Publications

2020

Tsokos, G. C. (2020). Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol, 21, Article 6. https://doi.org/10.1038/s41590-020-0677-610.1038/s41590-020-0677-6 [pii]
Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique 'interactome', which will dictate specific treatment.
Tsokos, G. C. (2020). Notch notches lupus. Kidney Int, 97, Article 2. https://doi.org/S0085-2538(19)31059-2 [pii]10.1016/j.kint.2019.10.018
The multifaceted Notch signaling pathway appears to tame the autoimmune response and protect lupus-prone mice from inflammation and damage.
Tsokos, G. C., & Terhorst, C. (2020). T Lymphocytes Cash Their Value in Clinical Medicine. Trends Mol Med, 26, Article 9. https://doi.org/S1471-4914(20)30154-4 [pii]10.1016/j.molmed.2020.06.003
Empowering the ability of cytotoxic T cells to kill tumor cells or the reframing of their receptor to eliminate cancer cells has revolutionized cancer treatment. Simultaneously, the empowering of regulatory subsets has met success in mitigating autoimmune diseases. T cells, the major first responders of the immune system, are produced in the thymus, an organ that serves as their 'training camp'. On their exit to the periphery, T cells are effector cells that control infections or regulatory cells, which limit excessive responses.
van Vollenhoven, R. F., Hahn, B. H., Tsokos, G. C., Lipsky, P., Fei, K., Gordon, R. M., Gregan, I., Lo, K. H., Chevrier, M., & Rose, S. (2020). Maintenance of Efficacy and Safety of Ustekinumab Through One Year in a Phase II Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Patients With Active Systemic Lupus Erythematosus. Arthritis Rheumatol, 72, Article 5. https://doi.org/10.1002/art.41179
OBJECTIVE: To evaluate the efficacy and safety of ustekinumab through 1 year in a phase II trial in patients with systemic lupus erythematosus (SLE). METHODS: Eligible patients were diagnosed as having clinically active SLE (based on Systemic Lupus International Collaborating Clinics criteria), despite standard background therapy. Active disease was defined by an SLE Disease Activity Index 2000 (SLEDAI-2K) score of >/=6 as well as having >/=1 British Isles Lupus Assessment Group (BILAG) A organ domain score and/or >/=2 BILAG B organ domain scores present at screening. Patients (n = 102) were randomized (3:2) to receive either ustekinumab ( 6 mg/kg of single intravenous infusion at week 0, then 90-mg subcutaneous injections every 8 weeks beginning at week 8) or a matching placebo added to standard therapy. At week 24, the placebo group crossed over to receive a subcutaneous 90-mg dose of ustekinumab every 8 weeks, and the original ustekinumab group continued to receive therapy through week 40. Maintenance of efficacy was assessed using the SLEDAI-2K, the SLE Responder Index 4 (SRI-4), physician global assessment, and mucocutaneous and joint disease measures in a modified intent-to-treat population. RESULTS: SRI-4 response rates were significantly greater in the ustekinumab group (62%) versus the placebo group (33%) in the week 24 primary end point analysis (P = 0.006) and were maintained at week 48 (63.3%) in the ustekinumab group. In the ustekinumab group, response rates across other disease measures were also maintained through week 48. Among patients in the placebo group who crossed over to ustekinumab treatment (n = 33), increased response rates across efficacy measures were noted. Among all ustekinumab-treated patients, 81.7% had >/=1 adverse event (AE), and 15.1% had >/=1 serious AE through week 56. No deaths, malignancies, opportunistic infections, or tuberculosis cases were observed. CONCLUSION: Ustekinumab provided sustained clinical benefit in patients with SLE through 1 year, with a safety profile consistent with other indications.
Vukelic, M., Kono, M., & Tsokos, G. C. (2020). T cell Metabolism in Lupus. Immunometabolism, 2, Article 2. https://doi.org/e200009 [pii]10.20900/immunometab20200009
Abnormal T cell responses are central to the development of autoimmunity and organ damage in systemic lupus erythematosus. Following stimulation, naive T cells undergo rapid proliferation, differentiation and cytokine production. Since the initial report, approximately two decades ago, that engagement of CD28 enhances glycolysis but PD-1 and CTLA-4 decrease it, significant information has been generated which has linked metabolic reprogramming with the fate of differentiating T cell in health and autoimmunity. Herein we summarize how defects in mitochondrial dysfunction, oxidative stress, glycolysis, glutaminolysis and lipid metabolism contribute to pro-inflammatory T cell responses in systemic lupus erythematosus and discuss how metabolic defects can be exploited therapeutically.