50 Year Perspective on Lupus Save

Hello, I'm Dafna Gladman, a rheumatologist from the University of Toronto. I'm actually speaking to you from Toronto this morning. I'm going to talk about what we've learned from an observational cohort study that was started in Toronto by Dr. Murray Urowitz in 1970.

By way of introduction, the late professor Alvin Feinstein suggested that clinical trials are insufficient for clinical management. Instead, he wrote and I quote, “analysis of events and observations that occur in non-experimental circumstances during the interaction of nature, people, technologic artifacts and clinical practitioners are important”, and

Murray Urowitz was actually a pioneer in this area, initiating the University of Toronto Lupus cohort in 1970. The program was set up as a specialized clinic to provide care for patients with lupus, to study clinical laboratory correlations in the disease, and to better understand long-term outcomes of the disease. A standardized data retrieval form was developed to produce valid observations. Patients were seen at regular intervals two to six months apart, regardless of medical condition, to better describe the disease and its effects and the mechanism to trace patients lost to follow-up was developed.

I should mention that at the time that this clinic was started, there were no computers to save the information. Everything was kept on paper-based protocols, which had to be searched manually for the early publications. The initial computerization occurred using a mainframe with cards in 1977 and then graduating to a desktop computer in 1980, which actually was used as SaaS editor and then to an Oracle database with keyboard entry in 1990. And this continues till today, although there is a plan to change to a web-based format.

At the time that the lupus clinic was started, there was no universally acceptable method to determine disease activity. We first developed the lupus activity criteria count, LACC, but that provided a state rather than a score. And therefore in 1985, we gathered a group of lupologists and methodologists to develop the SLE Disease Activity Index or SLEDIA, which was revised in 2000 as the SLEDAI 2K to reflect the reality in clinical trials.

Subsequently, we developed the adjusted mean SLEDAI to describe disease activity over time, and we further demonstrated that a SLEDAI 2K of four or more indicates a flare of disease. We define states of low disease activity and remission and show that achieving these states provides a good outcome.

At the conference to develop the SLEDAI, it was determined that to describe outcomes in patients with SLE, it was necessary to include an assessment of damage and quality of life in addition to disease activity. Therefore, the Systemic Lupus International Collaborating Clinic in support of the American College of Rheumatology developed the damage index, which was also validated. And then the short form SF 36 was adopted as the quality of life measure.

So what have we learned from more than 50 years of follow-up of patients with lupus? Some of the important observations include the following.

The bimodal mortality pattern in lupus was described in the early seventies showing that early mortality was related to disease activity, while late mortality was associated with atherosclerotic complications. This was confirmed by more recent studies in our clinic, in postmortem studies, and compared to the Ontario population. We found that over the first 36 years of the clinic there was an improved survival, however, there was an increase in damage in cardiovascular disease. Further studies of arterial and venous events demonstrated a prevalence of these events in 12.5% of inception for patients who presented within one year of diagnosis. The risk factors for these events were neuropsychiatric disease and vasculitis, as disease-related factors, and smoking history as the environmental factor.

Patients with SLE had more coronary artery disease risk factors than healthy controls in a study of 250 patients. But those patients with lupus who did or did not have AVEs had the same prevalence with regards to cardiovascular disease, risk factors and disease-related factors. Over the years, with judicial use of corticosteroids and treatment modifiable risk factors, the prevalence of AVEs has reduced, and this was also confirmed by the slick study for atherosclerosis.

In the course of the follow-up period, we described several clinical features in patients with lupus. We described the prevalence of nail lesions and their association with disease activity. More recent studies concentrated on specific organ disease. So we described neuropsychiatric lupus and the importance of severe headaches, which did not respond to narcotic analgesics, and like other neuropsychiatric SLE were associated with SPECT scan abnormalities. More recent studies under the leadership of Dr. Zahi Touma have concentrated on neurocognitive abnormalities, demonstrated their frequency in association with certain biomarkers.

Several studies of renal lupus demonstrated the prognostic role of kidney biopsy. Active and chronic lesions are highly predictive of mortality. A repeat kidney biopsy is necessary, and when patients have persistent proteinuria or abnormal kidney function to determine future management. We demonstrated that dialysis is not inevitable in lupus nephritis. 62% of our patients did not progress from chronic renal disease over 10 years on the average. Progression was associated with abnormal serology and prednisone use, while treatment with renin-angiotensin system blockers was associated with less risk for progression. We also found that low level proteinuria is commonly associated with proliferative lupus nephritis and adverse long-term outcomes. Dr. Laura Whittall Garcia in our center demonstrated the serum levels of neutrophil extracellular trap remnants, elastase-DNA and HGB 1DNA complexes at the time of lupus nephritis predict renal outcomes in the following 24 months.

In terms of clinical laboratory correlations, we identified a group of patients who are serologically active, but clinically quiescent. These patients have now been followed for prolonged periods of time and less than half of these patients flare - and if they do, it's usually very mild manifestations. We also identified another group who were clinically active, but serologically quiescent and had similar manifestations of the usual patients with lupus. We described the presence of ANA negative by immunofluorescence patients who have typical clinical manifestations, and those patients may actually have specific auto antibodies such as anti DNA or anti-Ro.

We studied an outcome of pregnancy showing that if the patient's disease is inactive, the pregnancy proceeds normally and the offspring are fine. We also studied the effect of menopause in the postmenopausal state showing that disease activity usually decreases, but it's more likely related to age. In a nested case control study, we showed that hormone replacement therapy was not associated with an increased risk of flares. We demonstrated that steroid withdrawal is safe in clinically quiescent lupus. Similarly, antimalarial withdrawal in patients with quiescent disease is possible, although antimalarials aid in preventing disease flare even in patients who have achieved prolonged clinical remission. We've also highlighted the presence of a cardiomyopathy as a complication of antimalarial therapy in patients with SLE. And this is associated with a specific MRI pattern, which can be helpful in identifying the mechanism of a cardiomyopathy.

We've demonstrated that our patients have done well being treated with azathioprine rather than cyclophosphamide, suggesting the cyclophosphamide is not absolutely necessary for the management of lupus nephritis.

And we've also participated in a number of clinical trials with a variety of medications. One of the trials using ustekinumab in the phase two study demonstrated the usefulness of a new SLEDAI 2K considering steroid dose as an outcome measure.

To review everything that's been done in the last 50 years would take probably several days. And therefore, I would like to summarize that the observational cohort has provided us with the opportunity not only to manage the patients, but also to learn about clinical manifestations, outcome measures, overall outcomes in various organ systems, as well as therapeutic management of the patients.

Thank you very much for your attention.