Retina. 2014 Jul;34(7):1451-9.

The role of methotrexate in resolving ocular inflammation after specific therapy for presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis.

OZLEM SAHIN, MD,* ALIREZA ZIAEI, MD†

*Department of Ophthalmology/Uveitis, Dunya Eye Hospital Ltd, Ankara, Turkey; †Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. A. Ziaei is now at Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts.

 

Abstract:

This study was designed to investigate whether the anti-inflammatory and anti-proliferative activity of oral and intravitreal methotrexate (MTX) suppresses intraocular inflammation in patients with presumed latent syphilitic uveitis and presumed tuberculosis related uveitis. This was an interventional prospective study including three cases with presumed latent syphilitic uveitis treated with intravenous penicillin and oral MTX, and two cases with presumed tuberculosis-related uveitis treated with standard anti-tuberculosis therapy and intravitreal MTX injections. Treatment efficacy of all cases was assessed by best-corrected visual acuity, fundus fluorescein angiography, and optical coherence tomography. Four eyes of 3 patients with presumed latent syphilitic uveitis had improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema in 6 months with oral MTX therapy. No recurrence of intraocular inflammation was observed in 6 months to 18 months of follow-up period after cessation of MTX. Two eyes of two patients with presumed tuberculosis-related uveitis showed improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema after intravitreal injections of MTX. No recurrence of intraocular inflammation was observed in 6 months to 8 months of follow-up period after cessation of anti-tuberculous therapy. For the first time in the treatment of presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis, we believe that MTX might have an adjunctive role to suppress intraocular inflammation, reduce uveitic macular edema, and prevent the recurrences of the diseases.

PMID: 24531737

 

Supplement:

Methotrexate, a folate antagonist, is a commonly used anti-inflammatory, anti-proliferative, and immunosuppressive drug.(1) Methotrexate is considered to mediate its effects through the suppression of activation of NF-kB, which is activated by a wide variety of inflammatory stimuli including tumor necrosis factor, IL-1, okadaic acid, phorbol ester, H2O2, ceramide, endotoxin, and radiation.(1) Methotrexate suppresses tumor necrosis factor-induced NF-kB activation through the adenosine release.(2) Methotrexate inhibits the conversion of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) to formyl-AICAR, a reaction catalyzed by the enzyme AICAR transformylase, and leads to the intracellular accumulation of AICAR. Excessive AICAR inhibits the conversion of adenosine monophosphate to inosine monophosphate by adenosine monophosphate deaminase.(2) Adenosine monophosphate is rapidly converted to adenosine, which is a potent endogenous immunoregulatory agent mediating the effect of MTX on NF-kB.(2) However, the effect of corticosteroids on the immune system is nonspecific and involves several important pathways, such as reducing the distribution and trafficking of leukocytes, blockage of various T-cell/macrophage functions, and decreasing the maturation of dendritic cells, as well as its potential side effects of inducing acute infections.(3) Corticosteroids are still considered to be the mainstay of therapy in noninfectious uveitis.(3) It is recommended that corticosteroids should be administered only after excluding an infectious origin or a possible masquerade syndrome.(3) It has been reported that erroneous long-term treatment with corticosteroids in infectious uveitis results in a high incidence of visual impairment and recurrence rate.(4) Moreover, the intravitreal administration of depot corticosteroids has been shown to lead to fulminant toxoplasmic retinochoroiditis even when used with appropriate anti-toxoplasmosis treatment.(5) Therefore, extreme caution is recommended while administering depot corticosteroids in eyes with panuveitis of unknown origin.(6) The intravitreal MTX injection has been reported to reduce the complications of endophthalmitis resulting from intravitreal injection compared with dexamethasone in a rabbit model.(7) Beside being used in treating vitreoretinal involvement of primary central nervous system lymphoma, the intravitreal administration of MTX is also being used to treat intraocular inflammation, uveitic macular edema, and to induce extended remission in some patients with noninfectious uveitis.(8,9) This study revealed for the first time that a significant reduction of intraocular inflammation and regression of CME occurred after the intravitreal MTX injection in the two cases with presumed TRU. (Fig. 1, 2)

 

OZ fig1

Fig. 1: Color fundus photograph of the right eye shows dense vitritis. Note 3+ vitreous haze and cells associated with asteroid hyalosis (A), and fundus fluorescein angiography venous phase manifests leakage from the optic nerve head, macula and retinal vessels (B). Spectralis OCT reveals a foveal thickness of 549 µm (C).Note the resolution of vitritis with 1 to 2+ vitreous haze and cells associated with asteroid hyalosis 4 weeks after the intravitreal MTX injection (D), fundus fluorescein angiography venous phase shows resolution of leakage from the optic nerve head, macula, and retinal vessels (E), and spectralis OCT discloses a slight reduction in foveal thickness to 469 µm (F) 4 weeks after the intravitreal MTX injection.
OZ fig2

Fig. 2: Represents the fundus examination of the right eye (OD) and left eye (OS) before and 4 weeks after the intravitreal MTX injection. Note serpiginous-like choroiditis noncontiguous to the optic disk associated with macular involvement and 4+ vitreous haze and cells in the OD (A), and 1 to 2+ vitreous haze and cells with serpiginous-like choroiditis noncontiguous to the optic disk in the OS (B). Follow-up color fundus photograph of the OD at the 12th week of anti-tuberculosis therapy discloses persistence of vitirtis (C), and color fundus photograph of the OS 4 weeks after the intravitreal MTX injection shows resolution of vitritis (D).

 

Methotrexate shows its anti-proliferative effect by inhibiting dihydrofolate reductase, which has been studied extensively as a drug target for bacterial, protozoal, and fungal infections, and also for neoplastic and autoimmune diseases.(10) The worldwide tuberculosis structural genomics initiative has identified several new drug targets for Mycobacterium tuberculosis. Dihydrofolate reductase catalyzes nicotinamide adenine dinucleotide phosphate-dependent reduction of dihydrofolate to tetrahydrofolate that is essential for DNA synthesis, and the inhibition of its activity leads to the arrest of DNA synthesis and hence cells death.(10) M. tuberculosis dihydrofolate reductase is an attractive novel drug target for developing anti-tuberculosis drugs.(10) The extent of pallidum cellular adherence parallels with the increase in DNA synthesis by mammalian cells.(11) It has been shown that MTX greatly inhibits DNA and protein synthesis in mammalian cells, and decreases the cellular attachment of T. Pallidum.(11) The 3 cases with presumed latent syphilis in this study showed resolution of intraocular inflammation and remissions ranging between 4 months and 15 months after cessation of the oral MTX therapy. (Fig 3,4,5)

 

OZ fig3

Fig. 3: Represents the fundus examination and fundus fluorescein angiography of the right eye (OD) and left eye (OS) at pretreatment and post-treatment phases. Color fundus photographs of the OD (A), and OS (B) disclose vitritis, creamy-yellow superficial retinal accumulations, and optic disk congestion. Fundus fluorescein angiography arterial phase shows increased choroidal fluorescence (C), and venous phase shows increased staining at the optic disk and bifurcations of the vessels (D). Note the resolution of the creamy-yellow superficial retinal accumulations and optic disc congestion after 3 months of treatment with MTX in the OD (E), and (F) OS. Fundus fluorescein angiography arterial phase at the third month of the MTX therapy discloses decreased choroidal fluorescence in the OD (G) and venous phase indicates the resolution of staining at the optic disc and bifurcations of the vessels in the OS (H).

 

OZ fig4

Fig. 4: Represents the fundus examination and fundus fluorescein angiography of the left eye (OS) at pre-treatment and post-treatment phases. Color fundus photograph of the OS shows vitritis and branch retinal artery occlusion inferotemporally associated with intraretinal hemorrhages (A). Note vessel sheathing extending from the optic disc along the inferotemporal arcade associated with 1+ vitreous haze and cells (A). Fundus fluorescein angiography late phase disclosed venous staining, leakage, and areas of non-perfusion (C). Note the resolution of vitritis and intraretinal hemorrhages associated with persistence of arterial sheathing inferotemporally at the third month of the MTX therapy (C). Fundus fluorescein angiography late venous phase discloses decreased areas of nonperfusion, vascular leakage, and staining associated with the areas of capillary occlusions after 3 months of the MTX therapy (D).

 

OZ fig5

Fig. 5: Spectralis OCT of the left eye shows CME with a foveal thickness of 693 µm associated with the retina pigment epithelial detachment and epiretinal membrane formation (A). Follow-up OCT at the third month of the MTX therapy shows the regression of CME and retina pigment epithelial detachment with a foveal thickness of 362 µm associated with persistence of epiretinal membrane (B).

 

Considering the facts that the corticosteroid therapy carries risks for creating secondary infections while controlling inflammation, not inducing long-term remissions, and having nonspecific effects on the immune system, we prefer to suppress the intraocular inflammation and CME in infectious uveitis with the systemic or intravitreal injection of MTX associated with specific antimicrobial therapy.

The importance of this study is for the first time in the treatment of presumed latent syphilitic uveitis and presumed TRU systemic or intravitreal injection of MTX have been used to suppress the intraocular inflammation, reduce uveitic macular edema, and prevent the recurrences of the disease.

 

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