Adalimumab

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Article initiated by:

Saurabh Deshmukh, MBBS, DNB, FVRS, MNAMS

All contributors:

Dipankar Das, MBBS, MS, Krati Gupta, MBBS, Ghazala D. O'Keefe, MD, Saurabh Deshmukh, MBBS, DNB, FVRS, MNAMS, 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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Adalimumab

DiseasesDB

32773

MeSH

D000068879

Adalimumab 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 adalimumab are commonly used for a variety of rheumatologic diseases. There has been increasing evidence for the use of adalimumab in the treatment of noninfectious 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

Adalimumab (brand names: Humira, Amgevita) is a recombinant human IgG1 monoclonal antibody that blocks the interaction between tumor necrosis factor α (TNF-α) and both its soluble and membrane-bound receptors. It has human-derived heavy and light chain variable regions and human IgG1κ constant regions. It is produced in mammalian cells using the recombinant DNA technology. It has a molecular weight of 148 kDa and is composed of 1,330 amino acids. It predominantly acts through two mechanisms of action. First, it binds specifically to TNF-α and blocks its interaction with the p55 and p75 cell surface TNF receptors. And second, it causes lysis of cells with surface TNF in the presence of complement.

Indications and Uses

Adalimumab was first approved by the US FDA in 2002 for use in patients with rheumatoid arthritis (RA). FDA approved indications for adalimumab include treatment for RA, juvenile idiopathic arthritis (JIA), psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn’s disease, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It was approved for the treatment of adults with intermediate, posterior, and panuveitis in June 2016.

Behçets

Behçets can affect any part of the uveal tissue. It causes a relapsing-remitting type of uveitis. Most patients present with bilateral disease, and panuveitis is the most common manifestation. AAO strongly favors treatment with anti-TNF therapy with infliximab or adalimumab as first- or second-line corticosteroid-sparing agents for patients with ophthalmic manifestations of Behçets. In a 2010 literature review by Arida et al, found adalimumab to be effective in all patients with ocular involvement from Behçets. In a large multicenter retrospective study published in 2015 by Vallet et al, they documented that adalimumab was highly effective in treating severe or refractory Behçets.

Sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder that affects eyes in 10%–80% of cases. Uveitis is the most common ocular manifestation. In a study by Erckens et al, 26 patients with sarcoidosis and refractory posterior uveitis were treated with adalimumab 40 mg SC weekly. The authors found it to be highly effective.

Spondyloarthropathies

The seronegative spondyloarthropathies are a diverse group of inflammatory diseases that affect the axial skeleton. The most common association is seen with psoriatic arthritis, inflammatory bowel disease, reactive arthritis, and ankylosing spondylitis. A multinational, open-label clinical trial by Rudwaleit et al, evaluated adalimumab for the treatment of uveitis in 1,250 patients with active ankylosing spondylitis and found that treatment decreased the overall flare rate by 51%. The AAO has strongly recommended that infliximab or adalimumab may be used as a corticosteroid-sparing agent for chronic uveitis resulting from seronegative spondyloarthropathies.

Pediatric Uveitis

The most common cause of pediatric uveitis is JIA. It most commonly affects the anterior chamber, is bilateral and is chronic in the majority of cases. In 2012, Simonini et al published a systematic review and meta-analysis on anti-TNF therapy in childhood chronic uveitis including five papers that found a pooled response rate of 87% for improving intraocular inflammation. One open-label, prospective trial for refractory non-infectious childhood uveitis compared the ability of adalimumab and infliximab to maintain remission. This study found that adalimumab had a higher probability of maintaining remission when compared to low-dose infliximab. In a study by National Italian Registry, they assessed the safety and efficacy of adalimumab and infliximab in patients with refractory uveitis secondary to JIA and found that the remission rates were better in the patients treated with adalimumab.The American Academy of Ophthalmology (AAO) recommends the use of methotrexate as the first line agent followed by adalimumab as the second-line treatment for JIA-associated uveitis.

Dosing and Administration

The most commonly used mode of administration is subcutaneous (SC). Once adalimumab is administered subcutaneously, absorption from the tissue to the circulation begins, at which point the drug then distributes to other tissue compartments, binding both soluble and cell-bound TNF-α. Intravitreal administration has also been evaluated in a pilot study. Hamam et al, evaluated the use of intravitreal adalimumab for noninfectious uveitis at a dose of 1.5 mg given at weeks 0 and 2 and every 4 weeks thereafter for a total of 26 weeks, with promising results. The dosage of adalimumab depends on indication and age. In adults, the standard dosage of adalimumab is 40 mg subcutaneous (SC) every other week for RA, psoriatic arthritis, and ankylosing spondylitis. For the treatment of JIA in children aged 2–17 years, the standard dosage for adalimumab ranges from 10 mg SC every other week (10 to <15 kg) to 20 mg every other week (15 to <30 kg) and 40 mg every other week (≥30 kg). For uveitis in children aged below 6 years and adolescents, Simonini et al, suggested a dose of 24 mg/m2 every 2 weeks with a maximum dose of 40 mg. Vasquez-Cobain et al, have used a weekly dosage of adalimumab for pediatric uveitis.

Dosage Forms and Strengths

Pen

• Injection: 40 mg/0.8 mL of HUMIRA is provided by a single-use pen (HUMIRA Pen), containing a 1 mL prefilled glass syringe with a fixed 27 gauge, ½ inch needle and a gray needle cover.
• Injection: 40 mg/0.4 mL of HUMIRA is provided by a single-use pen (HUMIRA Pen), containing a 1 mL prefilled glass syringe with a fixed 29 gauge thin wall, ½ inch needle and a black needle cover.

Prefilled Syringe

• Injection: 40 mg/0.8 mL of HUMIRA is provided by a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge, ½ inch needle and a gray needle cover.
• Injection: 40 mg/0.4 mL of HUMIRA is provided by a single-use, 1 mL prefilled glass syringe with a fixed 29 gauge thin wall, ½ inch needle and a black needle cover.
• Injection: 20 mg/0.4 mL of HUMIRA is provided by a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge, ½ inch needle and a gray needle cover.
• Injection: 10 mg/0.2 mL of HUMIRA is provided by a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge, ½ inch needle and a gray needle cover.

Single-Use Institutional Use Vial

• Injection: 40 mg/0.8 mL of HUMIRA is provided by a single-use, glass vial for institutional use only.

Safety and Adverse Effects

Serious Infections

• The risk of serious infections is drastically increased in patients on Adalimumab therapy. The serious infections include tuberculosis, bacterial sepsis, invasive fungal infections, and infections due to other opportunistic pathogens.
• It has also been associated with Hepatitis B reactivation.

Malignancy

• Adalimumab increases the risk of malignancies like lymphoma and leukemia.
• Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers.

Hypersensitivity reactions

• Anaphylaxis and angioneurotic edema have been reported.