Like snowflakes, no two patients with systemic lupus erythematosus (SLE) are exactly alike, making it one of the most difficult autoimmune diseases to diagnose and treat. Even in identical twins, the symptoms can vary widely and may change over time. Destructive, relentless and incurable, the disease can wax and wane unpredictably, with sudden flares wreaking havoc on every aspect of patients’ lives.1,2

Compounding the disease’s physical and emotional toll, it primarily strikes young women aged 19 to 44, says Roger A. Levy, global medical expert in immunology and specialty care at pharmaceutical firm GSK, which has been researching lupus and developing treatments for more than a decade.1,3,4 “Patients don’t know how they’re going to feel next week, next month, next year. They tell us, ‘I can’t make any plans. How can I start a new job, go out on a date, or commit to a relationship if in the future, I’m not going to be able to fulfill their expectations? There are many unanswered questions that make them feel isolated.”

Nine times more common in women than men,1,3 lupus affects about five million people globally.5 SLE is the most common form, accounting for 70 per cent of cases.2 The other forms are neonatal lupus, a rare condition found in babies born to women with lupus; cutaneous lupus, which only affects the skin; and drug-induced lupus, caused by taking certain prescription medicines.3 SLE occurs more frequently and severely in women of color, including Black, Asian, Hispanic/Latina, Native American and Pacific Islander women.1,3,6,7

Decades ago, many people with SLE died within a few years of diagnosis. Today, the outlook is brighter than ever. Not only has long-term survival increased, thanks to breakthroughs in drug development, but also the use of a best-in-practice medical approach called ‘treat-to-target’ is boosting outcomes and quality of life.8,9

A Proactive Approach to Stave off Serious Complications

Although each patient experiences SLE differently, they all have one thing in common: their immune system is attacking their body, mistaking healthy cells and organs for foreign invaders. The disease can affect any part of the body, with the skin, joints, central nervous system and kidneys being common targets.

Traditionally, treatment revolved around managing symptoms. “The standard approach has been that you add medicines, try to improve the patient’s status, and that’s it,” says David Roth, vice president and medicines development leader at GSK. Treat-to-target uses a more comprehensive strategy. “The goal is not only to help the patient feel better right now, but also to help prevent really bad outcomes from occurring in the long-term.”

Those bad outcomes include irreversible organ damage, which around half of SLE patients develop within five years of diagnosis. One of the most important manifestations is lupus nephritis (LN): inflammation of the kidneys. Within 10 years, up to 20 per cent of LN patients will progress to end-stage kidney disease, a life-threating condition that requires dialysis or a transplant.10,11,12,13 To try to avoid these outcomes, treat-to-target sets a specific, objective goal for improvement. With SLE, the aim is to lower overall disease activity, as measured by a scoring system that assigns points to various manifestations, including skin rashes, seizures, inflamed joints and abnormal kidney function.6,14 A drop in the score over time suggests that the treatment is working.   

“Instead of focusing only on where the patient is right now, the treat-to-target approach looks at where they should be: in a state where their disease is controlled and they can lead a relatively normal life,” says Roth. “High levels of disease activity—or flares—are major risk factors for permanent organ damage or even early death.”

The Search for Effective, Well-Tolerated Treatments

The driving force behind SLE drug development has been a hunt for therapies that are less toxic and work better than the two traditional mainstays of treatment: steroids and immunosuppressors. Both save lives and rapidly reduce symptoms, but also have dangerous downsides.

Steroids can cause heart attacks, stroke, diabetes, hypertension, bone fractures and eye diseases such as cataracts and glaucoma.15,16 They suppress the immune system, leaving patients easy prey for opportunistic infections, says Richard Furie, a rheumatologist at the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research in Manhasset, New York. “Using these medicines is always a tug of war between doing good and doing no harm.”

A burning question in research has been whether it’s possible to selectively target the immune system components that cause the damage in SLE. Since various types of autoantibodies have been implicated as key culprits, investigators set out to learn how these rogue antibodies are produced and the best ways to inhibit them.

In an intriguing scientific twist, researchers discovered that one of the best defenses against the autoantibodies involved in SLE may be to create antibodies against the cells that produce them and their stimulators. Investigators began to develop novel biologics that attack the B cells that unleash the immune system assault, thereby reducing disease activity. Think of this tactic as akin to blowing up the enemy’s tanks before they can launch their shells.

The 50-year drought for lupus medicines ended in 2011 with the FDA approval of a monoclonal antibody therapy that targets the protein that stimulates the autoreactive B cells.17 By binding to and inhibiting the protein, known as B-lymphocyte stimulator (BLyS), the therapy causes B cells to remain quiescent and not produce the destructive autoantibodies.

Today, a wide range of approaches to treat SLE are being explored, says Furie. “It’s an extremely exciting time in lupus research, with an unprecedented number of clinical trials in progress.” At the beginning of 2021, the FDA approved a drug for LN that targets T cells.18 And in August this year, the agency approved another SLE drug, this one targeting the interferon pathway.19 “Treatments have improved so much that patients are starting to ask, ‘Am I in remission?’” reports Furie. Prolonged, complete remission is still rare,20 and making it routine “is the next frontier”, he adds.

Although better tools are now available to improve disease activity, unmet challenges remain. One of the biggest is the need for more treatment options for SLE to avoid patients progressing to organ failure. Researchers are also working on optimizing current treatment options to see if they can help the patient feel well—not just less sick, says Levy. And there is progress, he adds. “When I started out, most people in the waiting room were on crutches or in wheelchairs. Now they’re wearing gym outfits, going to yoga classes and rocking high heels.”

For more information about lupus research at GSK, please visit GSK.com

References

  1. Us in Lupus. What is Lupus? Available at: https://www.usinlupus.com/basics-of-lupus/what-is-lupus. Last accessed August 202
  2. https://www.cdc.gov/lupus/basics/diagnosing.htm#:~:text=Lupus%20can%20be%20hard%20to,find%20out%20they%20have%20it.
  3. Pons-Estel GJ, Alarcón GS, Scofield L, Reinlib L, Cooper GS. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum. 2010;39(4):257-268.
  4. Lupus Foundation of America. Lupus facts and statistics. Available at: https://www.lupus.org/resources/lupus-facts-and-statistics. Last accessed August 2021.
  5. GfK Roper. (2012). Lupus Awareness Survey for the Lupus Foundation of America [Executive Summary Report]. Washington, DC.
  6. Somers EC, Marder W, Cagnoli P, et al. Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance program. Arthritis Rheumatol. 2014;66(2):369-378.
  7. Uribe AG, McGwin G Jr, Reveille JD, Alarcón GS. What have we learned from a 10-year experience with the LUMINA (Lupus in Minorities; Nature vs. nurture) cohort? Where are we heading? Autoimmun Rev. 2004 Jun;3(4):321-9.
  8. van Vollenhoven RF, Mosca M, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Annals of the Rheumatic Diseases, 2014;73:958-967. Available at https://ard.bmj.com/content/73/6/958. Last accessed August 2021.
  9. Roger A Levy, Tania Gonzalez-Rivera, Munther Khamashta, Norma Lynn Fox, Angela Jones-Leone, Bernie Rubin, Susan W Burriss, Kerry Gairy, Andre van Maurik, David A Roth, 10 Years of belimumab experience: What have we learnt? Lupus, First Published 8 Jul 2021.
  10. Imran, T. F., Yick, F., Verma, S., Estiverne, C., Ogbonnaya-Odor, C., Thiruvarudsothy, S., . . . Kothari, N. (2016). Lupus nephritis: an update. Clin Exp Nephrol, 20(1), 1-13.
  11. Anders HJ, Saxena R, Zhao MH, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nature reviews Disease primers. 2020;6(1):7.
  12. Hanly JG, O’Keeffe AG, Su L, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatol. 2016;55:252-62. [p. 3A]
  13. Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015: a systematic review and Bayesian meta-analysis. Arthritis Rheumatol. 2016;68(6):1432:1441.
  14. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Available at https://www.mdcalc.com/systemic-lupus-erythematosus-disease-activity-index-2000-sledai-2k. Last accessed August 2021.
  15. Mayo Clinic. Prednisone and other corticosteroids. Available at: https://www.mayoclinic.org/steroids/art-20045692. Last accessed August 2021.
  16. Pujades-Rodriguez M, Morgan AW, Cubbon RM, Wu J. Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study. PLoS Med. 2020 Dec 3;17(12):e1003432.
  17. Ledford, H. First lupus drug in half a century approved. Nature (2011).
  18. Heo YA. Voclosporin: First Approval. Drugs. 2021;81(5):605-610.
  19. AstraZeneca. Saphnelo (anifrolumab) approved in the US for moderate to severe systemic lupus erythematosus. Available at https://www.astrazeneca.com/media-centre/press-releases/2021/saphnelo-approved-in-the-us-for-sle.html. Last accessed August 2021.
  20. Urowitz MB, Feletar M, Bruce IN, Ibañez D, Gladman DD. Prolonged remission in systemic lupus erythematosus. J Rheumatol. 2005;32(8):1467-1472.