Summary

The complement pathway is critically involved in many autoimmune diseases including vasculitides. In a multinational effort, Triaille and colleagues studied the clinical manifestations and in vivo activation of the type 1 interferon pathway in twelve patients with hereditary C1q deficiency (C1QDef). Most patients demonstrated mucocutaneous manifestations such as malar rash, oral ulcers, urticarial, vasculitic or pustular rash and alopecia. CNS involvement occurred in 11 of the 12 patients, including CNS vasculitis in two patients. Conversely, renal disease and major infections were uncommon (2/12). Type 1 interferon signature genes (ISG) were strongly elevated in all studied patients (10/12) and were in the range of Aicardi-Goutieères syndrome and STING-associated vasculopathy of infancy (SAVI). Cerebrospinal fluid was analyzed in two patients with CNS involvement, and IFNα levels were shown to be clearly elevated. All patients had received various immune suppressive drugs and two were treated with HSCT, with mixed success. Three patients were treated with JAK antagonists, one of whom showed a good response with resolution of cutaneous vasculitis and CNS manifestations. However, one patient worsened and one showed no response.

Impact on Patient Treatment and Future Perspectives

Based on the findings of elevated ISG expression in all studied patients with C1QDef, targeting the type 1 interferon pathway, eg with anifrolumab, may offer a treatment option, not only in these patients but also others with CNS vasculitis or other forms of vasculitis.
More studies are needed to understand the molecular basis of type 1 interferon pathway activation in C1QDef. One potential mechanism may be the inhibitory function of C1q on dendritic cells, major producers of interferon α, via LAIR-1 [2].

References:

[1] Triaille C, et al. J Clin Immunol 2024; 44:185
[2] Son M, et al. Proc Natl Acad Sci US A. 2012;109(46):E3160–7.

Composed by
Stephan Gadola, MD, PhD. Clinic of Rheumatology and Pain Medicine, Bethesda Spital, Basel