Adalimumab

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Adalimumab
Classification and external resources
DiseasesDB 32773

Adalimumab (Humira; manufactured in the United States by AbbVie Inc.) 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. TNF-α is a proinflammatory cytokine and is a vital intermediary of the body’s normal inflammatory response. It can, however, lead to excess inflammation and tissue damage at high concentrations.

Overview

Uveitis refers to the presence of intraocular inflammation involving the vascular coat of the eye (the uvea), that is, the iris and ciliary body anteriorly and the choroid posteriorly.[1]In the past, corticosteroids and methotrexate were used to treat uveitis; however, newer biologic agents such as adalimumab have transformed therapy for noninfectious uveitis. The Standardization of Uveitis Nomenclature (SUN) Working Group has proposed classifying uveitis using an anatomic classification based on the site of inflammation. They have also given grading system based on the number of anterior chamber cells and flare. It also further classified uveitis based on the onset (sudden or insidious), duration (limited or persistent), and course (acute, recurrent, or chronic).[2]

Role of Tumor Necrosis Factor α (TNF-α)

TNF-α is a proinflammatory cytokine. It can be secreted by both immune (most commonly macrophages and lymphocytes) and nonimmune cells. It is a key molecule responsible for body’s normal inflammatory response. Both the forms, that is, the membrane-bound and the soluble TNF-α are biologically active and can interact with one of two receptors: TNFR1 (p55, CD120a) and TNFR2 (p75, CD120b), causing its various effects.[3] The most prominent effect of binding to the TNF receptors includes initiation of a proinflammatory cascade through the rapid induction of cytokines and subsequent can lead to tissue damage and destruction.[4]

Mechanism of action of Adalimumab

Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF-α. 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.[5] It acts through two mechanisms of action predominantly. Firstly, it binds specifically to TNF-α and blocks its interaction with the p55 and p75 cell surface TNF receptors, and secondly, it causes lysis of cells with surface TNF in the presence of complement.[3][5]

Indications and Uses

Adalimumab was first approved by the US FDA in 2002 for use in patients with rheumatoid arthritis (RA). Other 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.[5]

Pediatric uveitis

The most common cause of pediatric uveitis is JIA.[6] It most commonly affects the anterior chamber, is bilateral and is chronic in the majority of cases.[7] In 2012, Simonini et al published a systematic review and meta-analysis on anti-TNF therapy in childhood chronic uveitis including five papers found a pooled response rate of 87% for improving intraocular inflammation.[8] One open-label, prospective trial for refractory noninfectious childhood uveitis compared the ability of adalimumab and infliximab to maintain remission.[8] 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.[9]American Academy of Ophthalmology (AAO) recommends the use of methotrexate as the first line followed by adalimumab as second-line treatment for JIA-associated uveitis.[10]

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 inflammation of the entire uvea (panuveitis) is the most common manifestation of uveitis overall.[11] 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.[10] In a 2010 literature review by Arida et al, found adalimumab to be effective in all patients with ocular involvement from Behçets.[12] 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.[13]

Sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder that affects eyes in 10%–80% of cases.[14] Uveitis is the most common ocular manifestation.[15] 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.[16]

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.[17] 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%.[18] The AAO has strongly recommended that infliximab or adalimumab may be used as a corticosteroid-sparing agent for chronic uveitis resulting from seronegative spondyloarthropathies.[10]

Administration and Dosing

The most commonly used mode of administration is subcutaneous (SC). Once adalimumab is administered SC, absorption from the SC tissue to the circulation begins, at which point the drug then distributes to other tissue compartments, binding both soluble and cell-bound TNF-α.[19] The other mode of administration that was evaluated was intravitreal.[20] 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.[21] 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).[21] 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.[8] Vasquez-Cobain et al, have used weekly dosage of adalimumab for pediatric uveitis.[22] A recent open-label, prospective pilot study by 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.[20]

Dosage forms and strengths

• Pen[21]

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[21]

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[21]

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

Safety

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.[21]

• It has also been associated with Hepatitis B reactivation.[21]

Malignancy

• Adalimumab increases the risk of malignancies like lymphoma and leukemia.[21]

• 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.[21]

Hypersensitivity reactions

• Anaphylaxis and angioneurotic edema have been reported.[21]

References

  1. Dunn JP. Uveitis. Prim Care. 2015;42(3):305–323.
  2. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–516.
  3. 3.0 3.1 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244-79.
  4. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol. 2002;2:364-71.
  5. 5.0 5.1 5.2 Nestorov I. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum. 2005;34(5 Suppl 1):12-18.
  6. Rabinovich CE. Use of tumor necrosis factor inhibitors in uveitis. Curr Opin Rheumatol. 2007;19:482-6.
  7. Heinz C, Mingels A, Goebel C, Fuchsluger T, Heiligenhaus A. Chronic uveitis in children with and without juvenile idiopathic arthritis: differences in patient characteristics and clinical course. J Rheumatol. 2008; 35:1403-7
  8. 8.0 8.1 8.2 Simonini G, Taddio A, Cattalini M, et al. Prevention of flare recurrences in childhood-refractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab. Arthritis Care Res (Hoboken). 2011;63:612-8.
  9. Zannin ME, Birolo C, Gerloni VM, et al. Safety and effcacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year follow up data from the Italian Registry. J Rheumatol. 2013;40(74–-.
  10. 10.0 10.1 10.2 Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121:785–796.e3.
  11. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, Huseyin Altunbas H, Urgancioglu M. Uveitis in Behcet disease: an analysis of 880 patients. Am J Ophthalmol. 2004;138:373-80.
  12. Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behcet’s disease: analysis of published data on 369 patients. Semin Arthritis Rheum. 2011;41:61–70.
  13. Vallet H, Riviere S, Sanna A, et al. Efficacy of anti-TNF alpha in severe and/or refractory Behcet’s disease: multicenter study of 124 patients. J Autoimmun. 2015;62:67–74.
  14. Riancho-Zarrabeitia L, Calvo-Rio V, Blanco R, et al. Anti-TNF-alpha therapy in refractory uveitis associated with sarcoidosis: multicenter study of 17 patients. Semin Arthritis Rheum. 2015;45:361-8.
  15. Bodaghi B, Touitou V, Fardeau C, Chapelon C, LeHoang P. Ocular sarcoidosis. Presse Med. 2012;41(6 Pt 2):e349–e354.
  16. Erckens RJ, Mostard RL, Wijnen PA, Schouten JS, Drent M. Adalimumab successful in sarcoidosis patients with refractory chronic noninfectious uveitis. Graefes Arch Clin Exp Ophthalmol. 2012;250:713-20.
  17. Zeboulon N, Dougados M, Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: a systematic literature review. Ann Rheum Dis. 2008;67:955-9.
  18. Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis. 2009;68:696–701.
  19. Nestorov I. Clinical pharmacokinetics of tumor necrosis factor antagonists. J Rheumatol Suppl. 2005;74:13-8.
  20. 20.0 20.1 Hamam RN, Barikian AW, Antonios RS, et al. Intravitreal adalimumab in active noninfectious uveitis: a pilot study. Ocul Immunol Inflamm. 2016;24:319-26.
  21. 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 21.9 Humira® (adalimumab) [prescribing information]. Illinois: AbbVie, Inc; 2016.
  22. Vazquez-Cobian LB, Flynn T, Lehman TJ. Adalimumab therapy for childhood uveitis. J Pediatr. 2006;149:572-5.