Ophthalmology Times: Dry Eye 1
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Ophthalmology Times Resident Writer’s Award Program
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2Cornea
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A pharmacological approach to dry eye syndrome in a case of graftversus-host disease (GVHD)
Seanna Grob MD, MAS1, Reza Dana, MD, MPH, MSc1,2
1Department
of Ophthalmology, Harvard Medical School, Boston, Massachusetts
and Refractive Surgery, Massachusetts Eye and Ear Infirmary, Boston,
Massachusetts
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Corresponding Author:
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Seanna Grob, MD, MAS
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Massachusetts Eye and Ear Infirmary
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243 Charles Street
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Boston, MA 02114
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Telephone: 858.349.1813
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Email: Seanna_Grob@meei.harvard.edu
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Financial support: none
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Abstract:
65-year-old male with history of multiple myeloma and acute myeloid leukemia
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now status post multiple bone marrow transplants (including two allogeneic and 2
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autologous transplants) presented for evaluation of dry eye symptoms and photophobia
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that worsened after stopping oral Tacrolimus, which he was taking for graft-versus-host
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disease (GVHD) prophylaxis. The patient’s visual acuity was 20/50- in the right eye and
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20/100 in the left eye. Schirmer’s test was zero in both eyes. He had corneal fluorescein
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staining (National Eye Institute grading scale) of 12/15 in the right eye and 10/15 in the
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left eye with elevated subepithelial opacifications consistent with Salzmann degeneration.
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The patient was treated with punctual cauterization, anakinra 2.5% three times a day,
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autologous serum tears, and Boston Sight® PROSE lenses. The patient also used lubrication
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eye drops during the day and ointment at night. After close evaluation for a year, with the
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PROSE lenses in place, his vision improved to 20/25-3 in the right eye and 20/20-3 in the
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left eye. The treatment of dry eye disease in the setting of GVHD is complicated and
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requires close monitoring by an experienced cornea specialist and often needs a
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combination of multiple available treatments to control symptoms and disease
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progression.
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History:
A 65-year-old male was referred to the Cornea and Refractive Surgery Clinic at
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Massachusetts Eye and Ear Infirmary for evaluation of decreased vision, sensitivity to light,
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and the sensation of dryness in both eyes.
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The patient had a past medical history of multiple myeloma diagnosed 22 years
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prior when he presented with back pain and widespread bone disease. He underwent
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initial treatment of Vincristine-Dactinomycin-Cyclophosphamide (VAC) chemotherapy and
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then his first autologous hematological stem cell transplant (auto-HSCT) a year later. After
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several years, he had his second auto-HSCT. He then received thalidomide-based therapy
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followed by an allogeneic hematological stem cell transplant (allo-HSCT) from his sister.
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Thereafter, he was treated with bortezomib and went into remission. Follow up treatments
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included lenalidomide, bortezomib, and dexamethasone over the next 5 years.
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Unfortunately, he developed therapy-related acute myeloid leukemia three years prior to
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presentation, but successfully underwent an allo-HSCT from an unrelated donor. The
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patient did remarkably well throughout these treatments.
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However, the patient noticed worsening symptoms of dry eyes after stopping
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Tacrolimus, which he was taking for Graft-versus-host disease (GVHD) prophylaxis. He
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previously tried punctual plugs and several years prior had undergone lower punctal
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cautery in both eyes. He was currently using prednisolone 1% every two hours and Refresh
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PM (Allergan, Irvine, CA) every two hours in both eyes.
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Examination:
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At this time the patient’s visual acuity was best corrected to 20/200 with pinhole to
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20/50- in the right eye and 20/200 with pinhole to 20/100 in the left eye. The patient’s
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conjunctiva was injected and he had a low tear meniscus and rapid tear break up in both
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eyes. He had corneal staining (National Eye Institute grading scale) of 12/15 in the right
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eye and 10/15 in the left eye with elevated subepithelial opacifications consistent with
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Salzmann degeneration, more on the right than the left eye. Schirmer’s test was zero in
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both eyes. The patient had intraocular lens implants in both eyes. The pupils, motility,
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intraocular pressure and dilated fundus exam were unremarkable.
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Diagnosis and Discussion:
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Given the patient’s clinical history and examination, the likely diagnosis was Ocular
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GVHD in the setting of a recent allo-HSCT. GVHD is a common complication after allogeneic
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transplantation and frequently affects the skin, gastrointestinal tract and the liver.(1)
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Approximately 40-60% of patients who have received allo-HSCT are affected by ocular
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GVHD.(2-5) Both conjunctival (hyperemia, serosanguinous discharge, pseudomembranes,
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fibrovascular membranes or cicatricial changes in chronic) and corneal (dry eye syndrome,
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epitheliopathy, corneal epithelial sloughing) findings occur in ocular GVHD.(6)
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Pharmacologic agents often used for the prophylactic treatment of systemic GVHD
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are calcineurin inhibitors, including cyclosporine and tacrolimus, combined with
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methotrexate.(7, 8) Our patient specifically noticed worsening symptoms of dry eyes after
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the tacrolimus was discontinued. Fortunately, he never developed systemic symptoms of
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GVHD. However, if other systemic GVHD findings are present, therapy commonly includes
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systemic steroids.(6)
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In contrast, increasing systemic immunosuppression or the cumulative steroid dose
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is not recommended for the treatment of ocular GVHD. Treatment options focus on
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lubrication and tear film preservation, prevention of tear evaporation, reduction in
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inflammation, and epithelial support.(6) Topical lubrication with non-preserved phosphate-
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free tears is almost always combined with other modalities.(6) Therapies for tear
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preservation include punctual occlusion or thermal cautery, which can reduce
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supplemental tear dependence.(9) Also, the mucolytic properties of Acetylcysteine (5-10%)
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eye drops may be utilized in patients with adherent ocular surface filaments and oral
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secretagogues (pilocarpine or cevimaline) may contribute to the stimulation of tear flow.(6)
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Tear film instability and evaporative dry eye syndrome is closely associated with
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meibomian gland dysfunction (MGD). Treatments include warm compresses, lid hygiene,
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topical ointments such as erythromycin, tetracycline antibiotics (doxycycline or
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minocycline) and macrolides (azithromycin) for their anti-inflammatory effects, and flax
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seed or fish oil supplements.(6)
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Reduction in the inflammatory component of ocular GVHD and dry eye syndrome is
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also a key component of treatment. Topical cyclosporine (CsA) acts by inhibiting T-cell
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proliferation and their production and release of lymphokines and has shown some success
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in refractory ocular GVHD.(9-11) High frequency (greater than twice daily) 0.05% CsA has
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shown improved symptoms and clinical signs of ocular disease.(12) Topical steroids may
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also be beneficial due to their anti-inflammatory properties, but ocular side effects limit
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their use, especially in patients with a history (including family history) of ocular
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hypertension or glaucoma. Short-term, pulse steroids can have therapeutic potential in
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acute disease, but are not the optimal approach for long-term disease control. Off-label use
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of topical 2.5% interleukin-1 receptor antagonist (IL-1Ra) (anakinra, formulated by the
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Massachusetts Eye and Ear Infirmary pharmacy department, MA) has also shown
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promising results.(6, 13, 14) Systemic tacrolimus (FK506), a calcineurin inhibitor, has a
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beneficial effect in some cases of ocular GVHD, most likely by improving tear film
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production. Topical use is still in its early stages of evaluation, but has shown some clinical
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evidence of efficacy in dry eye disease.(15-17) Additionally, several other potential
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medications with anti-inflammatory properties are in the pipeline for use in dry eye
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disease.
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Epithelial support can be achieved with autologous serum eye drops and special
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contact lenses. Autologous serum eye drops have shown beneficial effects in the treatment
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of severe dry eye related to GVHD.(18, 19) The serum contains epithelioptrophic growth
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factors and other components essential for the health of the epithelial surface. However,
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use of serum tears requires specialized centers that can follow the regulations for drugs
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and blood products. Contact lenses, including bandage soft contact lenses, scleral lenses,
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and PROSE (prosthetic replacement of ocular surface ecosystem), have shown beneficial
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therapeutic effects in patients with severe dry eye and GVHD and can be an effective
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addition to the treatment plan.(20-24)
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Our patient was followed closely over the following year. Over this time, the topical
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steroids were tapered to reduce the cumulative dose of steroid. The upper puncta were
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cauterized during this period. Topical interleukin-1 receptor antagonist 2.5% three times a
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day was started in both eyes. Subsequently, the patient was started on autologous serum
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tears and was also fitted with Boston Sight® PROSE lenses (Boston Foundation for Sight,
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Needham, MA) in both eyes due to persistent symptoms of irritation and photophobia.
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Currently, the patient is using Boston Sight® PROSE lenses, Loteprednol (Bausch
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and Lomb, Bridgewater, NJ) every other day, Refresh PM ointment at night, anakinra 2.5%
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twice a day (before and after the PROSE), autologous serum drops twice a day (before and
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after PROSE) and Tears Natural® (Alcon, Fort Worth, TX) unmedicated while in PROSE
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lenses every two hours in both eyes. The patient felt that with this regimen, his symptoms
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and vision had vastly improved with this regimen. With the PROSE lenses in place, he had
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vision of 20/25-3 in the right eye and 20/20-3 in the left eye. He was still light sensitive
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with and without the lenses though. Future plans are to attempt taper of steroids further
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as tolerated.
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Conclusion:
The treatment of dry eye disease in the setting of Graft-versus-Host Disease is a
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complicated condition that can have devastating effects if not diagnosed and treated in a
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timely fashion. Patients require close monitoring by an experienced cornea specialist and
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often need a combination of multiple available treatments to control symptoms and disease
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progression.
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