Lupus: Will This Butterfly Soon Take Flight?

As a rheumatologist for almost 30 years now, I have witnessed firsthand the transformation of rheumatoid arthritis (RA) disease outcomes. This transformation has hinged on novel therapies driven by scientific breakthroughs but also, critically, on changes in our disease measures and strategies. Over the same 3 decades, I have become, regrettably, too skilled at explaining that there is no breakthrough treatment to offer patients with lupus. Even worse, I have honed my skills in breaking bad news to young women with lupus and to their families, which sometimes is that their young adult partner, sister, or daughter is going to die.

Eric Morand, MD, PhD

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So why are we failing in lupus while succeeding so spectacularly in diseases like RA? Does the lower prevalence of lupus result in insufficient observed experience for individual physicians of the long-term damage accrual, loss of life’s dreams of vocation and family, and shortening of life span that cohort data make so clear? We all remember our first “bad RA” patient treated successfully with anti-tumor necrosis factor (TNF), and how this motivated us to act earlier on every patient since. Perhaps our thinking is stuck because no rheumatologist practicing today has experienced this in systemic lupus erythematosus (SLE). We may be daunted by the clinical and biological heterogeneity of lupus, but does this give us an excuse to think it is all too hard?

I don’t actually believe that lupus is so different to RA that we cannot find solutions. So, why have 40 late-stage clinical development programs in lupus failed to yield a viable therapy?I believe we must start by shaking off our old ways of thinking about lupus, and like the character in Network (1976), join hands with our patients andshout “I’m as mad as hell, and I’m not going to take this anymore!” From my privileged vantage-point, now working with companies that are actively developing drugs for lupus, and as part of the Project ALPHA (a partnership between academia, industry, and the Lupus Foundation of America¹) I can say there is much cause for optimism. So, what do we need to do now?

First, we have to give up a little of our medical expert pride in clinical disease classification. While I am as proud of my diagnostic skills as the next rheumatologist, I know that my ability to assign a diagnosis of lupus tells me next to nothing about the real pathology evolving within my patient. If we are using molecular therapies, it is molecular diagnostics that must guide us, not Delphi-style judgements about which patient to call SLE and which dermatomyositis or Sjogren syndrome. Basket trials in cancer direct drugs against specific mutations, regardless of which organ is affected. Why should our approach in lupus be any different? Currently, lupus trials are like baskets turned inside out: using targeted molecular therapies in patients with similar clinical manifestations but with dissimilar pathologies. Meaningful change will mandate working with regulators to drive towards acceptance of molecular classification of autoimmune diseases, which we can then target accurately. Fortunately, “-omics” technologies now make such studies almost routine, and agencies such as the Lupus Research Alliance are directing more and more support towards characterising molecular variation in human SLE.² I have the somewhat radical hope that the next globally accepted classification criteria for SLE will rest on these foundations, rather than consensus, no matter how expert.

Next, we must re-invent how we determine clinical trial outcomes. We can no longer continue expensive trials of next-generation therapies using last-millennium outcome measures. Unprecedented levels of data-driven collaboration between companies, regulators, and academia will be needed to move to better measures. Even a clear negative result of a targeted therapy provides critical learning, and it is encouraging that the need for new approaches is gaining acceptance and momentum.

Thirdly, we need to adopt a treat-to-target (T2T) approach in SLE. Validation of meaningful targets is the first step towards designing T2T intervention studies that use failure to reach targets as the trigger for treatment escalation; effective therapies to escalate to are of course a necessary precondition for this strategy. I have been immensely proud to be involved in developing and validating the lupus low disease activity state (LLDAS) endpoint, attainment of which is now proven to be protective for damage accrual, flare and quality of life.^3,4 lthough remission remains the ambition, the more pragmatic LLDAS still delivers on the twin goals of low disease activity and low glucocorticoid exposure. This enables us to design T2T studies in lupus for the first time. So, let’s do it!

Finally, as new treatments emerge, we will have to ensure patients can access them equitably. From where I write, Australia, and in other countries, access to belimumab is not reimbursed, and so very few patients have received this treatment. Ensuring payer agreement to support novel therapies for SLE will require that we work to enhance the understanding of agencies about the harm that our patients endure. If only a few privileged patients can benefit, we will have done little to advance outcomes in lupus overall.

I believe that one day soon we will be able to change the conversations that we have with our lupus patients and their families. With at least 30 therapies currently in late-stage clinical trials, I hope that one day the butterfly emblem of lupus will no longer symbolize the malar rash but, instead, as a beautiful creature that has taken flight, embody our patients living a full and healthy life and leaving the slow-moving caterpillar of lupus progress a distant memory.

Professor Eric Morand, MD, PhD, is head of the School of Clinical Sciences at Monash Health, Monash University's largest clinical school, and a physician-scientist.

He specializes in the study of systemic lupus erythematosus. He is founder of the Monash Lupus Clinic, Australia's largest research-grounded clinic for patients with SLE, a founding member of the Australian Lupus Registry & Biobank, and Chair of the Asia-Pacific Lupus Collaboration. His clinical research focuses on improving endpoints for clinical research in lupus. His lab has studied the biology of glucocorticoids in rheumatic disease and lupus since 1996.

He is a clinical rheumatologist, and head of the Monash Health Rheumatology Unit, the largest in Australia.

Disclosures: Dr. Morand has previously received funding from AstraZeneca as a paid consultant and for research support, but he has not been compensated for the development of this article. The article is authored by Dr. Morand and represents his own views.

References:

[1] Manzi, S. et al. Global consensus building and prioritisation of fundamental lupus challenges: the ALPHA project. Lupus Science & Medicine. 2019, 6(1), e000342.

[2] Lupus Research Alliance. Research and Clinical Trials – Funding Opportunities. Available at:https://www.lupusresearch.org/research-and-clinical-trials/research/funding-opportunities/. Accessed June 2021.

[3] Golder, V. et al. Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. The Lancet Rheumatology. 2019, 1(2), E95-E102.

[4] Golder, V. et al. Association of the lupus low disease activity state (LLDAS) with health-related quality of life in a multinational prospective study [ABSTRACT]. Arthritis Rheumatology. 2016, 68(10).