Background/Purpose:

Fatigue is a major complaint in at least 80% of SLE patients, and is often listed as the most disabling symptom of the disease; however, fatigue often does not improve significantly with standard treatments that reduce disease activity assessed by standard measures (SLEDAI).  Defining altered biologic pathways in SLE patients with severe fatigue might provide clues to disease pathways that have not been previously identified – or have been identified but not appreciated for their importance in SLE fatigue.  One possible pathway of interest is the IFNa pathway, well appreciated in SLE disease activity and recently identified as important in patients with chronic fatigue syndrome.  We hypothesized that gene expression studies comparing patients classified by high fatigue scores and low disease activity and patients with low fatigue scores/low disease activity might identify new or previously underappreciated pathways of SLE pathogenesis.

Methods:

We administered the Fatigue Severity Score (FSS) to a subset of SLE patients participating in a longitudinal SLE in atherosclerosis cohort study.  Monocyte RNA was isolated from peripheral blood of 5 SLE patients with severe fatigue (defined as ≥6 on FSS) and 8 SLE subjects with mild fatigue (≤ 4 on FSS), all of whom had low disease activity (SELENA-SLEDAI ≤ 4).  Whole genome transcript analysis was performed using Affymetrix Human U133+2.0 chips.  dChip software (Li lab, Harvard) was utilized to determine differentially expressed transcripts.  The Database from Annotation, Visualization, and Integrated Discovery (DAVID) program (http://david.abcc.ncifcrf.gov) was utilized to examine if any functional groups of genes were altered. To examine whether a subset of IFNa-regulated genes were dysregulated, differentially expressed genes were entered into the Web-based database www.interferome.org.  Differential transcript expression was confirmed by quantitative PCR.

Results:

The mean FSS score in the high fatigue group was 6.7 ± 0.5 vs. 2.8 ± 0.8 in the low fatigue group.  Approximately 300 transcripts were differentially expressed between the high and low fatigue groups (fold change ≥1.2 or ≤-1.2, p≤0.05). Three gene families were significantly altered in this comparison: the immune response gene category (Benjamini corrected p-value 3.8 e-8), regulation of apoptosis (2.5 e-6), and response to virus (2.8 e-3).  35% of the dysregulated transcripts were IFNa-regulated genes (expected ‘interferome’ transcripts would be ~8%), and most were upregulated in patients with high fatigue.  Dysregulation of five interferome genes was confirmed by qPCR analysis: ICAM1 (1.86-fold up, p=0.01), IRF1 (2.24-fold up, p=0.03), JAK2 (3.60-fold up, p=0.04), OAS-L (1.94-fold up, p<0.01), and TLR4 (2.63-fold up, p=0.01).

Conclusion:

Upregulation of IFNa-regulated transcripts, already known to associate with SLE disease activity, appear to also associate with high fatigue in patients with low SLEDAI.  Targeting IFNa pathways with specific therapeutic agents might be beneficial in patients suffering from fatigue, even in the absence of traditional high disease activity measurements.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fatigue-in-sle-is-associated-with-upregulation-of-interferon-alpha-related-gene-transcripts/