Canine Keratoconjunctivitis Sicca Research Articles

Association of serum 25-hydroxyvitamin D concentrations with Schirmer tear test 1 and tear film breakup time in dogs.

The association between vitamin D and canine keratoconjunctivitis sicca (KCS) has not been investigated in dogs. To investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with Schirmer tear test 1 (STT-1) and tear film breakup time (TFBUT) in dogs. Sixty-one clinically healthy, client-owned dogs were enrolled. STT-1 and TFBUT were measured in 122 (61dogs) and 82 (41 dogs out of total 61 dogs) eyes, respectively. Serum 25(OH)D concentrations were evaluated by quantitative chemiluminescent immunoassay. The dogs were classified into 6 groups according to the evaluations (STT-1: group 1, normal [≥ 15 mm/min] in both eyes; group 2, normal in one eye and abnormal [< 15 mm/min] in the fellow eye; group 3, abnormal in both eyes; TFBUT: group 4, normal [≥ 20 sec] in both eyes; group 5, normal in one eye and abnormal [< 20 sec] in the fellow eye; group 6, abnormal in both eyes). STT-1 was positively correlated with TFBUT (p < 0.001). Among the STT-1 groups, the mean serum 25(OH)D concentration in group 1 was significantly higher than in groups 2 and 3 with positive correlation (p < 0.001). However, there were no significant differences among the TFBUT groups 4, 5, and 6. In dogs, it was found that serum 25(OH)D concentrations had a greater effect on quantitative KCS than qualitative KCS. Therefore, it is considered that measurement of serum 25(OH)D concentration could be included in the diagnostic tests in canine quantitative KCS patients.

Topical applications of allogeneic adipose-derived mesenchymal stem cells ameliorate the canine keratoconjunctivitis sicca

BackgroundCanine keratoconjunctivitis sicca (KCS) is predominantly an immune-mediated disease. Current therapy of canine KCS is mainly by immunosuppressant, but the effectiveness was limited in some patients. In the past few years, some studies showed the results of the use of mesenchymal stem cells in treating canine KCS via periocular injections. However, the periocular injection procedure requires sedation or general anesthesia, and may lead to iatrogenic or incidental injury during the injection process. The aim of this study was to investigate the efficacy of topical allogenic canine adipose-derived mesenchymal stem cells (cAD-MSCs) in clinical patients of canine KCS.ResultsThe cAD-MSCs used in this study were characterized for their capability of tri-lineage differentiation and immunomodulatory properties. In addition, preparation methods for eye drops of cAD-MSCs was developed and its optimal preservation was tested. The canine KCS patients were recruited for clinical trial and divided into two groups based on their history of previous treatment. All patients received topical cAD-MSCs treatment once per week for 6 consecutive weeks and complete ophthalmic examinations were performed 1 week before treatment (week 0) and at 3rd, 6th, 9th weeks, respectively. The results showed that the quantity and quality of tears have improved significantly following topical cAD-MSCs treatment based on Schirmers tear test-1 and tear break-up time. More than half of all patients were found improved in the tear quantity. In particular, 56.5% of the patients that were unresponsive to prior immunosuppressant therapy had an effective increase in tear volume. The severity of clinical signs was also ameliorated according to the numeric rating scale score from both patient owners and the clinician.ConclusionTo sum up, topical cAD-MSCs may be beneficial especially in KCS patients with poor owner compliance for frequent daily use of eye drops or those who are unresponsive to immunosuppressant therapy.

Влияние аутологичной плазмы, обогащенной тромбоцитами, на уровень слезопродукции при сухом кератоконъюнктивите у собак

Влияние аутологичной плазмы, обогащенной тромбоцитами, на уровень слезопродукции при сухом кератоконъюнктивите у собак

Assessment of corneal and conjunctival metaplasia by impression cytology during the treatment of canine keratoconjunctivitis sicca.

The purpose of this study was to assess the condition of cells in the conjunctiva and corneal epithelium prior to and during cyclosporine- or tacrolimusbased treatment of keratoconjunctivitis sicca (KCS). The study was performed on 40 dogs with KCS. The dogs were divided into two groups of 20 animals each. In Group I, 0.75% cyclosporine eye drops were administered three times a day, while in Group II 0.02% tacrolimus eye drops were administered twice daily. Additionally, each group was subdivided into three subgroups based on the results of the Schirmer I tear test (STT I). Evaluation of cellular metaplasia in the cornea and the palpebral and bulbar conjunctiva based on the Nelson-Adams scale was performed by impression cytology using Millipore round filters (Millipore VSWP 01300 DA) of 25 μm pore diameter applied to the studied area. Ophthalmological and cytological examinations were performed prior to the treatment as well as after one and two months of therapy. In both groups, a decrease in Nelson-Adams values was observed, corresponding to the increasing STT values [Rxy Spearman statistically significant correlation coefficient values between -0.75 (P < 0.001) and -0.45 (P < 0.01)]. The absence of goblet cells was observed in all dogs, regardless of the KCS stage. Goblet cells reappeared following both tacrolimus- and cyclosporine-based treatment in impression cytology specimens classified as 0 in the Nelson-Adams scale. The extent of corneal and conjunctival metaplasia in the course of tacrolimus- and cyclosporine-based treatment of KCS decreases with increasing STT values.

Efficacy of HL036 versus Cyclosporine A in the Treatment of Naturally Occurring Canine Keratoconjunctivitis Sicca

ABSTRACTPurposes: To (i) evaluate the efficacy and safety of HL036, a tumor-necrosis factor (TNF)-α-blocking protein, in the treatment of naturally occurring canine keratoconjunctivitis sicca (KCS) and (ii) compare these features with those of 1% cyclosporine A (CsA).Materials and Methods: Dogs (n = 29) diagnosed with KCS were randomly assigned to receive one drop topical aqueous HL036 (0.2, 1, or 5 mg/mL) or 1% CsA in the affected eye(s) at 12-h intervals for 42 days. Schirmer’s tear test (STT), fluorescein corneal staining (FCS), and clinical-sign scores were evaluated prior to application (day-0) and on days 14, 28, and 42 post-treatment. Of the 29 dogs enrolled, 19 (65.5%) received HL036 (HL036 group) and 10 (34.5%) received 1% CsA (CsA group). A linear mixed-effects model analysis was performed to determine score differences between groups and over time.Results: After treatment, clinical-sign scores and STT values had significantly improved compared with baseline levels in dogs of both treatment groups. Decreases in total clinical-sign scores for the HL036-group were greater than those of 1% CsA group. No severe adverse reactions were noted in either group.Conclusions: Our findings suggest that topical aqueous HL036 is well-tolerated and more effective than 1% CsA for treating naturally occurring canine KCS.

Optimising tear replacement rheology in canine keratoconjunctivitis sicca.

Dry eye is a substantial problem in a large number of human and canine patients. Numerous laboratory models for tear deficiency exist using genetically predisposed rodent models, animals treated with topical anti-muscarinics, or those kept in environments with increased air flow to produce the ocular surface changes seen in human patients. Canine keratoconjunctivitis sicca, seen in many thousands of dogs kept as companion animals, can provide a valuable spontaneous model for testing tear replacement medications that might better model disease in human patients, existing as it does in an outbred population that live in the same environments as their owners. Here the development of a crosslinked hyaluronic acid topical drop is described together with the results of trials on dogs with spontaneous keratoconjunctivitis sicca. Although hyaluronic acid in its native form in tear replacement drops shows a Newtonian rheology, the crosslinked product described here behaves in a non-Newtonian manner, with the same shear thinning shown by the tear film itself. The crosslinked product thus shows itself as a potentially valuable tear replacement medication for the human dry eye population as well as for dogs with the same condition.

Immunohistochemical evaluation of lymphocyte populations in the nictitans glands of normal dogs and dogs with keratoconjunctivitis sicca.

Idiopathic canine keratoconjunctivitis sicca (iKCS) is a common condition of the canine eye involving a deficiency in aqueous tear production which is commonly held to have an immune-mediated, as most probably an autoimmune aetiopathogenesis. Yet to date no direct evaluation has been made of the inflammatory cell populations in the lacrimal tissue of dogs with iKCS. Here we sought to quantify T and B lymphocyte populations in the lacrimal tissue of the nictitans glands of dogs with iKCS those with neurological KCS (nKCS)and also in dogs with tear production within the recognized normal levels and no ocular surface signs of KCS. Nictitans glands were obtained from 10 healthy dogs with no signs or history consistent with KCS at post-mortem or after enucleation. Nictitans glands were also obtained at parotid duct transposition surgery from ten dogs with idiopathic KCS and three with neurogenic KCS. Histological sections form the lacrimal tissue were processed immunohistochemically with primary monoclonal antibodies recognizing the T lymphocyte CD3 antigen and the B lymphocyte CD79a antigen. Cell numbers were counted in 10 randomly sampled representative high-power fields in five sections. Statistical significance of differences in cell numbers was determined using analysis of variance with significance achieved at p=0.05.Nictitans glands from dogs with iKCS showed elevated numbers of T and B lymphocytes compared with those from dogs with normal tear production. The increase in the T cell population was highly statistically significant (p=0.0025) while the increase in B cells, while statistically significant was less pronouncedly so (p=0.049). T and B lymphocyte numbers were not significantly elevated in nictitans glands from dogs with neurogenic KCS compared with those in dogs with normal tear production. The elevation in the T cell population seen in dogs with idiopathic KCS strongly supports the widely held assumption that this disease is an immune-mediated and probably autoimmune. The lack of increase in T cell populations in dogs with nKCS strongly suggests that the changes in iKCS are causing the tear deficiency and not resulting from it.

Preformulation Studies of a Liposomal Formulation Containing Sirolimus for the Treatment of Dry Eye Disease.

The aim of this study was to develop and characterize a liposomal product containing sirolimus to be administered subconjunctivally for the treatment of nonresponsive keratoconjunctivitis sicca (KCS) or dry eye. Formulations were prepared using an ethanol injection method and an adaptation of the heating method in pursuance of the most suitable methodology for future industrial production. Liposomes were loaded with either a high dose of 1 mg/mL of sirolimus or a less toxic dose of 0.4 mg/mL. The effects of critical process and formulation parameters were investigated. Liposomes were characterized in terms of size, zeta potential, polydispersity, differential scanning calorimetry, morphology, entrapment efficiency, phospholipid content, thermal stability, and sterility. The formulation was evaluated clinically in dogs with spontaneous KCS. Sterile liposomal dispersions with sizes ranging from 140 to 211 nm, were successfully obtained. High entrapment efficiency of 93%-98% was achieved. The heating method allowed an easier production of liposomes with high entrapment efficiency, to significantly shorten production time and the elimination of the use of alcohol. The poor stability of the obtained liposomes in aqueous dispersion made the inclusion of a lyophilization step necessary to the manufacturing process. In vivo testing of the liposomal sirolimus formulations in the spontaneous KCS dog model have produced promising results, particularly with a sirolimus dose of 1 mg/mL, indicating the need for further development and study of proposed formulations in the treatment of canine KCS. Clinical improvement in tear production in dogs with spontaneous KCS treated with the 1 mg/mL dose product was observed. The heating method allowed easier production of high entrapment efficiency liposomes to significantly shorten production time and the elimination of the use of alcohol. Tear production was increased in dogs administered with the formulation.

Canine keratoconjunctivitis sicca: an overview

Keratoconjunctivitis sicca (KCS) is a relatively common condition in dogs, which is caused by a deficiency of the aqueous component of the tear film. The most common cause is immune-mediated disease but other aetiologies include neurogenic, congenital, endocrine and infectious disease, drug-induced, iatrogenic, evisceration/prosthesis and irradiation. Diagnosis is made by performing a Schirmer Tear Test. Clinical signs include ocular discomfort, conjunctival hyperaemia, a tenacious mucopurulent ocular discharge and a lacklustre appearance to the corneal surface. Topical medication forms the mainstay of treatment but in refractory cases surgical intervention should be considered. This article gives an up-to-date overview into the management of canine KCS.

Lack of effects on lymphocyte function from chronic topical ocular cyclosporine medication: a prospective study

Topical cyclosporine has been widely used in the treatment of canine keratoconjunctivitis sicca without apparent documented clinical side effects. Thus the finding of reduced lymphocyte proliferation in animals treated with the drug at a concentration of 2% was both surprising and concerning. This study aimed to repeat the previous study and to compare the systemic effects of 2% cyclosporine in corn oil and 0.2% topical cyclosporine ointment (Optimmune, Intervet-Schering Plough, Welwyn, UK). Twenty dogs treated with Optimmune or with topical 2% cyclosporine in corn oil where previous treatment with Optimmune had failed were included in this study. Blood samples were taken at the time of first evaluation and at 1, 3 and 6 months of treatment to provide a biochemical and hematological health evaluation of the dogs and at each examination to measure circulating levels of cyclosporine and to obtain a lymphocyte population with which to determine a mitogen stimulation index (MSI) on treatment with phytohaemagglutinin-P (PHA) and conconavlin A (con-A). Levels of circulating cyclosporine were measured with an enzyme-multiplied immunoassay method and also the more sensitive quantification technique of mass spectroscopy (MS). No blood samples contained over 15 ng/ml cyclosporine, the lower limit of detection using the radioimmunoassay or the enzyme-multiplied immunoassay technique. Positive control samples taken from dogs treated with oral cyclosporine for anal furunculosis showed measurable levels in blood, demonstrating that the technique worked. Mean MSI values at 0, 1, 3 and 6 months of treatment were 10.2, 11.4, 11.6, and 10.5 for dogs treated with 0.2% cyclosporine and 10.4, 11.9, 11.7, and 12.9 for dogs treated with 2% cyclosporine. Mitogen stimulation index values were not statistically different between the first examination and any subsequent examination time-point. The findings of the study contradict those of the previous studies. No change in lymphocyte stimulation index was noted, neither were significant blood levels of cyclosporine documented after topical administration of either 0.2% or 2% cyclosporine. This study shows that topical cyclosporine is safe to use in the canine eye in line with the drug's safety record in this therapeutic regime over the past 20 years since its first use.

Cyclosporine A topical administration in dogs affected by immune‐mediated keratoconjunctivitis sicca

Abstract Purpose To study the effect of Cyclosporine A (CsA) on immune‐mediated canine keratoconjunctivitis sicca (KCS) or dry eye, and to evaluate the potential therapeutic action of this molecule. Methods The present study was conducted on a sample of randomized dogs affected by immune‐mediated KCS. It consists of 12 cases (24 eyes), various ages (from 3 to 11 years old) and different sexes (9 males ‐ 3 females). All dogs exhibited: different stages of muco purulent filaments and redness; they were negative to fluorescein; STT I on right eye was 4,4 ± 2,5 mm/1 min on left one was 5,5 ± 2,3 mm/1 min; cytology showed many inflammatory cells. The dogs were topically treated with CsA ointment (0,2%) for 8 weeks 0,6 cm strip (1/4 inch) of ointment every 12 hours. Results The result of these studies presented a significant improvement as evaluated by STT I . Thus, the right eye was 12 ± 4,6 mm/1 min (p &lt; 0,05) and the left one was 11,8 ± 4,1 mm/1 min (p &lt; 0,05). Moreover, dogs treated with CsA showed decreased purulent corneal secretion and marked regression of chronic corneal neovascularization and granulation tissue. Cytology analysis indicated a significant reduction in the number of corneal inflammatory cells. Conclusion This report confirmed that CsA is involved in the regulation of tears production, most probably by acting on reduction lacrimal gland inflammation and possible regeneration of lacrimal acinar lobules. CsA caused also a marked anti‐inflammatory action of the dog’s cornea. Neverthless, further clinical studies are necessary to assess the consistency corneal toxic effect of this mulecole in the eye.

Clinical evaluation of pimecrolimus eye drops for treatment of canine keratoconjunctivitis sicca: A comparison with cyclosporine A

The aim of this study was to evaluate the efficacy of pimecrolimus oil-based eye drops in alleviating the clinical signs of keratoconjunctivitis sicca (KCS) in dogs and to compare the efficacy with that of cyclosporine A (CsA) ointment. An open-label, multicenter study enrolling 44 dogs previously untreated with CsA was conducted. Dogs were randomly assigned to a treatment group and medicated twice daily for 8 weeks. After that time the mean increase (±SEM) in the Schirmer tear test was 9.2 ± 1.6 mm/min in the pimecrolimus group and 5.8 ± 1.1 mm/min in the CsA group ( P = 0.085). The improvement in clinical signs of inflammation in eyes treated with pimecrolimus was significantly greater than in eyes treated with CsA ( P = 0.02). The results show that 1% pimecrolimus oily eye drops are as safe as and more effective than CsA ointment in controlling KCS in dogs.

Abstracts

Punctal occlusion in the treatment of dogs with keratoconjunctivitis sicca Williams, D. L. (2002) Use of punctal occlusion in the treatment of canine keratoconjunctivitis sicca. Journal of Small Animal Practice...

Conjunctival impression cytology from dogs with keratoconjunctivitis sicca. Pre- and post-treatment with topical cyclosporine.

Keratoconjunctivitis sicca (KCS), or dry eye, is a major cause of ocular morbidity in humans and dogs.1,2 Although the cause of KCS in dogs often cannot be determined, as in non-Sjögren’s dry eyes, histopathologic and serologic studies suggest that canine KCS frequently results from immune-mediated lacrimal gland destruction or dysfunction. Tear film deficiencies cause changes in the conjunctival epithelium that may account for many of the clinical symptoms and the corneal morbidity in these cases. The normal conjunctival surface is composed of nonkeratinized, stratified, squamous epithelium with goblet cells. These cells and the products from them, including mucin, are critical for ocular surface integrity. Squamous metaplasia from cuboidal epithelium to increasing keratinization and goblet cell loss is associated with KCS in patients with Sjögren’s syndrome and with ocular problems in postmenopausal women.2–4 Methods for staging squamous metaplasia by impression cytology have been established for use in humans.2,5–7Although KCS in dogs and response to treatment with cyclosporine have been characterized histologically by biopsy of lacrimal glands, there are no reports on conjunctival cytology from dogs with KCS.1,8 Clinical trials in dogs and humans have supported the validity of treating KCS with cyclosporine. In this project we characterized conjunctival cytology from dogs with KCS before and after treatment with cyclosporine in order to determine the effect of topical cyclosporine treatment on the conjunctival epithelium.

A New Perspective on Canine Keratoconjunctivitis Sicca: Treatment with Ophthalmic Cyclosporine

Keratoconjunctivitis sicca is the major cause of chronic or recurrent conjunctivitis in dogs. The diagnosis of KCS is often delayed or mistaken for allergic or bacterial conjunctivitis and inappropriate or insufficient treatment leads to progressive corneal scarring and blindness in many dogs. The cause of KCS in dogs has not been proven, but evidence supports an immune-mediated etiology for the majority of cases. In an attempt to specifically treat the cause of KCS, a new immunosuppressant drug, cyclosporine, has been used in a topical preparation. Treatment results using ophthalmic cyclosporine are dramatic compared with historical treatments. Resolution of corneal scarring and increased lacrimation are seen in most dogs. Investigations of the mechanism of action of ophthalmic cyclosporine suggest the efficacy may have been serendipitous. A local neuroendocrine effect of cyclosporine on the lacrimal gland may actually be responsible for the increased lacrimation. Early diagnosis of KCS and treatment with ophthalmic cyclosporine may avert a major cause of blindness in dogs.

Spontaneous canine keratoconjunctivitis sicca. A useful model for human keratoconjunctivitis sicca: treatment with cyclosporine eye drops.

Thirty-six sequential cases of canine keratoconjunctivitis sicca (KCS) were treated with ophthalmic cyclosporine. The effects of topical cyclosporine were twofold: (1) cyclosporine increased tear production by 5 mm/min or greater in all cases of spontaneous KCS having an initial Schirmer's Tear Test value greater than 2 mm/min and in 59% of eyes with an initial Schirmer's Tear Test value of 0 to 2 mm/min, and (2) cyclosporine caused marked regression of chronic corneal neovascularization and granulation even in eyes in which lacrimation failed to improve. Additional benefits of topical cyclosporine were reduced mucopurulent conjunctivitis, rapid healing of nonhealing corneal ulcers, and reduced dependence on frequent topical treatments of KCS. Twelve normal beagles treated with topical cyclosporine also had a reversible increase in lacrimation compared with baseline or placebo control-treated dogs.