Advancing research in Systemic Lupus Erythematosus

WRITTEN BY

Catharina Lindholm & Katie Streicher

Catharina Lindholm, MD, PhD

Director, Global Medicines Development

Katie Streicher, PhD

Associate Director, Translational Medicine

In the Respiratory and Immunology therapy area, with its common pathways and underlying disease drivers, AstraZeneca is following the science from chronic lung diseases to immunology-driven diseases, targeting dermatology, gastrointestinal diseases, systemic eosinophilic-driven diseases and rheumatology including type I interferon-driven diseases such as systemic lupus erythematosus (SLE or lupus).

Our ambition is to achieve disease modification and durable remission for millions of patients worldwide. For more than a decade, we’ve worked to understand how biological processes in the immune system play a role in SLE. For patients living with this chronic and complex autoimmune condition, these insights are leading to the development of new treatment approaches, as well as implications for clinical thinking on how to categorise and treat other immunological conditions.1

The immune system is a carefully regulated system in which cytokines play a key role in orchestrating how the body responds to pathogens, or foreign bodies. Cytokines are molecules that act as ‘signallers’ regulating processes along immune pathways that coordinate the overall immune response.2,3 The immunology community now understands more about how dysfunction in the levels of these cytokines, and interactions between the pathways they regulate, can contribute to the emergence of autoimmune conditions.4

For people living with SLE, the immune system inappropriately attacks healthy tissue in the body.5 While the exact cause of lupus is not fully understood, a combination of genetic and environmental factors likely plays a role.6 These external factors can trigger immune dysregulation that can be further amplified by aberrant and sustained production of various cytokines, including interleukin-6, interleukin-10, interferon type I and type 2, among others.6 This results in an over-activated immune response, which along with the creation of autoantibodies (antibodies formed in response to its own tissues), activate the body’s defences against its own tissue, leading to injury, inflammation, and long-term organ damage.6,7

By targeting specific pathways within the body’s immune response, researchers are developing treatments to help bring regulation back to the immune system. Type I interferon expression is one pathway that we have explored as a potential approach to treating SLE, as some research has revealed how type I interferons are upregulated in certain tissues and are correlated with increased disease activity.2,3 We are also investigating a wide range of other immunological diseases that are also driven by the interferon pathway.

In healthy people, the type I interferon pathway plays a critical role in triggering both innate and adaptive immune responses, generalised and targeted responses respectively.2,6  But in 60%-80% of adults with SLE, there is an increased and sustained type I interferon pathway activation, measured by an interferon-inducible gene signature.2 These higher levels of interferon have also been shown to correlate with disease activity.3 Inhibiting interferon type I has also been shown to reduce SLE disease activity and severity in clinical trials.8,9

The increasing ability to profile a patient’s immune system is also helping immunologists recognise commonalities between autoimmune conditions, as well as between conditions not traditionally seen as autoimmune in nature. The association of high type I interferon signature with Gougerot-Sjögren syndrome, myositis, and systemic scleroderma, may help unlock future treatments for these conditions through type I interferon inhibition. In recent years, we’ve also convened of experts to discuss the implications of interferon research.1 As we collectively think outside the traditional boundaries of rheumatology, our research moves into other areas where immune dysregulation has been shown to play an important role in disease progression. This has required bringing together a range of medical experts from across fields as broad as oncology, HIV and heart disease.9

Research into the underlying drivers of SLE is supporting the potential development of new treatment options for this complex autoimmune condition. At the centre of this scientific work lies new insights into the function and dysfunction of the immune system and presents exciting possibilities to advance the use of precision medicine in rheumatology and other therapeutic areas throughout the field of immunology.

 

References

1. Crow MK. Interferon-alpha: a therapeutic target in systemic lupus erythematosus. Rheumatic Disease Clinics of North America. 2010 Feb 28;36(1):173-86.

2. Crow, M. K, Type I Interferon in the Pathogenesis of Lupus. The Journal of Immunology. 2014;192(12);5459-5468.

3. Lauwerys B.R., Ducreux J, Houssiau F.A., et al. Type I interferon blockade in systemic lupus erythematosus: where do we stand?. Rheumatology. 2013;53(8);1369-1376.

4. Crow MK, Rönnblom L. Report of the inaugural Interferon Research Summit: interferon in inflammatory diseases. Lupus Science & Medicine2020欧洲杯体育在线平台. 2018 June 15.

5. The Lupus Foundation of America. Available at . Accessed April 2020.

6. Choi J, Kim ST, Craft J. The pathogenesis of systemic lupus erythematosus—an update. Current opinion in immunology. 2012 Dec 31;24(6):651-7.

7. Craft JE. Dissecting the immune cell mayhem that drives lupus pathogenesis. Science translational medicine. 2011 Mar 9;3(73):73ps9.

8. Morand E, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. New England Journal of Medicine. 2020欧洲杯体育在线平台2020;382:211-221.

9. Furie R, Khamashta M, Merrill J.T, et al. Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus. Arthritis & Rheumatology. 2017;69(2);376-386.

 

Veeva ID: Z4-23797
Date of Preparation: April 2020
Date of Expiry: April 2022