Rationale: Antiphospholipid syndrome (APS) is a leading cause of blood clotting and pregnancy loss. Roughly one-third of patients with systemic lupus erythematosus (SLE) harbor antiphospholipid antibodies, and many will eventually be diagnosed with APS. Although APS is often first recognized in the setting of a time-stamped blood clotting event, up to half of patients with APS will also acquire other types of more insidious damage to their bodies over time, including premature dementia, accelerated heart disease, and progressive kidney failure.

Livedo reticularis and racemosa are netlike skin discolorations found on the bodies of many patients with APS. The presence of livedo indicates sluggish or even occluded blood flow in the small blood vessels of the skin and–importantly–tracks closely with various “internal” manifestations of APS, including abnormal brain imaging and even strokes. Here, the plan is to apply cutting-edge molecular profiling to the easily accessible blood vessels of the skin. In doing so, we endeavor to discover what causes APS blood vessels of the deep organs to fail over time. This will allow us to identify APS patients at risk for organ (brain, heart, kidney, etc.) damage proactively. We will also learn what types of medications should be deployed in at-risk individuals.

Objective: The proposed research will define the biological processes that cause small blood vessels (and the organs they supply) to fail over time in many individuals with APS.

Approach: Building upon what we have already learned from preliminary skin biopsies of APS patients, Aim 1 will characterize the gene expression and function of authentic APS endothelial cells (the blood vessel-lining cells that are in direct contact with blood). The hypothesis is that APS endothelial cells, under constant attack from antiphospholipid antibodies in the blood, are key orchestrators of blood vessel failure over time.

In pursuit of personalized medicine for our patients, Aim 2 will expand the number of patients with APS who undergo upper-thigh skin biopsies for cutting-edge molecular and cellular profiling (30 new patients). This profiling should identify the genes and proteins that drive blood vessel failure. Furthermore, this Aim will develop a model to predict which patients carry these insidious changes and therefore require proactive therapy.

Relationship of the proposed work to the specific Focus Area(s) of this program announcement: The research proposed here will understand the biological mechanisms of lupus disease by being the first to directly study authentic blood vessel cells of patients with APS. Our strong preliminary data have already demonstrated the feasibility and potentially paradigm-shifting nature of this work. The research will also determine the pathobiology of end organ injury related to lupus disease in target human tissues by leveraging skin blood vessels as an accessible window deep inside APS where organ blood vessels fail over time. Through this research, we endeavor to understand problems of great and immediate interest to our patients such as why their thinking and memory deteriorate at an earlier age than expected.

Questions: What types of patients will this research help? Antiphospholipid antibodies (which cause APS) are among the most common autoantibodies detected in patients with SLE. Tens of thousands of patients may therefore be helped by the proactive treatments this research should reveal. What are the potential clinical applications, benefits, and risks of this research? The risk of an upper-thigh skin biopsy (similar to that which happens regularly in Dermatology clinic) is low and is justified by the unprecedented nature of this work and what it may reveal. What is the projected time it may take to achieve a patient-related outcome? Given that our collaboration is fully active (as evidenced by the strong preliminary data), completion of the project in 3 years should suggest new biomarkers for the clinic and, most importantly, new drug candidates for prospective clinical trials. What is the likely impact of this study on the quality of life for individuals living with lupus?

We began developing new research partnerships (without which this project would not be possible) several years ago in direct response to problems such as premature dementia and progressive kidney failure that our patients advised us were among their top concerns. While blood thinning medications are currently our only approach for combatting antiphospholipid antibodies, they are simply ineffective against many of the problems that our patients experience. New, smarter therapies are desperately needed.