Methotrexate has been shown to be effective for treatment of ocular inflammation in general [15] as well as specific ocular diseases such as mucous membrane pemphigoid [19], rheumatoid arthritis-associated scleritis and episcleritis [20], sympathetic ophthalmia [21], Vogt–Koyanagi–Harada disease [22], anterior and intermediate uveitis [23], sarcoidosis-related panuveitis [24], birdshot retinochoroidopathy [25, 26], optic neuropathy associated with sarcoidosis [27], and orbital inflammatory disease [28]. In addition, the efficacy of methotrexate in treatment of ocular inflammation has been reported by many small case series. The largest series reported outcomes of methotrexate used in 384 patients with uveitis and ocular inflammation as a single immunosuppressive agent. In a conservative analysis, it was found to be effective in control of ocular inflammation in 66 % of patients and have a corticosteroid-sparing success in 58 % of patients within 1 year [15]. Several additional patients were controlled to a minimal/“trace” level of activity. Samson et al. evaluated outcomes in 160 patients; control of inflammation was found in 76 % of patients and a corticosteroid-sparing response in 64 % [16]. Other smaller retrospective case series found inflammation reduction in 56–100 % of patients [23, 24, 29–32] and corticosteroid reduction in 50–100 % of patients [24, 29, 33]. Baker et al. studied retention time of conventional immunosuppressive agents; there was a twofold risk of not continuing treatment with azathioprine, mycophenolate mofetil, and cyclosporin and a fourfold risk of not being retained on cyclophosphamide compared with methotrexate, which had the best retention time among these agents [34]. This study suggested that methotrexate may have a superior combination of effectiveness and tolerability over other immunosuppressive drugs. Methotrexate treatment has been reported to reduce the number of flare-ups in patients with recurrent anterior uveitis from 3.4 to 0.89/year [35]. It has been shown to be effective in treatment of uveitis-associated juvenile idiopathic arthritis [36–39] and is widely accepted as the first-line immunosuppressive agent used in children because of the extensive experience of safety and tolerability in this setting [37, 40].

There are other approaches to use of methotrexate for treatment of ocular diseases locally including intravitreal and periocular injection. Intravitreal methotrexate has been used for treatment of intraocular B-cell lymphoma [41]. It can be used with success in treatment of ocular inflammation [42–45]and uveitic macular edema, and a moderate amount of data exist suggesting this approach may lead to long-term remission in a substantial number of cases [43, 44]. Subconjunctival methotrexate has been used for treatment of leukemic infiltration [46].

Azathioprine has been used for treatment of noninfectious uveitis [49], sympathetic ophthalmia [50], Vogt–Koyanagi–Harada disease [51], iridocyclitis [52], Behçet disease [53–55], juvenile idiopathic arthritis [56], scleritis with relapsing polychondritis [57], mucous membrane pemphigoid [58], retinal vasculitis, [59] and serpiginous choroiditis [60, 61]. A 2-year double masked, randomized, controlled study patients with Behçet disease demonstrated that azathioprine reduced development of new eye disease and decrease occurrence of the second eye disease [53]. Moreover, the long-term follow-up of the clinical trial showed early use of azathioprine may benefit the long-term prognosis of patients with Behçet disease (with respect to placebo) [54]. Small retrospective studies have reported improvement of inflammation in 55–96 % of patients with chronic uveitis [49, 55, 62, 63]. Recently, data from the SITE Cohort Study retrospectively studied 145 patients with ocular inflammatory diseases who were treated with azathioprine. In this conservative analysis, azathioprine was found to be effective in control of ocular inflammation in 62 % of patients and to have corticosteroid-sparing success in 47 % of patients within 1 year with additional patient gain improvement to “trace” levels of inflammation [48].

Mycophenolate mofetil has been used in chronic ocular inflammatory diseases, scleritis [69–71], uveitis in children [72], and mucous membrane pemphigoid [73, 74]. Eighty-two percent of the patients had treatment success in a retrospective study [75]. Other small retrospective studies found 77–91 % [65, 76, 77] of the patients had a favorable response, 65–71 % [65, 78, 79] of the patients had inflammation reduction, and 54–100 % [72, 76, 78, 79] of the patients had decreased corticosteroid use. A direct comparison of efficacy and side effects of methotrexate, azathioprine, and mycophenolate mofetil in 257 patients with active uveitis (anterior, intermediate, or posterior) or scleritis found the proportion of patients with treatment success after 6 months of treatment to be highest in the MMF group (70 %) [80]. Teoh and colleagues reported efficacy in 100 patients and showed 68.4 % and 84.6 % of the patients achieving corticosteroid-sparing success after 6 months and 1 year, respectively [81]. The largest retrospective review of efficacy of mycophenolate mofetil used in 236 patients found control of inflammation achieved 53 and 73 % within 6 months and 1 year and corticosteroid-sparing effects in 55 % of the patients in a conservative analysis with more patients achieving “trace” levels of inflammation [67].

Experience in the use of leflunomide for treatment of ocular inflammatory disease has been limited. Animal studies have shown leflunomide to be effective in inhibiting experimental autoimmune uveitis [89, 90] and in suppressing corneal allograft rejection in the rat [91]. Leflunomide was shown to decrease ocular inflammation in 23 of 28 patients (82 %) in patients with sarcoidosis [84]. Molina et al. studied efficacy of leflunomide in juvenile idiopathic arthritis-associated uveitis and found 61.5 % achieved and maintained an ocular response to the drug [86].

Cyclosporine has been reported to be effective in Behçet disease, Vogt–Koyanagi–Harada syndrome, birdshot retinochoroiditis, serpiginous choroiditis, multifocal choroiditis and panuveitis, and intermediate uveitis [98, 99]. Masuda et al. conducted a double-blinded study of 96 patients comparing cyclosporine to colchicine in the treatment of Behçet disease and demonstrated better outcomes with cyclosporine [100]. Nussenblatt and colleagues reported a randomized controlled trial demonstrating cyclosporine was effective in controlling inflammation in endogenous uveitis [101]. This group subsequently showed that cyclosporine used as monotherapy in corticosteroid-resistant patients was effective in decreasing inflammation [102]. The doses of cyclosporine used in early studies were high (8–10 mg/kg/day). However, low-dose therapy (2–5 mg/kg/day) also has been found to be effective and with fewer side effects compare to high-dose therapy [98, 103]. Vitale et al. found low-dose cyclosporine controlled inflammation in 74 % of the patients [104]. Mathews and associates also reported efficacy of low-dose cyclosporine and found intraocular inflammation was improved or stable in 97 % of patients [105]. Cyclosporine is well tolerated when used in children. An uncontrolled, retrospective study of 15 children with uveitis treated with cyclosporine reported that 82 % of those patients had an improvement or stabilization of visual acuity [106]. In the SITE Cohort Study report of 373 patients with noninfectious uveitis and ocular inflammation using cyclosporine as a single agent, 33.4 % achieved control of inflammation by 6 months and 51.9 % by 1 year [94]. Corticosteroid-sparing success was achieved by 22.1 % at 6 months and 36.1 % at 1 year [94]. Success was about 20 % higher if “trace” activity was considered a success.

Tacrolimus has been shown to be effective for the treatment of noninfectious uveitis such as Behçet disease, Vogt–Koyanagi–Harada syndrome, and sympathetic ophthalmia [115]. A randomized trial of 37 patients studied the efficacy of tacrolimus in treatment of posterior segment intraocular inflammation, showing no significant differences between cyclosporine and tacrolimus in terms of improvement of ocular inflammation and visual acuity. The response rate, defined by an improvement in visual acuity of at least two lines in either eye or a decrease in binocular indirect ophthalmoscope (BIO) score to zero in either eye within 3 months of commencing treatment, occurred in 68 % of the patients taking tacrolimus [111]. Mochizuki et al. found the efficacy of tacrolimus in refractory uveitis to be 76.5 % at 12 weeks [108]. Lee et al. conducted a randomized controlled trial comparing tacrolimus and tacrolimus with corticosteroid and demonstrated the proportion of patients who tolerated treatment and maintained disease remission for 9 months was similar in both groups (monotherapy, 62.5 %; dual therapy, 68.4 %; P = 0.694) [116]. Sloper and colleague reported a case series of six patients refractory to cyclosporine; tacrolimus controlled inflammation in all patients [117]. Hogan and associates reported 85 % of 62 patients had corticosteroid-sparing success (prednisone taper to 10 mg daily) after 1 year and 2 months of treatment, 81 % probability of taking ≤5 mg daily, and a 61 % probability of discontinuing systemic corticosteroid therapy completely [118].