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Dry eye is one of the major symptoms of chronic graft versus host disease (CGVHD).1,2 Although effective therapy for dry eye associated with CGVHD has not been well established, successful treatment with systemic FK506,3,4 topical retinoic acid,5 topical cyclosporin A,6 and topical autologous serum have been reported.7,8 However, improved tear secretion was reported only in one patient with systemic FK506 by Masaoka et al,3 with limited description of ocular findings. We present a patient with dry eye associated with CGVHD, where systemic administration of FK506 resulted in improved ocular surface findings along with the Schirmer test value.
A 33 year old man had HLA matched sibling allogeneic peripheral blood stem cell transplantation in December 2000 for acute myeloid leukaemia in remission. He received cyclosporine A as GVHD prophylaxis, but it was discontinued on day 85. On day 98, he was referred to an ophthalmologist for screening of CGVHD. On examination, slight tarsal and bulbar conjunctival injection, and slight superficial punctate keratitis (SPK) were noted bilaterally. The Schirmer test value was 10 mm in the right eye and 9 mm in the left eye.
On day 105, he developed bilateral pseudomembranous conjunctivitis, lichenoid oral lesions, skin eruptions in the upper half of the body, and liver dysfunction. The diagnosis of CGVHD was made. On day 123, oral cyclosporin A (5 mg/kg /day) and oral prednisolone (60 mg/day) were started, and then skin eruptions and liver dysfunction gradually subsided. On day 140, although pseudomembranous conjunctivitis was settled down, SPK worsened (fig 1) in both eyes. Prednisolone was discontinued on day 186. On day 196, the Schirmer test values decreased to 1 mm in the right and 3 mm in the left eye, and tear break up time (BUT) was 1 second bilaterally. Because lichenoid oral lesions and SPK were unchanged and skin eruptions gradually worsened, oral cyclosporine A was discontinued and oral FK506 was started on day 221.
On day 287, the trough level of FK506 was 8.5 ng/ml and the Schirmer test values improved to 4 mm in the right and 5 mm in the left eye. SPK had gradually improved in both eyes. On day 322, the Schirmer test value improved to 16 mm and SPK disappeared in both eyes. On day 421, the trough level of FK506 was 7.9 ng/ml. The Schirmer test value was maintained over 10 mm up to day 553 without recurrence of SPK (fig 2) in both eyes, although BUT remained 1 second bilaterally.
Ogawa et al4 reported that in two patients with CGVHD, the symptoms of dry eye and the findings of the ocular surface markedly improved after the administration of systemic FK506 with corticosteroids. However, in their cases the results of Schirmer tests were not normalised in contrast with the result of Masaoka et al.3 Ogawa et al4 speculated that this difference is probably the result of the degree of lacrimal gland destruction. They demonstrated the result of biopsy of the lacrimal gland with prominent interstitial fibrosis and T cell infiltration in one of their patients.
The degree of lacrimal gland destruction may vary with the duration and/or severity of CGVHD. In two patients reported by Ogawa et al,4 FK506 had been administered 246 days after the onset of CGVHD in one patient, and the other had mild dry eye before haematopoietic stem cell transplantation. The lacrimal gland in these patients might have been irreversibly damaged before the administration of FK506. We speculate that in our patient, because FK506 substituted for cyclosporin A 101 days after the onset of CGVHD before irreversible damage of the lacrimal gland occurred, thereby may effective in improving tear secretion. The lack in the improvement of BUT in our case may be the result of severe damage to goblet cells with preceding pseudomembranous conjunctivitis.
This case indicates that systemic administration of FK506 is effective for dry eye associated with CGVHD, although the degree of improvement in tear secretion may vary between cases with the duration and/or severity of CGVHD.