New Biomarker Predicts Poor Outcomes in Scleroderma PDF Print E-mail
Tuesday, 24 December 2013 22:05
A novel biomarker may aid in establishing the prognosis of Systemic Sclerosis (Scleroderma), and particularly in predicting the most common lethal complications, an international group of researchers reported.

Patients with Systemic Sclerosis who had high levels of circulating CXCL4 were more than three times as likely to develop early pulmonary fibrosis as shown by a 30% or more loss in forced vital capacity, compared with patients with low levels of this protein (HR 3.67, 95% CI 2.31-4.31, P<0.001), according to Timothy R.D.J. Radstake, MD, PhD, of the University Medical Center Utrecht in the Netherlands, and colleagues.

They also were much more likely to develop early pulmonary arterial hypertension (HR 8.33, 95% CI 4.43-15.72, P<0.001), the researchers reported online in the New England Journal of Medicine.

Pulmonary fibrosis and pulmonary arterial hypertension today are the most common causes of death in patients with systemic sclerosis, also known as Scleroderma.

"The identification of CXCL4 as a marker for fibrosis and pulmonary arterial hypertension may be helpful in early diagnosis and risk assessment, an important factor in patients who require aggressive treatment," they observed.

"Currently there are no biomarkers that can predict which patients will have severe disease and may require last-resort treatment such as with cyclophosphamide or autologous stem cell transplantation, which have high rates of morbidity and mortality," Radstake told MedPage Today.

Study co-author Sandeep K. Agarwal, MD, PhD, of the University of Texas Health Science Center in Houston, told MedPage Today that “the ability of serum levels of CXCL4 to identify a subset of patients who need more intensive screening for these complications would be of use to physicians. Additional confirmation studies and prospective studies will be important to determine the predictive value of CXCL4 as a biomarker, and it is not likely to be clinically useful in the immediate future.”

CXCL4 is an antiangiogenic chemokine that also can inhibit expression of antifibrotic interferon-gamma and activate profibrotic cytokines of the interleukin family. The chemokine is produced by plasmacytoid dendritic cells, and has previously been implicated in other fibrotic and inflammatory conditions, including atherosclerosis and hepatic fibrosis.

To date, most research into the pathogenesis of systemic sclerosis has focused on the fibroblast, but immune cells also have begun to emerge as potential players.

To explore a possible role for plasmacytoid dendritic cells and CXCL4 in systemic sclerosis, especially in association with disease phenotype, Radstake and colleagues enrolled 779 patients with systemic sclerosis from five cohorts, along with 257 matched healthy controls.

They also obtained stored samples from 93 patients with ankylosing spondylitis and 109 with systemic lupus erythematosus.

A total of 462 patients had the limited cutaneous form of scleroderma, and 317 had the diffuse cutaneous form.

About three-quarters were women. Mean age at disease onset was 43, and mean disease duration was 9 years for those with limited cutaneous disease and 6 years for those with diffuse cutaneous disease.

Current therapies included mycophenolate mofetil (CellCept), cyclophosphamide (Cytoxan), prednisone, and hydroxychloroquine.

Among patients with systemic sclerosis, the mean level of CXCL4 was 25,624 pg/mL. This was significantly greater than levels in healthy controls (92.5 pg/mL), patients with ankylosing spondylitis (1,368 pg/mL), or systemic lupus erythematosus (1,346 pg/mL).

CXCL4 levels correlated with the degree of skin fibrosis in both the diffuse cutaneous group (R2=0.74, P<0.001) and the limited cutaneous group (R2=0.59, P<0.001).

To determine the suitability of CXCL4 as a biomarker for disease progression, the researchers also looked at levels in a group of 79 patients who were followed prospectively for 18 months.

In this cohort, they found a more rapid decrease in pulmonary diffusion capacity for carbon monoxide (P=0.002), more rapid progression of fibrosis of the skin (P<0.001), and a greater prevalence of pulmonary fibrosis as demonstrated on high-resolution CT (22% versus 8%, P<0.001).

The researchers also examined the effects of CXCL4 in vitro, and found various responses including secretion of endothelin 1, down-regulation of a transcription factor known as FLI1, and inhibition of vascular endothelial growth factor on endothelial cells from the dermis.

They noted that the down-regulation of FLI1 was particularly noteworthy, in that in FLI1 knockout mice, the expression of endothelial cell markers is down-regulated -- a pattern also seen in blood vessels of patients with systemic sclerosis.

In addition, in a mouse model there was a pronounced influx of inflammatory cells and thickening of the skin following administration of CXCL4. However, in mice, no fibrosis was seen despite the inflammation.

"In this light, it is tempting to speculate that although CXCL4 may sensitize various cells to inflammatory stimuli, culminating in fibrosis, the presence of CXCL4 alone is not sufficient," they observed. "Taken together, our observations suggest that CXCL4 and plasmacytoid dendritic cells are central to the pathogenesis of systemic sclerosis."

"We are now following up on these observations to better understand the precise roles of CXCL4 in the various pathologic hallmarks of scleroderma and also to develop CXCL4 as a candidate for therapeutic targeting," Radstake explained to MedPage Today.

Source: MedPage Today
 
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