ABSTRACT
Vemurafenib is a potent inhibitor of genetically activated BRAF, which is responsible for tumoral proliferation in cutaneous melanoma. A 56-year-old man receiving vemurafenib therapy presented with uveitis. Over the course of the disease, he developed bilateral, granulomatous uveitis with multiple peripheral chorioretinal lesions. Serum angiotensin-converting enzyme levels increased. The patient was diagnosed with probable ocular sarcoidosis related to vemurafenib and was treated with an intravitreal dexamethasone implant. This case is the first report that shows the clinical and angiographic features of a patient with vemurafenib-related sarcoid-like granulomatous uveitis.
Introduction
Vemurafenib is a potent inhibitor of the BRAF-mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. BRAF mutation is present in almost half of melanoma patients and is responsible for tumoral proliferation in the absence of growth factors. Vemurafenib has been used for the treatment of BRAF mutation-positive late stage (Stage III-C and Stage IV) melanoma since 2011.1,2 Vemurafenib-related uveitis has been reported in phase I, II, and III clinical trials, case reports, and case series in the literature.3,4,5,6,7 In addition to this, there is an article in the literature that reported 5 patients with sarcoidosis related to vemurafenib therapy for metastatic melanoma.8 Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Genetically susceptible individuals may develop an exaggerated immune response to unknown antigens including tumor cells or drugs.9 Vemurafenib may stimulate the immune system and then induce sarcoidosis in some patients.
We present here the clinical and angiographic features of a patient with sarcoid-like granulomatous intraocular inflammation which was induced by vemurafenib therapy for metastatic melanoma.
Discussion
The introduction of vemurafenib and other BRAF inhibitors has been a great improvement in the treatment of advanced cutaneous melanoma. However, they have adverse effects including cutaneous symptoms, arthralgia, nausea, diarrhea, headache, and neutropenia.1 Ocular adverse events including uveitis, conjunctivitis, dry eye, episcleritis, and keratitis were also reported with vemurafenib therapy. Uveitis was the most common ocular side effect of vemurafenib in clinical trials.3
Lheure et al.8 suggested that vemurafenib may induce sarcoidosis or sarcoid-like reactions by increasing serum levels of tumor necrosis factor-a and interferon-g, which induce granuloma formation. They reported 5 patients diagnosed with vemurafenib-related sarcoidosis. Two of the patients had intraocular inflammation. One of them met the criteria for systemic sarcoidosis and the other had Heerfordt syndrome that had been in remission for 15 years and presented with a relapse.8 Even though sarcoidosis was not a definitive diagnosis in our patient, bilateral involvement, granulomatous appearance, presence of snowballs, multiple peripheral chorioretinal lesions, negative tuberculin test, and increased serum ACE levels supported probable ocular sarcoidosis according to the international criteria for the diagnosis of ocular sarcoidosis.10
Ocular inflammation can usually be controlled by topical, local, and/or systemic corticosteroid therapy in this group of patients. However, treatment guidelines have not been established and management of these patients demands close cooperation with oncologists. Temporary discontinuation of vemurafenib may be suggested to control uveitis. However, some patients need to continue taking the medicine due to the life-threatening nature of the primary disease.3 In our case, we cooperated with the patient’s oncologist and decided to treat the patient with local steroids.
Lheure et al.8 argued that patients who develop sarcoidosis have a better prognosis with vemurafenib therapy than others. They explained this situation by saying that the activation of the immune system by cytokines may induce both sarcoidal reaction and antitumor response. In our case, cutaneous melanoma has been controlled successfully for 3 years with vemurafenib therapy.
This case is the first report that shows clinical and angiographic features of a patient with vemurafenib-related sarcoid-like granulomatous uveitis and highlights that ocular sarcoidosis should be considered in patients with vemurafenib-related uveitis.
