Researchers led by a team at NIH have identified a potential treatment to reduce the risk of cardiovascular disease in people with systemic lupus erythematosus (SLE), a chronic autoimmune disease. The researchers examined the effects of tofacitinib, an anti-inflammatory drug, on 30 people diagnosed with SLE, which is often referred to as lupus. The study appeared in the journal Nature Communications.
The findings suggest that short-term use of tofacitinib is not only safe with no serious side effects, but also appears to lower some of the risk factors associated with cardiovascular disease in people with lupus.
Lupus, which has no cure, results from the body’s immune system attacking otherwise healthy tissues. The resulting inflammation can cause permanent damage and can affect many parts of the body, including the skin, joints, heart, lungs, kidney and brain. People living with lupus are at higher risk for developing cardiovascular disease, including heart attacks and stroke due to atherosclerosis, a condition in which plaque builds up inside the arteries. People who have lupus have increased inflammation markers, including elevated levels of interferons (proteins that fight infection) and white blood cells called low-density granulocytes.
Low-density granulocytes have a higher propensity to form structures known as neutrophil extracellular traps, or NETs. The body uses NETs to fight infection, but the structures are also thought to contribute to cardiovascular disease and lupus.
Lupus is also associated with overproduction of cytokines and interferons, molecules that allow communication between immune cells. The signals provided by cytokines and interferons are transmitted within cells by JAKs and STATs. JAK refers to Janus kinase while STAT stands for signal transducer and activator of transcription. Genomewide association studies previously performed by NIH scientists have identified a variation of a gene called STAT4 that is associated with lupus. The JAK/STAT pathway has also been implicated in NET formation.
Tofacitinib is a Janus kinase inhibitor developed in the 1990s by Pfizer in partnership with NIH. Developed for the treatment of rheumatoid arthritis, the drug is now approved for other inflammatory diseases such as psoriatic arthritis, juvenile arthritis and ulcerative colitis.
- The study showed that short term treatment with tofacitinib increased the levels and function of the so called “good cholesterol”, or high-density lipoprotein (HDL), without increasing the “bad cholesterol” or low-density lipoprotein (LDL), or triglyceride levels. Treatment also reduced arterial stiffness and improved other markers of vascular health.
- Tofacitinib significantly decreased the levels of low-density granulocytes and circulating NETs.
- Some of the improvements with tofacitinib treatment were more robust in people who had a STAT4 risk allele, a gene variant that is associated with a higher risk for autoimmunity and a more severe form of lupus. Patients with that risk allele produced more NETs overall.
- This the first treatment trial in lupus using a genetic polymorphism to stratify treatment.
“This early phase clinical trial was designed to test in humans the safety of blocking the JAK/STAT pathway in lupus and its effects on lipids and blood vessels. One of the key features of the trial design was to stratify patients based on presence of high-risk allele to develop a personalized treatment approach in treating lupus. Next steps are to confirm our findings in a larger number of lupus patients for a much longer duration.” Sarfaraz Hasni, M.D., study author, Director, Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
“No drug to this date has been found to consistently modulate cardiovascular risk in lupus. The results of the study suggest that suppressing the JAK/STAT pathway can have multiple effects on modifying several factors that have been proposed to contribute to premature blood vessel damage in lupus. If future studies confirm these findings, the use of JAK/STAT inhibitors could represent an important strategy to mitigate cardiovascular risk in this disease. However, given concerns that JAK/STAT inhibitors may confer a risk for thrombosis and heart problems in individuals with conditions other than lupus, it will be important to carefully balance risk versus benefit before establishing the role of these drugs in SLE.” Mariana J. Kaplan, M.D. study author, NIAMS Deputy Scientific Director; Senior Investigator and Branch Chief, Systemic Autoimmunity Branch, NIAMS.
NIH researchers from NIAMS, the National Heart, Lung, and Blood Institute (NHLBI), NIH Clinical Center, the Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation contributed to this study.
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Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus Hasni, S.A., Gupta, S., Davis, M. et al. Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus. Nat Commun12, 3391 (2021). https://doi.org/10.1038/s41467-021-23361-z