Why test for CC chemokine ligand 18 (CCL18)?
CCL18, previously known as pulmonary and activation-regulated chemokine (PARC), is secreted by Gaucher cells and considered indicative of the overall Gaucher-cell burden.1,2 CCL18 plasma levels were found to be elevated in patients with Gaucher disease, suggesting its use as a surrogate disease biomarker.1 However, CCL18 is not a specific biomarker for Gaucher disease; it can also be used to monitor outcomes in patients with interstitial lung diseases associated with connective tissue diseases and idiopathic pulmonary fibrosis.3 Nevertheless, during evaluation of patients with Gaucher disease, it is recommended that levels of CCL18 be assessed.4,5
What is the CCL18 test?
Plasma CCL18 levels are measured by a sandwich enzyme-linked immunosorbent assay (ELISA).1,6 In 55 symptomatic patients with Gaucher disease Type 1, aged 12‒67 years (53% male), levels of CCL18 were elevated 29-fold compared with 36 unaffected individuals without the disease. Median plasma CCL18 values in healthy individuals were 33 ng/mL (range, 10‒72 ng/mL) versus 948 ng/mL (range, 237‒2285 ng/mL) in patients with Gaucher disease Type 1. The source of the elevated CCL18 in these patients was Gaucher cells, and levels were shown to decrease in those who received treatment: 47 patients received enzyme replacement therapy and 2 patients received substrate reduction therapy. These findings indicate that plasma levels of CCL18 could serve as a biomarker for determining treatment effectiveness in patients with Gaucher disease.1
CCL18 as a biomarker for disease severity in patients with Gaucher disease Type 1
The suitability of CCL18 as a biomarker for disease severity was assessed in 48 patients aged 12‒81 years (44% male) with Gaucher disease Type 1. Prior to treatment, median plasma CCL18 levels in patients with Gaucher disease were 875 ng/mL compared with 54 ng/mL in 67 individuals without the disease (p<0.0001). There was a significant correlation between plasma CCL18 levels and the clinical parameters of Gaucher disease: spleen volume (p=0.01), splenic plus excess liver volume (p=0.0016), excess liver volume (intact spleen; p=0.0015), platelet count (intact spleen; p=0.0083) and excess liver volume (splenectomised; p=0.0097). However, there was no association between plasma levels of CCL18 and avascular necrosis, fragility fracture, osteoporosis, liver disease, or polyclonal or clonal gammopathy.7
In 20 patients with Gaucher disease Type 1 (n=7 splenectomised) who received enzyme replacement therapy, plasma levels of CCL18 showed unbiased correlation with splenic and platelet responsiveness to therapy, whereas chitotriosidase activity did not. Therefore, plasma CCL18 levels were more closely reflective of splenic volume and platelet count during treatment than chitotriosidase activity. These findings indicate that determination of plasma CCL18 levels in patients with Gaucher disease Type 1 correlates with certain clinical parameters of the disease and enables monitoring of the effects of treatment.7
Systematic review and meta-analysis of plasma CCL18 levels and chitotriosidase activity in patients with Gaucher disease Type 1
An advantage of measuring plasma CCL18 levels is that unlike chitotriosidase activity, CCL18 is not subject to genetic variation and can be measured in all patients with Gaucher disease Type 1.1,2,7 A systematic review and meta-analysis aimed to compare the accuracy of chitotriosidase activity and plasma levels of CCL18 for assessing disease severity associated with Gaucher disease Type 1 (1109 observations from 334 patients). The accuracy for assessing the severity of haematological and visceral parameters of Gaucher disease Type 1 was a 5.3-fold (95% confidence interval [95% CI] 4.2‒6.6; p<0.001) and 3.0-fold (95% CI 2.6‒3.6; p<0.001) increase of the geometric mean for chitotriosidase activity and plasma CCL18 levels, respectively, compared with the absence of outcome. Meta-analysis revealed that the accuracy of chitotriosidase activity and plasma CCL18 levels for assessing Gaucher disease severity was similar (summary difference, 0.02 [95% CI -0.02‒0.05]; p=0.32). Moreover, assessing chitotriosidase activity did not improve the accuracy of outcome for CCL18 plasma levels (p=0.18). Measurement of plasma CCL18 levels was found to be more accurate than chitotriosidase activity for assessing disease severity in patients receiving enzyme replacement therapy (difference in area under the curve, 0.7 [95% CI 0.01‒0.12]; p=0.02). These data indicate that, since both biomarkers are comparable in terms of accuracy, monitoring of CCL18 plasma levels may be more useful in routine clinical practice, as CCL18 is not subject to genetic variation (unlike chitotriosidase activity).2
C-ANPROM/INT//7567; Date of preparation: September 2020
- Boot RG, Verhoek M, de Fost M, et al. Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 2004; 103: 33-39.
- Raskovalova T, Deegan PB, Mistry PK, et al. Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher disease severity. A systematic review with meta-analysis of individual participant data. Haematologica 2020; Epub ahead of print.
- Elhai M, Avouac J, Allanore Y. Circulating lung biomarkers in idiopathic lung fibrosis and interstitial lung diseases associated with connective tissue diseases: Where do we stand? Semin Arthritis Rheum 2020; 50: 480-491.
- Deegan P, Hughes D, Mehta A, et al. UK National Guideline for adult Gaucher disease. April 2005. Available at https://www.researchgate.net/publication/265282933_UK_National_Guideline_for_Adult_Gaucher_Disease_April_2005. Accessed September 2020.
- Haute Autorité de Santé. Gaucher disease: national diagnosis and treatment protocol. January 2007. Available at https://www.has-sante.fr/upload/docs/application/pdf/ven_gaucher_web.pdf. Accessed September 2020.
- Dekker N, van Dussen L, Hollak CE, et al. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood 2011; 118: e118-e127.
- Deegan PB, Moran MT, McFarlane I, et al. Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease. Blood Cells Mol Dis 2005; 35: 259-267.