Vitreous inflammation, or vitritis, may result from many causes, including both infectious and noninfectious, including rheumatologic and autoimmune processes. Vitritis is commonly vision threatening and has serious sequelae. Treatment is frequently challenging, but, today, there are multiple methods of systemic treatment for vitritis. These categories include corticosteroids, antimetabolites, alkylating agents, T-cell inhibitors/calcineurin inhibitors, and biologic agents. These treatment categories were reviewed last year, but, even over the course of just a year, many therapies have made progress, as we have learned more about their indications and efficacy. We discuss here discoveries made over the past year on both existing and new drugs, as well as reviewing mechanisms of action, clinical dosages, specific conditions that are treated, adverse effects, and usual course of treatment for each class of therapy.
Vitreous inflammation, or vitritis, may result from many causes, including both infectious and noninfectious. Epidemiologic studies indicate that uveitis accounts for 2–10% of prevalent blindness in the European and North American population and is therefore an underrated and significant public health problem [
The first line of treatment for noninfectious uveitis is corticosteroids. This group of drugs is used to suppress inflammation, either systemically or intraocular. The accepted algorithm for treatment begins with topical glucocorticoids, with frequency depending upon severity and not necessarily etiology. However, topical corticosteroids have been shown to have poor penetration into the posterior segment and are thus not used often for posterior segment disease; they are more commonly used to reduce anterior chamber inflammation and have only a minor effect on vitreous inflammation [
Intravitreal delivery systems include injection or implantation of periocular or intravitreal steroid compounds (triamcinolone acetonide) [
On the other hand, those undergoing systemic corticosteroid therapy often encounter nonocular adverse events, such as arthralgia and hypertension. Other common complications range from those affecting the musculoskeletal system (osteoporosis, aseptic bone necrosis, and myopathy), gastrointestinal system (ulcers and pancreatitis), endocrine (hyperglycemia and cushinoid features), infectious, (delayed wound healing, secondary infection, and reactivation of latent herpes simplex or tuberculosis), or even psychosis. If patients develop adverse effects, or are refractory to treatment with corticosteroid therapy, switching to an intravitreal delivery system or considering systemic immunosuppressive therapy is indicated [
Systemic immunosuppressive therapy can either supplement or completely replace corticosteroid therapy, for the reasons touched upon above. There are several conditions that have been found to be refractory to corticosteroid treatment but instead respond to immunosuppressives. Examples of these conditions ran the gamut of several autoimmune diseases such as Behcet’s, Wegener’s, or juvenile idiopathic arthritis-associated uveitis [
Disease indications for immunosuppressive agents.
Strong Indications | Relative Indications |
---|---|
Behcet’s disease with retinal involvement | Noninfectious uveitis |
Vogt-Koyanagi-Harada syndrome | Retinal vasculitis with central vascular leakage |
Sympathetic ophthalmia | Severe chronic iridocyclitis |
Juvenile idiopathic arthritis-associated uveitis | Relapsing polychondritis with scleritis |
Ocular manifestations of Wegener’s granulomatosis | Ocular cicatricial pemphigoid |
Rheumatoid necrotizing scleritis or peripheral ulcerative keratitis | Serpiginous choroiditis |
There are several categories of immunosuppressive agents: antimetabolites, alkylating agents, T-cell inhibitors/calcineurin inhibitors, and biologic agents. Information about these categories is available in Table
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 [ |
(i) Vitritis |
(i) Oral |
(i) Common: fatigue, nausea, vomiting, and anorexia [ |
Baseline: CBC, serum chemistry, BUN, Cr, LFT it, UA, pregnancy test. |
(2) Azathioprine | Imidazolyl derivative; active metabolite is a purine synthesis inhibitor. Since lymphocytes have no method of nucleotide salvage, they are particularly affected [ |
(i) Serpiginous choroiditis |
Oral |
(i) GI upset |
Baseline: CBC, LFT’s, thiopurine methyltransferase enzyme activity |
(3) Mycophenolate mofetil | Reversibly inhibits guanosine nucleotide synthesis, which particularly affects B- and T-cells [ |
(i) Chronic ocular inflammation [ |
(i) Oral |
(i) GI upset (nausea, vomiting, and diarrhea) |
Baseline: CBC, LFTs |
(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 [ |
Systemic rheumatology (severe rheumatoid and psoriatic arthritis). |
Oral |
(i) Serious hepatotoxicity (jaundice, hepatitis, and fatalities) |
Baseline: CBC and LFTs. |
| |||||
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 [ |
(i) Behcet’s disease |
IV |
(i) Bone marrow suppression |
Baseline: CBC, LFTs, UA |
(2) Chlorambucil | Cytotoxic properties from addition of an alkyl group and forming DNA crosslinks [ |
(i) Sympathetic ophthalmia |
Oral |
(i) Heme/Onc: myelosuppression, bone marrow aplasia, and secondary cancers |
Baseline: CBC w. differential, LFT’s. |
| |||||
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 [ |
(i) Behcet’s disease |
Oral |
(i) Hypertension, gingival hyperplasia, lymphoma nephrotoxicity |
Baseline: LFT’s, CBC w. differential, BUN, Cr, UA, blood pressure |
(2) Tacrolimus | Macrolide antibiotic, whose mechanism is similar to that of cyclosporine; both inhibit calcineurin and suppress T-cell signaling and IL-2 transcription [ |
Used with systemic corticosteroids [ |
(i) Oral |
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. |
Used with other immunosuppressive agents [ |
Oral |
Elevated LFT’s, anemia, thrombocytopenia, hypercholesterolemia, nausea, abdominal pain, eczema, and increased risk of malignancy |
Similar to cyclosporine and tacrolimus |
| |||||
Biologic agents | |||||
(1) Etanercept | Targets TNF- |
Indeterminate; see paper | Subcutaneous |
Infection, increased risk for latent TB and hepatitis B reactivation, CNS demyelination, pancytopenia, congestive heart failure, and lymphoma [ |
Baseline: CBC, LFT’s, TB skin test, hepatitis B serologic testing |
(2) Infliximab | Binds to and inhibits TNF- |
(i) Sarcoidosis |
Intravenous |
Infection (urinary tract, upper respiratory), GI (nausea, emesis), vasculitis, anemia, and thrombocytopenia [ |
Baseline: CBC, LFT’s, TB skin test |
(3) Adalimumab | Binds to and inhibits TNF- |
(i) Birdshot retinochoroidopathy |
Subcutaneous |
Injection site reactions, infections (urinary tract, upper respiratory), headache and confusion, CNS demyelination, hepatotoxicity, congestive heart failure, and lymphoma [ |
Similar to infliximab. |
(4) Daclizumab | Binds to CD25, a subunit of the IL-2 receptor on T lymphocytes [ |
(i) Birdshot retinochoroidopathy |
Intravenous |
Rash, lymphadenopathy, chest discomfort, and fever [ |
Baseline: CBC, LFTs |
(5) Rituximab | Binds to CD20, found on B lymphocytes. It thus suppresses B-cell differentiation, and decreased production of IgG and IgM [ |
(i) Wegener’s granulomatosis [ |
(i) Death from infection ( |
||
(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 [ |
(i) Rheumatoid and systemic juvenile idiopathic arthritis [ |
(i) Common: infections, hypertension, headache, and transient increases in ALT [ |
||
(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 [ |
Dose: IFN- |
(i) Common: fever, chills, myalgias, alopecia, and depression [ |
Baseline: CBC, LFTs, and thyroid function tests |
(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 [ |
Categories of vitritis drugs and what diseases they are indicated for.
Drug | Indications |
---|---|
Antimetabolites | |
Methotrexate | Noninfectiouschronic uveitis, ocular inflammation, ocular sarcoidosis |
Azathioprine | Chronic uveitis, Behcet’s, choroidal neovascularization, ocular cicatricial pemphigoid, retinal vasculitis, serpiginous choroiditis |
Mycophenolate mofetil | Chronic uveitis, noninfectious ocular inflammation, refractory uveitis, scleritis |
Leflunomide | Sarcoidosis |
| |
Alkylating agents | |
Cyclophosphamide | Refractory uveitis, nonnfectious ocular inflammation, ANCA-associated vasculitides |
Chlorambucil | Serpiginous choroiditis, refractory uveitis, Behcet’s |
| |
T-cell inhibitors/calcineurin inhibitors | |
Cyclosporine | Serpiginous choroidopathy, Behcet’s, scleritis, rheumatoid arthritis, nonnfectious uveitis |
Tacrolimus | The above indications but usually in conjunction with systemic corticosteroids or adjunct immunosuppressants |
Rapamycin | |
| |
Biologic agents | |
Etanercept | Juvenile idiopathic arthritis, noninfectious uveitis, ocular inflammatory disease |
Infliximab | Refractory uveitis, childhood uveitis, Behcet’s |
Adalimumab | Refractory uveitis, ankylosing spondylitis, juvenile idiopathic arthritis |
Daclizumab | Juvenile idiopathic arthritis, recalcitrant ocular inflammation, birdshot chorioretinopathy |
Rituximab | Primary Sjogren’s syndrome, thyroid eye disease, Wegener’s granulomatosis |
Tocilizumab | Severe refractory posterior uveitis |
Gevokizumab | Behcet’s |
| |
Other | |
Interferons | Behcet’s, noninfectious uveitis |
Anakinra | Behcet’s, refractory juvenile idiopathic disease |
In general, treatment with immunosuppressives starts after or with corticosteroid therapy, with local treatment attempted before systemic treatment, if the disease process is amenable. Systemic treatment attempts to start with the least toxic medications in the case of mild-moderate disease; methotrexate and cyclosporine are most commonly used after corticosteroids, followed by more antimetabolites. Severe, vision-threatening disease may require the use of biologic or cytotoxic agents, although they are avoided whenever possible due to their severe adverse effects.
Leflunomide is a noncytotoxic drug that works on both the cellular and humoral immune response. It is most commonly used for systemic rheumatologic diseases, examples being severe rheumatoid or psoriatic arthritis. Ocular use in treating chronic inflammation associated with sarcoidosis is currently under investigation [
Biologic agents are one of the newest classes of therapeutic proteins. They were originally developed for preventing organ transplant rejection but were found to be useful for treating systemic inflammatory diseases as well. They are now used off label in treating uveitis, and have been used with some success for refractory cases. Biologic agents’ major mechanisms of action all revolve around targeting specific inflammatory molecules, with the goal of inhibiting mediators or cytokines. Examples of these inflammatory mediators include tumor necrosis factor alpha and interleukin-2. Due to their strong immunologic suppression, serious adverse effects revolve around infectious processes or malignancies such as lymphoma. Latent and opportunistic infections are especially important to monitor for and include those such as tuberculosis, histoplasmosis, coccidiomycosis and herpes viruses.
Biologic agents are categorized into two groups: monoclonal antibodies and fusion proteins. Monoclonal antibodies are further classified and suffixes named based on their regions (either human, murine, or a combination of regions). Fusion proteins are created by joined genes, and are a combination of a receptor and another protein fragment.
Adalimumab is a recombinant, full-length humanized immunoglobulin directed against tumor necrosis factor (TNF). It is able to bind with both high affinity and specificity to soluble TNF
A more recent retrospective analysis of 60 patients, the largest case series to date, showed a positive effect of adalimumab in 82% of these patients with different uveitis types, independent of additional systemic disease [
Another prospective study evaluated the efficacy and outcomes of using adalimumab to treat uveitis associated with juvenile idiopathic arthritis [
Rituximab is an antibody that binds CD20, with many effects. Most commonly used in hematologic and autoimmune disorders, it has been found to be effective as a sole treatment for Wegener’s uveitis and retinal vasculitis [
Tocilizumab is a humanized antibody that binds both to IL-6 receptors, originally used for treating rheumatoid arthritis and systemic juvenile idiopathic arthritis [
In one retrospective study, tocilizumab was found to be efficacious in treating uveitis patients with cystoid macular edema that was refractory to intraocular steroids or other immunosuppressive therapies [
IL-1
Interferons (IFN) are endogenous cytokines, released in response to external pathogens. IFN-
Anakinra is an interleukin-1 receptor antagonist, which competitively inhibits IL-1 binding to its receptor. IL-1 has been found to have significance in systemic autoinflammatory diseases, where excessive IL-1 signaling will occur. It plays a key role in auto inflammatory diseases such as Muckle-Wells and neonatal onset multisystem inflammatory disease (NOMID), which are rare causes of uveitis in childhood [
Uveitis is a vision-threating group of diseases that encompasses a variety of etiologies, which are either infectious or noninfectious. Both groups are commonly treated with steroids. Uveitis resulting from infection, however, focuses on eradicating the source with antibiotics or antivirals. Those of noninfectious origin may need additional immunosuppressive agents. These antimetabolites, cytotoxic agents, biologics, and immunomodulators can be used either alone or together, to control inflammation of the vitreous. As with any medication, especially immunosuppressants, side effects must be balanced with therapeutic benefit—a determination still in process for many drugs and indications. The complexities in investigating these therapies result from the innate heterogeneity of uveitis. Even with its difficulties, research on expanding indications for existing therapies and the discovery of new systemic agents continues to progress.
The authors declare that there is no conflict of interests related to any topic in this paper.