Peri-lacrimal gland injection of allogenic adipose-derived mesenchymal stem cells compared to tacrolimus eyedrops in the treatment of canine keratoconjunctivitis sicca

Abstract

Objective To describe and compare the efficacy in treatment between a single peri-lacrimal gland injection of adipose-derived mesenchymal stem cells (Stem Cells group) and a twice-daily application of tacrolimus eyedrops (Tacrolimus group) in client-owned dogs suffering from unilateral or bilateral early-stage immune-mediated keratoconjunctivitis sicca (KCS). Animals Studied Twenty-two, client-owned dogs (44 eyes), suffering from presumed unilateral or bilateral immune-mediated keratoconjunctivitis sicca (KCS) were enrolled in the study. The immune-mediated aetiology was made by exclusion, with animals suffering from unilateral or bilateral disease with no concurrent systemic disease or neurological deficits. The inclusion criteria were dogs of any age or breed with unilateral or bilateral, immune-mediated KCS (symptoms consistent with KCS and a Schirmer Tear Test type 1 [STT-1] ≤ 15 mm/min; confirmed on examination and previous history); with no co-existing ocular pathologies; and no previous history of treatment, including tear replacements or artificial tears. Exclusion criteria were dogs with bilateral end-stage KCS (advanced corneal pigmentation, fibrosis and/or recurrent corneal ulceration with possible corneal perforation and blindness), as well as the presence of concurrent systemic disease and medications. Procedures The dogs were followed for a 2-month period beginning at Day 0, with subsequent follow-ups at Day 30 and Day 60. Dogs were assigned to the various treatment groups based on owner preference. Dogs in the Stem Cells group received a one-time, bilateral, peri-lacrimal gland injection under heavy sedation using a commercially available mesenchymal stem cell solution (5 million viable MSC/mL; 2 mL per vial; VetRenew; South Africa). Dogs in the Tacrolimus group received a twice-daily application of eyedrops using a standard tacrolimus 0.02% eyedrop solution with the same oil carrier, from the same compounding pharmacy and batch. With investigators not being masked to the treatment groups, STT-1 and Tear Break Up Time (TBUT) were recorded, and corneal health subjectively scored using an author-derived simple descriptive scale (0: best; 5: end-stage cornea). Data for each eye was classified as either healthy (STT-1 > 15 mm/min) or having KCS (STT-1 ≤ 15 mm/min), then data within each classification were compared between treatments using a mixed effect model (fixed effect: time, treatment; random effect: dog, eye) using the following interactions: treatment, time, and treatment x time. Significance was interpreted a P < 0.05. All data is reported as mean (95% confidence interval of the mean). Results Dogs included in the study had a mean (min; max) of 8.7 (1.5 ; 14.0) years, with no difference between treatment groups. A total of 22 dogs began the study, however, 17 dogs (9 in Stem Cells group and 8 in Tacrolimus group) completed the study. One dog in Stem Cells group and 2 dogs in Tacrolimus group were excluded from the study for not meeting STT-1 inclusion criteria, and 2 dogs in Tacrolimus group were lost at the 60-day follow up. In KCS eyes (n = 26), STT-1 before treatment Day 0 in were 11 (9, 13) and 11 (8, 14) mm/min for Stem Cells and Tacrolimus, respectively. The STT-1 increased in both treatment groups over time and measured as 18 (16, 21) and 19 (15, 22) mm/min for Stem Cells and Tacrolimus at Day 30, respectively (both P < 0.001). The STT-1 stabilised at Day 60 with values of 18 (15, 22) and 19 (15, 23) mm/min for Stem Cells and Tacrolimus, respectively (both P < 0.001). The TBUT at Day 0 were 21 (11, 32) and 18 (12, 25) seconds for Stem Cells and Tacrolimus, respectively. The TBUT increased in both treatment groups over time and measured as 23 (16, 30) and 27 (21, 33) seconds at Day 30, and at Day 60 were 36 (27, 44) and 30 (22, 39) seconds for Stem Cells and Tacrolimus, respectively (both P < 0.001). Corneal scores improved over time (i.e., healthier corneas) and were significantly different to Day 0 at Day 30 (P < 0.001) and Day 60 (P < 0.001) for both treatment groups but not different between groups. Conclusion A single peri-lacrimal gland injection of adipose-derived mesenchymal stem cells may be an effective treatment in dogs with early-stage immune-mediated KCS and demonstrated similar outcomes as twice-daily application of 0.02% tacrolimus eyedrops over a 60-day period.