Vogt-Koyanagi-Harada disease developed during chemotherapy for Hodgkin lymphoma: a case report

Ocular manifestations are known for non-Hodgkin lymphoma, but are rare for Hodgkin lymphoma. An ocular manifestation is uveitis, which is a general term for inflammatory diseases that occur in uveal tissue, such as the iris, ciliary body, and choroid, and in the adjacent retina. Uveitis in persons under 18 years or younger has been reported to account for 2.6–6% of all cases of uveitis in Japan [1, 2]. When classifiable uveitis is divided into 4 etiologies: infectious, noninfectious, paraneoplastic syndrome, and masquerade syndrome [3]. The noninfectious form is the most common, with major causes being sarcoidosis and Vogt-Koyanagi-Harada (VKH) disease in Japan. Reported causes of the infectious form include human herpes virus and cytomegalovirus. Masquerade syndrome is most often caused by non-Hodgkin lymphoma in adult patients. We report a case of VKH disease, presenting as serous retinal detachment and uveitis in both eyes, in a young boy undergoing chemotherapy for Hodgkin lymphoma. We address the pathogenesis and treatment of VKH disease that has developed during chemotherapy for Hodgkin lymphoma.

Cases of VKH disease as a complication of Hodgkin lymphoma are rare; few cases have been reported in adults [6, 7]. To our knowledge, the present case is the first to be reported in a child with Hodgkin lymphoma. In the present patient, serous retinal detachment and uveitis in both eyes were observed after completion of 2 cycles of the OEPA regimen and 1 cycle of the COPDAC regimen to treat Hodgkin lymphoma. Complete VKH disease was finally diagnosed according to the diagnostic criteria proposed by the First International Workshop on VKH disease [5].

The believed cause of VKH disease is an autoimmune disease against melanin pigment cells [8]. The disease is caused by an attack on melanin pigment cells, resulting in inflammation of melanin-rich tissues, such as the eyes, ears, meninges, skin, and hair. The immune response to melanin pigment cells is of unknown cause, but is suggested to be related to histocompatibility antigens in leukocytes [8]. Our patient had HLA-DR4, which was a likely predisposition to the development of autoimmune diseases, including VKH disease. One year after Hodgkin lymphoma treatment had been completed, multiple vitiligo appeared on the skin of the abdomen.

Possible causes of the development of VKH disease, other than autoimmune diseases, include paraneoplastic syndrome, masquerade syndrome, infection, and drug-related causes [9]. In the present case, paraneoplastic syndrome could not be ruled out as a possible cause because serum autoantibody testing for retinal antibodies was not performed. Masquerade syndrome is a common term used when the symptoms and findings of the underlying disease are similar to those of other diseases, meaning that the underlying disease is hidden under a mask. The most common causative diseases of uveitis masquerade syndrome are primary intraocular lymphoma [3, 10, 11]. The intraocular lymphomas most often reported are non-Hodgkin lymphomas of histologic type large B-cell lymphoma. The present patient had a Hodgkin lymphoma (nodular lymphocyte predominant type) of the left inguinal region, without findings to suggest bilateral intraocular or central nervous system metastasis. Vitreous opacity and subretinal exudative lesions seen in intraocular lymphomas were not observed. Although vitrectomy and the collection of tumor cells are required to diagnose intraocular lymphoma, we considered the possibility of this disease in our case to be low. Moreover, known causes of VKH disease include such infections as human papilloma virus, bacteria, fungi, cytomegalovirus, and toxoplasma [3], but none of them were detected in the patient. The patient had previously been infected with Epstein-Barr virus, but no evidence of viral reactivation was found during chemotherapy. Furthermore, although drug-related uveitis can be caused by immune checkpoint inhibitors [12], uveitis has not been reported to be caused by any of the antitumor medications administered to patients before VKH disease develops.

During its acute phase, VKH disease in children is generally treated with corticosteroids, but a standard dose has not been established [13]. In the present patient, the treatment of VKH disease overlapped in time with the COPDAC regimen for Hodgkin lymphoma. Because the COPDAC regimen included oral prednisolone at 40 mg/m²/day daily for 15 days, the patient was treated with intravenous prednisolone at an increased dose of 60 mg/m²/day for 20 days. Thereafter, prednisolone was switched from intravenous to oral administration, and then the dose was gradually decreased. However, intraocular inflammation had been worse when the prednisolone dose had been reduced to avoid adverse effects, such as suppression of adrenal function and growth retardation, suggesting that the rate of prednisolone should be noted.

The onset of VKH disease occurred during chemotherapy for Hodgkin lymphoma. The patient was HLA-DR4-positive and might have had a predisposition to develop autoimmune diseases, including VKH disease. However, anticancer drugs administered to this patient have not been reported to cause uveitis. Whether Hodgkin lymphoma triggered the development of VKH remains unclear. Early diagnosis of VKH disease and prompt treatment with high-dose prednisone for an extended period enabled the patient’s visual function to be well maintained. The establishment of dosage and duration of corticosteroids administration for treating VKH disease in patients with underlying diseases is challenging, and additional cases must be reported.