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 Table of Contents  
Year : 2019  |  Volume : 57  |  Issue : 2  |  Page : 139-145

Immunosuppressives and biologicals in uveitis: The way forward – Current concepts

1 Department of Ophthalmology, Dr. Agarwal's Eye Hospital, Chennai, Tamil Nadu, India
2 Department of Uveitis and Intraocular Inflammation, Sankara Nethralaya, Chennai, Tamil Nadu, India

Date of Web Publication10-Sep-2019

Correspondence Address:
Dr. Karpagam Damodaran
No. 51, Rajan Nagar Main Road, Rajan Nagar, Kolathur, Chennai - 600 099, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjosr.tjosr_14_19

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Uveitis constitutes a sight-threatening group of diseases, which includes infectious and noninfectious entities. In this review, we consider the current evidence base for treatments in noninfectious uveitis including immunosuppressives and biologicals. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects.

Keywords: Biologicals, immunosuppressives, uveitis

How to cite this article:
Damodaran K, Sridharan S. Immunosuppressives and biologicals in uveitis: The way forward – Current concepts. TNOA J Ophthalmic Sci Res 2019;57:139-45

How to cite this URL:
Damodaran K, Sridharan S. Immunosuppressives and biologicals in uveitis: The way forward – Current concepts. TNOA J Ophthalmic Sci Res [serial online] 2019 [cited 2020 Jun 1];57:139-45. Available from: http://www.tnoajosr.com/text.asp?2019/57/2/139/266380

  Introduction Top

Uveitis, a significant cause of blindness worldwide, continues to pose a formidable challenge to ophthalmologists. The treatment for each type of uveitis is often a difficult therapeutic decision as no clear recommendations are found in the literature. Corticosteroids are quite popular among ophthalmologists universally and continue to have a vital role in terms of “rescue” therapy, but their use as a maintenance therapy is limited by their associated side effects; hence, steroid-sparing agents may be an effective alternative. Immunosuppressives and biologicals are potent medications which prove to be useful when the conventional steroid therapy has failed. It has also been used in patients where steroids are poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation such as those with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), Behcet's disease (BD), and inflammatory bowel disease (IBD).[1],[2],[3],[4]

This review aims to present, in order, the mechanisms and main indications of the most modern and commonly used immunosuppressive drugs and biologicals in uveitis [Table 1].
Table 1: Classification of immunosuppresives and biologics

Click here to view

The following are the key points that should be kept in mind before initiating and monitoring patients:

  • Informed consent
  • Complete systemic evaluation to rule out cardiac diseases, malignancy, neurological disorders, demyelinating diseases, infections, or pregnancy
  • Complete blood count and a comprehensive metabolic panel including liver function tests, renal function tests, and blood glucose test to be done before commencing and thereafter at regular intervals
  • Screening for tuberculosis (TB), human immunodeficiency virus, and hepatitis
  • Patients planned for antitumor necrosis factor (anti-TNF) therapy should be up to date for pneumococcal, influenza (nonlive virus), and hepatitis B vaccines
  • In case of fever, sore throat, bleeding, or any infection, the patient must be instructed to consult a physician immediately.

Although the use of immunosuppressives and biologicals as first-line therapy is not recommended in most patients, they can be initiated in specific sight-threatening conditions such as Vogt–Koyanagi–Harada (VKH) syndrome, sympathetic ophthalmia (SO), JIA, and BD.

  Immunosuppressives Top


The term antimetabolites refer to compounds that compete with or antagonize a particular metabolite essential to nucleotide synthesis and therefore impair cell survival and/or cell division.


Mechanism of action

Methotrexate (MTX) is a folic acid analog and an inhibitor of dihydrofolate reductase, and therefore inhibits DNA reproduction, thus downregulating both cellular and humoral immune responses.


2.5–25 mg/week orally/subcutaneously/intramuscularly.

The full effect of MTX takes 6–8 weeks to occur. Supplementation with folic acid (5–10 mg/weekly) or folinic acid (5 mg/weekly) the day after MTX should be performed to reduce its toxic effects.

MTX is relatively safe and well tolerated by most patients and is the most widely used immunosuppressive drug for the treatment of uveitis in children. It is indicated in almost all types of ocular inflammation, including anterior, intermediate, posterior uveitis, panuveitis. retinal vasculitis, scleritis and childhood chronic uveitis. Other specific indications include BD, multifocal choroiditis with panuveitis, sarcoidosis, VKH, SO, and birdshot chorioretinopathy.

The Systemic Immunosuppressive Therapy for Eye Diseases (SITE), a retrospective cohort study, was carried out to evaluate the efficacy and safety of immunomodulatory therapy in the treatment of ocular inflammatory disorders. The most frequent side effects are gastrointestinal problems, including nausea, vomiting, and diarrhea; leukopenia; and increase in opportunistic infections (OIs). The most worrisome side effect of MTX, however, is the risk of malignancy and the development of pneumonitis. The SITE showed no increased risk of mortality or cancer with MTX therapy when compared with controls never having received immunosuppressive therapy.[5]


Mechanism of action

Azathioprine is an imidazolyl derivative of 6-mercaptopurine. Following ingestion, the drug is rapidly metabolized to 6-mercaptopurine, which in turn is converted into thioinosine-5-phosphate. The latter is a purine analog that acts as a false precursor for adenine and guanine synthesis, thus interfering with DNA, RNA, and eventually protein synthesis in immunocompetent lymphoid cells in a cell cycle-specific manner.


100–250 mg/day orally.

Azathioprine has demonstrated efficacy in some patients with JIA, intermediate uveitis, and chronic uveitis.[6] The most common side effect includes gastrointestinal intolerance. Rarer side effects include hepatotoxicity, occurring in 2%, and myelosuppression. Polymorphism in the thiopurine methyltransferase gene predicts hematological adverse drug reactions; hence, it is advisable to test for enzyme activity before commencing therapy whenever feasible. Azathioprine was found to have an overall cancer mortality similar to that of patients who never took immunosuppressive drugs.[5]

Mycophenolate mofetil

Mechanism of action

Mycophenolate mofetil (MMF) is an inosine monophosphate dehydrogenase inhibitor that disrupts purine synthesis and preferentially inhibits DNA synthesis by B- and T-cells.


500–1000 mg twice daily orally.

MMF has been shown to be effective in combination with steroids or another immunomodulatory treatment as well as monotherapy. Few authors have concluded that the time to control ocular inflammation was faster with MMF than with MTX or azathioprine. The most common side effects are gastrointestinal, and these can be minimized by using mycophenolate sodium. Uncommon side effects include leukopenia, lymphocytopenia, and elevation of liver enzymes.[7] A randomized trial comparing MTX and MMF for the treatment of noninfectious intermediate uveitis, posterior uveitis, or panuveitis found that a higher, although not statistically significant, proportion of patients on MTX achieved treatment success (69% vs. 47%).[8] The results of the First-line Antimetabolites as Steroid-sparing Treatment Uveitis Trial, to establish which immunosuppressive therapy, MTX or MMF, is more effective as a first-line, corticosteroid-sparing agent for the treatment of noninfectious uveitis are awaited [Figure 1].[9]
Figure 1: Simple algorithm for treatment approach

Click here to view

Alkylating agents


Mechanism of action

Cyclophosphamide is a cell cycle nonspecific drug which exerts a cytotoxic effect on rapidly proliferating cells by alkylating nucleophilic groups on DNA bases. Immunosuppressive effects are thought to be mediated by these cytotoxic effects on immunocompetent lymphocytes.


1–2 mg/day orally.

One of the main indications would be antineutrophil cytoplasmic antibody (ANCA)-associated necrotizing scleritis as in Wegener's granulomatosis and also in systemic lupus erythematosus (SLE).

The most common side effect is dose-dependent myelosuppression that is reversible with the discontinuation of therapy as well as OIs. Bladder toxicity from acrolein, one of the metabolites, and the risk of bladder cancer can be minimized with intermittent pulsed intravenous (IV) therapy and premedication with 2-mercaptoethane sulfonate. Cyclophosphamide is a known teratogen and causes sterility in both men and women beyond certain cumulative doses. Other common side effects include nausea, vomiting, and alopecia.[10]


Mechanism of action

Chlorambucil is a nitrogen mustard with a mechanism of action similar to cyclophosphamide, replacing hydrogen ions with alkyl groups on DNA bases and thereby interferes with DNA replication and transcription.


2–12 mg/day orally.

Side effects include reversible bone marrow suppression, OIs, nausea, and gonadal dysfunction including sterility and amenorrhea. It is teratogenic and contraindicated in pregnancy. Because of the risks associated with chlorambucil, its use is generally restricted to severe sight-threatening uveitis such as in BD or SO.

T-cell inhibitors


Mechanism of action

Cyclosporine is a fungal antimetabolite which reversibly inhibits T-cell-mediated alloimmune and autoimmune responses. It binds to and inhibits calcineurin, preventing the nuclear translocation of nuclear factor of activated T-cells.


2.5–5 mg/kg/day orally.

Cyclosporine has demonstrated efficacy for patients with uveitis associated with immune-mediated conditions such as BD, sarcoidosis, and VKH syndrome. The main side effects are nephrotoxicity, arterial hypertension, gingivitis, and hirsutism.[11] Cyclosporine did not have an increased risk of mortality or cancer according to the SITE cohort study.[5]


Mechanism of action

Tacrolimus is a macrolide derived from Streptomyces tsukubaensis and binds to FK506 binding protein 12; this complex interferes with the calcineurin phosphatase pathway similar to cyclosporine and regulates T-cell-based immune system.


0.1–0.2 mg/kg/day orally.

Major side effects include renal impairment, neurologic symptoms, gastrointestinal symptoms, and hyperglycemia. Tacrolimus should not be given in combination with cyclosporin given their shared risk of renal toxicity.


Mechanism of action

Voclosporin is a novel calcineurin inhibitor whose structure is a modification of cyclosporine, resulting in a molecule which is a four-time more potent inhibitor of calcineurin phosphatase and subsequently TH1- and TH17-mediated responses.


0.4 mg/kg orally twice daily.

Voclosporin was evaluated in the LUMINATE trial, and the results demonstrated superiority to placebo for the clearance of vitreous haze.[12]

Sirolimus or rapamycin

Mechanism of action

Sirolimus or rapamycin is also a macrolide antibiotic derived from Streptomyces hygroscopicus. It mediates its actions via the inhibition of the molecular target of rapamycin pathway and is believed to be 100 times more potent than cyclosporine.


2 mg/day.

Sirolimus is currently under study for the treatment of refractory uveitis and in uveitis-induced choroidal neovascular membranes. The SAVE and SAKURA studies are being performed to seek indication for intravitreal sirolimus in the management of noninfectious uveitis of the posterior segment.[13],[14],[15]

  Biologicals Top

Biologicals can be an alternative in patients with inadequate response to or to those who are intolerant to conventional immunotherapy. They are manufactured by recombinant DNA technology and include different drugs such as monoclonal antibodies, soluble receptors, cytokines themselves (such as interferons [IFNs]), and natural cytokine antagonists (such as anakinra). Randomized controlled trials were found to be effective in many systemic conditions and have subsequently revolutionized the treatment and prognosis of RA, JIA, seronegative arthropathies, and IBD. There is growing evidence of these drugs for the treatment of uveitis.[16],[17]

Tumor necrosis factor inhibitors

TNF-α is a pro-inflammatory cytokine produced by various cells, including macrophages and neutrophils, and exacerbates immune diseases including uveitis. A total of five TNF inhibitors are currently available; however, the second-generation agents are not yet in general use for the management of uveitis.


Mechanism of action

Infliximab is a chimeric monoclonal antibody that irreversibly and competitively inhibits both membrane-bound and circulating TNF-α rapidly.


Loading dose of 3–5 mg/kg IV at 0, 2, and 6 weeks and then maintenance doses are administered every 4–8 weeks at 5–10 mg/kg.

It is to date the most commonly used biologic agent in the treatment of uveitis, and its efficacy has been particularly promising, especially in sight-threatening Behcet's uveitis, (BD), birdshot chorioretinopathy, JIA,[18] AS, sarcoidosis, and Crohn's disease.[19] Caution is required in patients with preexisting heart disease and neurological disease. Studies of infliximab in ocular inflammatory disease have shown an increased incidence of thromboembolism, drug-induced lupus-type reactions, and possibly solid organ malignancy.[20],[21]


Mechanism of action

Adalimumab is a fully humanized recombinant anti-TNF-α-specific monoclonal immunoglobulin G1 (IgG1) antibody. Like IFN, it can cause sustained neutralization of membrane-bound TNF-α. The drug blocks the interaction between TNF and the cell surface receptors p55 and p75, and being highly specific for TNF-α, it does not inhibit the lymphotoxin TNF-β.


40 mg (in children, 24 mg/m2) subcutaneously every 2 weeks.

Studies have shown that adalimumab can be effectively used in anterior uveitis in patients with active AS.[22],[23] The SYCAMORE trial to assess the clinical effectiveness, safety, and cost-effectiveness of adalimumab in combination with MTX for the treatment of JIA-associated uveitis is underway.[24]


Mechanism of action

Golimumab is a fully humanized monoclonal antibody against TNF-α, with the same indications of etanercept.


50-mg subcutaneous dose once a month.

Golimumab has demonstrated treatment success in refractory uveitis secondary to BD,[25] JIA, retinal vasculitis, seronegative spondyloarthropathy-associated disease, and HLA-B27-positive disease. No controlled trials have been published, and no direct comparisons against cyclosporine have yet been made. Golimumab has been approved for the treatment of RA, psoriatic arthritis, and AS.


Mechanism of action

Certolizumab consists only the pegylated humanized Fab fragment of a monoclonal antibody directed against TNF-α.


400 mg subcutaneously once every 2 weeks.

There is a single case report documenting the successful treatment of RA-associated scleritis, in which quiescence was achieved at 6 months.[26] However, there are currently no studies reporting outcomes in noninfectious uveitis.


Mechanism of action

Etanercept is a dimeric soluble form of the extracellular ligand-binding protein-linked p75 TNF receptor. It can bind to soluble TNF-α and TNF-β, thereby blocking binding to cell surface TNF receptors.


25 mg subcutaneously twice a week.

Its side effects are similar to those of infliximab and adalimumab. However, it is less favored because its efficacy is much lower than that of infliximab or adalimumab. In a comprehensive literature review, it has been reported that ocular inflammation is a paradoxical potential adverse event following the use of etanercept.[27],[28]


Mechanism of action

Efalizumab is a humanized monoclonal antibody to CD11a, which is a subunit of lymphocyte function-associated antigen-1 that is involved in antigen presentation and T-cell adhesion to vascular endothelium.

Initial ophthalmic data were promising, with one case report and one prospective trial both reporting the resolution of uveitic macular edema with efalizumab therapy.[29] However, it was later shown to increase the risk of progressive multifocal leukoencephalopathy, and thus the drug was withdrawn from the market.


Mechanism of action

Rituximab is a human/murine chimeric monoclonal IgG antibody directed against the cluster of differentiation (CD) 20 on the surface of B-cells. CD20 regulates the early differentiation and maturation of B-cells, and its inhibition results in cell death by apoptosis.


375 mg/m2 body area, or 1000 mg per infusion on days 1 and 15 and then at months 12 and 21.[30]

Initially developed for the treatment of B-cell lymphomas, rituximab is licensed also for RA and other autoimmune diseases including SLE, Sjogren's syndrome, and ANCA -associated vasculitis. There are some case reports on the successful use of rituximab in the treatment of uveitis associated with JIA.[31]


Mechanism of action

Abatacept is a fusion protein composed of the Fc region of the IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte antigen 4 molecule.


500–1000 mg IV every 4 weeks.

In a study, seven patients with JIA-related uveitis refractory to immunosuppressives and anti-TNF-α agents were treated with abatacept.[32]


Mechanism of action

Anakinra competitively inhibits the binding of interleukin (IL) IL-1.


1 mg/kg/day subcutaneously.

There is a single case report describing the successful treatment of posterior uveitis associated with chronic infantile neurological, cutaneous, and articular syndrome in a 4-year-old boy, which had responded poorly to corticosteroids, MTX, and etanercept.[33]


Mechanism of action

Gevokizumab is a humanized monoclonal antibody to IL-1β, which is a pro-inflammatory cytokine involved in a wide range of pathological processes.


Single infusion at 0.3 mg/kg.

Its use in anti-TNF refractory uveitis has been reported in specific cases.[34] The EYEGUARD studies are underway to evaluate its efficacy in patients with active and controlled noninfectious intermediate uveitis, posterior uveitis, or panuveitis.[35]


Mechanism of action

Daclizumab is a humanized monoclonal antibody to the alpha subunit of the IL-2 receptor on the surface of T-cells. It binds to CD25 on the IL-2 receptor of activated human lymphocytes.[36]


1 mg/kg once every 2 weeks.

Daclizumab has been demonstrated to be effective for refractory birdshot retinochoroidopathy in one study.[37] Despite showing promise in the treatment of uveitis, daclizumab was discontinued by the manufacturer in 2009 due to decreasing market demand.


Mechanism of action

Tocilizumab is a fully humanized monoclonal antibody recognizing IL-6 receptor (IL-6 R) in both its soluble form or bound form.


4–12 mg/kg IV at 2- to 4-weekly intervals.

Tocilizumab has shown to be effective at reducing macular thickness and increasing visual acuity in uveitic macular edema.[38] The STOP-UVEITIS study is currently underway in the United States. Interestingly, episodes of paradoxical ocular inflammation have been reported in patients receiving tocilizumab therapy for systemic diseases.[39],[40]


Mechanism of action

Secukinumab is a selective, high-affinity, fully human monoclonal antibody that binds and neutralizes human IL-17A, which is an inflammatory cytokine secreted by Th17 CD4+T-cells.


300 mg 2- or 4-weekly.

It has been evaluated in a range of inflammatory conditions, including AS, RA, and psoriasis. The SHIELD, INSURE, and ENDURE studies were conducted to test its efficacy. Unfortunately, on completion of the SHIELD study, there was insufficient evidence of the drug efficacy, resulting in the early termination of the remaining studies.[41]

Interferon- α

Mechanism of action

IFNs are a group of cytokines synthesized by a variety of cell types with immunomodulatory, antiproliferative, and antiviral properties. The Type I IFNs (IFN-α and IFN-β) act to increase the expression of major histocompatibility complex class 1 molecules and activate macrophages and natural killer cells.[42]


3–6 million IU/day subcutaneously.

IFNs have been used to treat ocular inflammation since 1994, with strong evidence of efficacy in the management of uveitis secondary to BD[43] and multiple sclerosis.[44],[45] Infliximab is considered to be a drug with low toxicity, although reactions are frequent during infusion and usually treated without consequences with antihistamines and analgesics. Mood disturbances such as depression and suicidal ideation have been less frequently reported.[46]


Alemtuzumab is a humanized monoclonal antibody to CD52 primarily used in the management of B-cell chronic lymphocytic leukemia, which has also shown benefit in conditions such as RA and multiple sclerosis.[47]

Canakinumab is a humanized monoclonal antibody to IL-1β licensed for use in systemic JIA and cryopyrin-associated periodic syndromes in adults and children aged 4 years or older.

It has been used to successfully treat uveitis associated with BD and Blau syndrome,[48] but data are currently limited to case reports only.

The SATURN study, a multicentric, randomized clinical trial of sarilumab (another IL-6 inhibitor) in intermediate uveitis, posterior uveitis, and panuveitis, is being conducted in Europe and the USA.[49]

Fingolimod prevents T-cell migration to inflammatory sites by reducing the expression of the sphingosine-1 phosphate receptor normally required for egress from secondary lymphoid tissues. However, there were reports of the occurrence of macular edema; hence, the drug was withdrawn.[50]

  Challenges in India Top

In a TB-endemic country like India, reactivation of latent TB and increased susceptibility to new tuberculous infection is always a concern, especially with TNF-blocking agents. Moreover, given the high cost as well as the limited long-term safety data, biologics are not recommended as first-line therapy for noninfectious uveitis in most patients. These agents should always be used with caution by experienced clinicians.

  Conclusion Top

A large proportion of uveitis cases do not have any defined etiology, and quite often ophthalmologists end up undertreating or not treating at all. There is now enough evidence to go ahead and treat the patient appropriately with steroid-sparing agents whenever necessary. However, the ineludible question when faced with a patient with sight-threatening inflammatory eye disease is as to which drug to choose. The wide array of choices of immunosuppressives and biologicals serve both as an opportunity and a challenge. However, it is vital that one determines the efficacy and safety profile of both established and emerging therapies so that treatment decisions can be informed and appropriately titrated to the needs of the individual.

The future definitely looks promising…

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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