Background/Purpose:

Cryopyrin associated periodic syndromes (CAPS) are a group of IL-1β mediated autoinflammatory diseases characterized by fever, urticaria and conjunctivitis, and in severe cases, CNS abnormalities, hearing loss, and bone overgrowth.  Patients treated with IL-1 targeted therapy have resolution of a majority of clinical symptoms, although bone lesions are known to progress despite treatment.  Follistatin-like protein 1 (FSTL-1) is a pro-inflammatory protein secreted by mesenchymal cells, including osteoblasts.  This study was performed to determine how serum FSTL-1 levels correlate with clinical and laboratory markers in the most severe form of the CAPS, Neonatal Onset Multisystem Inflammatory Disease (NOMID).   

Methods:

FSTL-1 serum levels were measured by ELISA in 10 patients at pre-treatment and post-treatment time points and compared to values from a group of 53 normal controls.  FSTL-1 levels were correlated with ESR, CRP, as well as complete blood counts, and clinical characteristics, including presence of bony overgrowth at baseline. To gain insights into the expression of FSTL-1 relative to IL-1  blockade, FSTL-1 levels were measured in CAPS knock-in mice expressing an NLRP3 mutation, as well as in mice with the NLRP3 mutation on an IL-1 receptor knockout background.

Results:

FSTL-1 serum levels were elevated in NOMID patients vs. normal controls (182 ng/ml vs. 139 ng/ml, p=0.037) and remained elevated after treatment with anakinra (160 ng/ml), even though other markers of inflammation, including ESR, high sensitivity CRP, WBC, and platelet counts all declined to normal levels.   The highest levels of FSTL-1 were observed in patients with bony overgrowth at baseline as compared to patients without bony overgrowth (204 ng/ml vs. 149 ng/ml, p = 0.01), whereas FSTL-1 levels did not correlate with other clinical abnormalities.  A trend of correlation was seen between FSTL-1 and high sensitivity CRP (Pearson r = 0.38, p = 0.08). Finally, FSTL-1 serum levels were elevated in mice expressing NLRP3 mutation compared to wild type controls (502 ng/ml vs. 201 ng/ml, p <0.001) and were similarly elevated in mice expressing NLRP3 mutation on an IL1 receptor knockout background (440 ng/ml, p = 0.07 vs. controls). 

Conclusion:

Serum FSTL-1 is elevated in patients with NOMID and FSTL-1 levels remain elevated despite anakinra treatment.  Similarly, FSTL-1 levels are elevated in a mouse model of CAPS and remain elevated despite the absence of IL-1 receptor.  Serum FSTL-1 levels are most elevated in NOMID patients with greater baseline bony overgrowth and remain elevated despite treatment with anakinra, suggesting that FSTL-1 may play a role or be a marker of bone abnormalities in this disorder.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-serum-follistatin-like-protein-1-suggests-an-interleukin-1-independent-pathway-for-inflammation-in-patients-with-cryopyrin-associated-periodic-syndromes/