Systemic immunosuppressive therapies for uveitis in developing countries.

There are multiple approaches to inhibit inflammatory molecules and pathways in noninfectious uveitis. The cornerstone of local and systemic anti-inflammatory treatment is corticosteroid therapy. Corticosteroids remain the most potent and efficacious drugs for treating intraocular inflammation. However, their long-term use is limited by their medium- and long-term side effects, which are a major concern. The approach taken to limit corticosteroid side effects is to introduce steroid-sparing agents that suppress the inflammatory pathways and immune response differently than corticosteroids. There are several classes of such drugs that are affordable, effective, and generally well-tolerated. Relatively recently, an increasing range of biologic agents has become available to treat intraocular inflammation. However, the relatively expensive cost of these therapies limits their use in the developing world. This systemic review aimst to discuss the use of corticosteroids and different immunosuppressive regimens in the management of various uveitides.

Uveitis is a term that encompasses a number of inflammatory, infectious, and neoplastic disorders that can involve the uveal tract.[1] It can affect both adults and children. Although a rare disorder and classified as an orphan disease, uveitis is among the most common causes of blindness and is responsible for 10%–15% of blind registrations.[2] Because many of those affected are children or working-age adults, the years of potential vision loss and economic impact of each case of vision loss are higher, on average, than with eye diseases of the elderly.

The standardization of the uveitis nomenclature project (SUN) has greatly advanced our ability to accurately classify and describe uveitis in affected patients.[3] SUN classifies uveitis anatomically into anterior, intermediate, posterior, and panuveitis [Table 1].

Table 1

The SUN working group anatomic classification of uveitis[3]

Type	Primary cite of inflammation	Includes
Anterior	Anterior Chamber	Iritis
		Iridocyclitis
		Anterior cyclitis
Intermediate	Vitreous	Pars planitis
Uveitis		Posterior cyclitis
		Hyalitis
Posterior	Retina or choroid	Focal, multifocal, diffuse choroiditis
Uveitis
		Chorioretinitis
		Retinochoroiditis
		Retinitis
		Neuroretinitis
Panuveitis	Anterior chamber, vitreous, and retina or choroid

Noninfectious anterior, intermediate, posterior, and panuveitis are commonly associated with systemic inflammatory diseases such as sarcoidosis, Adamantiades–Behçet's disease, Vogt–Koyanagi–Harada disease, HLA B27 related disorders, and uveitis associated with juvenile idiopathic arthritis apart from other immune-mediated, inflammatory systemic inflammatory conditions.[4]

The management approach to patients with uveitis is fundamentally based on careful clinical assessment. A careful thorough history and a detailed clinical examination of both the eyes is critical to determine the clinical phenotype of the uveitis, and whether there are any clinical symptoms or signs that suggest an associated systemic disease. Following this, targeted investigations are performed to rule in or rule out specific disorders. At a minimum, syphilis serology and a chest X-ray and Mantoux test to exclude tuberculosis, and serology for HIV are ordered for all patients with uveitis.[5] There is a wide range of investigations that target specific systemic diseases such as tuberculosis and sarcoidosis, and others such as multimodal ocular imaging that target clinical features of disorders such as serpiginous choroidopathy and occlusive retinal vasculitis.[5]

Treatment is individualized depending upon the diagnosis. Infectious uveitis is treated with antimicrobial drugs and judicious anti-inflammatory therapy.

Inflammatory and undifferentiated uveitis may be treated with topical, regional, or systemic anti-inflammatory therapy. Typically the unilateral disease is managed with local therapy whenever possible while the majority of those with bilateral involvement are treated with systemic therapy. It is common for patients on systemic therapy to require supplemental local therapy.

There are multiple approaches to inhibit inflammatory molecules and pathways in uveitis and other diseases. Fig. 1 illustrates the protean processes involved in inflammation as well as selected pharmacologic agents, from antimetabolites to biologics to other classes of inhibitors that are employed to inhibit various pathways.

Figure 1

The protean processes that are involved in inflammatory diseases, including uveitis, as well as selected pharmacologic agents that are employed to inhibit various pathways

The cornerstone of local and systemic anti-inflammatory treatment is corticosteroid therapy. The use of corticosteroids for uveitis was first described in 1950 and even today, they remain the most potent and efficacious drugs for treating intraocular inflammation.[678] The challenge limiting corticosteroid use is their medium- and long-term side effects, which are a major concern for systemic corticosteroid therapy.[8] Currently, there are no curative therapies for noninfectious uveitis. The aim of treatment is to suppress the inflammation, causing the disease to regress over time and allowing therapy to be slowly tapered and discontinued. Some forms of uveitis require many years of immunosuppressive therapy.

Immunosuppressive drugs are used to treat many potentially blinding cases of ocular inflammation, primarily in 3 settings[78]

As corticosteroid-sparing therapy when the disease can be controlled with oral corticosteroids, but substantial toxicity is expected at the dose required

For inflammation that is recalcitrant to corticosteroids

For the management of specific diseases expected to fare poorly with corticosteroids alone.

The first described use of immunosuppression for uveitis was in 1951 when Roda Perez described the use of nitrogen mustard in treating steroid-resistant uveitis.[9]

Over the past few years, immunomodulatory therapy (IMT) has become a standard part of our treatment regimen for uveitis and other ocular inflammatory diseases. These drugs are commonly used in combination with low-dose corticosteroids and/or other IMT agents.

The approach taken to limit corticosteroid side effects is to introduce steroid-sparing drugs that suppress the inflammatory pathways and immune response differently than corticosteroids.[78] There are several classes of such drugs that are affordable, effective, and generally well-tolerated. Relatively recently, an increasing range of biologic agents has become available to treat intraocular inflammation. However, the relatively expensive cost of these therapies greatly limits their use in the developing world.

This review aims to discuss the use of corticosteroids and different immunosuppressive regimens in the management of various uveitides.

Oral Corticosteroids

Corticosteroids are synthetic compounds that have both anti-inflammatory and immunosuppressive properties. They exert their anti-inflammatory action by their action on neutrophils: increased production, decreased migration to inflammatory sites, decreased adhesion to vascular endothelium, and decreased bactericidal activity. They exert their immunosuppressive effects by their action on mononuclear phagocytes (monocytes and macrophages) and T and B lymphocytes, namely inhibiting transcription of cytokines vital to chronic inflammation.[10]

Oral corticosteroids are considered to be the first-line treatment in controlling ocular inflammation. The initial dose of oral prednisolone is believed to be in the range of 1–1.5 mg/kg/day, which then needs to be tapered based on the extent of inflammation with the goal of achieving disease quiescence at a dose ≤7.5 mg per day.

No tapering is needed if a patient has been on systemic therapy for less than 7 to 14 days. If a patient has a completely suppressed hypothalamic pituitary adrenal axis (serum values of morning cortisol levels <10 mg/dL) or has been on the oral steroid for >6 months, replacement therapy (5–7.5 mg/day), or alternate day therapy (equivalent to the dose that would have been employed over a 48-h period) is mandatory [Table 2].

Table 2

Recommended dosage of Prednisone for Chronic Ocular Inflammation[8]

Initial dose	1-1.5 mg/kg body weight/day
Maximum Adult dose	60-80 mg/day
Maintenance dose	<7.5 mg/day

Intravenous corticosteroids

Methylprednisolone is an intermediate-acting steroid with anti-inflammatory activity similar to prednisolone but with no sodium retention. Used in pulsed intravenous therapy for rapid control of inflammation, it is recommended in severe sight-threatening ocular inflammatory conditions, such as necrotizing scleritis, Adamantiades–Behçet's disease, sympathetic ophthalmia, Vogt–Koyanagi–Harada disease, serpiginous choroiditis, optic neuritis, and others.

Dose- 500 mg-1 g pulses/day over 60 min in 100 mL normal saline × 3 days followed by the oral steroid.[10]

Adverse effects

Cushingoid changes (moon faces, weight gain, fat redistribution, acne)

Delay in pubertal growth in children below the age of 15 years

Diabetes mellitus (glucose levels should be monitored every 2–3 months in patients on long term corticosteroids)

Dyslipidemia.

Other less common adverse effects include impaired wound healing, increased risk of infections, glaucoma and cataracts, mood changes, and insomnia, among a very large list of potential adverse events.

Patients also need to be monitored for osteoporosis. The prevalence of glucocorticoid-induced avascular necrosis (AVN) is between 3% and 38%.[11]

Glucocorticoid-induced AVN most commonly affects the femoral head, but can also occur in knees, shoulders, ankles, and hands. Glucocorticoid-induced AVN accounts for about 10% of all cases of total hip replacement in the United States.[12] Therefore, careful inquiry about a history of painful joint movements is important.

It is also recommended to provide 1500 mg of calcium and 800 IU of vitamin D daily, in addition to replacing sex hormones if decreased or if postmenopausal to all patients on long-term oral corticosteroid therapy.[8]

While corticosteroids are the mainstay of treatment of noninfectious uveitis, their long-term use is associated with several adverse effects. Therefore, all patients who require chronic oral corticosteroid therapy may require immunosuppressive drugs or IMT.

Immunosuppressive Agents

Antimetabolites

Antimetabolites are drugs that antagonize or compete with a metabolite, which is essential for nucleotide synthesis, leading to impaired cell division and proliferation. The three main antimetabolites used in the treatment of ocular inflammation are azathioprine, methotrexate, and mycophenolate mofetil.

Azathioprine

Azathioprine is a purine nucleoside analog that acts as an antimetabolite by interfering with deoxyribonucleic acid and ribonucleic acid synthesis. Azathioprine is a precursor to 6-mercaptopurine (6-MP), a purine analog competitive inhibitor of de novo purine synthesis, blocking DNA replication and RNA synthesis, thereby inhibiting the proliferation of actively dividing immune cells. Azathioprine decreases circulating lymphocytes, suppresses lymphocyte proliferation, and inhibits antibody production.

The bioavailability of azathioprine, as measured by 6-MP levels achieved after oral administration, varies between 27% and 83% in healthy volunteers.[1314]

Two enzymes, xanthine oxidase and thiopurine methyl transferase (TPMT) create relatively inactive compounds whereas other enzymes are responsible for producing the cytotoxic and immunosuppressive thiopurine nucleotides. Inhibition of xanthine oxidase by drugs such as allopurinol can therefore greatly increase the therapeutic efficacy as well as the toxicity of azathioprine. The half-life of intracellular, active thiopurine nucleotides is estimated to be w1–2 weeks, and the concentrations do not vary over 24 h in patients receiving daily dosages.

Pashadika et al. investigated 145 patients (255 eyes) treated with azathioprine. The study showed that 62% of patients with active disease gained complete inactivity of inflammation, which sustained over at least 28 days within 1 year of therapy, and 47% of patients tapered systemic corticosteroids to <10 mg daily while maintaining control of inflammation within 1 year of therapy.[15]

A 2-year double-masked, placebo-controlled trial of azathioprine therapy in 73 Turkish male patients with Adamantiades–Behçet's disease found that azathioprine reduced the incidence of ocular involvement in patients initially free of ocular inflammation by more than 50%.[16]

Recommended dose: The use of azathioprine in ocular inflammatory disease is limited to low doses of 2–3 mg/kg/day orally.

Adverse effects: Common adverse effects are mostly gastrointestinal side effects such as nausea, vomiting, and diarrhea. Mild elevation of hepatic enzymes is also observed in less than 2% of patients. The most serious side effect is myelosuppression, which is common, dose-dependent, reversible, and varies highly among individual patients. Low-dose azathioprine therapy (1–2 mg/kg/d) resulted in leukopenia in 4.5% and thrombocytopenia in 2% of patients.[15] However, these patients were already suffering from chronic renal failure and had already received a renal transplant. Nevertheless, dose-related myelosuppresion is a serious adverse effect.

Monitoring: Complete blood counts and liver function tests should be monitored every 4–6 weeks.

Methotrexate

Methotrexate is a folic acid analog and an inhibitor of dihydrofolate reductase, the enzyme responsible for converting dihydrofolate to tetrahydrofolate. As such, methotrexate inhibits rapidly dividing cells, such as leukocytes, producing an anti-inflammatory effect [Fig. 2].

Figure 2

Metabolic pathway of mechanism of action of methotrexate. 5-CH3-THF: 5-methyl-tetrahydrofolate; 5,10-CH2-THF: 5,10-methylenetetrahydrofolate; DHFR: dihydrofolate reductase; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate

Methotrexate can be metabolized up to 35% in the intestinal flora when given orally. As the dose increases, the percentage of absorption decreases. Methotrexate is eliminated primarily through the kidney. The half-life of methotrexate is approximately 3 to 10 h, and at higher dosages, the half-life may be prolonged up to 15 h.

A series of 160 patients with chronic noninfectious uveitis published by Samson et al. were treated with methotrexate either as primary therapy or as a corticosteroid-sparing agent. A steroid-sparing response was achieved in 56% of patients, ocular inflammation was controlled in 76% of patients, and visual acuity improved or was maintained in 90% of patients.[17]

Recommended dose: A low dose of methotrexate therapy can usually be initiated as an oral dose of 7.5 mg once per week. The dose is often increased to 15 mg/week over weeks to months, depending on response. Doses greater than 20 mg/week are usually given subcutaneously or intramuscularly. Folic acid at 1–5 mg/day should be given concurrently to maintain adequate folate stores and to reduce toxicity.

Adverse effects: The more serious potential side effects include hepatotoxicity, bone marrow suppression, and interstitial pneumonia, which present as cough or dyspnea. Abnormal liver function tests occur in about 15% of patients, whereas only 0.3% of patients develop hepatic cirrhosis.[18]

Alopecia and rash may occur less commonly. Patients must also be counselled about the teratogenic potential of methotrexate and its contraindications in pregnancy. In addition, patients must abstain from alcohol consumption while taking methotrexate.

Monitoring: At the time of initiation of therapy, complete blood counts, hepatitis B surface antigen, and hepatitis C antibody should be done. Complete blood counts and liver function tests should be repeated every 1–2 months.

Mycophenolate Mofetil

Mycophenolate mofetil suppresses the immune system by selectively inhibiting the purine biosynthesis enzyme inosine monophosphate dehydrogenase (IMPDH), thereby depleting guanosine nucleotides that are essential for purine synthesis used in the proliferation of B and T lymphocytes.[1920]

Galor et al. previously reported that scleritis and posterior uveitis/panuveitis were more likely to gain corticosteroid-sparing success with mycophenolate mofetil compared to other antimetabolite treatments.[21]

In 73 patients who received mycophenolate mofetil for ocular inflammation, corticosteroid-sparing success was achieved in 82% and 70% of patients at the <10 mg and the <5 mg prednisone thresholds, respectively, the majority within 6 months, and 40% were able to discontinue prednisone completely.[20]

Mycophenolate mofetil has high oral bioavailability and should be ingested on an empty stomach. Antacids reduce drug bioavailability by 15%.

Recommended dose: In uveitis, the suggested dose is 1 g twice daily taken orally.

Adverse effects: The most common side effects are gastrointestinal symptoms, including diarrhea, nausea, abdominal pain, and vomiting. Leukopenia, lymphocytopenia, and elevation of liver enzymes occurred infrequently.

Monitoring: Patients should be monitored with complete blood counts weekly for 4 weeks, then twice monthly for 2 months, thereafter monthly. Liver function tests need to be done every 3 months.

Alkylating agents

These agents act by alkylating DNA, leading to cross-linking of DNA, inhibition of DNA synthesis, and cell death. Alkylating agents induce remission but are not prescribed as first-line therapy due to toxicity.

Cyclophosphamide

Cyclophosphamide acts by exerting a cytotoxic effect on rapidly proliferating cells by alkylating nucleophilic groups on DNA bases, particularly the 7-nitrogen position of guanine, resulting in cross-linking, aberrant base pairing, ring cleavage, and depurination. It is cytotoxic to both resting and dividing lymphocytes. It suppresses both primary and established cellular and humoral immune responses, including delayed-type hypersensitivity. Cyclophosphamide was initially developed for cancer chemotherapy, was subsequently introduced in 1952 for the treatment of idiopathic uveitis, and has been used subsequently for various forms of ocular inflammation.[22]

Cyclophosphamide has been reported to be effective for the treatment of ocular manifestations of systemic autoimmune diseases, including Wegener's granulomatosis[2324] rheumatoid vasculitis,[25] polyarteritis nodosa,[26] systemic lupus erythematosus,[27] and mucous membrane pemphigoid (MMP),[28] as well as for primary ocular inflammatory conditions including Mooren's ulcer, Behçet's disease,[29] and Vogt–Koyanagi–Harada syndrome.[30]

Cyclophosphamide gets extensively metabolized before excretion. Acrolein, one of its metabolites, is thought to be responsible for the urologic toxicity. 2-mercaptoethane sulfonate, a compound that binds acrolein, can be given to reduce bladder toxicity.

Recommended dose: Cyclophosphamide can be administered both orally (1–2 mg/kg daily) and intravenously (750–1000 mg/m2 body surface area every 3 to 4 weeks). A consensus panel on immunosuppression for ocular disease concluded, based on previous available studies, that pulsed cyclophosphamide therapy for uveitis is less effective than oral cyclophosphamide.[8]

Adverse effects: The most common adverse event noted with cyclophosphamide is dose-dependent bone marrow suppression. Leukocyte counts of less than 2500–3500 cells/mL warrant discontinuation. Another serious complication is hemorrhagic cystitis (patients should be advised good intake of fluid to avoid) and increased risk of bladder cancer. Intermittent intravenous “pulse” cyclophosphamide is one of the approaches to avoid hemorrhagic cystitis.

It can cause ovarian suppression, testicular atrophy, azoospermia, alopecia, nausea, and vomiting. Other side effects are granulocytopenia, lymphopenia, and opportunistic infections.

Monitoring: CBC, urinalysis weekly initially and when dosing is stable, at least every 4 weeks

Chlorambucil

Chlorambucil is an alkylating agent that cross-links DNA by substituting an alkyl group for hydrogen ions in organic compounds, leading to faulty DNA replication, transcription, and nucleic acid function.

Recommended dose: In the treatment of uveitis, chlorambucil is typically given at a dose of 0.1–0.2 mg/kg/d as a single dose, which is continued for 1 year after disease quiescence. Tapering of corticosteroids may begin once the eye is quiet. Short-term high-dose therapy for 3–6 months also exists.[313233]

A single dose of 6–12 mg/day can be given in these patients for 1 year.[313233]

Adverse effects: Bone marrow suppression, opportunistic infections, permanent sterility in men, and amenorrhea in women.

Monitoring: Complete blood count initially weekly after that monthly.

T-Cell Inhibitors

T-cell inhibitors, as the name suggests, inhibit replication and activation of T-cell lymphocytes by inhibiting a phosphatase known as calcineurin, which dephosphorylates the nuclear factor of activated T-cells, which is a transcription factor regulating IL-2 production.

Cyclosporine

Cyclosporine preferentially affects immunocompetent T-lymphocytes, which are in the G0 and G1 phase of their cell cycle and leads to blocking replication. It reduces the ability of lymphocytes to produce lymphokines, such as IL-2.[34]

Cyclosporine A preferentially inhibits antigen-triggered signal transduction in T- lymphocytes, blunting the expression of many lymphokines, including IL-2 and antiapoptotic proteins. This pharmacologic action is mediated by the binding of cyclosporine to its immunophilin, cyclophilin, which inhibits the phosphatase calcineurin, thereby preventing the generation of the potent nuclear factor of activated T-cells. The drug is metabolized in the liver and excreted in the bile.

The efficacy of cyclosporine has been well-documented for Behcet's disease.[35] It has also been shown to be useful in the treatment of birdshot retinochoroidopathy, serpiginous choroiditis,[36] sympathetic ophthalmia, scleritis,[37] and panuveitis.

Recommended dose: 2.5–5.0 mg/kg/day (in 2 divided doses).

Adverse effects: Nephrotoxicity is the most serious adverse effect noted with cyclosporine, but it is more common at higher doses. It has been reported even for patients using lower dosages, leading to a recommendation that doses of 3 mg/kg/day or less to be used.[38] Cyclosporine can also cause hepatotoxicity, gingival hyperplasia, myalgia, tremors, paresthesia, hypomagnesemia, and hirsutism.

Monitoring: Blood pressure should be checked monthly for the initial 3 months and then every 3 months. Serum creatinine should be checked every 2 weeks initially and then monthly once the dosage has stabilized.

Tacrolimus

Tacrolimus, also called FK506, is a macrolide antibiotic produced by Streptomyces tsukubaensis. Tacrolimus inhibits the activation of T lymphocytes by a mechanism similar to that of cyclosporine. Oral absorption of tacrolimus is poor and highly variable, ranging from 4%–93% (average: 25%). The drug is lipophilic, 99% of which becomes bound to serum proteins. Drug metabolism occurs via the cytochrome P-450 enzyme system in the liver and metabolites are excreted in the bile.[39]

As with cyclosporine, drugs that interfere with tacrolimus hepatic metabolism will result in increased serum concentrations. Impaired hepatic, but not renal function will affect the bioavailability. Absorption of tacrolimus from the gastrointestinal tract is both incomplete and variable, ranging from 4% to 93%.

A multicenter clinical trial in Japan examined the use of tacrolimus in 53 patients with noninfectious uveitis,[40] of whom had Behcet's disease.[40] The effectiveness was 38% in patients treated with an initial dosage of 0.05 mg/kg/day, 60% with 0.10 mg/kg/day, 83% with 0.15 mg/kg/day, and 79% with 0.20 mg/kg/day.

Recommended dose: Tacrolimus is available for both intravenous and oral administration. It is significantly more potent than cyclosporine and is given at initial oral doses of 0.05–0.15 mg/kg/day in uveitis patients.[3940]

Adverse effects: Tacrolimus can cause renal impairment (28%), neurologic symptoms (21%), gastrointestinal symptoms (19%), hyperglycemia (13%), hypomagnesemia, tremor, headache, trouble sleeping, paresthesia, and hypertension.[40]

Monitoring: Blood pressure, weekly liver function tests; bilirubin; blood urea nitrogen; creatinine; electrolytes including calcium, magnesium, phosphate; cholesterol; and triglycerides levels also need to be monitored.

Tables 3 and 4 provide a summary of immunosuppressant drugs and their indications.

Table 3

Summary of all Immunosuppressant drugs

Drug	Dose	Common Uses	Adverse effects
Azathioprine	2-3 mg/kg/day	VKH, Sympathetic ophthalmia	Gastrointestinal upset Cytopenia
			Hepatitis
Methotrexate	15 mg/weekly	JIA	Hepatitis
		Behcet’s disease	Cytopenia
		Sarcoidosis
Mycophenolate mofetil	1 gm BID	JIA, Intermediate uveitis	Diarrhea
			Cytopenia
Cyclophosphamide	2 mg/kg/day	VKH, Wegener’ s granulomatosis	Cytopenia
			Bladder toxicity
Chlorambucil	0.1 mg/kg/day	Adamantiades-Behcet’s disease	Cytopenia
		Sympathetic Ophthalmia
Cyclosporine	2-5 mg/kg BID	Behcet’s disease	Hypertension
			Nephrotoxicity
			Hirsutism
Tacrolimus	2-3 mg BID	Behcet’s disease	Nephrotoxicity
			Neurotoxicity

Table 4

Indications of Immunosuppressants[8]

Power of association	Diseases
Strong	Behcet disease
	Sympathetic ophthalmia
	Vogt-Koyanagi-Harada syndrome
	Rheumatoid necrotizing scleritis
	Wegener granulomatosis
	Relapsing polychondritis with scleritis
	Juvenile idiopathic arthritis
Relative	Intermediate uveitis
	Retinal vasculitis
	Severe chronic iridocyclitis
Questionable	Intermediate uveitis in children
	Sarcoid-associated uveitis not adequately responsive to steroid

Recent Advances in Biologics and Selective Pharmacologic Agents for Uveitis and Ocular Inflammatory Diseases

The new group of medicines, the biological agents are therapeutic proteins designed to block the activity of biologically active molecules. These drugs belong to several different classes depending on their action such as Anti TNF agents, Anti IL 1 blockade, Anti IL6, Anti IL 17, B-cell blockers, and costimulatory blockade such as Abatacept. These are specifically targeted therapies with concomitant reduced side effects but come with certain risks such as unmasking of latent tuberculosis with anti- TNF agents and lack of vaccine response for 6–12 months with B-cell blockade.

Infliximab and Adalimumab are the two most commonly used biologics for noninfectious uveitis (NIU).[41]

Infliximab

Infliximab is a chimeric monoclonal antibody against tumor necrosis factor-alpha (TNF-α) with both human and murine components. Infliximab is currently FDA-approved for the treatment of rheumatoid arthritis (RA), ulcerative colitis, Crohn's disease, psoriatic arthritis (PsA), plaque psoriasis, and ankylosing spondylitis.[41] Infliximab is used off-label for NIU.

Infliximab can be used as first-line therapy for selected systemic diseases such as Adamantiades–Behçet's disease[42434445464748] or in cases of moderate to severe idiopathic retinal vasculitis and optic disc inflammation, or as third-line therapy in uveitis refractory to corticosteroids and conventional IMT.

Infliximab is given intravenously at doses of 5, 7.5, 10, or 20 mg/kg[495051] every 4 to 8 weeks with or without concomitant intravenous methylprednisolone at doses of 500 to 1000 mg for 1 to 3 days monthly. Doses can be tapered, and intervals are extended based on the clinical response. The mean number of infusions to show initial effectiveness is 2.05 and the mean number of infusions to achieve quiescence is 9.17 among patients with Vogt–Koyanagi–Harada (VKH), sarcoidosis, juvenile idiopathic arthritis (JIA), and idiopathic uveitis.[50] Initial anecdotal evidence suggests that the standard dose of infliximab (less than 10 mg/kg/dose) is less effective in the treatment of chronic uveitis.[5051] One study showed the rapid efficacy of infliximab characterized by 96% resolution of acute inflammation 1 day after infusion.[52]

The half-life of infliximab is 10 days; however, its effects may persist for up to 2 months.[53] Because of its chimeric nature, infliximab is recommended to be administered concurrently with methotrexate or other immunomodulatory agents to decrease anti-chimeric antibody formation and increase the duration of drug efficacy.[54]

TNF-α inhibitors like infliximab are contraindicated in multiple sclerosis. Infections such as tuberculosis (TB), human immunodeficiency virus (HIV), syphilis, hepatitis B virus (HBV), hepatitis C virus (HCV), and toxoplasma must be ruled out before initiating therapy. Common side effects of TNF-α inhibitors include hypersensitivity while more severe side effects include serious infections, hematologic reactions, malignancies, and myocardial infarctions.

Patients on TNF-α inhibitors require regular blood evaluations including complete blood count, liver function tests, blood urea nitrogen, and serum creatinine levels every 6 to12 weeks.

Adalimimab

Adalimumab is a fully-humanized monoclonal antibody against TNF-α, which binds soluble and transmembrane TNF-α. The United States Food and Drug Administration (FDA) approved adalimumab for the treatment of NIU after two successful phase 3 multicenter randomized controlled clinical trials, VISUAL I and II, demonstrated that time to treatment failure was significantly longer in the adalimumab group (>18 months) compared to the placebo group (8.3 months).[5556]

Currently, adalimumab may be considered as first-line therapy for JIA-associated anterior uveitis or Adamantiades–Behçet's disease-related panuveitis.[57] Additional studies have supported the use of adalimumab in patients with Adamantiades–Behçet's disease-related panuveitis,[5859] sarcoidosis-related uveitis, VKH syndrome, and birdshot chorioretinopathy (BSCR).[60616263]

Adalimumab is given subcutaneously with a loading dose of 80 mg followed by biweekly doses of 40 mg in adults and 20 to 40 mg in children, depending on body weight, every other week. Patients weighing ≥40 kg received 20 to 40 mg every other week, whereas patients weighing ≤40 kg received 10 to 20 mg every other week. The doses can escalate to weekly if needed[64] or be extended to every 3 weeks.[65] Such frequency was chosen due to a half-life of 15–19 days.[66] The rapid onset of response for uveitis was found after 2 to 16 weeks (mean 6 weeks) and was effective in 83% of children with severe JIA-associated uveitis.[65] Adalimumab can be used as monotherapy or in combination with systemic steroids or disease-modifying antirheumatic drugs (DMARDs), such as mycophenolate mofetil, azathioprine, methotrexate, or cyclosporin A.

TNF-α inhibitors such as adalimumab are contraindicated in multiple sclerosis. Infections such as tuberculosis (TB), human immunodeficiency virus (HIV), syphilis, hepatitis B virus (HBV), hepatitis C virus (HCV), and toxoplasma must be ruled out before initiating therapy. Common side effects of TNF-α inhibitors include hypersensitivity while more severe side effects include serious infections, hematologic reactions, malignancies, and myocardial infarctions.

Patients on TNF-α inhibitors require regular blood evaluations including complete blood count, liver function tests, blood urea nitrogen, and serum creatinine levels every 6 to12 weeks.

Other biologic agents

Recent emerging and adopted therapies, including tocilizumab (STOP study),[67] sarilumab (SATURN study),[68] and S irolimus as a Therapeutic A pproach UVE itis (SAVE)-2 study (sirolimus),[69] have shown encouraging outcomes of these agents in the treatment of NIU with regard to minimizing corticosteroid dosage, reducing vitreous haze score (≥2 steps), and improving visual acuity with a relatively benign safety profile. However, other therapies such as secukizumab (INSURE study),[70] gevokizumab (EYEGUARD study),[71] ustekizumab (STELABEC study), apremilast,[74] and sotrastaurin[73] have shown no difference in the recurrence rate between placebo and treatment groups or lack of efficacy. Other promising therapies, including certolizumab,[74] canakinumab,[75] anakinra,[76] IFN-α,[777879] abatacept,[808182838485] filgotinib,[86] tofacitinib,[87] alemtuzumab,[8889] and adrenocorticotropic hormone[90] have demonstrated efficacy in small case reports. Phase 2 clinical trials evaluating the safety and efficacy of filgotinib,[77] tofacitinib,[87] and adrenocorticotropic hormone[90] in NIU are currently ongoing.

At this point of time, a major restraint in the use of biological agents is the cost involved in using these agents [Table 5]. However, they have added a new dimension in treating refractory and recalcitrant noninfectious uveitis and are evolving as the first line treatments also in some uveitic entities.

Table 5

Average monthly cost of immunosuppressants drug prescription in India

Drug	Dose	Cost Rs/tab	Total monthly cost Rs
Azathioprine	50 mg/BD	Rs 10/50 mg tab	600
Methotrexate	15 mg/weekly	Rs 35/15 mg tab	140
MMF	1000 mg/BD	Rs 50/500 mg tab	6000
Cyclosporine	50 mg/BD	Rs 50/50 mg tab	3000
Tacrolimus	2-3 mg/OD	Rs 40/1 mg tab	2400
Cyclophosphamide	50 mg/BD	Rs 4/50 mg tab	240
Chlorambucil	5 mg/OD	Rs 200/5 mg tab	6000
Adalimumab	40 mg biweekly	Rs 25000/40 mg	50000
Etanercept	25 mg twice a week	Rs 6500/25 mg	68000
Infliximab	250 mg/8 weekly maintenance dose	Rs 42000/100 mg	52000

Special Note: Immunosuppression in Pediatric age-group and Pregnancy

Immunosuppression In Pediatric Age Group

Noninfectious uveitis in children can be vision threatening with severe ocular morbidity. It is important to understand the role of immunosuppressive in pediatric uveitis. The systemic therapeutic options can be divided into systemic steroids (oral or intravenous), conventional synthetic disease-modifying agents (csDMARDs) such as methotrexate, antimetabolites, calcineurin inhibitors, alkylating agents, and finally biological DMARDs (bDMARDs).

In children, systemic steroids are a concern because prolonged use can cause delayed or reduced axial height and other side effects including weight gain, acne, insomnia, mood swings, glucose intolerance, osteoporosis, cataract, glaucoma, and psychiatric problems.[99192] Steroids are generally used at doses of about 1 mg/kg/day, and up to 2 mg/kg/day for acute severe disease. They need to be tapered as quickly as possible and with the goal of less than 0.1 mg/kg per day, which is not likely to contribute to decreased or reduced growth.

Methotrexate is a first-line steroid-sparing therapy in most pediatric uveitis. It can be given orally or subcutaneously. Subcutaneous administration provides better bioavailability, particularly at higher doses. The dosage can be per 0.5–1.0 mg/kg per week or 10–20 mg/m2 with a maximum dose of 25 mg/wk. Methotrexate is effective in 60%–80% of the patients and takes 3 months to reach full efficacy.[1893]

Other options include azathioprine, which besides being more cost-effective, works better in intermediate uveitis. The other antimetabolite that is used is mycophenolate, which is dosed at about 600 mg/m2 given twice daily.[19] The toxicity includes gastrointestinal disturbances and leukopenia. Calcineurin inhibitors like cyclosporine are also used as a second-line therapy. They are metabolized at a higher rate in children, so the dosage is higher in children (up to 7 mg/kg).[3738] These agents, however, require drug level monitoring as they can cause hirsutism, hypertension, and gum hypertrophy in addition to the well-described renal toxicity. The alkylating agents are less commonly used currently because of these side effects and the theoretical risk of malignancy.

The new group of medicines, the biological response modifiers, are used currently to achieve a therapeutic response when the csDMARDs are ineffective.

Adalimumab, a fully-humanized monoclonal antibody against TNF has been tried in pediatric uveitis and approved by various regulatory authorities. The first phase 3 trials to demonstrate the role of adalimumab in uveitis is the VISUAL studies published in the New England Journal of Medicine and the Lancet in 2016, which showed the response in patients with inflammation not fully controlled with anti-metabolites.[5557] The dosage in children is 20 mg every 2 weeks in children less than 30 kg, as seen in the SYCAMORE trial.[94] Other trials show that the dose can be escalated to once a week in refractory cases and has been shown to be beneficial.

The other biologics that have been used is infliximab, which is a chimeric monoclonal antibody against TNF alpha. It is used as an IV infusion with the loading dose of 3–10 mg/kg/day in children and is given as a monthly dose.[95] In India, because of the risk of tuberculosis, generally 5 mg/kg is used.

Other TNF blockers such as golimumab and certolizumab have been used and have shown efficacy in children. IL-6 inhibitors like tocilizumab have been used and have been found to be beneficial in patients with macular edema. B-cell inhibitors such as rituximab have been tried in resistant pediatric uveitis; they generally take about 3–5 months to act and retreatment is required at 6 to 12 months.[95]

Other biologics such as abatacept have been employed in a small series as shown by the European multinational interdisciplinary working group for uveitis in childhood. More drugs are in the pipeline. Early aggressive therapy has been shown to improve ocular and visual outcomes and is associated with reduced risk of complications and improved control of inflammation within 3 years. It is important to remember that oral steroids may be an option for adults, but steroids should not be used in children for more than 3 months at a time.[96]

There is no consensus on the optimum time to initiate antimetabolites or biologic agents, but experience shows that the aim of treatment should be to make the child steroid-free by 3 months (i.e. avoid oral or topical steroid drops). Some studies show that up to two drops of steroids have been shown to limit complications such as cataract and glaucoma.[96]

Controversy exists about the length of therapy for both csDMARDs and bDMARDs and the correct tapering schedule. The majority of studies suggest that a minimum of 2–3 years of steroid-free remission of uveitis should precede any attempts to reduce the dose of immunosuppression.

Megan Cann et al. have published outcomes of noninfectious pediatric uveitis in the era of biological therapy, which shows that approximately 30% of the patients of pediatric uveitis will require the use of biologicals.[95] It has been shown that the use of systemic immunosuppression has resulted in fewer ocular surgeries in pediatric noninfectious uveitis.[96]

Within the Indian context, the cost of TNF inhibitors is prohibitive. Other options include using two DMARDS like methotrexate and mycophenolate. The challenge managing a child with noninfectious uveitis can be a daunting one. For best visual outcomes, it is very important that the child be evaluated and managed by pediatric uveitis and pediatric rheumatology teams who can coordinate and offer the child the proper choice of csDMARD or bDMARD depending upon the disease activity and complications of uveitis and/or systemic disease.

Immunosuppression in pregnancy

Pregnancy presents another challenge in the management of uveitis. It is important to understand that pregnancy and immunosuppression create issues regarding fetal well-being in which the fetus can have fetal abnormalities or prematurity-related issues. During the first trimester in pregnancy, uveitis can flare up while in the second and third semester, the inflammation can reduce on its own because of the increase in intrinsic hormones. The commonly used drugs including oral steroids, IMT agents such as methotrexate and mycophenolate, and TNF inhibitors such as adalimumab and infliximab, may affect pregnancy, especially methotrexate. Since we do not have randomized control trials due to ethical issues, retrospective case studies and animal studies guide us in the management of the use of these drugs.

It is important that all patients on immunosuppressants are advised regarding family planning. The various drugs, which are advised not to be taken when planning a pregnancy are methotrexate, mycophenolate, cyclophosphamide, and leflunomide.[97] The drugs, which have been shown to be safe in pregnancy are steroids (low dose) hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine, and TNF blockers like infliximab, adalimumab, and certolizumab. There is, however, a placental transfer of these drugs. Infliximab can be limited to the first trimester, adalimumab to the second trimester, and certolizumab to the third trimester since it has a low placental transfer.[9899100] Children whose mothers have been exposed to TNF blockers should not be given live-attenuated vaccines until 7 months of age. Other biologicals like rituximab and tocilizumab have limited data so they should be avoided in pregnancy. Various drugs such as methotrexate, mycophenolate, and cyclophosphamide should be avoided in both men and women at least 3–6 months before planning a pregnancy.[97]

It is important that rheumatologists and obstetricians discuss with patients the risk of the disease and the risk to the fetus. It is also important to have a detailed ultrasound between 12 and 16 weeks of pregnancy. In isolated uniocular disease, it is possible to use periocular/intraocular steroids, which reduces the side effect of the drugs. To conclude, it is important to understand that pregnancy in uveitis is a challenging situation for uveitis specialists.[9899100]

Conclusion

Corticosteroids are the mainstay of treatment in patients with ocular inflammation. However, long-term use of corticosteroids is associated with significant adverse effects. The addition of immunosuppressive agents helps in achieving a steroid-sparing effect and long-term remission. However, immunosuppressive agents also have their own potential adverse effects that ophthalmologists, including uveitis specialists, need to be aware of. In a tuberculosis-endemic country such as India, immunosuppressive therapy needs to be used with significant caution. The use of these agents also requires close monitoring and individualized dosing. Biological agents are limited in their use at this point of time because of the costs involved. If used properly, the introduction of immunomodulatory medications may lead to safe and long-term suppression of ocular inflammation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

1. Antimetabolites	Azathioprine
	Methotrexate
	Mycophenolate Mofetil
2. T-cell inhibitors	Cyclosporine
	Tacrolimus
3. Alkylating agents	Cyclophosphamide
	Chlorambucil