Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jul;40(7):1191-9.
doi: 10.3899/jrheum.121131. Epub 2013 May 15.

Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis

Mark Gorelik  1 , Ndate Fall, Mekibib Altaye, Michael G Barnes, Susan D Thompson, Alexei A Grom, Raphael Hirsch
Affiliations

Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis

Mark Gorelik et al. J Rheumatol. 2013 Jul.

Abstract

Objective: Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein overexpressed in certain inflammatory diseases. Our objective was to correlate FSTL-1 levels with gene expression, known biomarkers, and measures of disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS).

Methods: FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, and 30 healthy controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin, and soluble interleukin-2 receptor-α (sIL-2Rα). Gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMC).

Results: Serum levels of FSTL-1 were elevated at time of presentation of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p < 0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal following treatment (p < 0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin. Ferritin/ESR ratio was superior to ferritin, sIL-2Rα, and FSTL-1 in discriminating MAS from new-onset sJIA. PBMC from patients with FSTL-1 levels > 200 ng/ml showed altered expression of genes related to innate immunity, erythropoiesis, and natural killer cell dysfunction. Two patients with the highest FSTL-1 levels at disease onset (> 300 ng/ml) ultimately developed MAS.

Conclusion: Elevated pretreatment serum FSTL-1 levels in sJIA are associated with dysregulated gene expression suggestive of occult MAS, and may have utility in predicting progression to overt MAS. Ferritin/ESR ratio may be superior to ferritin alone in discriminating overt MAS from new-onset sJIA.

Keywords: BIOMARKERS; FOLLISTATIN-LIKE PROTEIN 1; MACROPHAGE ACTIVATION SYNDROME; SENSITIVITY; SPECIFICITY; SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS.

PubMed Disclaimer

Figures

Figure 1
Figure 1
A. Serum FSTL-1 levels during the course of sJIA. Sera were assayed by ELISA from sJIA patients pretreatment and 24 months after initiation of therapy and compared to matched controls. The interior line represents the median; upper and lower boundaries of the box represent the 75th and 25th percentiles; top and bottom whiskers represent the 95th and 5th percentiles. Dots represent individual values for patients’ FSTL-1. Two patients whose disease onset was with MAS were not included. B. Paired sera collected from 4 patients during and after an episode of MAS were assayed (p = 0.0096). FSTL-1: Follistatin-like protein 1; sJIA: systemic juvenile idiopathic arthritis; MAS: macrophage activation syndrome.
Figure 2
Figure 2
Correlation of FSTL-1 with serum markers of inflammation in patients with sJIA, including sIL-2Rα (A, B), ferritin (C, D), and ESR (E, F). Left-side panels represent all patient samples at all timepoints (including MAS); right-side panels represent only the MAS subset. R values are uncorrected for presence of correlation between dependent data; p values were corrected through generalized estimating equations. FSTL-1: Follistatin-like protein 1; sJIA: systemic juvenile idiopathic arthritis; MAS: macrophage activation syndrome; ESR: erythrocyte sedimentation rate; sIL-2Rα: soluble interleukin-2 receptor-α.
Figure 3
Figure 3
Receiver-operating characteristics (ROC) curve shows an optimal sensitivity and specificity for MAS, obtained by use of ferritin/ESR ratio. Comparison of ROC curves with other biomarkers is shown; table gives details of ferritin/ESR sensitivity and specificity. A cutpoint of ferritin/ESR ratio of 80 provides optimum sensitivity and specificity for MAS, as shown in the detailed analysis. MAS: macrophage activation syndrome; ESR: erythrocyte sedimentation rate; FSTL-1: Follistatin-like protein 1; sIL-2Rα: soluble interleukin-2 receptor-α.
Figure 4
Figure 4
A. Gene expression profiles from pretreatment sJIA PBMC. RNA was collected from PBMC and assayed for differentially expressed genes based on FSTL-1 serum level above or below 200 ng/ml. Gene clusters are represented on the left with approximate locations of genes. B. Schema for utility of FSTL-1 and ferritin/ESR ratio as biomarkers in sJIA. FSTL-1 and ferritin are useful as markers of patients with altered gene expression suggestive of MAS, and of active MAS. Ferritin/ESR ratio can discriminate between active MAS and subclinical MAS or sJIA alone. PBMC: peripheral blood mononuclear cells; sJIA: systemic juvenile idiopathic arthritis; FSTL-1: Follistatin-like protein 1; ESR: erythrocyte sedimentation rate; MAS: macrophage activation syndrome; CRP: C-reactive protein.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Vastert SJ, Kuis W, Grom AA. Systemic JIA: New developments in the understanding of the pathophysiology and therapy. Best Pract Res Clin Rheumatol. 2009;23:655–64. - PMC - PubMed
    1. Grom AA, Mellins ED. Macrophage activation syndrome: advances towards understanding pathogenesis. Curr Opin Rheumatol. 2010;22:561–6. - PMC - PubMed
    1. Mellins ED, Macaubas C, Grom AA. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol. 2011;7:416–26. - PMC - PubMed
    1. Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology. 2005;44:1350–3. - PubMed
    1. Singh-Grewal D, Schneider R, Bayer N, Feldman BM. Predictors of disease course and remission in systemic juvenile idiopathic arthritis: significance of early clinical and laboratory features. Arthritis Rheum. 2006;54:1595–601. - PubMed

Publication types