Background/Purpose: Peptidylarginine deiminases (PADs), specifically PAD4,  have recently been implicated in the pathogenesis of systemic lupus erythematosus (SLE) through their role in citrullinating histones in myeloid cells and promoting neutrophil extracellular trap (NET) formation. Systemic administration of  the pan-PAD inhibitors Cl-amidine and BB-Cl-amidine were previously shown to abrogate lupus manifestations and vascular damage in various murine models of SLE, including improvements in skin disease in the MRL/lpr model. Whether topical administration of PAD inhibitors can modulate skin involvement in murine lupus once disease is clinically apparent, without promoting other systemic effects, remains to be determined.  

Methods: MRL/lpr mice received topical administration of either vehicle, the pan-PAD irreversible inhibitor Cl-amidine or the PAD4-specific reversible inhibitor GSK484 twice daily at 20 mg/kg, upon the development of skin rash. Only affected skin areas were treated.  Mice were euthanized  at 17 weeks of age. Autoantibodies were quantified by ELISA. Urinary albumin:creatinine ratios  were calculated. Cell subsets in the spleen were quantified by flow cytometry and bone marrow NETosis was measured by fluorescent microscopy.

Results: Upon development of facial alopecia, treament with topical Cl-amidine and GSK484 induced an initial improvement in the area and severity of the lesions compared to the vehicle-treated mice. However, the skin effects observed in the GSK484-treated mice were transient, whereas the Cl-amidine treated mice continued improving to the point that no facial alopecia could be detected at euthanasia. By histology, no mice treated with Cl-amidine developed ulcers, while 25% of GSK484 and vehicle-treated mice did. Otherwise, preliminary histology analysis showed that skin inflammatory scoring was not statistically different between groups. Further, total body, spleen or lymph node weight did not differ among the 3 groups.  Skin topical treatment did not modify bone marrow NETosis or circulating autoantibodies. Analysis of splenic immune cell subsets revealed that Cl-amidine-treated mice displayed significant decreases in CD4+ T cells and significant increases in neutrophils.There were no significant differences between GSK484 and vehicle-treated mice in any systemic features.Topical administration was well tolerated by mice. 

Conclusion: Topical administration of pan-PAD inhibitors may modulate skin disease in lupus animal models. Future studies should further assess the role of topical PAD inhibition in SLE. This study supports a putative role for PAD inhibition as a therapeutic approach in this disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-topical-administration-of-peptidylarginine-deiminase-inhibitors-in-murine-lupus/