Infliximab

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Article initiated by:

Bruce J. Markovitz, MD, Sara L. Hojjatie, Saumya Copparam, MD

All contributors:

Ghazala D. O'Keefe, MD, Bruce J. Markovitz, MD, Alan Palestine, MD, Homaira Ayesha Hossain, MD

Assigned editor:

Homaira Ayesha Hossain, MD

Review:

Assigned status Up to Date

 by Homaira Ayesha Hossain, MD on June 30, 2024.

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Contributing Editors:	add

Infliximab for the Treatment of Uveitis

Overview

The goal of treatment of noninfectious uveitis is to control inflammation and to prevent the devastating sequelae of chronic inflammation, such as loss of vision. Initial treatment of noninfectious uveitis is typically with topical, periocular, intraocular, or systemic corticosteroids. While corticosteroids have been a mainstay of treatment for noninfectious uveitis, there are serious side effects associated with their long-term use, and this has led to the utilization of alternate systemic noncorticosteroid immunomodulatory agents. Immunomodulatory agents include the categories of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), T-cell inhibitors (cyclosporine, tacrolimus), biologic agents (adalimumab, infliximab, rituximab), and alkylating agents (cyclophosphamide, chlorambucil). Biologic agents such as infliximab are commonly used for a variety of rheumatologic diseases. There has been increasing evidence for the use of infliximab in the treatment of noninfectous uveitis.

Role of Tumor Necrosis Factor α (TNF-α)

Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine in the body produced by many different types of immune cells, including macrophages, T-cells, mast cells, granulocytes, and natural killer (NK) cells. TNF-α can serve as a ligand or a receptor. Its production leads to NF-κB production, cell activation, or apoptosis, depending on the type of cell it acts upon. It plays a role in the inflammatory cascade by inducing the production of other inflammatory cytokines, such as IL-1, interferon gamma, and IL-2. The production of TNF-alpha is highly regulated, and can be initiated by various stimuli, including infections, trauma, hypoxia, and cytokines. It is barely detectable in quiescent cells. At low doses, TNF-α augments the body’s immune response against infections. However at higher doses, TNF lead to excess inflammation and organ damage. Acute release of large amounts of TNF can lead to septic shock.

Mechanism of Action

Infliximab (brand names: Remicade, Inflectra) is a mouse/human chimeric, monoclonal anti-tumor necrosis factor α (TNF-α) antibody that specifically binds TNF-α antigen with high affinity and prevents its proinflammatory effects. It is derived from B cells that clonally express copies of a heavy chain and light chain which are linked covalently to form a unique antibody molecule. With this structure, infliximab binds strongly to circulating and membrane-bound TNF-α ligands in order to inhibit the action of TNF-α.

Indications and Uses

Infliximab is used to treat several systemic inflammatory conditions, including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn’s disease. It has been reported to be effective for the treatment of uveitis associated with juvenile idiopathic arthritis (JIA), Behcet's disease, sarcoidosis, Vogt-Koyanagi-Harada syndrome, and Takayasu disease. Infliximab may also be effective for birdshot retinochoroidopathy, recalcitrant uveitis, cystoid macular edema, pars planitis, multifocal choroiditis, HLA B-27 related anterior uveitis and idiopathic uveitis.

Juvenile Idiopathic Arthritis

Uveitis is the most common extraarticular presentation of JIA, with the most common form being chronic anterior uveitis. It is important to control inflammation to decrease the risk of vision loss. Initial treatment includes topical glucocorticoids, however the use of long-term topical glucocorticoids can lead to cataracts and increased intraocular pressures. Thus, to maintain inflammation control patients are often given systemic therapy in the form of methotrexate or monoclonal TNF-α inhibitors. Infliximab and adalimumab are the preferred TNF-α inhibitors over etanercept.

Behcet’s Disease

Behcet’s disease is a chronic multisystem disease manifesting as ocular, oral, cutaneous, genital, vascular, and neurologic lesions. Ocular manifestations occur in 70% of patients and manifests as bilateral panuveitis. This can occur as recurrent inflammatory attacks with episodes of remission. Repetitive attacks can result in permanent ocular tissue damage. Many studies have shown uveitis secondary to Behçet’s disease to be especially responsive to infliximab. In Japan, infliximab is approved as first-line treatment for ocular Behçet’s disease. An expert panel has recommended FDA approval for first-line treatment of ocular manifestations of Behçet’s disease.

Dosing and Administration

Infliximab must be given intravenously by infusion. It has a half-life of 8 to 10 days and a clearance of 11 mL/hour. Administration typically begins at a dosage of 3 to 5 mg/kg at weeks 0, 2, and 6, and then every 4-8 weeks depending on disease control. The dose and frequency can be increased up to 10 mg/kg every 4 weeks based on patient response and side effects. After achieving clinical remission, the infusion interval can be slowly prolonged; there is limited evidence regarding the ideal protocol for extending infusion intervals and eventually discontinuing the drug. As recommended by the American College of Rheumatology, infliximab is commonly given with another immunosuppressive drug, such as methotrexate. This may reduce the risk of allergic reactions or antibody production against the chimeric monoclonal antibody, and allows for a smaller dose to be used.

Safety and Adverse Effects

Side Effects

The most common side effects of infliximab are respiratory infections, headache, rash, coughing, fatigue, and stomach pain. During infusion, patients may experience discomfort around the infusion site, fever or chills, itching or allergic skin rash, chest pain, and changes in blood pressure.

Serious Infections

There is a reported increased risk of infection in patients treated with TNF-α inhibitors. Prior to therapy, patients must receive up to date vaccinations and should be screened for hepatitis B, hepatitis C, and HIV. There is a greater chance for the reactivation of latent TB in patients taking infliximab and adalimumab as compared to other TNF-α inhibitors. Screening for latent TB with tuberculin skin tests and/or chest radiographs prior to starting therapy is recommended for all TNF-α antagonists. Patients with serpiginous choroidopathy, which may be associated with TB, should be monitored cautiously.

Malignancy and Other Syndromes

An increased rate of lymphomas and systemic lupus erythematous-like syndromes have also been reported, but their associated with TNF-α antagonists as opposed to the underlying disease is controversial. Patients should be counseled to immediately report any symptoms to their physician.

Autoantibody Formation

Because infliximab is a chimeric mouse-human monoclonal antibody, there is a chance that prolonged treatment with infliximab may lead to new autoantibody formation. To reduce this risk, patients may be given combination therapy with methotrexate or similar agent to suppress the immune system and decrease the chance of autoantibody formation.

Limitations

Infliximab is not FDA approved for uveitis or ocular inflammation. It is currently FDA approved for Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis and plaque psoriasis, and ankylosing spondylitis.

Infliximab is contraindicated in patients with underlying malignancy and immune compromised status. It is also expensive and has limited long-term safety data.

Current Research

A 6.5-year retrospective cohort study showed 72 of 88 (81.8%) of patients with refractory uveitis achieved clinical remission with infliximab treatment; 84.7% of the patients achieved remission at 6 months, and 37.5% of the patients were able to discontinue all additional topical or oral therapies within 180 days of beginning infliximab therapy. Of the patients who achieved clinical remission, only five were successfully tapered off infliximab to achieve infliximab-free long-term remission during the course of the study, suggesting that prolonged maintenance dosing for infliximab may be necessary to maintain remission. 17 (19.3%) patients had to discontinue treatment secondary to serious side effects.

A 2-year prospective trial of infliximab treatment for refractory uveitis had initial remission in 24 of 31 patients (77%). Of these patients, 60% retained effectiveness in the first year and 60% in the second year. 6 of 31 (19.4%) patients had to discontinue treatment due to serious side effects. 3 of 31 patients developed drug-induced lupus.

A retrospective longitudinal case series of 31 patients with chronic noninfectious uveitis treated with infliximab achieved corticosteroid-sparing control of inflammation in 33.3% of patients at 3 months, 60.7% at 6 months, and 60.9% at 12 months. The median time to sustained control of inflammation was 63 days.

Studies have shown infliximab to be more effective than etanercept in the treatment of uveitis. As reported in the Systemic Immunosuppressive Therapy for Eye Disease (SITE) Cohort Studies, one study may indicate that infliximab and adalimumab are potentially more effective or quicker at controlling inflammation than conventional corticosteroid-sparing drugs (methotrexate, cyclosporine, azathioprine, cyclophosphamide). It should be noted that the definitions of treatment success, dosing regimen, severity of disease in the study population, and other factors vary between the referenced published reports.

Conclusions

Infliximab is an effective treatment for refractory uveitis. It appears to have a relatively low rate of treatment-ending adverse events, although there is limited long-term safety data. Long-term maintenance therapy with infliximab may be needed to maintain remission. Given the high cost, possibly severe adverse effects, and limited long-term safety data, infliximab is not recommended as first-line therapy, but off-label use may be very useful when conventional therapy has failed or has been poorly tolerated.

Additional Resources

http://www.uveitis.org/

https://nei.nih.gov/health/uveitis/uveitis

https://www.mayoclinic.org/diseases-conditions/uveitis/symptoms-causes/syc-20378734