Lupus research is hobbled by a history of poor choices in both basic and clinical research.
- One, misplaced reliance on misleading pre-clinical animal models ( , ). How does lupus start? What goes on in affected tissues and organs? Unsurprisingly, mouse models have been the mainstay in basic lupus research for the past few decades as indeed they’ve been across much of basic biomedical research. Unfortunately, the poor fate of promising drug candidates in the clinic suggests the two most popular mouse lupus models, MRL/lpr and NZB/NZW, aren’t directly applicable to the human disease.
- Two, poor Clinical Trial study design ( , 3, ). Factors include insufficient size (and hence poor statistical power), simultaneous use of standard lupus Rx such as glucocorticoids or other immunosuppressants, extremely poor patient segmentation by disease specifics, genetic features and ethnicity, and regulators pushing for the higher threshold of superiority rather than non-inferiority.
These two factors intertwine to create an unproductive loop that continues to feed on itself and engenders a scattershot approach to lupus therapeutics.
Though Genetics Alone Doesn’t Explain It, Clinical Trials Have Overlooked Effective Patient Segmentation
Clearly, there’s a genetic component to lupus predisposition. However, getting to grips with it is far from simple or straightforward.
- For e.g., results of genome-wide association studies (GWAS) have been largely disappointing (5).
- Monozygotic twin concordance for SLE ( ) is only ~30% (6, ), suggesting as-yet undecoded gene-environment linkages.
- SLE rates are ~3X higher among Hispanics and African-Americans in the US. However, contrary to what genetic disposition would predict, SLE prevalence is much higher in African Americans compared to West Africans (8), again harkening to as-yet incompletely decoded gene-environment linkages.
Such types of data strongly suggest ethnicity contributes to lupus risk. However, it has been woefully overlooked in lupus clinical trial design (, 3).
Rather Than A Single Disease, Lupus Is Extremely Heterogeneous So More Accurately A Clinical Syndrome: Clinical Trials Would Benefit From Better Patient Segmentation
Lupus isn’t a single disease, rather it’s a clinical syndrome with different diseases lumped together largely out of historical practice. This is apparent by the fact that it targets different tissues and organs in different patients, ranging from skin to kidney, lungs, brain and heart (see table below from 9).
Arguably, patients with lupus nephritis, i.e., lupus kidney disease, are those with the worst prognosis (, , 3, 9). Unfortunately, they’re also the ones with the fewest Rx options.
An illustrative example of the structural problems in lupus research that continue to deprive the neediest from the most benefit comes from(Benlysta, Human Genome Sciences/GlaxoSmithKline), a fully human anti-BAFF ( ) antibody recently approved as lupus Rx. When it was approved by the FDA in March 2011, it became the 1st drug of any type or class approved for SLE in >50 years. Yet, according to a review ( ), two key Belimumab Phase III trials excluded patients with severe active nephritis or CNS (central nervous system) disease, i.e., groups considered to have the greatest unmet therapeutic need.
Unlike Other Common Autoimmune Diseases, Lupus Marches To A Different Tune That Remains Undeciphered
With a 9:1 female:male predisposition, lupus predominantly affects women (10,). In this, lupus is similar to other common autoimmune diseases like Grave’s, Hashimoto’s thyroiditis, MS (Multiple Sclerosis), RA (rheumatoid arthritis), Primary Biliary Cirrhosis and Sjogren’s Syndrome. However, unlike RA and psoriasis that go into remission during pregnancy, lupus tends to worsen (12).
Illustrative examples suggest immune dysfunction in lupus is extremely complicated and different from other autoimmune diseases. Thus, approaches that alleviate other autoimmune disease symptoms are counter-productive in lupus.
- Recent years have seen an explosion in biologics targeting the cytokine Tumor-Necrosis Factor (TNF-alpha). Such biologics have been approved for Ankylosing spondylitis, Crohn’s disease, Psoriasis, Psoriatic arthritis, RA (13). However, clinical benefit of TNF inhibition in lupus is far from clear, and indeed sometimes counter-productive. Hence, none of these newer biologics have as yet been approved for lupus.
- While Type I interferons like IFN-beta 1a and 1b are first-line drugs for relapsing-remitting , another common autoimmune disease, sustained secretion of type I interferon is instead a cardinal feature of lupus (14).
- The fact that many recent clinical trials testing the latest biologics targeting B cells or cytokines were terminated early due to unexpected toxicity ( , 3) only underscores that immunology of lupus is still poorly understood. This brings us back to where we started, poorly predictive pre-clinical models. Drug candidates that show promise in pre-clinical models end up not so promising after all.
1. Stohl, William. “Future prospects in biologic therapy for systemic lupus erythematosus.” Nature Reviews Rheumatology 9.12 (2013): 705-720.;
2. Houssiau, Frédéric A. “Biologic therapy in lupus nephritis.” Nephron Clinical Practice 128.3-4 (2014): 255-260.
3. Velo-García, Alba, Eleana Ntatsaki, and David Isenberg. “The safety of pharmacological treatment options for lupus nephritis.” Expert Opinion on Drug Safety just-accepted (2016).
4. Rodríguez-Pintó, Ignasi, Gerard Espinosa, and Ricard Cervera. “The problems and pitfalls in systemic lupus erythematosus drug discovery.” Expert Opinion on Drug Discovery just-accepted (2016).
5. Yang, Chin-An, and Bor-Luen Chiang. “Inflammasomes and human autoimmunity: A comprehensive review.” Journal of autoimmunity 61 (2015): 1-8.
6. JÄRVINE, P., et al. “Systemic lupus erythematosus and related systemic diseases in a nationwide twin cohort: an increased prevalence of disease in MZ twins and concordance of disease features.” Journal of internal medicine 231.1 (1992): 67-72.
7. Javierre, Biola M., et al. “Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.” Genome research 20.2 (2010): 170-179.
8. Symmons, D. P. “Frequency of lupus in people of African origin.” Lupus 4.3 (1995): 176-178.
9. Javierre, Biola M., and Bruce Richardson. “A new epigenetic challenge: systemic lupus erythematosus.” Epigenetic Contributions in Autoimmune Disease. Springer US, 2011. 117-136.
10. Nussinovitch, Udi, and Yehuda Shoenfeld. “The role of gender and organ specific autoimmunity.” Autoimmunity reviews 11.6 (2012): A377-A385.
11. Ngo, S. T., F. J. Steyn, and P. A. McCombe. “Gender differences in autoimmune disease.” Frontiers in neuroendocrinology 35.3 (2014): 347-369.
12. Whitacre, Caroline C., Stephen C. Reingold, and Patricia A. O’Looney. “A gender gap in autoimmunity.” Science 283.5406 (1999): 1277.
13. Brenner, Dirk, Heiko Blaser, and Tak W. Mak. “Regulation of tumour necrosis factor signalling: live or let die.” Nature Reviews Immunology 15.6 (2015): 362-374.
14. Crow, Mary K. “Type I interferon in the pathogenesis of lupus.” The Journal of Immunology 192.12 (2014): 5459-5468.