Keratoconjunctivitis Sicca (KCS)

Keratoconjunctivitis Sicca, commonly known as “dry eye”, is a condition in which the animal does not produce enough tears and thus cannot adequately lubricate the eyes.

This condition can be very uncomfortable for the patient, predispose them to corneal ulcerations as well as corneal damage, and cause impaired vision. Clinical signs of KCS include a thick, “ropey” mucus discharge, squinting, dull looking cornea, redness, and sometimes may affect the nostril resulting in xeromycteria or “dry nostril”. KCS is often over-looked as an infection due to the thick mucus discharge, so it is important to schedule a comprehensive ophthalmic examination. Please understand that if your pet is diagnosed with KCS, it is very likely that they will need ongoing topical medical treatment for the remainder of their life. These medications may include tear stimulants, anti-inflammatory medications, and/or high quality artificial tears to improve comfort. If left untreated, it is possible that your pet may lose all functional vision, so we highly recommend periodic ophthalmic examinations to maintain comfortable, cosmetic, and visual eyes for your companion animal.

More Resources:

American College of Veterinary Ophthalmologists: KCS Brochure

Tacrolimus for the Treatment of Keratoconjunctivitis Sicca (Dry Eye)

Steve Dugan, DVM, MS, Diplomate of the ACVO

Keratoconjunctivitis sicca (KCS or dry eye) is a common problem of dogs which typically causes conjunctival inflammation, keratitis associated with vessel infiltration, fibrosis and pigment deposition within the cornea, discomfort, and a mucoid discharge.  Lymphocytic infiltration of lacrimal gland acini and ducts has been documented as a hallmark of KCS.  While topical Cyclosporine A (CsA) is approved for use, well-documented to be effective, and currently the treatment of choice for dogs with immune-mediated KCS, other similar drugs are beginning to emerge as effective therapeutic alternatives.

In the majority of KCS cases, an underlying etiology is not identified and in these cases it is believed an immune-mediated phenomenon creates inflammation and destruction of the lacrimal glands.  In immune-mediated lacrimal disease, the balance between T- suppressor and T-helper cells plays an important role in lacrimal gland regulation.  T- suppressor cells normally predominate, but in immune-mediated KCS, T-helper cells become the prevalent T lymphocytes.  It is believed that by inhibiting T-helper cells in KCS, CsA allows T-suppressor cells to sustain normal lacrimal function.

CsA is a derivative of the fungus Tolypocladium inflatum whereas tacrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis.   Both CsA and tacrolimus are T cell activation inhibitors initially developed for their systemic use in preventing graft rejection after organ transplantation.  The mechanism of action of CsA and tacrolimus is similar in that T cell proliferation and activation are altered by the inhibition of interleukin-2 (IL-2) gene expression in CD 4+ helper lymphocytes.  IL-2 transcription blockage leads to impaired T-helper and T-cytotoxic proliferation.  In addition to reduction of IL-2 release from lymphocytes, these drugs interfere with IL-2 receptors on lymphocyte surfaces. CsA and tacrolimus have also been reported to reduce eosinophil production, block mast cell degranulation and suppress tumor necrosis factor cells. Additional therapeutic effects may be achieved via CsA and tacrolimus’ anti-inflammatory effects, stimulatory effect on lacrimal glands, proliferative effect on mucin-producing conjunctival goblet cells, and inhibitory effect on lacrimal cell apoptosis.  Despite similar mechanisms of action between CsA and tacrolimus, tacrolimus has been demonstrated to be 10 to 100 times more potent than CsA in its ability to inhibit cytotoxic T lymphocytes and production of IL-2, IL-3 and gamma interferon in vitro.

Two clinical studies have demonstrated that tacrolimus is similarly effective in the treatment of canine KCS to topically administered CsA.  In addition, tacrolimus was also effective in some dogs in which treatment with CsA had failed.  In the first study reported by Chambers et al in 2002, 0.02% tacrolimus in oil or ointment was instilled BID in 50 eyes affected by KCS in 26 dogs.  Significant improvement in clinical signs was noted in 48 of 50 eyes (96%) and the Schirmer tear test results were improved in 46 of 50 eyes (92%).   In the second study reported by Berdoulay et al in 2005, 0.02% tacrolimus in aqueous suspension was instilled BID in 164 eyes of 105 dogs and showed that topical tacrolimus is a promising alternative to topical CsA for treatment of KCS and may be beneficial in patients with less than optimal response to topical CsA.  All dogs previously diagnosed with KCS and controlled with topical CsA were successfully switched to tacrolimus therapy.  In addition, 51% of dogs that were poorly responsive to prior CsA treatment responded positively to topical tacrolimus which may have been a reflection of differences in bioavailability of the medications.

Topical CsA has been reported to improve tear production in 71-86% of dogs with KCS.  In the study reported by Berdoulay et al, 83% of dogs with presumed immune-mediated KCS were successfully treated with topical 0.02% tacrolimus based upon an increase in tear production of > 5 mm/min.  Thus, the study by Berdoulay et al concluded that topical tacrolimus may represent an alternative treatment for canine KCS patients receiving CsA when irritation prevents the use of CsA (the primary side effect of topical CsA administration is ocular irritation) or when there is an inadequate response to CsA.   In addition, combining tacrolimus with CsA in cases refractory to each administered alone may help improve overall response as tacrolimus has been shown to act synergistically with CsA in suppressing the proliferation of T cells in vitro.

Tacrolimus doses of 0.03% to 0.02% in aqueous or oil based suspensions as well as ointment formulations are available through many compounding pharmacies in the U.S.  Because tacrolimus has demonstrated success in the treatment of canine KCS, it is being prescribed with increased frequency by veterinary ophthalmologists.  However, considerable anecdotal clinical information currently exists to support tacrolimus’ efficacy as being equivalent or superior to CsA and further evidence-based research is needed.  In addition, high toxicity with systemic administration has precluded the use of tacrolimus in dogs for most situations in veterinary medicine and concerns regarding the carcinogenic potential of tacrolimus applied to the skin have recently been raised.  As a result, I believe we are obligated to begin treatment of presumed immune-mediated canine KCS with CsA since it is approved for use and a plethora of data has shown it is safe and usually effective.  If the patient fails to respond in a positive or adequate manner following a treatment trial with CsA for 6 to 12 weeks, then initiating treatment with tacrolimus may be indicated.

Pimecrolimus, a new ascomycin derivative, also interferes selectively with the activation of T cells and mast cells and inhibits the production of inflammatory cytokines.  A recent preliminary report by Nell et al in 2005 showed that 1% pimecrolimus in corn oil instilled TID in eight dogs with KCS produced a positive increase in tear production in six of eight (75%) dogs.  Theoretically, in comparison with CsA, pimecrolimus may be found to be superior because of its intrinsic higher potency and increased tissue permeability due to its lower molecular weight (811 pimecrolimus versus 1202 CsA).  However, as per tacrolimus, concerns regarding the carcinogenic potential of pimecrolimus have recently been raised.

References

  1. Berdoulay A, English RV, Nadelstein B. Effect of topical 0.02% tacrolimus aqueous suspension on tear production in dogs with keratoconjunctivitis sicca.  Vet Ophthal 2005; 8: 225-232.
  2. Regnier A. Clinical pharmacology and therapeutics. In: Gelatt KN, ed.  Veterinary Ophthalmology. Ames, Iowa: Blackwell Publishing, 2007: 339-340.
  3. Giuliano EA, Moore CP. Diseases and surgery of the lacrimal secretory system. In: Gelatt KN, ed. Veterinary Ophthalmology Ames, Iowa: Blackwell Publishing, 2007: 633-661.
  4. Nell B, Walde I, Billich A, Vit P, Meingassner JG.  The effect of topical pimecrolimus on keratoconjunctivitis sicca and chronic superficial keratitis in dogs: results from an exploratory study. Vet Ophthal 2005; 8: 39-46.
  5. Chambers L, Fischer C, McCalla T, Parshall C, Slatter D, Yakley Wm.  Topical tacrolimus in treatment of canine keratoconjunctivitis sicca: a multi-center preliminary clinical trial (poster). 33rd Annual Meeting of the American College of Veterinary Ophthalmologists, 2002.