Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a poorly understood preclinical stage of immune dysregulation and symptom accrual. Accumulation of antinuclear autoantibody (ANA) specificities is a hallmark of impending clinical disease. Yet, many ANA-positive individuals remain healthy, suggesting that additional immune dysregulation underlies SLE pathogenesis. Indeed, we have recently demonstrated that interferon (IFN) pathways are dysregulated in preclinical SLE. To determine if other forms of immune dysregulation contribute to preclinical SLE pathogenesis, we measured SLE-associated autoantibodies and soluble mediators in samples from 84 individuals collected prior to SLE classification (average timespan = 5.98 years), compared to unaffected, healthy control samples matched by race, gender, age (±5 years), and time of sample procurement. We found that multiple soluble mediators, including interleukin (IL)-5, IL-6, and IFN-γ, were significantly elevated in cases compared to controls more than 3.5 years pre-classification, prior to or concurrent with autoantibody positivity. Additional mediators, including innate cytokines, IFN-associated chemokines, and soluble tumor necrosis factor (TNF) superfamily mediators increased longitudinally in cases approaching SLE classification, but not in controls. In particular, levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were comparable in cases and controls until less than 10 months pre-classification. Over the entire pre-classification period, random forest models incorporating ANA and anti-Ro/SSA positivity with levels of IL-5, IL-6, and the IFN-γ-induced chemokine, MIG, distinguished future SLE patients with 92% (±1.8%) accuracy, compared to 78% accuracy utilizing ANA positivity alone. These data suggest that immune dysregulation involving multiple pathways contributes to SLE pathogenesis. Importantly, distinct immunological profiles are predictive for individuals who will develop clinical SLE and may be useful for delineating early pathogenesis, discovering therapeutic targets, and designing prevention trials.

Herpes zoster vaccination in SLE: a pilot study of immunogenicity.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) are at increased risk of herpes zoster (HZ). Although a vaccine for HZ has been approved by the US Food and Drug Administration, its use in immunocompromised individuals remains controversial because it is a live-attenuated virus vaccine. We performed a pilot study of the immunogenicity of the HZ vaccine (Zostavax) in patients with SLE. METHODS: Ten patients with SLE and 10 control subjects ≥ age 50 years participated in this open-label vaccination study. All were seropositive for varicella zoster virus (VZV). Patients with SLE were excluded for SLE Disease Activity Index (SLEDAI) > 4, or use of mycophenolate mofetil, cyclophosphamide, biologics, or > 10 mg prednisone daily. Followup visits occurred at 2, 6, and 12 weeks. Clinical outcomes included the development of adverse events, particularly HZ or vesicular lesions, and SLE flare. Immunogenicity was assessed with VZV-specific interferon-γ-producing enzyme-linked immunospot (ELISPOT) assays and with antibody concentrations. RESULTS: All subjects were women. Patients with SLE were slightly older than controls (60.5 vs 55.3 yrs, p < 0.05). Median baseline SLEDAI was 0 (range 0-2) for patients with SLE. No episodes of HZ, vesicular rash, serious adverse events, or SLE flares occurred. Three injection site reactions occurred in each group: mild erythema or tenderness. The proportion of subjects with a > 50% increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls. Antibody titers increased only among controls following vaccination (p < 0.05). CONCLUSION: The HZ vaccination yielded a measurable immune response in this cohort of patients with mild SLE taking mild-moderate immunosuppressive medications. No herpetiform lesions or SLE flares were seen in this small cohort of patients. ClinicalTrials.gov ID:NCT01474720.