pyrimidinones and Uveitis

Lay abstract This study aims to report the long-term outcome of intra-ocular inflammation (uveitis) associated with cancer immunotherapy (CIT). Serial patients complaining of blurred vision and painful eyes showed intra-ocular inflammation that was related to CIT, after infectious, inflammatory and tumoral causes of uveitis have been ruled out. The length of follow-up was more than 12 months for most patients. Eight serial patients treated with rituximab (anti-CD20), nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4), vemurafenib and dabrafenib (anti-BRAF), trametinib (anti-MEK) and ibritunib showed intra-ocular inflammation with hypopion (one patient), macular edema (five patients) and choroiditis (two patients). Various regimens of corticosteroid therapy showed a favorable ophthalmological outcome, whether the CIT was continuing or suspended. Local corticosteroid injections in combination with CIT could be suggested as a first-line treatment. This could help to preserve the quality of life without threatening the vital prognosis.

Topics: Adrenal Cortex Hormones; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Middle Aged; Neoplasms; Nivolumab; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Rituximab; Uveitis; Vemurafenib

We report a case of ocular drug toxicity consistent with bilateral Vogt-Koyanagi-Harada (VKH) like disease in a patient with cutaneous melanoma treated with Dabrafenib/Trametinib therapy. A 53-year-old man with a history of metastatic cutaneous melanoma, treated with Dabrafenib/Trametinib, developed a severe acute panuveitis with granulomatous anterior uveitis and multiple serous retinal detachments. The ocular inflammatory reaction was classified as a bilateral Vogt-Koyanagi-Harada disease. Intraocular inflammation resolved after discontinuation of chemotherapeutic agents and aggressive topical and systemic corticosteroid therapy. The present case outlines the importance of recognizing VKH-like syndrome as a possible consequence of therapy with dabrafenib and trametinib.

Topics: Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Uveitis; Uveomeningoencephalitic Syndrome

Topics: Aged; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Epiretinal Membrane; Female; Glucocorticoids; Humans; Imidazoles; Liver Neoplasms; Lymphatic Metastasis; Melanoma; Neoplasm Staging; Oximes; Prednisolone; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence; Uveitis

To report the diagnosis of acute VKH-like syndrome as a complication from dabrafenib (a serine/threonine inhibitor of BRAF V600) and trametinib (a MEK inhibitor). In combination, these targeted agents have been shown to prolong overall survival and progression free survival in BRAF mutant metastatic melanoma.. Retrospective medical chart review including radiologic and ophthalmologic investigations.. A patient with metastatic melanoma being treated with dabrafenib and trametinib for 2 months presented with 1 week of visual blurring. He had developed bilateral optic disc swelling and uveitis that responded to pulsed steroid therapy.. VKH-like syndrome is a rare but serious complication of targeted therapy that should be considered when evaluating a patient with visual disturbances on dabrafenib and trametinib therapy.

Topics: Antineoplastic Agents; Disease-Free Survival; Drug Therapy, Combination; Humans; Imidazoles; Male; Melanoma; Middle Aged; Optic Disk; Oximes; Papilledema; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence; Uveitis

To report a case of uveitis and neuroretinal detachment in a patient treated with Trametinib and Dabrafenib due to metastatic cutaneous melanoma stage IV.. We evaluated slit lamp examination, fundoscopy, optical coherence tomography, fluorescein and indocyanine green angiography in a 66 years old man suffering visual loss. Fundoscopy showed serous neuroretinal detachment of the fovea accompanied with white spots surrounding the fovea in both eyes. Although therapy with Trametinib and Dabrafenib was stopped uveitis anterior was seen 2 weeks later. After a year, the therapy was started again and the serous neuroretinal detachment appeared once more, however without inflammatory reaction of the anterior chamber.. Patients treated with Trametinib and Dabrafenib should undergo consecutive eye examinations from the beginning of the therapy.

Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Male; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retinal Detachment; Uveitis

Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA2 may limit macrophage activation and protect the tissue. Utilising Lp-PLA2 gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA2 (SB-435495) we aimed to determine the effect of Lp-PLA2 suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA2 enzyme activity in Lp-PLA2 KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45+ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA2 depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA2 KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA2 suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA2 activity.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Autoimmune Diseases; Biphenyl Compounds; Cells, Cultured; Disease Models, Animal; Gene Expression; Immunization; Leukocytes; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Peptides; Phospholipases A2; Pyrimidinones; Retinitis; Reverse Transcriptase Polymerase Chain Reaction; Uveitis