Elizabeth C Goodale1, Katarina E Varjonen1, Catherine A Outerbridge1, Petra Bizikova2, Dori Borjesson3, Dedee F Murrell4, Angelina Bisconte5, Michelle Francesco5, Ronald J Hill5, Mohammad Masjedizadeh5, Philip Nunn5, Steven G Gourlay5, Stephen D White1. 1. Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA, 95616, USA. 2. Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA, 95616, USA. 3. Department of Clinical Sciences, College of Veterinary Medicine, NC State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA. 4. Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales, 2052, Australia. 5. Principia Biopharma Inc., 400 E Jamie Ct, South San Francisco, CA, 94080, USA.
Abstract
BACKGROUND: Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is the most common canine autoimmune skin disease. OBJECTIVES: To determine the safety and efficacy of a BTKi in cPF treatment. ANIMALS: Nine privately owned dogs. METHODS AND MATERIALS: Nine dogs diagnosed with PF were administered BTKi PRN473. Initial dosages were ≈15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for a maximum of 20 weeks, attempting decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels, urinalyses and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin G (IgG) titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells. RESULTS: All nine dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. At the end of the study, four responses were considered "good", two "fair", two "poor" and one dog withdrawn due to recurrence of a previously excised mast cell tumour. Four dogs continued to improve by Week 4; three sustained near complete remission by study's end. The anti-DSC-1 IgG titre decreased in three dogs, increased in two, was undetected in three and was not performed in the withdrawn dog. No dogs had detectable IgG to DSG1. Possible adverse effects occurred in three dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Bruton's tyrosine kinase inhibitor monotherapy may have beneficial effects in some cases of cPF.
BACKGROUND: Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is the most common canine autoimmune skin disease. OBJECTIVES: To determine the safety and efficacy of a BTKi in cPF treatment. ANIMALS: Nine privately owned dogs. METHODS AND MATERIALS: Nine dogs diagnosed with PF were administered BTKi PRN473. Initial dosages were ≈15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for a maximum of 20 weeks, attempting decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels, urinalyses and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin G (IgG) titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells. RESULTS: All nine dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. At the end of the study, four responses were considered "good", two "fair", two "poor" and one dog withdrawn due to recurrence of a previously excised mast cell tumour. Four dogs continued to improve by Week 4; three sustained near complete remission by study's end. The anti-DSC-1 IgG titre decreased in three dogs, increased in two, was undetected in three and was not performed in the withdrawn dog. No dogs had detectable IgG to DSG1. Possible adverse effects occurred in three dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Bruton's tyrosine kinase inhibitor monotherapy may have beneficial effects in some cases of cPF.
Authors: D F Murrell; A Patsatsi; P Stavropoulos; S Baum; T Zeeli; J S Kern; A-V Roussaki-Schulze; R Sinclair; I D Bassukas; D Thomas; A Neale; P Arora; F Caux; V P Werth; S G Gourlay; P Joly Journal: Br J Dermatol Date: 2021-06-15 Impact factor: 9.302