Intravitreal methotrexate in therapeutically resistant exudative age‐related macular degeneration (2009)

Editor, Recent innovations in anti-vascular endothelial growth factor (VEGF) have dramatically improved the prognosis of exudative age-related macular degeneration (AMD) (Brown et al. 2006; Rosenfeld et al. 2006). Even with anti-VEGF therapies that stabilize vision in the majority of patients, some remain refractory to anti-VEGF therapy. We present two patients who were refractive to standard therapy, managed in a non-conventional manner. An 84-year-old White man with exudative AMD in his right eye (OD) was referred after five monthly injections of ranibizumab without therapeutic response. Visual acuity measured 5/200 OD and 20/40 left eye (OS). Anterior segment examination was unremarkable in both eyes (OU). The posterior segment in the right eye demonstrated large confluent drusen and a juxtafoveal choroidal neovascular membrane with florid macular oedema (MO). Initial optical coherence tomography (OCT) showed subretinal fluid consistent with exudative AMD. The patient received bevacizumab at the initial visit. At the subsequent visit intravitreal triamcinolone was administered, because no appreciable therapeutic response was evident. One month later, the patient’s vision had not improved with persistent MO on OCT (Fig. 1A). After discussing the failed therapies and refusal of the patient to consider laser therapy, compassionate off-label use of 400 μg intravitreal methotrexate (IV-MTX) was offered and subsequently administered. (A) Patient 1 before injection with intravitreal methotrexate (IV-MTX). Optical coherence tomography (OCT) (horizontal cut) demonstrates florid macular oedema. (B) Patient 1 after injection. A similar cut of OCT demonstrated significant decrease in oedema. (C) Patient 2 before injection with IV-MTX. OCT (horizontal cut) demonstrated macular oedema overlying a large lesion associated with subretinal fluid. (D) Patient 2 after injection: OCT showing reduction in subretinal fluid. At the 2-week follow up visit, visual acuity OD improved from 5/200 to 20/300. Anterior exam was unremarkable. A decrease in the perifoveal subretinal fluid was observed OD with some residual MO (Fig. 1B). Perifoveal leakage on fluorescein angiography (FA) was decreased. An 89-year-old White man was referred for further treatment of exudative AMD. He had received ranibizumab injections monthly for the previous 8 months. Initial-exam vision was counting fingers OD and 20/40 OS. Anterior exam was unremarkable. There was a macular haemorrhagic epithelial detachment. FA revealed diffuse central macular late leakage, corresponding with diffuse oedema and subretinal fluid on OCT (Fig. 1C). There was significant subretinal fibrosis and areas of subretinal fluid collection. After careful informed consent and discussion, the patient agreed to off-label IV-MTX. At the 2-week follow up appointment the patient reported subjective improvement, although visual acuity remained counting fingers. Anterior exam was unremarkable. OCT demonstrated improvement of the subretinal fluid collection (Fig. 1D). FA revealed decreased right perifoveal leakage. Both of our patients had significant exudative AMD managed on widely accepted therapies with no improvement. Innovative measures have often arisen out of dire needs in medical management. There were widely available data for the safety of IV-MTX in other disease processes (Samson et al. 2001; Velez et al. 2001) and data to support a role for MTX in interrupting the angiogenesis cascade at various levels (Joussen et al. 1999). This was the justification for this off-label use of a chemotherapeutic teratogenic drug. The first patient showed improvement in visual acuity, while the second had subjective improvement in vision. OCT revealed significant differences after IV-MTX therapy at 2 weeks. This may well offer some indirect proof of principle of the role of inflammation in AMD. While anti-VEGF therapy is now the mainstay of therapy, selected patients that are refractory to traditional therapy may benefit from newer approaches. The potential of more intensive MTX therapy in exudative AMD is intriguing. However, this must be tempered by evaluating for concomitant toxicity because the safety indices are unknown. We are following these patients for long-term effects as well as drug effects. While a case report has limited value, further research in intraocular methotrexate as a possible adjunctive AMD drug may be warranted.