Subconjunctival methotrexate in the treatment of non infectious ocular inflammatory diseases

We studied the effect of subconjunctival injections ofmethotrexate (MTX) in 18 patients with non-infectious ocular inflammatory processes (unilateral anterior uveitis 1 1 patients, corneal graft rejection 3 patients, nodular sclerouveitis with no systemic disease 2 patients, Vogt-Koyanagi-Harada's disease 1 patient, and Behcet's disease 1 patient). Weekly subconjunctival injections of 7.Smg of MTX were given. Daily slit lamp examination was performed to evaluate the degree of in_flammatory activi(y in the anterior chamber or sclera and conjunctiva during the treatment. Patients were clinically followed for an average of 7.8 months (3 to .12 months) and no patient had evidence of local or systemic side effects. The conjunctiva remained yellowish and edematous for approximately 24hs after the injections and returned to the previous aspect after that. Our results showed that subconjunctival weekly injections oflow dose MTX have a favorable response in the treatment in nine of 1 1 cases of anterior uveitis, three cases of corneal graft rejection, and one patient of Vogt-Koyanagi-Harada disease. One patient with Behcet disease, and two with scleritis did not respond to the treatment.


INTRODUCTION
Methotrexate (MTX) is a cyto toxic immunosupressi ve drug, ana log of the folie acid, that acts by inhi biting dihydrofolate reductase, an en zyme necessary to convert folie acid to reduced folate cofactors. The inhibi tion of this enzyme results in deple tion of folates necessary for both thymidylate and purine synthesis; thus formation of DNA is blocked and as a consequence the cellular synthesis is inhibited 1 • Hepatic and renal toxicity , pneumonitis and toxic reactions such as nausea, vomiting, mucositis and leukopenia are the most frequent adverse effects obser ved. These problems are usually rela ted to the long term use of a high dose of the medication and it can be mana ged through appropriate reduction of the drug 2 -4 _ The use of systemic methotrexate in the treatment of autoimmune ocular diseases, such as sympathetic ophthal mia and chronic cyclitis, has been re ported, and systemic dose of 25mg/m 2 of body surface area has shown good results 5 -7 • Local MTX, in low dose (1 Omg), for intra-articular injection for the treatment of rheumatoid and psoriatic arthropaties as well as the use of low dose of systemic MTX in oph thalmology have been reported with good results X-1(> .
This pilot study was perfo rmed to evaluate whether periocular injections of MTX is a suitable treatment of non infectious ocular inflammatory disor-ders and also to evaluate its possible local and systemic side effects.

MATERIAL AND METHODS
Eighteen patients with non infec tious ocular disease were studied at the Uveitis Section of the Department of Ophthalmology of the Escola Paulista de Medicina.
The patient selection was based on the clinicai history, the ophthalmolo oic examination and a laboratorial b work up that included the hematological profile and renal and hepatic fu nctions, which were repeated every two weeks throughout the · treatment period. Patients were previously trea ted with steroids for one week and the ones that did not respond or had a contraindication for the use of corti costeroids were included in the study.
No patient had any clinicai or labo ratorial evidence of systemic infection.
Methotrexate aqueous solution (25mg/ml concentration) was injected in a dose of 7 .5mg/week in the superior subconjunctival region of the affected eye. Daily slit lamp examination was performed until day three after the injection to evaluate the degree of inflammatory activity in the anterior chamber and also the conjunctival aspect after the injection. The patient was reexamined after seven days, and if there was no sign of improvement he received another injection of MTX, and the sarne routine was applied in the following weeks. The patient was swit ched on to systemic immunesupression if the inflammation was worse. lnflam matory activity was graded in a score of O to 4 according to the number of in flammatory cells in the anterior cham ber and the presence of flare as descri bed previously in the cases of uveitis 11 •

RESULTS
Eighteen patients were treated with subconjunctival injections of MTX (13 304 Subconjunctival methotrexate in the treatment of non infectious ocular inflammatory diseases males and 5 females). The mean age was 38.6 years (range: 15-58 years). Thirteen were white (72 % ) and 5 were non white (28%). The average follow up period was 7.8 months (range from 3 to 12 months). Non granulomatous anterior acute uveitis not associated with systemic disease represented 61.1 % (11 patients) of our cases, the inflammation af fecting one eye in ali of them, the total number of injections was 22, with an average of 2.2 per patient (range: 1 to 4 per week), five patients showed a com plete remission of the inflammatory picture, four presented a reduction of inflammatory cells and flare in the an terior chamber, and two did not im prove.
Three patients with corneal graft rejection (16.8%) presented a remis sion of the anterior chamber reaction and decrease in the number and size of KPs after an average of 1.6 injections of methotrexate (range: 1-2 injec tions). Two patients with nodular scleritis not associated to systemic disease ( 11.1 % ) related a change for the worse after 1 injection. One patient with Vogt-Koyanagi-Harada's disease with granulomatous iridocyclites and no systemic manifestation (5.5%) presented remission of the inflamma tion after 5 injections. And 1 patient with Behcet' s disease with retini tis and anterior chamber reaction (5.5%) presented only a decrease of the in flammation in the anterior chamber after 1 injection.
The conjunctiva remained yello wish and edematous for approximately 24hs after the injections and returned to the previous aspect after that. None of the patients presented any side effect related to the use of MTX.

DISCUSSION
We have observed that subconjunc tival injections of MTX was effective in reducing the anterior chamber inflammation in uveitis and corneal graft rejection. To our knowledge this is the first report in the literature about subconjunctival injection of MTX for the treatment of non infectious ocular inflammation. The selection of MTX in the present study was justified to the following considerations: low toxicity when used in non-neoplastic disease, well understood pharmacological ac tion, antiinflammatory properties, qui te rapid onset of effect when compared to many of other agents, and capability to induce suppression of the mono nuclear cells response 1 2 . And finally, the necessity for a new therapeutic approach suggested by the adverse effects from the chronic use of systemic and topical steroids in the treatment of ocular inflammation.
Low-dose MTX has been used for the treatment of non infectious uveitis. ln these studies an oral dose from 7 .5 to 15mg/week was used to treat patients and most of them responded satisfac tory to the treatment with reduction of the inflammatory activity in the eye and few systemic side effects 9 • 10• ln our study subconjunctival injec tions of MTX were given in a pulse form, once a week, in a dose of 7 .5 mg. This route was chosen in attempt to have a maximal intraocular concen tration of medication associated to the minimal systemic side effect. Some authors reported ocular irritation in patients using high-dose MTX to treat malignancy, they correlated symp toms like burning and pluritus to the presence of the drug in the tears 1 3 . ln our study, although the medication was injected subconjunctivally, none of the patients presented any ocular side effect.
The mechanism of action of MTX as an anti-inflammatory drug is still not well understood. Recent studies show that administration of low dose MTX is associated with an increase in the concentration of the anti-inflam matory autocoid adenosine at the sites of inflammation, which results in decrease of leukocyte accumulation at the inflamed areas 14 • Other studies show that low dose MTX inhibits leukotriene B4 and complement C5a induced neutrophil migration into the sites of inflammation 15 • We believe the local injection of MTX will promote this effects in the anterior chamber faster than given systemically.
Our results have shown, despite of the limitations of no appropriate con trols, promising results in the treatment of ocular inflammatory process with low doses of weekly subconjunctival injections of this anti-neoplastic drug. Further controlled studies are needed to confirm our impression that this treatment is safe, simple and relatively effective in the treatment of non infec tious ocular inflammation.