A recent prospective, observational cohort study of potential clinical biomarkers for progression to interstitial lung disease (ILD) in patients with early systemic sclerosis (SSc) found that higher levels of CCL2 circulating in their plasma predicted both faster ILD progression and poorer survival rates than in those with lower levels.1
CCL2, also known as monocyte chemoattractant protein-1, is a small cytokine belonging to the CC chemokine family. Cytokines are substances, such as interferon, interleukin and growth factors, secreted by cells in the immune system that have immunologic effects on other cells. Cytokines can be either pro-inflammatory or anti-inflammatory, and can be further subdivided into Th1-type and Th2-type cytokines.
The new study’s results combine two independent cohorts of patients with early SSc in Texas and Canada to examine the predictive significance of cytokines and chemokines for long-term progression of SSc-related ILD, says lead author Minghua Wu, MD, of the University of Texas Health Sciences Center in Houston. She and colleagues in Texas measured plasma levels obtained at baseline for 11 key cytokines using a highly sensitive multiplex sandwich immunoassay.
The Genetics vs. Environment in Scleroderma Outcome Study (GENISOS) in Texas tested a total of 266 patients with early SSc, along with 97 matched healthy controls. The companion replication cohort study by the Canadian Scleroderma Research Group looked for several of the same cytokines, including CCL2, in serum samples of 171 patients.
Researchers adjusted for age, sex and ethnicity, and the results remained independent of other biomarkers. The most significant finding indicated higher levels of CCL2 predicted faster decline in forced vital capacity (FVC), a measure of lung function that served as a surrogate for the severity of SSc-related ILD. Researchers tested FVC at patients’ initial visit and annually thereafter, with a mean follow-up from 4.36–5.72 years.
Among the 11 cytokines under examination by the Texas group, the data showed IL-10 was a significant predictor of ILD progression as well, but in the opposite direction: Higher IL-10 levels in the plasma meant slower progression. The Canadian data did not repeat this IL-10 finding.
Higher levels of CCL2 … predicted faster decline in forced vital capacity (FVC), a measure of lung function.
A New Therapeutic Target?
SSc, an autoimmune fibrotic disease that presents a distinct cytokine profile, is associated with high mortality, with few treatment options and no single Food and Drug Administration-approved medication for SSc-related ILD, says Dr. Wu’s UT colleague, Shervin Assassi, MD. “ILD, along with other pulmonary involvement, is the primary cause of mortality in this population,” he says. “The course of ILD is highly variable. The few existing clinical predictors of progression [we have] have not [proved] sufficient.
“We have been looking for predictive biomarkers and novel therapeutic targets,” he continues. “We postulated that inflammatory cytokines might predict the course of ILD. [And] with this research, we have demonstrated for the first time that CCL2 levels in the circulation [do predict] faster long-term decline.”
Previous experimental studies pointing to CCL2 as possibly correlated with the ILD severity used an animal model to reflect human disease, with murine sclerodermatous growth-vs.-host disease approximating the inflammation found in a subset of scleroderma, and with gene expression in skin transcript biopsy samples as an alternative to obtaining lung samples.2,3
The new findings provide further support for CCL2 as a research target, the authors conclude. Higher CCL2 levels in the circulation, after adjusting for other potential biomarkers, do predict faster ILD progression and poorer survival, supporting the notion CCL2 plays a role as a biomarker and may be a therapeutic target, Dr. Assassi says.
Predictive biomarkers can lead to more effective and individualized monitoring and treatment strategies, making it possible to more closely monitor SSc patients for progression of disease and potentially treat their disease more aggressively.
Larry Beresford is a freelance medical journalist in Oakland, Calif.
- Wu M, Baron M, Pedroza C, et al. CCL2 in the circulation predicts long-term progression of interstitial lung disease in patients with early systemic sclerosis: Data from two independent cohorts. Arthritis Rheumatol. 2017 Sep;69(9):1871–1878.
- Greenblatt MB, Sargent JL, Farina G, et al. Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. Am J Pathol. 2012 Mar;180(3):1080–1094.
- Assassi S, Wu M, Tan FK, et al. Skin gene expression correlates of severity of interstitial lung disease in systemic sclerosis. Arthritis Rheum. 2013 Nov;65(11):2917–2927.