Table 2.

Immunosuppressive agents, organized into categories, and with information on mechanism of action, administration, side effects, and clinical management.

	Mechanism of action	Indications	Administration	Side effects	Management
Antimetabolites
(1) Methotrexate	Folic acid analog; dihydrofolate reductase inhibitor, thus inhibiting synthesis of purines and therefore DNA, RNA, thymidylate, and proteins [7]. Reduces T-cell role in inflammation by inhibiting its activation and suppressing intercellular adhesion molecule expression [37]. With all administrations of methotrexate, it is critical to supplement folinic acid, to restore thymidylate and purine biosynthesis.	(i) Vitritis (ii) Vasculitides (iii) Anterior uveitis (iv) Orbital pseudo-tumor (v) Sarcoidosis	(i) Oral (ii) Subcutaneous (iii) IM (iv) IV Dose: 7.5–25 mg/week and May require 3–8 weeks for effects to take full effect. Course: two years after reduction of inflammation, to avoid recurrence [38].	(i) Common: fatigue, nausea, vomiting, and anorexia [39] (ii) Rare: hepatotoxicity, marrow suppression, and vasculitis (cutaneous) (iii) Teratogen Overall, long-term side effect profile is preferable compared to high-dose steroids.	Baseline: CBC, serum chemistry, BUN, Cr, LFT it, UA, pregnancy test. Follow-Up: CBC and LFT's every 4 weeks, with dose adjustment if LFT's double on two measurements. Stopped if LFT's stay elevated even after dose reduction [40].
(2) Azathioprine	Imidazolyl derivative; active metabolite is a purine synthesis inhibitor. Since lymphocytes have no method of nucleotide salvage, they are particularly affected [41].	(i) Serpiginous choroiditis (ii) Multifocal choroiditis (iii) Panuveitis (iv) Ocular cicatricial pemphigoid (v) Juvenile idiopathic arthritis [42–44]	Oral Dose: initially 2-3 mg/kg/day. Course: two years after reduction of inflammation, to avoid recurrence [45].	(i) GI upset (ii) Hepatotoxicity, bone marrow suppression, alopecia, and pancreatitis [46].	Baseline: CBC, LFT's, thiopurine methyltransferase enzyme activity (If low enzyme activity withhold treatment [46].) Follow-Up: CBC and LFT's every 4–6 weeks, with dose adjustment or temporary stop if abnormalities arise [47].
(3) Mycophenolate mofetil	Reversibly inhibits guanosine nucleotide synthesis, which particularly affects B- and T-cells [48]. it disrupts cellular adhesion to vascular endothelial cells, thus affecting lymphocytic chemotaxis [49].	(i) Chronic ocular inflammation [50] (ii) Scleritis, uveitis; used with cyclosporine and methotrexate [50].	(i) Oral (ii) IV Dose: initially 500 mg twice daily, thereafter increaseing to 1 g twice daily if well tolerated [45]. Course: two years following ocular quiescence [45].	(i) GI upset (nausea, vomiting, and diarrhea) (ii) Bone marrow suppression, hepatotoxicity [8]	Baseline: CBC, LFTs Follow-Up: CBC weekly for first month, twice monthly for next two months, and then monthly. LFT's monthly for duration of treatment [51].
(4) Leflunomide	Pyrimidine synthesis inhibitor, by inhibiting dihydroorotate dehydrogenase. In this manner, it suppresses B- and T-cell proliferation by interfering with cell cycle progression [52]. Nonlymphoid cells use a salvage pyrimidine pathway to synthesize ribonucleotides [52]. Leflunomide also has proven anti-inflammatory action, due to suppression of lymphocyte proliferation, tyrosine kinase, cyclooxygenase, and histamine release [53, 54].	Systemic rheumatology (severe rheumatoid and psoriatic arthritis). Ocular use in treating chronic inflammation associated with sarcoidosis is currently under investigation (see main text).	Oral Dose: loading dose100 mg and then 10–20 mg daily. A loading dose may result in initially increased adverse effects, but more rapid efficacy [55, 56]. To increase tolerability, patients may be given prednisolone rather than a loading dose [55]. Course: currently not certain.	(i) Serious hepatotoxicity (jaundice, hepatitis, and fatalities) (ii) Bone marrow suppression, interstitial lung disease, paresthesias, and headaches (iii) Teratogen [57] Due to its hepatotoxic effects, concurrent use with methotrexate is not recommended.	Baseline: CBC and LFTs. Follow-Up: both biweekly for the first six months, then bimonthly for the duration of treatment.
Alkylating agents
(1) Cyclo-phosphamide	Cytotoxic properties are due to addition of an alkyl group to the guanine base of DNA and forming irreversible inter- and intrastrand DNA cross-links at guanine positions. This results in toxicity to rapidly-dividing cells (lymphocytes) and suppression of antibody production and delayed type hypersensitivity [58].	(i) Behcet's disease (ii) Polyarteritis nodosa (iii) Wegener's granulomatosis (iv) Mooren's ulcer [59–64]	IV Dose: starts at 1 g/m2 and adjusted on response and side effects [51]. At the beginning of treatment, given biweekly. Discontinued if hematuria occurs, with urology consult indicated if hematuria persists beyond three weeks [51]. Course: once ocular quiescence is achieved, space treatment intervals to every 3-4 weeks continued for 1 year.	(i) Bone marrow suppression (ii) Hemorrhagic cystitis (iii) Secondary cancers (bladder, AML) (iv) Testicular atrophy (v) Ovarian suppression (vi) Known teratogen	Baseline: CBC, LFTs, UA Follow-Up: CBC and urinalysis are initially repeated weekly then spaced out to monthly intervals when blood counts are stabilized.
(2) Chlorambucil	Cytotoxic properties from addition of an alkyl group and forming DNA crosslinks [65].	(i) Sympathetic ophthalmia (ii) Behcet's disease (iii) Serpiginous choroiditis [66, 67]	Oral Dose: two treatment algorithms. One starts at 0.1 mg/kg/day; maximum dosage 12 mg daily. The other uses short-term higher doses for 3–6 months [52]. Course: one year after ocular quiescence [47].	(i) Heme/Onc: myelosuppression, bone marrow aplasia, and secondary cancers (ii) Endocrine: male sterility, amenorrhea (iii) GI: hepatotoxicity (iv) CNS: seizures (v) Infectious: reactivation of latent herpes simplex virus [52, 68, 69].	Baseline: CBC w. differential, LFT's. Follow-Up: CBC initially repeated weekly, then spaced out to monthly intervals after stable dose. LFTs monthly.
T-cell inhibitors/calcineurin inhibitors
(1) Cyclosporine	Suppresses T lymphocyte activity and thus the immune response. Binds lymphocytic protein cyclophilin, which inhibits calcineurin. Since calcineurin normally activates interleukin-2 transcription, there is decreased T lymphocyte function [70].	(i) Behcet's disease (ii) Sympathetic ophthalmia (iii) Sarcoidosis (iv) Birdshot retinochoroidopathy (v) VKH [71, 72]	Oral Dose: initially 2.5 mg/kg/day, increased in increments of 50 mg; maximum 5 mg/kg/day [47]. Course: two years after ocular quiescence [47].	(i) Hypertension, gingival hyperplasia, lymphoma nephrotoxicity (ii) Myalgia, tremor, or paresthesias	Baseline: LFT's, CBC w. differential, BUN, Cr, UA, blood pressure Follow-Up: blood pressure and electrolytes initially repeated biweekly spaced out to monthly after dose is stable. Other labs monthly [51].
(2) Tacrolimus	Macrolide antibiotic, whose mechanism is similar to that of cyclosporine; both inhibit calcineurin and suppress T-cell signaling and IL-2 transcription [73].	Used with systemic corticosteroids [73]. Often used when cyclosporine treatment fails [74, 75].	(i) Oral (ii) IV Dose: 0.10–0.15 mg/kg/day. The more serious adverse effects are seen at higher doses [76–78].	Hypertension, nephron-toxicity, electrolyte abnormalities, anorexia, neurologic (insomnia, confusion, depression, catatonia, tremors, and seizures), non-Hodgkin's lymphoma	Similar to cyclosporine.
(3) Rapamycin	Inhibits cellular response to IL-2 and inhibits activation of B and T lymphocytes. Rapamycin acts on “mammalian target of rapamycin” (mTOR), rather than on a calcineurin inhibitor, as cyclosporine and tacrolimus do.	Used with other immunosuppressive agents [79, 80].	Oral Dose: loading 6 mg; daily 2–6 mg/day [79].	Elevated LFT's, anemia, thrombocytopenia, hypercholesterolemia, nausea, abdominal pain, eczema, and increased risk of malignancy Markedly less nephrotoxic than other calcineurin inhibitors.	Similar to cyclosporine and tacrolimus
Biologic agents
(1) Etanercept	Targets TNF-α and TNF-β receptor, preventing molecules from binding, thus inactivating TNF. Thus it suppresses neutrophil migration and cytokine synthesis.	Indeterminate; see paper	Subcutaneous Dose: 25 mg twice a week, for two years.	Infection, increased risk for latent TB and hepatitis B reactivation, CNS demyelination, pancytopenia, congestive heart failure, and lymphoma [81, 82].	Baseline: CBC, LFT's, TB skin test, hepatitis B serologic testing Follow-Up: monthly CBC and LFTs [52, 83].
(2) Infliximab	Binds to and inhibits TNF-α (bound or circulating) [84].	(i) Sarcoidosis (ii) Wegener's granulomatosis (iii) Juvenile inflammatory arthritis (iv) Behcet's disease [85–89]	Intravenous Dose: loading infusions weeks 0, 2, and 6; maintenance infusions every eight weeks [89]. For monotherapy, dose of 5 mg/kg; for concurrent noncorticosteroid treatment, dose of 3 mg/kg. Treatment for two years after ocular quiescence is achieved [40].	Infection (urinary tract, upper respiratory), GI (nausea, emesis), vasculitis, anemia, and thrombocytopenia [89–91].	Baseline: CBC, LFT's, TB skin test Follow-Up: monthly CBC and LFTs.
(3) Adalimumab	Binds to and inhibits TNF-α [92].	(i) Birdshot retinochoroidopathy (ii) VKH (iii) Behcet's disease (iv) Rheumatoid arthritis scleritis [12–16].	Subcutaneous Dose: 40 mg every two weeks [93]. Course: 2 years after ocular quiescence is achieved [40].	Injection site reactions, infections (urinary tract, upper respiratory), headache and confusion, CNS demyelination, hepatotoxicity, congestive heart failure, and lymphoma [94, 95].	Similar to infliximab.
(4) Daclizumab	Binds to CD25, a subunit of the IL-2 receptor on T lymphocytes [96].	(i) Birdshot retinochoroidopathy (ii) Posterior uveitis (iii) Juvenile inflamm arthritic uveitis [97–99].	Intravenous Dose: 1 mg/kg every two weeks; maximum daily dose of 200 mg [100]. Dose independent of concurrent immunomodulatory treatment. Course: two years after ocular quiescence is achieved [97].	Rash, lymphadenopathy, chest discomfort, and fever [101].	Baseline: CBC, LFTs Follow-Up: repeat baseline labs prior to each infusion.
(5) Rituximab	Binds to CD20, found on B lymphocytes. It thus suppresses B-cell differentiation, and decreased production of IgG and IgM [102].	(i) Wegener's granulomatosis [19] (ii) Retinal vasculitis [20] (iii) Ocular cicatricial pemphigoid [22]		(i) Death from infection (Pneumocystis jiroveci, progressive multifocal leukoencephalopathy) (ii) Toxic epidermal necrolysis (iii) Pulmonary toxicity [103, 104] (iv) Severe infusion reaction, cytokine release syndrome, and acute renal failure [22].
(6) Tocilizumab	Blocks T/B-lymphocyte and monocyte IL-6 receptors, hindering its expression and proinflammatory effects. it increases Th1 cell specific regulatory binding protein of retinal photoreceptors, suggesting possible treatment of refractory uveitis associated with inflammatory or autoimmune processes [105].	(i) Rheumatoid and systemic juvenile idiopathic arthritis [23] (ii) Refractory uveitis [25]		(i) Common: infections, hypertension, headache, and transient increases in ALT [106] (ii) Rare: neutropenia, thrombocytopenia, GI (perforations or gastritis), infections (TB, fungal) [107]
(7) Gevokizumab	Binds IL-1b and downregulates its activity.	Behcet's		None known currently
Other
(1) Interferons	Endogenous cytokines released in response to external pathogens.	Nonophthalmologic [28, 29]: (i) Melanoma (ii) Hepatitis C (iii) Multiple sclerosis Ophthalmologic [30–33]: (i) Behcet's disease (IFN-α 2a) (ii) Multiple sclerosis uveitis (IFN-β 1a)	Dose: IFN-α 2a given at 3–6 million international units, with frequency ranging from daily to three times weekly [108]. Course: maintain treatment after ocular inflammatory quiescence achieved for two years [7].	(i) Common: fever, chills, myalgias, alopecia, and depression [109]. (ii) Interferon retinopathy Unlike other immunosuppressants and biologic agents, IFNs rarely cause infectious complications and are also not carcinogenic.	Baseline: CBC, LFTs, and thyroid function tests Follow-Up: CBC and LFTs every four weeks; thyroid function tests every three months.
(2) Anakinra	IL-1 receptor antagonist; competitively inhibits binding of IL-1 to its receptor. IL-1 has been found to have significance in systemic autoinflammatory diseases, where excessive IL-1 signaling will occur [36].