Key to new lupus treatment could depend on protein in the blood

by SingHealth 

Serum CXCL5 levels are lower in Asian SLE patients and Faslpr mice, compared to healthy individuals and ICR mice controls, and negatively correlated with disease activity. (A) Serum CXCL5 levels in healthy individuals and Asian active SLE patients. (B)Correlation of serum CXCL5 and SLE disease activity index (SLEDAI) scores in Asian SLE patients. (C) Human receptor CXCR1/2 expression in the blood neutrophils. (D)Plasma levels of CXCL5 in healthy immunocompetent ICR mice and Faslpr mice with increasing age.(E)Anti-dsDNA antibody levels with increasing age of Faslpr mice. Six to 8 Faslpr mice per time point. (F)Urinary albumin-creatinine ratio (ACR) with increasing age of Faslpr mice. Six to 8 Faslpr mice per time point for the first 4 time points; three mice per time point for the last 2 time points. In total, 16 healthy and 20 SLE patient blood samples, 15 ICR and 57 Faslpr mice were used for this experiment.The results are expressed as the mean ± SD. Statistical significance was defined as * p<0.05, ** p<0.01, *** p<0.001, and **** p<0.0001 based on Student’s t-test for single comparisons and one-way ANOVA Dunnett’s test for multiple comparisons with 95% confidence interval, respectively. Credit: Arthritis & Rheumatology (2022). DOI: 10.1002/art.42383

A new study has shown that restoring the balance of a protein in blood may be a promising treatment option for systemic lupus erythematosus, or lupus, an incurable autoimmune disease.

The protein, CXCL5, helps to regulate the immune system through neutrophils, a type of white blood cell. In patients with lupus, the immune system which normally protects them against infections, paradoxically attacks their healthy tissues and organs, making them inflamed.

Researchers from the Singapore General Hospital (SGH) discovered that CXCL5 levels in the blood of patients with lupus were significantly lower than healthy individuals, suggesting that the protein may be a reason for lupus activity. Similar results were found in mice models of lupus.

Additionally, the team found that weekly injections of CXCL5 to mice with severe lupus restored CXCL5 balance, and improved survival from 25 percent to over 70 percent at 10 weeks. There was improved kidney function and reduced lupus activity compared to saline-treated mice. When CXCL5 was given together with cyclophosphamide (a conventional potent immunosuppressive treatment for lupus), CXCL5 seemed to prevent the toxic side effects of cyclophosphamide, enabling the mice to survive up to two years.

The study findings were published in Arthritis & Rheumatology, and highlighted as an important study in Nature Reviews Rheumatology in November 2022. A patent covering these results was filed by SingHealth, a public health care cluster which SGH is a part of, and has now been granted in the U.S. and Singapore. 

“We are excited about the possibility of a new treatment option for lupus as 30 to 60 percent of patients do not respond to conventional medications despite aggressive regimens. In the past 65 years, only three drugs for lupus have been approved by the United States Food and Drug Administration but these drugs have modest efficacy. There is therefore a real and urgent need for better therapies, particularly for the more severe spectrum of lupus that we see in Asia,” said senior author Associate Professor Andrea Low, Head and Senior Consultant, Department of Rheumatology & Immunology, SGH.

“Our study has shown CXCL5 to be safe. There was no liver or kidney toxicity or cancer inducing effects. Major components of the immune system were also not compromised. We hope to take our findings further to improve the care of patients with lupus,” said principal investigator Dr. Fan Xiubo, Senior Research Fellow, Department of Clinical Translational Research, SGH.

Lupus can potentially be life-threatening as it affects major organs such as the kidneys, heart, lungs and brain. Prevalence of lupus is reported to be about 100 per 100,000 people worldwide. The condition is more severe in Asians, affecting more women than men commonly between the ages of 15 and 45.

“It is gratifying to see that this research that started over 8 years ago, has led to a discovery that has the potential to offer patients with lupus new treatment options in future,” said Professor William Hwang, Senior Consultant, Department of Hematology, SGH, who co-led the early phases of the study. Prof Hwang is also CEO of the National Cancer Center Singapore.

“To be in the forefront of medicine means we have to constantly further our understanding of diseases and offer patients better treatment options through rigorous scientific research. I’m heartened that the team has shed new light on lupus and the possibility of a more efficacious therapy for patients some years down the road,” said Professor Fong Kok Yong, Deputy Group CEO (Medical and Clinical Services), SingHealth, and Senior Consultant, Department Rheumatology & Immunology, SGH.