May is Lupus Awareness Month, an opportunity for patients, caregivers, physicians, and researchers to share their experiences with the disease in an effort to increase awareness and advance therapeutic research. In this piece, Nemanja Damjanov, M.D., Ph.D., reflects on his work in lupus research in a career that spans almost four decades.
Lupus treatments, then and now
In my years as a researcher, I have seen survival rates and quality of life improve significantly for lupus patients. In the 1960s and 1970s, treatments for patients with the most severe forms of lupus were successful only 10% of the time. By the 1990s, we saw this statistic rise to more than 90%. We had new diagnostic tools to recognize lupus earlier and were able to identify the moderate or mild disease forms more easily so that we could diagnose and start treatment much earlier. In addition to earlier diagnosis, we were able to treat patients with more active — you could say aggressive — drugs, which were extremely successful.
Although we benefit from these improvements today, we still need better treatment options for lupus patients. We would like to be able to treat them with less aggressive drugs. For this, we need to gain a better understanding of the disease itself and to be more strategic in our clinical trial design.
Variable symptoms, variable outcomes
The heterogeneity of lupus creates treatment challenges for patients. For example, systemic lupus erythematosus (SLE) has a list of 11 diagnostic criteria, affecting several systems and organs in the body, including kidneys, lungs, joints, skin, and many more. This heterogeneity not only makes diagnosis difficult but also can complicate patient outcomes. A physician may begin by paying attention to one organ, let’s say the kidneys, and then during treatment something else might emerge to create a different problem. Genetic influences may arise in response to treatment, creating new problems that change the treatment outcomes.
Screening challenges
The complexity of lupus makes it challenging to successfully operationalize a study. Recruitment and enrollment have been affected by decisions made about inclusion and exclusion criteria. There is quite a list of exclusion criteria in lupus trials; some of them are very important, and others are not as important. Because of some less-important criteria, we may face exclusion of patients who potentially could contribute to, and benefit from, the trial. We may have willing participants, but sometimes we cannot easily predict how many patients will pass the inclusion process and how many will have screen failures.
Retention challenges
During clinical trials, we may have patients who want to stop participating in the trial. Trials typically run 6-12 months in duration, and some may extend even longer. We sometimes lose patients because they experience flare-ups that we cannot anticipate. Such events can make the patient want to discontinue treatment, sometimes even before we’ve had enough time to see that the drug really works. Sometimes a patient might learn, or suspect, that they are on the placebo arm of the study and decide that they no longer want to participate. It is important to manage patients’ expectations as they come into the study so that they don’t get discouraged if the results do not come as quickly as they hope.
A need for patient diversity
We all know that lupus differs in different geographic regions and among different ethnicities. We know, for example, that there is a higher prevalence of lupus in North America than in Europe or in some parts of Asia. There are higher occurrences of lupus in African Americans and in Native Americans than in Caucasians. While we know that there are more cases of lupus among some populations, we are also aware that non-White patients are underrepresented in clinical trials. Women are more frequently affected than men for every age and ethnic group. To make our lupus clinical trials more effective, we need to find ways to include patients from more diverse populations.
Communication between doctors and patients
I want to emphasize the value of communication and cooperation between the doctors and the patients. By patients, I don’t mean the individuals; I mean the patients organized in patient societies, which define their problems and try to seek help. I am active in EULAR, the European League Against Rheumatism, an organization that advocates on behalf of patients with rheumatic and musculoskeletal diseases. One of the pillars of EULAR is that at least two representatives from the association be actively involved in the design of a clinical trial to ensure that the patient experience informs therapeutic development. This cooperation is important to improve diagnosis and treatment and to design more effective clinical studies in the future to help our patients.
Learning from successes, learning from failures
In recent years, we have had some disappointing efforts in testing new treatment options in patients with systemic lupus. I confess it can be quite discouraging when we see success with new treatments in early phases of study but then fail in later phases. However, we learn from our failures as much as we learn from our successes. We need to be cautious, and we need to analyze carefully the studies that have been done before. We need to study not only the previous success stories but also the unsuccessful stories to learn the real reasons for our successes and our failures. This is how we improve study design. This is how we improve treatment options for lupus patients.
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