Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a recently described early-onset autoinflammatory disease caused by autosomal recessive mutations in genes encoding the proteasome subunits, mainly the subunit β type 8 gene (PSMB8). It was previously shown that CANDLE patients present with increased expression of Interferon (IFN) regulated genes and unregulated stat1 phosphorylation on peripheral blood monocytes. We therefore suggested that drugs inhibiting Janus kinases (JAKs), mediators of IFN signaling, might be used as a treatment in CANDLE. The objectives of this study were to assess the interferon regulated genes expression in additional CANDLE patients and to describe the effect of oral treatment with JAK inhibition on IFN-induced genes in CANDLE patients.
Methods:
Two new and 4 previously evaluated CANDLE patients had whole blood microarray analysis performed and their IFN signaling was compared with 5 healthy controls. Total RNA was extracted from PAXgene tubes blood samples and complementary DNA synthesis and target amplification were done. Affymetrix HU-133 Plus 2.0 gene chips were used for hybridization and data analysis was performed with GeneSpring 11.5 and Partek softwares. Patients and healthy control groups were compared using unpaired t test with Welch’s correction. IFN regulated gene expression profiles were assessed before and after treatment with the JAK inhibitor baricitinib in 2 CANDLE patients.
Results: Compared to controls, two new CANDLE patients presented with increased expression of IFN-induced genes, as in the previously evaluated 4 CANDLE patients. We have found that 202 genes were >2-fold upregulated compared to the 5 healthy controls, of those 89 are IFN regulated. The difference between the expression values was strikingly marked for the following genes: IFI27 (12.85 ± 0.85 vs. 6.10 ± 0.31, p<0.0001), ISG15 (12.86 ± 0.35 vs. 9.60 ± 0.69, p=0.0002), RSAD2 (12.75 ± 0.18 vs. 9.19 ± 0.70, p=0.0004), SP100 (11.75 ± 0.12 vs. 10.89 ± 0.34, p=0.0062), USP18 (9.95 ± 0.33 vs. 6.25 ± 0.68, p=0.0001), DDX60 (11.71± 0.09 vs. 9.72 ± 0.33, p=0.0002), EIF2AK2 (12.24 ± 0.21 vs. 10.64 ± 0.35, p=0.0001) and GBP1(12.02 ± 0.54 vs. 9.68 ± 0.43, p<0.0001). Upon treatment with the JAK inhibitor, 136 of the 202 up-regulated genes get down-regulated and 65 of those are IFN regulated genes. The others were genes that were associated with cytokine regulation including IL-22, IL-9, IL-15, IL-3, IL-2, GM-CSF, IL-17A. Of those 66 genes that did not change, 24 were IFN regulated genes. Interestingly, the expression of 37 proteasome-associated genes either increase or do not change with JAK inhibitor treatment.
Conclusion: We have found that CANDLE patients present a high expression of IFN-regulated genes and that this finding is present in all patients. This study also suggests that treatment with a JAK inhibitor is able to downregulate IFN induced genes as well as genes associated with the regulation of other inflammatory cytokines.
Disclosure:
A. Almeida de Jesus,
None;
Y. Liu,
None;
G. A. Montealegre,
None;
A. L. Reinhardt,
None;
D. Brown,
None;
A. Torrelo,
None;
A. V. Casano,
None;
L. Das,
None;
Y. Chen,
None;
Y. Huang,
None;
D. Stone,
None;
D. C. Chapelle,
None;
N. Plass,
None;
S. H. Zuckerman,
None;
W. Macias,
Eli Lilly and Company,
3,
Eli Lilly and Company,
1;
R. T. Goldbach-Mansky,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-subset-of-up-regulated-ifn-regulated-genes-in-candle-patients-decrease-with-treatment-with-a-jak-inhibitor/