A pharmacological approach to dry eye syndrome in GVHD

By Seanna Grob MD, MAS, and Reza Dana, MD, MPH, MSc

Abstract: A 65-year-old male with history of multiple myeloma and acute myeloid leukemia now status post multiple bone marrow transplants (including two allogeneic and 2 autologous transplants) presented for evaluation of dry eye symptoms and photophobia that worsened after stopping oral Tacrolimus, which he was taking for graft-versus-host disease (GVHD) prophylaxis. The patient’s visual acuity was 20/50^- in the right eye and 20/100 in the left eye. Schirmer’s test was zero in both eyes. He had corneal fluorescein staining (National Eye Institute grading scale) of 12/15 in the right eye and 10/15 in the left eye with elevated subepithelial opacifications consistent with Salzmann degeneration.  The patient was treated with punctual cauterization, anakinra 2.5% three times a day, autologous serum tears, and Boston Sight PROSE lenses. The patient also used lubrication eye drops during the day and ointment at night. After close evaluation for a year, with the PROSE lenses in place, his vision improved to 20/25-3 in the right eye and 20/20-3 in the left eye. The treatment of dry eye disease in the setting of GVHD is complicated and requires close monitoring by an experienced cornea specialist and often needs a combination of multiple available treatments to control symptoms and disease progression.

Boston-A 65-year-old male was referred to the Cornea and Refractive Surgery Clinic at Massachusetts Eye and Ear Infirmary for evaluation of decreased vision, sensitivity to light, and the sensation of dryness in both eyes.

The patient had a past medical history of multiple myeloma diagnosed 22 years prior when he presented with back pain and widespread bone disease. He underwent initial treatment of Vincristine-Dactinomycin-Cyclophosphamide (VAC) chemotherapy and then his first autologous hematological stem cell transplant (auto-HSCT) a year later. After several years, he had his second auto-HSCT. He then received thalidomide-based therapy followed by an allogeneic hematological stem cell transplant (allo-HSCT) from his sister. Thereafter, he was treated with bortezomib and went into remission. Follow-up treatments included lenalidomide, bortezomib, and dexamethasone over the next 5 years. Unfortunately, he developed therapy-related acute myeloid leukemia three years prior to presentation, but successfully underwent an allo-HSCT from an unrelated donor. The patient did remarkably well throughout these treatments.

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However, the patient noticed worsening symptoms of dry eyes after stopping Tacrolimus, which he was taking for Graft-versus-host disease (GVHD) prophylaxis. He previously tried punctual plugs and several years prior had undergone lower punctal cautery in both eyes. He was currently using prednisolone 1% every 2 hours and Refresh PM (Allergan) every 2 hours in both eyes.

Examination

At this time the patient’s visual acuity was best corrected to 20/200 with pinhole to 20/50^- in the right eye and 20/200 with pinhole to 20/100 in the left eye. The patient’s conjunctiva was injected and he had a low tear meniscus and rapid tear break up in both eyes.  He had corneal staining (National Eye Institute grading scale) of 12/15 in the right eye and 10/15 in the left eye with elevated subepithelial opacifications consistent with Salzmann degeneration, more on the right than the left eye. Schirmer’s test was zero in both eyes. The patient had intraocular lens implants in both eyes. The pupils, motility, IOP, and dilated fundus exam were unremarkable.

Diagnosis and Discussion

Given the patient’s clinical history and examination, the likely diagnosis was ocular GVHD in the setting of a recent allo-HSCT. GVHD is a common complication after allogeneic transplantation and frequently affects the skin, gastrointestinal tract and the liver.¹Approximately 40% to 60% of patients who have received allo-HSCT are affected by ocular GVHD.^2-5Both conjunctival (hyperemia, serosanguinous discharge, pseudomembranes, fibrovascular membranes or cicatricial changes in chronic) and corneal (dry eye syndrome, epitheliopathy, corneal epithelial sloughing) findings occur in ocular GVHD.⁶

Pharmacologic agents often used for the prophylactic treatment of systemic GVHD are calcineurin inhibitors, including cyclosporine and tacrolimus, combined with methotrexate.^{7, 8}Our patient specifically noticed worsening symptoms of dry eyes after the tacrolimus was discontinued. Fortunately, he never developed systemic symptoms of GVHD. However, if other systemic GVHD findings are present, therapy commonly includes systemic steroids.⁶

In contrast, increasing systemic immunosuppression or the cumulative steroid dose is not recommended for the treatment of ocular GVHD. Treatment options focus on lubrication and tear film preservation, prevention of tear evaporation, reduction in inflammation, and epithelial support.⁶Topical lubrication with non-preserved phosphate-free tears is almost always combined with other modalities.⁶Therapies for tear preservation include punctual occlusion or thermal cautery, which can reduce supplemental tear dependence.⁹Also, the mucolytic properties of Acetylcysteine (5% to 10%) eye drops may be utilized in patients with adherent ocular surface filaments and oral secretagogues (pilocarpine or cevimaline) may contribute to the stimulation of tear flow.⁶Tear film instability and evaporative dry eye syndrome is closely associated with meibomian gland dysfunction (MGD). Treatments include warm compresses, lid hygiene, topical ointments such as erythromycin, tetracycline antibiotics (doxycycline or minocycline) and macrolides (azithromycin) for their anti-inflammatory effects, and flax seed or fish oil supplements.⁶

Reduction in the inflammatory component of ocular GVHD and dry eye syndrome is also a key component of treatment. Topical cyclosporine (CsA) acts by inhibiting T-cell proliferation and their production and release of lymphokines and has shown some success in refractory ocular GVHD.^9-11High frequency (greater than twice daily) 0.05% CsA has shown improved symptoms and clinical signs of ocular disease.¹²Topical steroids may also be beneficial due to their anti-inflammatory properties, but ocular side effects limit their use, especially in patients with a history (including family history) of ocular hypertension or glaucoma. Short-term, pulse steroids can have therapeutic potential in acute disease, but are not the optimal approach for long-term disease control. Off-label use of topical 2.5% interleukin-1 receptor antagonist (IL-1Ra) (anakinra, formulated by the Massachusetts Eye and Ear Infirmary pharmacy department) has also shown promising results.^{6, 13, 14}Systemic tacrolimus (FK506), a calcineurin inhibitor, has a beneficial effect in some cases of ocular GVHD, most likely by improving tear film production. Topical use is still in its early stages of evaluation, but has shown some clinical evidence of efficacy in dry eye disease.^15-17Additionally, several other potential medications with anti-inflammatory properties are in the pipeline for use in dry eye disease.

Epithelial support can be achieved with autologous serum eye drops and special contact lenses. Autologous serum eye drops have shown beneficial effects in the treatment of severe dry eye related to GVHD.^{18, 19}The serum contains epithelioptrophic growth factors and other components essential for the health of the epithelial surface.  However, use of serum tears requires specialized centers that can follow the regulations for drugs and blood products. Contact lenses-including bandage soft contact lenses, scleral lenses, and PROSE (prosthetic replacement of ocular surface ecosystem)-have shown beneficial therapeutic effects in patients with severe dry eye and GVHD and can be an effective addition to the treatment plan.^20-24

Our patient was followed closely over the following year. Over this time, the topical steroids were tapered to reduce the cumulative dose of steroid. The upper puncta were cauterized during this period. Topical interleukin-1 receptor antagonist 2.5% three times a day was started in both eyes. Subsequently, the patient was started on autologous serum tears and was also fitted with Boston Sight PROSE lenses (Boston Foundation for Sight) in both eyes due to persistent symptoms of irritation and photophobia.

Currently, the patient is using Boston Sight PROSE lenses, Loteprednol (Bausch + Lomb) every other day, Refresh PM ointment at night, anakinra 2.5% twice a day (before and after the PROSE), autologous serum drops twice a day (before and after PROSE), and Tears Natural (Alcon Laboratories) unmedicated while in PROSE lenses every 2 hours in both eyes. The patient felt that with this regimen, his symptoms and vision had vastly improved. With the PROSE lenses in place, he had vision of 20/25-3 in the right eye and 20/20-3 in the left eye. He was still light sensitive with and without the lenses though. Future plans are to attempt taper of steroids further as tolerated.

Conclusion

The treatment of dry eye disease in the setting of GVHD is a complicated condition that can have devastating effects if not diagnosed and treated in a timely fashion. Patients require close monitoring by an experienced cornea specialist and often need a combination of multiple available treatments to control symptoms and disease progression.

Seanna Grob, MD, MAS, is a first-year resident with the Department of Ophthalmology, Harvard Medical School, Boston. She reports no financial support in relation to the subject matter.

Reza Dana, MD, MPH, MSc, is holder of the Claes H. Dohlman Chair in Ophthalmology at Harvard Medical School, Boston, and director of the Cornea and Refractive Surgery Service, Massachusetts Eye and Ear Infirmary, Boston. He did not indicate any proprietary interest in the subject matter.

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