Background/Purpose: SLE is a multifaceted disease characterized by immune dysregulation and varied disease activity. Identifying mechanistic mediators of altered disease activity would help prevent damage and improve disease management. This study seeks to identify markers that correlate with disease activity and distinguish African American (AA) SLE patients with impending flare.

Methods: We evaluated changes in plasma soluble mediators preceding SELENA-SLEDAI defined flare in AA SLE patients who developed disease flare 6 or 12 weeks after baseline assessment compared to race, gender, and age (± 5 years)-matched SLE patients without impending flare (non-flare, NF) and healthy controls (n=13 in each group). In addition, mediators were assessed in 18 additional AA SLE patients with impending disease flare compared to a corresponding clinically stable period (self non-flare, SNF) from the same individual. Fifty-two soluble mediators, including innate, adaptive, and shed TNF-receptor superfamily members, were assessed; p-values were corrected for multiple comparisons (q-values). A combined soluble mediator score algorithm was calculated utilizing normalized (Flare vs NF or Flare vs SNF) soluble mediator levels for each patient at baseline (pre-flare) weighted by each patient’s SELENA-SLEDAI score at time of disease flare.

Results: Patients with impending flare had significant (q<0.01) alterations in 32 soluble mediators at baseline preceding clinical flare by 6 to 12 weeks with significantly higher levels of pro-inflammatory mediators, including innate and adaptive cytokines. Baseline levels of regulatory cytokines, including IL-10 (q=0.0045) and TGF-β (q=0.0004), were higher in non-flare SLE patients, while pre-flare patients exhibited elevated levels of both innate and adaptive mediators, including IFN-α (q=0.0008), IFN-β (q=0.0080), IL-6 (q=0.0004), IL-12p70 (q=0.0008), IL-5 (q=0.0004), and IL-17A (q=0.0004). In addition, baseline levels of shed TNF-receptor superfamily members TNFRI (q=0.0017), TNFRII (q=0.0394), TRAIL (q=0.0008), FasL (0.0004), and CD40L (q=0.0008), but not BLyS (q=0.5784), were significantly greater in pre-flare patients compared to NF patients. These mediators were also significantly altered when comparing Flare and SNF samples from the same patient (q<0.01). The soluble mediator score was significantly higher in pre-flare SLE patients versus NF patients (p<0.0001) or SNF periods of stable disease (p<0.0001); every AA SLE patient followed longitudinally exhibited higher soluble mediator scores during their pre-flare period. No differences in the number or type of autoantibody specificities, nor differences in medication use, between pre-flare and NF or SNF SLE patients were noted.

Conclusion: Pro-inflammatory innate, adaptive, and TNF family mediators are elevated in pre-flare lupus patients, while elevated regulatory mediators were noted in AA SLE patients with stable disease. Alterations in the balance between inflammatory and regulatory mediators may help identify AA patients at risk of disease flare and help decipher SLE pathogenic mechanisms.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-innate-adaptive-and-tnf-superfamily-soluble-inflammatory-mediators-mark-impending-disease-flare-while-regulatory-mediators-distinguish-lack-of-impending-disease-flare-in-african-american-s/