Refractory recurrent ocular graft versus host disease

Abstract

Ocular graft-versus-host disease (GVHD) is one of the most frequent and long-term complications affecting patients after haematopoietic stem cell transplantation. It is associated with significant morbidity and a marked reduction in quality of life. Although common, currently there are no widely accepted guidelines available for its management, and no suggested regime of treatment that is completely satisfactory. So far, prophylactic treatment strategies for ocular GVHD have yet to be developed and treatment is normally initiated based on symptoms often after permanent ocular tissue changes and surface damage has occurred. Here we describe a case of recurrent ocular GVHD and its associated complications that was highly refractory to treatment.

Background

Allogenic haematological stem cell transplantation (HSCT) from related or unrelated human leukocyte antigen (HLA)-matched donors is a well-established and potentially curative form of treatment for a wide range of benign and malignant haematological malignancies, as well as aplastic anaemia, severe immunosuppression, and some metabolic diseases such as mucopolysaccharidosis and lysosomal storage disorders.¹ Since its introduction in 1957 the number of HSCTs has continued to rise year on year with an estimated 25 000 undertaken annually worldwide.² If current trends continue the number of unrelated HLA-matched transplants is expected to double in the coming 5 years.³ Improvements in infection prophylaxis, immunosuppression, myeloablative conditioning regimes, DNA-based tissue typing and supportive care has expanded the indications for HSCT, increasing the treatment options available to older patients and overall enhancing patient outcomes.^{4 5} However despite such progress, the most common and serious complication of HSCT, graft-versus-host disease (GVHD) still affects 25%–70% of recipients and remains a major cause of non-relapse related patient morbidity and mortality.^{6 7}

Ocular manifestations of GVHD develop in 40%–60% of patients after allogenic-SCT and can lead to severe ocular surface complications.^{8 9} Studies have shown that patients rarely regain a normal tear film in the years following HSCT.^{10 11} The disease can affect all parts of the eye and its associated adnexa, although keratoconjuncitivits sicca is the most common finding and is present in 90% of cases. Other ocular signs and symptoms include conjunctival hyperaemia, pseudomembranous conjunctivitis dysfunction of the lacrimal and meibomian glands, corneal ulceration, scarring and perforation.^{12 13} The posterior segment is rarely affected although mention of retinal and choroidal lesions have been previously been made in the literature.¹⁴ Treatment options for ocular GVHD include topical agents to provide lubrication directly to the ocular surface, as well as both systemic and topical agents to suppress T cell over activation and to target the dysregulated inflammatory response.

Despite recent progress in the understanding of the pathogenesis of GVHD and expanding treatment options, neither a targeted treatment regime nor an effective preventative treatment option has been established. This is illustrated with the following case of refractory overlap ocular GVHD and its complications as treated over a 10-month period.

Case presentation

A 24-year-old woman was referred to our service with a 2-month history of decreased visual acuity and symptoms of keratoconjunctivitis sicca. She had a history of chemorefractory diffuse large B cell lymphoma, stage IVb with marrow and central nervous system involvement. The patient was transplanted using marrow from her HLA-matched sister with cyclophosphamide and total body irradiation (12 Gy) conditioning and standard cyclosporine prophylaxis for GVHD. She developed acute graft versus host disease (aGVHD) grade 3 with skin, gastric and mild ocular involvement, as per the National Institutes of Health Consensus, which was controlled with oral prednisolone 2 mg/kg, tapered by 10% every 5–7 days.¹⁵ She then developed ocular chronic graft versus host disease (cGVHD) which was of moderate intensity but well managed with topical corticosteroids and lubricants until she developed a urinary tract infection. This rapidly triggered acute left hip pain with associated swelling and reduced function (presumed to be reactive arthritis) along with severe oral and ocular inflammation. Treatment with systemic steroids resolved her joint and oral symptoms. However, her ocular inflammation continued relentlessly and she was referred to the ocular immunology and anterior segment service for further management.

By this time, her visual acuity had reduced to 6/30 in the right eye and 6/12 in the left best corrected. This was attributed to bilateral corneal epithelial defects measuring 6×2.5 mm in the right and 2.5×2.5 mm in the left, along with severe bilateral pseudomembranous conjunctivitis, and early symplepharon formation (figure 1). Her treatment to this point had consisted of a combination of intravenous methylprednisolone, followed by high dose oral and topical steroids, chloramphenicol eye drops and an intensive regime of lubrication. This had provided little to no relief. MRI brain and orbits were normal, and conjunctival swabs produced no growth. A Prokera ring was inserted into the right eye to assist with healing of the persistent epithelial defect. The patient was prescribed g-maxidex 2 hourly, g-ofloxacin 2 hourly, g-timolol oculus dexter (OD) (right eye) and hourly lubrication with preservative free eye drops and gels nocte for both eyes. Systemically she was commenced on prednisolone 40 mg, cyclosporine A (CsA) 50 mg BD (twice daily) for continued immunological and inflammatory suppression, along with prophylactic antiviral and antifungal cover with posaconazole, valcyclovir and doxycycline 100 mg OD to aid re-epithelisation and reduce ocular surface inflammation.

Figure 1.

Anterior segment photographs demonstrating periocular erythema, diffuse hyperaemia and oedema of the bulbar conjunctival, with pseudomembranous conjunctivitis visible nasally. Bilateral epithelial defects with mucous secretions, and early symblepharon formation.

The Prokera ring was poorly tolerated and was removed a week after insertion. Her condition continued to deteriorate and a month later she still showed a bilateral mucopurulent discharge with marked conjunctival chemosis and a total corneal epithelial defect in the right eye (figure 2). Conjunctival swabs were taken for herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), polymerase chain reaction (PCR), culture and sensitivity, Gram staining as well as a scraping of the right cornea applied to blood agar, chocolate agar and Sabouraud’s agar plates. All results were negative. A conjunctival biopsy was taken and was noted to contain CD3 cells, T lymphocytes, non-specific inflammation and was negative for B lymphocytes and malignancy.

Figure 2.

Right eye shown above with a total epithelial defect. Marked conjunctival chemosis and early cicatrical changes can be seen in both eyes.

Treatment was altered as follows: Topically, g-ofloxacin was changed to g-chloramphenicol minims four times a day, autologous serum drops 2 hourly and oc-tacrolimus 0.03% BD were added, g-maxidex was switched to g-dexafree four times a day, oc-vitapos nocte along with continued use of g-timolol and an intensive lubrication regime as before. Systemically mycopholate mofetil (MMF) 1 g BD was commenced, along with extracorporeal photophoresis (ECP), while continuing CsA, doxycycline 100 mg OD, and 30 mg oral prednisolone daily. Surgically, the patient underwent bilateral amniotic transplants, and right eye lower lid everting sutures to correct an early cicatricial entropion.

Over the following 4 weeks, the patient’s conjunctiva became less inflamed. However treatment failed to improve the corneal epithelial defects and a mucopurulent discharge persisted. Inflammatory changes continued with symblepharon formation, trichiasis and haze of the right cornea (figure 3). Systemically, her serum C-reactive protein (CRP) was raised and it was felt that the autologous serum eye drops might be exacerbating her condition so they were replaced with allogeneic serum drops. In an attempt to resolve the epithelial defects, a repeat bilateral amniotic membrane transplant was performed and combined with a lateral tarsarrhaphy in the right eye. G-cyclosporine (Ikervis) nocte was added into the regime along with g-acetylcysteine 5% four times a day, and g-chloramphenicol was changed to g-moxifloxacin our times a day. Hourly preservative free lubricating eye drops and gels at night, along with g-timolol and g-dexafree were all continued as before. Systemically the patient was commenced on immunosuppressive infliximab infusions, and continued with ECP, CsA, MMF and oral prednisolone 20 mg OD.

Figure 3.

Marked chemosis, in the right more so than the left, and corneal hazing. Symblepharon formation with triachasis is also noted, mainly effecting the right eye.

The amniotic transplants remained in place over the following 2 months. But despite this the inflammatory changes continued. Adverse side effects from prolonged usage of high dose steroids began to develop and the patient started to show signs and symptoms of Cushing’s syndrome. Systemically, empiric erythromycin was commenced to help reduce the conjunctival inflammation and discharge, but was not tolerated and stopped soon after. After a poor response to infliximab infusions over an 8 week period, she was commenced on monthly cyclophosphamide intravenous infusions.

Six months since initial presentation, the patient’s ocular condition was deteriorating and inflammatory changes continued in an unyielding fashion (figure 4). CT orbits and sinuses were negative. Further ocular samples were sent; conjunctival biopsy for 16 s and 18 s RNA were negative, as was conjunctival culture and sensitivity using blood agar, chocolate agar and Sabouraud’s agar plates. CMV PCR from the conjunctiva was positive and corneal scrapings floridly grew corynebacterium, which was shown to be sensitive to vancomycin. Treatment was altered accordingly. A 3-week course of valganciclovir was commenced along with oral augmentin. Topically g-vancomycin was prescribed hourly. G-cyclosporine, and g-dexafree were stopped on a trial basis. Allogenic serum drops, g-timolol and lubrication was continued as before. Subsequently, she received a once off dose of intravenous methylprednisolone 1 g followed by a high dose oral prednisolone taper.

Figure 4.

There is conjunctival chemosis and fibrosis with bilateral symblepharon formation due to subtarsal fibrosis. Cicatrical occlusion of the lower punctae has led to outflow obstruction in both eyes. Rght eye shows rapid deterioration, with significant corneal hazing and sloughing, preventing visualisation of the anterior chamber and its structure.

A moderate benefit from this regime of systemic steroid therapy combined with cyclophosphamide and topical vancomycin was achieved over the following month. The trial without dexafree, CsA and serum drops had led to worsening of inflammation indicating the benefits of topical corticosteroids in particular. Chemosis worsened, and visual acuity dropped to hand movements in the right and 3/60 best corrected in the left. Bilateral conjunctival discharge returned and conjunctival cicatrisation continued to develop with ankyloblepharon formation. The right corneal surface began to thin with a central epithelial defect (figure 5). Repeat corneal scrapings this time yielded a rich growth of mycoplasma sensitive to moxifloxacin, which was commenced on an hourly basis for 2 days initially following which it was tapered. The discharge resolved following topical moxifloxacin treatment, although other signs of conjunctival inflammation persisted. G-azithromycin (Azyter) was added BD for 3 days along with a 2-week course of oral clindamycin. Systemic immunosuppression was changed to the anti-B-cell monoclonal antibody rituximab, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib and oral prednisolone which was tapered to 5 mg daily along with continued use of CsA.

Figure 5.

Right eye shows a central epithelial defect and severe corneal thinning with risk of perforation. Below are two pictures of the left eye showing chronic fibrotic changes of the anterior surface as well as corneal surface haze beginning to develop.

The combination of intensive topical corticosteroids, topical antibiotics and systemic rituximab and ruxitinib yielded a significant improvement in the conjunctival inflammation and an improvement in her visual acuity to 6/24 left eye. However, 8 weeks later the right eye developed a persistent corneal ulcer measuring 1.5×3 mm, stromal thinning and a descemetocoele. Conjunctival chemosis returned in both eyes along with significant pain. Her visual acuity was reduced to hand movements (HM) right eye and CF left eye. A multilayered amniotic membrane graft along with a central tarsorrhaphy to give 80% lid closure was performed in the right eye under general anaesthesia. In an effort to combat conjunctival chemosis, subconjunctival dexamethasone was given at the same time under anaesthesia. Rituximab was recommenced with weekly infusions for 4 weeks.

Outcome and follow-up

After 10 months of unremitting ocular GVHD-related inflammation the patient’s right ocular surface began to show improvement, with healing of the corneal ulcer and stabilisation of the descemetocoele and the conjunctival inflammation has finally resolved (figure 6). And over the following 2 months both ocular surfaces became completely keratinised. Visual acuity has reduced to hand movements in the right eye and 2/60 in the left eye due to corneal opacification. There is marked restriction of eye movement due to conjunctival cicatrisation is present and signs of severe aqueous deficient dry eye disease persist. She remains on an intensive lubrication regime, to both eyes, and oral doxycycline 100 mg OD. Systemic immunosuppressive therapy consists of hydrocortisone 10 mg OD, tacrolimus 1.5 mg BD and ruxolitinib 10 mg BD, with additional cover with Valtrex, a proton pump inhibitor and calcium supplementation. Most recent clinical images can be seen in figure 7, and a summary of the patient’s treatment to date can be seen in table 1.

Figure 6.

The right eye has undergone a layered amniotic membrane transplant in conjunction with a generous lateral tarsorrhaphy in an effort to prevent perforation. The left corneal surface is hazy, due to surface fibrosis and calcification.

Figure 7.

Both ocular surfaces have become completely keratinised. The patient is due to undergo a right eye ocular orthodontic keratoprosthesis over the coming months.

Table 1.

Summary of treatment

Topical treatment	Systemic treatment	Surgical treatment
Lubrication Preservative free drops Preservative free ointments Punctae occlusion (scarred over)	Steroids Intravenous methylprednisolone High dose, pulsed oral prednisolone	Amniotic membrane transplants OU (multiple)
Antibiotics Chloramphenicol Ofloxacin Moxifloxacin Vancomycin Azithromycin	Antibiotics Doxycycline Erythromycin Co-amoxiclav	Right lower lid everting sutures
Serum drops Autologous Allogenic	Antiviral Valacyclovir	Lateral tarsorrhaphy OU, with repeat central tarsorrhaphy on the right eye
Anti-inflammatory Pred minums Dexafree Cyclosporine A Tacrolimus	Immunosuppression: Cyclosporine A Tacrolimus Infliximab Rituximab Ruxolitinib
Intraocular pressure control Timolol	Extracorporeal photophoresis
Subconjunctival dexamethasone
Prokera ring

OU, oculus uterque (both eyes).

With such significant ocular inflammation, and auto-rejection, the patient was thought to be unsuitable for a Boston type 2 and is currently undergoing workup for ocular orthodontic keratoprosthesis (OOKP).

Discussion

Ocular GVHD is a complex condition that can be extremely difficult to treat and manage, as demonstrated by the case report described above.

Topical therapy is the mainstay of treatment aimed at both the symptoms of dry eye disease and the underlying inflammatory component. It should revolve around four main principles, as suggested by the National Institutes of Health (NIH) consensus guidelines in 2006; (1) lubrication, (2) tear preservation and evaporation prevention, (3) decreased ocular surface inflammation and (4) ocular surface epithelial support.¹⁶ Preservative free medication is preferred as phosphate containing eye drops can damage the ocular surface epithelia as well as promote corneal calcification in the presence of corneal erosions and ulcers.¹⁷ Surgical and systemic treatment should be initiated only when topical therapy alone cannot control ocular symptoms and ideally management should be multidisciplinary with active input from both ophthalmology and haematology teams.

Lubrication can be achieved with the frequent use of artificial tears, minimising epithelial defects, decreasing discomfort and improving visual function as well as diluting inflammatory mediators. Viscous ointments are also useful especially when used at bedtime.^18–20 In previous studies, no difference in efficacy was observed between specific lubrication products or brands.²¹ Although our patient was unable to tolerate a bandage contact lens, they may also be used to stabilise tear film and to restore normal cellular turnover.²² Acetylcysteine eye drops have mucolytic and anticollagenase properties, but as of yet, their efficacy has not been proven in clinical trials. The use of oral muscarinic agonists, such as pilocarpine, has been shown to have some benefit in patients with dry eye disease associated with Sjogrens Syndrome; however, their use is associated with undesirable side effects and contraindications, and as such were not used.²³

Tear drainage can be reduced temporarily with the use of punctal plugs or permanently with surgical cauterisation. Our patient’s puncta fibrosed over due to the extensive inflammatory component of her ocular disease. Control of tear evaporation can also be aided with treatment to improve meibomian gland dysfunction. Topical eye drops, such as g-azithromycin, as well as oral doxycycline were used to challenge eyelid inflammation, treat possible bacterial infection and to improve glandular secretion and the tear lipid layer.²⁴

In treating ocular GVHD is vital to address not only ocular dryness, but also the related inflammatory component underpinning the disease. Topical steroids promote lymphocyte apoptosis and suppress cell mediated inflammation.²⁵ However, their long-term use is associated with unwanted side effects such as ocular hypertension, glaucoma, cataract formation, corneal thinning and increased susceptibility to infection. Topical cyclosporine (CsA) can be used alone or in conjunction with corticosteroids, and acts as a steroid sparing agent. CsA suppresses T cells, reducing inflammation, apoptosis and increases the number of conjunctival goblet cells and its use has been shown to be effective in various forms of dry eye disease, including cGVHD.^{26 27} Topical tacrolimus has a similar mechanism of action to that of CsA, although evidence for its use in the treatment of ocular GVHD is limited to a single reported case.²⁰ Unfortunately, our patient’s inflammation was never controlled sufficiently to allow her to be independent of topical steroids.

Epithelial cell support can be achieved through the use of autologous or allogeneic serum eye drops. They are rich in vitamin A, growth factors and fibronectin, are valuable in the treatment of epithelial defects and support the integrity of the cornea and conjunctival surfaces.^{28 29} Amniotic membrane transplants were used on multiple occasions to treat the patient’s refractory epithelial defects and corneal ulceration, and in order to prevent further thinning and perforation along with surgical closure of her eyelids.

Corticosteroids, with their potent antilymphocyte and anti-inflammatory effect, are the gold standard for the treatment for both aGVHD and cGVHD, and results in the complete remission in nearly half of all affected patients.^30–32 Cyclosporine or tacrolimus can be used in conjunction with corticosteroids, and similar to topical treatment allows for the reduction of steroid dosage and thus reducing unwanted side effect profiles with their long-term use.³³ ECP has been shown to be useful as a second line agent in steroid resistant cGVHD or in patients with steroid intolerance.³⁴ It has been shown to be of particular use in patients with mucous membranous disease and ocular GVHD.³⁵ ECP induces T-cell apoptosis, monocyte differentiation and T-cell regulation. Our patient received further immunosuppression with the use of tumour necrosis factor (TNF) blocking medications, supressing antigen presenting cell (APC) production as well as inhibition of tyrosine kinase with JAK 1/2 inhibitors. The combination of rituximab, ruxolitinib, low-dose oral prednisolone and intensive topical corticosteroids, preservative-free lubrication and antibiotic therapy was eventually successful at achieving remission from the inflammation. Long-term topical therapy will be required to manage the severe aqueous tear deficiency that persists.

Learning points.

• Ocular graft-versus-host disease (GVHD) is a common complication following haematological stem cell transplantation, and it is important that both physicians and ophthalmologists are familiar with the treatment of the condition, as it has long-lasting implications for those patients affected.

• The above case report has exasperated all known treatment options and is a demonstration of the catastrophic results of uncontrolled ocular inflammation when this condition is at its worst.

• It highlights the need for further research into the pathogenesis of ocular GVHD, in the hope of identifying diagnostic and therapeutic biomarkers and more effective and targeted treatments.