5 Questions About Patients With STAT3 LOF and Lupus-Like Autoimmunity

Recently, researchers at the National Institutes of Health (NIH) began noticing systemic lupus erythematosus (SLE)-like autoimmunity with predominant renal involvement among a subset of patients with signal transducer and activator of transcription 3 (STAT3) loss-of-function (LOF). 

In order to optimally monitor and treat these patients, a team of researchers, including Sarthak Gupta, MD, assessed the relationship between STAT3 LOF and systemic autoimmunity.¹

Dr Gupta, an assistant research physician with the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the NIH, answered our questions about his team’s findings and how they may impact the future of management.

AUTOIMMUNE LEARNING NETWORK: What was the impetus for your review? 

Sarthak Gupta: Autosomal dominant hyper-IgE syndrome (AD-HIES or Job syndrome) is a rare primary immunodeficiency caused by dominant negative LOF mutations in STAT3. Patients with STAT3 LOF have recurrent skin and lung infections; dermatitis; elevated serum IgE; and vascular, connective tissue, and skeletal abnormalities. The NIH Clinical Center in Bethesda, Maryland, has one of the largest natural history cohorts of patients with STAT3 LOF in the world, and we started noticing SLE-like autoimmunity with predominant renal involvement in a subset of these patients. Autoimmunity and autoinflammation are frequent complications of primary immunodeficiencies. However, the relationship between STAT3 LOF and systemic autoimmunity remains unclear. Thus, we decided to explore it further in a systematic and comprehensive way.

ALN: What key findings do you want clinicians to take away from this research?

SG: We found that patients with STAT3 LOF mutations have significant dysregulation of the immune system, like increased interferon response, neutrophil extracellular trap (NET) formation, and anti-NET autoantibodies, that may predispose them to SLE-like systemic autoimmune disease with predominant renal involvement. These findings have important implications not only for the management of STAT3 LOF, but also in understanding the role of STAT3 in patients with SLE but without STAT3 LOF.

ALN: Based on your findings, you recommend that clinicians screen for SLE-like disease in patients with STAT3 LOF to minimize end-organ complications. Why do you make this recommendation?

SG: Many patients in our cohort had significant renal involvement that progressed to end-stage renal disease. Based on the significant immune dysregulation we see in these patients and the possibility of severe manifestations, we recommend that patients with STAT3 LOF be routinely screened for systemic autoimmunity with a focus on kidney disease. Early rheumatology consult should also be considered to minimize chronic complications associated with autoimmune disease, including possible end-stage renal disease.

ALN: How can your findings help guide clinicians’ future treatment decisions for patients with STAT3 LOF and SLE?

SG: Our findings may have important implications for the management of STAT3 LOF, as targeted therapy directed at some of the dysregulated pathways like interferons and NETosis could help in treating these patients without causing broad immunosuppression. Also, STAT3 upregulation has been implicated in SLE, and there has been interest in targeting STAT3 to manage lupus nephritis in mouse models. In contrast, our data indicate that STAT3 LOF is also associated with profound dysregulation of the immune system that may predispose toward autoimmune disease, and that STAT3 may have broad contributions to immune homeostasis.

ALN: What knowledge gaps still exist and need to be further researched?

SG: We are still expanding our understanding of the spectrum of autoimmunity in patients with STAT3 LOF. Ongoing research is also exploring the role of medications commonly used to manage lupus in patients with STAT3 LOF. It would also be important to understand further the role STAT3 LOF has in immune homeostasis and lupus.

Reference:

1. Goel RR, Nakabo S, Dizon BLP, et al. Lupus-like autoimmunity and increased interferon response in patients with STAT3-deficient hyper-IgE syndrome. J Allergy Clin Immunol. 2020;S0091-6749(20)31098-8. doi:10.1016/j.jaci.2020.07.024