Prognosis Studies in Systemic Lupus Erythematosus
1. Lupus Database Research Program
In order to introduce scientific rigor and systematic analyses to the study of SLE, a complex multi-system, chronic disease, Dr. Urowitz established a cohort of SLE patients in 1970 who have been followed prospectively, examined by clinical and immunological measures according to a rigorous, predetermined protocol carried out at defined intervals. This extensive longitudinal database is one of the largest such databanks in the world (1200 patients) and has allowed for numerous findings which have changed the way lupus is diagnosed and managed. This approach has culminated in the establishment of the Centre for Prognosis Studies in The Rheumatic Diseases, which Dr. Urowitz directs, and where SLE patients are followed in close proximity with the research team who analyze their data. This is a novel approach to the study of chronic disease.
2. Development and Validation of Outcome Measures
Disease activity: The definition of meaningful outcomes measures in a disease as variable and complicated as SLE had proven a challenge for investigators. Dr. Urowitz's studies have defined measures to accomplish this goal: Initially the Lupus Activity Criteria Count was developed. However, it proved to be difficult to use since it did not quantify disease activity. Therefore, the SLE disease activity index or SLEDAI was developed and validated based on a conference on Prognosis in SLE. In order to improve the use of the SLEDAI for clinical trials, modifications were made and validated in 2000. Dr. Urowitz and colleagues have also developed the Adjusted Mean SLEDAI (AMS), a measure to describe disease activity over time. These measures are now used worldwide.
A measure of damage which was initially conceived during the conference on Prognosis of SLE was further developed and validated through the collaborative effort of the Systemic Lupus International Collaborating Clinics (SLICC) which led to the SLICC/ACR Damage Index to measure damage accrued during the course of SLE. Further studies from the Toronto cohort have highlighted the role of early damage as a predictor for mortality in patients with SLE, and the role of corticosteroids in the accrual of damage over time.
To complete the investigation of the domains important in the description of prognosis in patients with SLE Dr. Urowitz also studied health related quality of life and fatigue in these patients.
3. Diagnosis in SLE
Studies examining diagnostic criteria in SLE have been carried out. These have highlighted the presence of a group of patients with ''latent'' or ''incomplete'' lupus, as well as the fact that replacing the LE cell with anticardiolipin antibodies in the 1997 ACR classification criteria was not particularly helpful.
4. Studies Describing Disease Flare
Using prospectively gathered data from the lupus databank, studies describing the course of disease activity over time have shown that an increase of SLEDAI of greater than or equal to 4 represents flare, whereas a decrease of more than 3 represents improvement.
5. Clinical/Laboratory Correlations
Dr. Urowitz introduced the concept of discordance between clinical and serologic disease in SLE in the late 1970s, initially with LE negative ANA negative lupus, and later with serologically active clinically quiescent lupus. Subsequent studies described the long-term outcome in these patients. The concept of clinical serological discordance was later expanded to include patients who have clinically active disease who are serologically quiescent. These findings have alerted clinicians treating lupus to the fact that patient presentation rather than their serologic findings should be the major determinant of the most appropriate therapy.
6. Pregnancy & Hormone Studies
Studies of successful outcome of pregnancy in women with inactive SLE and the safety of hormone replacement therapy in these patients challenged existing medical dogma that guided management of SLE and forced clinicians to rethink therapeutic options in these patients.
7. Mortality Studies
Mortality and survival studies from a single centre have highlighted causes, predictor variables and have described improving standardized mortality ratios over 3 decades.
8. Malignancy in SLE
The issue of malignancy in an autoimmune disease has been addressed in a number of studies, initially in the Toronto Databank, and more recently as the major contributor to an international study through SLICC.
9. Specific organ disease in SLE
In addition to studying global disease activity and damage in SLE, Dr. Urowitz has also studied individual organ systems both in terms of activity and damage.
a) Renal disease:
The series on clinical implications of renal pathology (Kidney Biopsy in SLE: I, II, III 1989, 1991, and 1994) set the standard for methodological rigor in addressing clinical-pathological correlations. Further studies demonstrated the role of repeat renal biopsies, the fact that renal insufficiency and dialysis do not suppress lupus activity, and the role of non compliance in refractory renal disease in SLE patients. Importantly Dr. Urowitz's team has shown that isolated hematuria and pyuria reflect active disease in SLE, not just limited to the kidney.
b)Central nervous system disease:
Neuropsychiatric involvement and damage have become major morbidities in SLE. These have been studied by Dr. Urowitz over the years and have highlighted the role of brain scans, CT scans and neurocognitive testing in assessing both disease activity and damage in CNS-SLE.
Dr. Urowitz and colleagues reported the largest experience with outcomes and associated factors for osteonecrosis in SLE.
A major focus of Dr. Urowitz's research has been in the area of coronary artery disease in women with SLE. Dr. Urowitz was the first to document that women with SLE are at risk for early coronary artery disease when he described the bimodal mortality pattern in 1976. These observations were confirmed in subsequent studies from the Toronto cohort. Since then it has been demonstrated that women with SLE have a much higher risk for the development of coronary artery disease then the general population resulting in increased risk for myocardial infarction and stroke at an earlier age. Dr. Urowitz's studies demonstrated that this premature atherosclerosis is related to both traditional risk factors for coronary artery disease as well as to SLE itself.
Dr. Urowitz has fostered international collaboration throughout his research. He gathered 22 investigators, experts in lupus and methodologists for the Committee on Prognosis Studies in SLE in 1985. Through the work of this committee the disease activity index and damage index were derived. This led to the collaboration through the NATO group, which resulted in several studies comparing activity instruments in SLE, and subsequently culminated in the establishment of SLICC. To further enhance the studies into the causes and outcomes of premature atherosclerosis in SLE Dr. Urowitz initiated the SLICC Registry for Atherosclerosis, which is an inception cohort of patients with SLE followed prospectively in 26 centers internationally according to a common protocol. This cohort provides the opportunity not only to determine incidence, prevalence, and nature of atherosclerotic coronary artery disease in SLE, but also to identify associated risk factors for the development of CAD and its outcomes and to discern the contribution of disease and therapy to the occurrence of these risk factors, as well as develop interventional approaches to modify identified risk factors.
Dr. Urowitz has been recognized as a major contributor to lupus research and has been invited to speak about his research internationally.
In addition to his research activities and extensive publication record, Dr. Urowitz has trained and mentored at least 80 rheumatology trainees and scores of medical and science students, many involved in lupus studies and who later proceeded to train in rheumatology. Dr. Urowitz has been recognized for his teaching excellence by a number of teaching awards at the University of Toronto and by the Royal College of Physicians and Surgeons of Canada. Most of the Lupus Clinic trainees are still involved in lupus care and research around the world.
- Clinical Director, Centre for Prognosis Studies in the Rheumatic Diseases, part of the UHN Arthritis and Autoimmunity Research Centre.