trials are followed at monthly intervals it was necessary to validate SLEDAI-2K 30 days
against SLEDAI-2K 10 days. Two prospective studies were accomplished for this purpose.
SLEDAI-2K 30 days was used to develop the new responder index, SLEDAI-2K Responder
Index-50 (SRI-50). The SRI-50 data retrieval form was developed to standardize the
documentation of the descriptors. The construct validity of SRI-50 was prospectively evaluated
against an external construct. The reliability of SRI-50 was tested in a multi-centre study. A
retrospective analysis over 10 years was used to further validate SRI-50. SRI-50 ability to
enhance the SLE Responder Index (SRI) in detecting “responders” was evaluated. The
performance of SRI-50 was investigated against SLEDAI-2K and SRI over 12 months.

Results: SLEDAI-2K 30 days was validated to describe disease activity over the previous 30
days. The responder index to SLEDAI-2K, SRI-50 was developed including the SRI-50
Definitions and SRI-50 Data Retrieval Forms. The initial validation of SRI-50 confirmed its
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construct validity to identify ≥ 50 % improvement. SRI-50 is reliable and can be used by both
rheumatologists and trainees. The retrospective analysis confirmed that SRI-50 is valid in
identifying ≥ 50 % improvement in an efficient time. SRI-50 enhances the performance of SRI
and identifies more “responders” than SLEDAI-2K and SRI at 6 and 12 months.

Conclusions: SRI-50, is a valid and reliable responder index to identify patients with partial,
≥50% improvement in disease activity in an efficient time. SRI-50 can be used as an independent
outcome measure of improvement in patients with SLE.

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Acknowledgments

First and foremost I would like to acknowledge and express my gratitude and appreciation to Dr.
Murray Urowitz and Dr. Dafna Gladman, my thesis supervisors for their guidance and
encouragement. It has been a privilege to work with them and I am very thankful for their time,
new ideas, support and for being role models and mentors. Both their energy and dedication for
their research and patients is an example that I wish to achieve in my career.
Special thanks are also extended to Dr. Earl Silverman and Dr. Edward Keystone for their help
and recommendations as members of the thesis committee.
A very special thanks must be given to the Toronto Lupus Clinic team for their help, kindness
and enthusiasm in contacting the patients and the management of the data. I am especially
grateful for Dominique Ibañez for the statistical analysis of this project. Special thanks to
Shahrzad Taghavi-Zadeh for handling the data entry related to this project. Sincere thanks and
appreciation must be extended to Anne Mackinnon who was involved directly in all aspect of the
research project.
I would also like to thank the examiners that were part of the PhD transfer exam and the PhD
oral defense committee, Dr. Brian Feldman, Dr. Gerald Devins, Dr. David Wofsy, Dr. Elizabeth
Badley and Dr. Harvey Moldofsky, for their time and insightful questions and recommendations.
I would like to thank Lupus Ontario for the Geoff Carr Fellowship and the University of
Toronto Arthritis Centre of Excellence for its fellowship award.
Lastly, I would like to thank my friends and family for all their love and encouragement who
supported me in all my pursuits.
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Table of Contents

Acknowledgments .......................................................................................................................... iv
List of Figures, Tables and Abbreviations ................................................................................... xiv
Chapter 1 Literature Review ........................................................................................................... 1
1.1 Principles for assessing lupus patients ................................................................................ 2
1.2 Approaches to disease activity measurement in lupus ........................................................ 4
1.2.1 Global indices ......................................................................................................... 4
1.2.1.1 Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and its
versions ................................................................................................................. 4
1.2.1.1.1 The Mexican version of SLEDAI (MEX-SLEDAI) ........................................ 7
1.2.1.1.2 SELENA-SLEDAI ........................................................................................... 7
1.2.1.1.3 SLEDAI-2000 (SLEDAI-2K) .......................................................................... 8
1.2.1.2 Systemic Lupus Activity Measure (SLAM) ......................................................... 9
1.2.1.3 European Consensus Lupus Activity Measurement (ECLAM) ......................... 10
1.2.1.4 Lupus Activity Index (LAI) ................................................................................ 11
1.2.1.5 SLE Activity Index Score (SIS) ......................................................................... 12
1.2.2 Organ Specific Indices .......................................................................................... 12
1.2.2.1 British Isles Lupus Assessment Group (BILAG) ............................................... 12
1.2.2.2 Renal outcome measures .................................................................................... 14
1.2.2.3 Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) ... 15
1.2.3 Measures of disease activity over time ................................................................. 16
1.2.3.1 Adjusted Mean SLEDAI-2K (AMS) .................................................................. 16
1.2.4 Disease activity in pregnancy ............................................................................... 17
1.3 Clinically meaningful change in disease activity measures .............................................. 17
1.3.1 Improvement ......................................................................................................... 17
1.3.2 Flare ...................................................................................................................... 18
1.3.3 Responder measures .............................................................................................. 19
1.3.3.1 Flares 19
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1.3.3.1.1 SELENA-SLEDAI Flare Index (SFI) ............................................................ 19
1.3.3.2 Improvement ....................................................................................................... 20
1.3.3.2.1 Responder Index For Lupus Erythematosus (RIFLE) ................................... 20
1.3.3.2.2 SLE Responder Index (SRI) .......................................................................... 20
1.4 The advantages and disadvantages of the most commonly used indices .......................... 21
Chapter 2 Hypotheses and Aims ................................................................................................... 23
2
2.1 Rationale ........................................................................................................................... 24
2.1.1 Results from clinical trials over the last decade .................................................... 24
2.1.2 Choice of outcome measures in SLE therapeutic trials and their impact on
results .................................................................................................................... 24
2.2 Hypothesis ......................................................................................................................... 25
2.3 Aims .................................................................................................................................. 26
Chapter 3 Validation of SLEDAI-2K 30 Days Against SLEDAI-2K 10 days in Cross-
sectional and Longitudinal Evaluation ..................................................................................... 27
3
3.1 Background ....................................................................................................................... 28
3.2 Methods ............................................................................................................................. 29
3.2.1 Patient Enrollment ................................................................................................ 29
3.2.1.1 Part 1: 29
3.2.1.2 Part 2: 29
3.2.2 Patient Assessment ................................................................................................ 29
3.2.2.1 Part 1 and Part 2: ................................................................................................ 29
3.2.3 Patient Analysis .................................................................................................... 30
3.3 Results ............................................................................................................................... 30
3.3.1 Part 1: .................................................................................................................... 30
3.3.2 Part 2: .................................................................................................................... 33
3.4 Discussion ......................................................................................................................... 37
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Chapter 4 Development and Initial Validation of the Systemic Lupus Erythematosus Disease
Activity Index 2000 (SLEDAI-2K) Responder Index 50 (SRI-50) ......................................... 39
4
4.1 Background ....................................................................................................................... 40
4.2 Methods ............................................................................................................................. 41
4.2.1 Derivation of SRI-50 definitions, SRI-50 data retrieval form, and SRI-50
scores ..................................................................................................................... 41
4.2.2 SRI-50 definitions ................................................................................................. 41
4.2.3 Assessment of construct validity .......................................................................... 48
4.2.4 Patient selection .................................................................................................... 48
4.2.5 Patient assessment ................................................................................................. 48
4.2.6 Clinician scoring of disease activity ..................................................................... 49
4.2.7 Method and analysis ............................................................................................. 49
4.2.8 External construct ................................................................................................. 49
4.3 Results ............................................................................................................................... 50
4.3.1 Derivation of SRI-50 definitions, SRI-50 data retrieval form, and SRI-50
score ...................................................................................................................... 50
4.3.2 Practical applicability, administration, scoring ..................................................... 51
4.3.2.1 Administration .................................................................................................... 51
4.3.2.2 Scoring ................................................................................................................ 51
4.3.3 Testing of concurrent construct validity ............................................................... 52
4.3.4 Change in SLEDAI-2K and SRI-50 scores in patients as determined by
external physician ................................................................................................. 54
4.3.5 Change in SLEDAI-2K and SRI-50 scores in patients who improved in
association with the external construct ................................................................. 55
4.4 Discussion ......................................................................................................................... 57
Chapter 5 Reliability of SRI-50 .................................................................................................... 60
5
5.1 Background ....................................................................................................................... 61
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5.2 Methods ............................................................................................................................. 62
5.2.1 Patient selection .................................................................................................... 62
5.2.2 Assessment of disease activity. ............................................................................. 62
5.2.2.1 SLEDAI-2K 30 days .......................................................................................... 62
5.2.2.2 SRI-50 63
5.2.2.3 Physician global assessment ............................................................................... 63
5.2.2.4 Likert scale ......................................................................................................... 64
5.2.3 “Standard” SLEDAI-2K and SRI-50 scores ......................................................... 64
5.2.4 Raters, site selection, and procedure at each site .................................................. 64
5.2.5 Statistical analysis ................................................................................................. 65
5.2.6 Sample size calculation ......................................................................................... 66
5.3 Results ............................................................................................................................... 66
5.3.1 Patient demographic data ...................................................................................... 66
5.3.2 Common pitfalls .................................................................................................... 68
5.3.3 Reliability (interrater and intrarater) ..................................................................... 70
5.4 Discussion ......................................................................................................................... 74
Chapter 6 SLEDAI-2K Responder Index (SRI-50) captures 50% improvement in disease
activity over 10 years ............................................................................................................... 77
6
6.1 Background ....................................................................................................................... 78
6.2 Methods ............................................................................................................................. 79
6.2.1 Patients’ selection and assessment ........................................................................ 79
6.2.2 Study design .......................................................................................................... 80
6.2.3 Outcome measures ................................................................................................ 80
6.2.4 Identification of patients with active descriptors .................................................. 82
6.2.5 Identification of patients’ descriptors with ≥ 50% and complete recovery .......... 82
6.2.5.1 Time to partial and complete recovery for active descriptors ............................ 82
6.2.6 Possible situations for progression in disease activity in active descriptors as
determined by SRI-50 and SLEDAI-2K ............................................................... 83
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6.2.7 Statistical analysis ................................................................................................. 84
6.3 Results ............................................................................................................................... 85
6.3.1 Demographics ....................................................................................................... 85
6.3.2 Partial and complete recovery in active descriptors over 10 years ....................... 85
6.3.3 Partial and complete recovery in active descriptors with 1 year .......................... 87
6.3.3.1 Time to partial and complete recovery in active descriptors over the course
of 10 years .......................................................................................................... 88
6.4 Discussion ......................................................................................................................... 90
Chapter 7 SRI-50 Enhances the Ability to Identify Responders .................................................. 92
7
7.1 Background ....................................................................................................................... 93
7.2 Methods ............................................................................................................................. 94
7.2.1 Patient enrollment and selection ........................................................................... 94
7.2.2 Outcome measures ................................................................................................ 95
7.2.3 Patient assessment ................................................................................................. 96
7.2.4 Study design .......................................................................................................... 96
7.2.5 Statistical analysis ................................................................................................. 96
7.3 Results ............................................................................................................................... 97
7.3.1 Patient demographics ............................................................................................ 97
7.3.2 Disease activity results .......................................................................................... 99
7.4 Discussion ....................................................................................................................... 102
Chapter 8 Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
Responder Index 50 (SRI-50): Sensitivity to Response at 6 and 12 Months ......................... 105
8
8.1 Background ..................................................................................................................... 106
8.2 Methods ........................................................................................................................... 107
8.2.1 Patients’ enrollment and selection ...................................................................... 107
8.2.2 Outcome measures .............................................................................................. 108
8.2.2.1 SLEDAI-2K ...................................................................................................... 108
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8.2.2.2 SRI-50 (SLEDAI-2K Responder Index-50) ..................................................... 108
8.2.2.3 BILAG .............................................................................................................. 109
8.2.2.4 Physician Global Assessment ........................................................................... 109
8.2.2.5 SLE Responder Index ....................................................................................... 109
8.2.3 Patient assessment ............................................................................................... 110
8.2.3.1 Baseline visit .................................................................................................... 110
8.2.3.2 Follow up visits at 6 and 12 months ................................................................. 110
8.2.4 Treatment ............................................................................................................ 110
8.2.5 Endpoints ............................................................................................................ 110
8.2.5.1 Aim 1: Responders at 6 months and 12 months as compared to baseline visit 110
8.2.5.2 Aim 2: Determine if SRI-50 responders are true responders and not false
responders. ........................................................................................................ 111
8.2.6 Statistical analysis ............................................................................................... 111
8.3 Results ............................................................................................................................. 111
8.3.1 Patient demographics .......................................................................................... 111
8.3.2 Disease activity results ........................................................................................ 113
8.3.2.1 SLEDAI-2K and SRI-50 results ....................................................................... 113
8.3.2.2 Responders at 6 and 12 months as compared to baseline visit ......................... 116
8.3.2.3 Comparison between SRI responders “Gold Standard” and SRI-50
responders at 6 and 12 months ......................................................................... 117
8.4 Discussion ....................................................................................................................... 118
9
Chapter 9. Conclusions and Future Directions .......................................................................... 121
9.1 Achieved aims ................................................................................................................. 122
9.1.1 Validation of SLEDAI-2K 30 days ..................................................................... 122
9.1.2 Derivation and validation of SRI-50: Responder index to SLEDAI-2K ............ 122
9.1.3 Reliability of SRI-50 ........................................................................................... 123
9.1.4 SRI-50 enhances the ability of other indices to identify responders .................. 124
9.1.5 SRI-50 captures 50% improvement in disease activity over 10 years ................ 125
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