Exploring the role of the interferon pathway in autoimmune diseases

AstraZeneca and MedImmune are committed to the development of best-in-class and first-in-class treatments for a breadth of inflammatory and autoimmune diseases. Our work toward this ambition relies on building a deep understanding of the genetic, molecular and biological mechanisms that drive pathogenesis.

 

This research focus is particularly central to bringing therapeutic options to patients with diseases characterised by heterogeneous clinical manifestations such as systemic lupus erythematosus (SLE or lupus).

SLE is a complex condition. There are many challenges to treating lupus as the symptoms wax and wane and are not consistent between patients – no two patients are alike. Currently, lupus treatment is following a ‘one size fits all’ paradigm which is ineffective and leaves considerable unmet medical needs. There is limited efficacy and/or poor tolerability with current standard care treatments and only one new drug has been approved for lupus in nearly 60 years.1-3

Thus there is a great lag in innovation in SLE indicating a serious need for targeted therapies with improved efficacy and safety.

 

Breaking the lupus code

SLE is a multisystem autoimmune disease where interplay of environmental and genetic risk factors leads to progressive loss of tolerance to nuclear antigens over time.  AstraZeneca’s disruptive research, complementing outside research, are making increasingly clear that Type I interferons (Type I IFN) play a critical role in lupus. Approximately 75% of SLE patients show a high interferon gene signature,4-5 central to the immune dysregulation observed in patients and key to driving disease pathogenesis.6

There is a growing body of evidence linking Type I IFN to SLE:

  • Elevated IFN activity is found in the serum of SLE patients and it is associated with disease activity7,8
  • Presence of autoantibodies specific to nucleic acids (including autoantibodies of the IgE subclass [9] capable of triggering the robust secretion of IFNα by plasmacytoid dendritic cells10
  • Most SLE patients have detectable IFNα levels in blood, or more commonly, increased expression of type I IFN-inducible genes, which is termed the IFN signature11,12
  • Use of Type I IFNs as a therapy for cancer and viral infections is frequently associated with the appearance of autoimmune manifestations, including SLE-like disease13
  • Polymorphisms in two important genes in the interferon pathway, interferon regulatory factor 5 and tyrosine kinase 2, are strongly associated with SLE14

 

One step closer to personalised treatments

The recognition of the importance of the IFN-pathway in SLE led to the development of investigational therapeutics that inhibit the activity of IFN activity. Patients receiving an inhibitor of the Type I IFN receptor – thus blocking all Type I IFN – had significantly greater rates of improvement across a broad range of composite and organ-specific disease activity measures, as well as a reduction in oral corticosteroid use versus patients taking placebo.4 We are developing a diagnostic tool to help identify patients with elevated interferon activity, which could identify patients who may be more likely to benefit from therapies that inhibit the interferon pathway.

The role of the interferon pathway may go beyond lupus. The Type I IFN signature has also been found in other autoimmune diseases such as dermatomyositis, polymyositis, systemic sclerosis and Sjogren’s syndrome.15,16 Future clinical trials will show whether these patients preferentially benefit from treatments inhibiting the IFN pathway. The ability to categorise patients not only by their symptoms but also by the mechanisms triggering their illness will bring us a step closer to a future where molecular medicine approaches are commonly used by doctors for diagnosing and deciding on the best individualised treatment for patients with autoimmune diseases.

As a leader in precision medicine, AstraZeneca’s goal is to fully explain the constellation of symptoms that are present in patients by identifying their biological drivers. We are currently employing our expertise on molecular diagnostics, imaging, and analytics/software to make this ambition a reality for patients. Ultimately, we aspire to match each patient with the medicine that treats the underlying cause of his or her disease.

 

 

References

  1. Mosca M, et al. New drugs in systemic lupus erythematosus: when to start and when to stop. Clin Exp Rheumatol 2013; 31 (Suppl. 78): S82-S85.
  2. Chambers SA, et.al. Treatment adherence and clinical outcome in systemic lupus erythematosus. Rheumatology, 2007;46:895–898.
  3. FDA.gov. Benlysta approval. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm. Accessed June 2016.
  4. Furie, R., et al., Anifrolumab, an anti-interferon alpha receptor monoclonal antibody, in moderate to severe systemic lupus erythematosus (SLE). Arthritis Rheumatol, 2015. 67(suppl 10).
  5. Khamashta M, et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus (NCT01283139).
  6. Hagberg, N. and L. Ronnblom, Systemic Lupus Erythematosus--A Disease with A Dysregulated Type I Interferon System. Scand J Immunol, 2015. 82(3): p. 199-207.
  7. Hooks, J.J., et al., Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med, 1979. 301(1): p. 5-8.
  8. Ytterberg, S.R. and T.J. Schnitzer, Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum, 1982. 25(4): p. 401-6.
  9. Henault, J., et al., Self-reactive IgE exacerbates interferon responses associated with autoimmunity. Nat Immunol, 2016. 17(2): p. 196-203.
  10. Bave, U., et al., Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG. J Immunol, 2003. 171(6): p. 3296-302.
  11. Bennett, L., et al., Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med, 2003. 197(6): p. 711-23.
  12. Yao, Y., et al., Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-alpha Monoclonal Antibody Trials in Systemic Lupus Erythematosus. Hum Genomics Proteomics, 2009. 2009.
  13. Ioannou, Y. and D.A. Isenberg, Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum, 2000. 43(7): p. 1431-42.
  14. Sigurdsson, S., et al., Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet, 2005. 76(3): p. 528-37.
  15. Emamian, E.S., et al., Peripheral blood gene expression profiling in Sjogren's syndrome. Genes Immun, 2009. 10(4): p. 285-96.
  16. Higgs, B.W., et al., Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis, 2011. 70(11): p. 2029-36.

Page ATLAS ID: 989825.011
Date of next review: June 2017