Continuing Education Activity

Adalimumab is a fully human, high-affinity, recombinant anti-tumor necrosis factor (TNF) alpha monoclonal antibody used to treat rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn disease, ulcerative colitis, etc. This activity covers the indications, mechanism of action, dosing, contraindications, and adverse events of this drug, as needed by the interprofessional healthcare team members to utilize it effectively for patient treatment.

Objectives:

• Summarize the mechanism of action of adalimumab.
• Describe the potential adverse effects of adalimumab.
• Review the appropriate monitoring for patients on adalimumab.
• Outline interprofessional team strategies for improving care coordination and communication when adalimumab is being administered.

Indications

The FDA first approved the original molecule of adalimumab for the treatment of rheumatoid arthritis. It was the third tumor necrosis factor (TNF) alpha inhibitor to be approved by the FDA after infliximab and etanercept. Subsequently, the FDA has approved adalimumab for the following indications:[1][2]

• Rheumatoid arthritis
• Ankylosing spondylitis
• Crohn disease
• Ulcerative colitis
• Hidradenitis suppurativa
• Juvenile idiopathic arthritis
• Plaque psoriasis
• Psoriatic arthritis
• Uveitis

The off label uses of adalimumab include:

• Neutrophilic dermatosis – pyoderma gangrenosum, Behcet disease
• Granulomatosis with polyangiitis (also known as Wegener granulomatosis)
• Sarcoidosis
• Pemphigus
• Multicentric reticulohistiocytosis
• Alopecia areata.

Several biosimilar molecules have now been developed, e.g., ABP 501, BI 695501, and SB5.[3]

Mechanism of Action

Adalimumab is a fully human, high-affinity, recombinant immunoglobulin G (IgG) anti-TNF alpha monoclonal antibody. It is a molecule comprising 1330 amino acids and has a molecular weight of approximately 148 kDa.[4] It inhibits the binding of TNF alpha (both soluble and membrane-bound) to its receptor. Specifically, it inhibits TNF alpha's interaction with p55 (TNFR1) and p75 (TNFR2) cell surface TNF receptors, which in turn interferes with cytokine-driven inflammatory processes. It is identical in structure and function to the naturally occurring human IgG1 and thus has high selectivity for TNF alpha and has low immunogenic potential.[5][6]

It does not affect or bind to other cytokines like lymphotoxin or interleukins. Its efficacy in various types of arthritis owes to its potent osteogenic action. TNF mediates activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) ligand (RANKL) receptors on stromal or osteoblast cells. TNF blockade thus inhibits subsequent destruction of cartilage and bone. TNF also plays a role in osteoclast maturation and activation, which remains in check with TNF blockade. Anti-TNF agents also downregulate serum matrix metalloproteinases 1 and 3 (MMP-1 and MMP-3). All of these factors contribute to the efficacy of TNF inhibitors in the treatment of arthritis.[6]

Administration

Administer injection subcutaneously at separate sites in the thigh or lower abdomen (avoid areas within 2 inches of the navel); rotate injection sites; may leave at room temperature for 15 to 20 minutes before use; do not remove cap or cover while allowing the product to reach room temperature; not for administration to the skin which is red, tender, bruised, hard, or that scars, stretch marks, or psoriasis plaques.[7][1]

The recommended doses for each indication are:

• Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: 40 mg every other week.[6]
• Juvenile idiopathic arthritis or pediatric uveitis[8]:
  • 10 kg to less than 15 kg: 10 mg every other week
  • 15 kg to less than 30 kg: 20 mg every other week
  • Greater than 30 kg: 40 mg every other week
• Adult Crohn disease and ulcerative colitis[9]:
  • Initial dose (day 1): 160 mg
  • The second dose is two weeks later (day 15): 80 mg
  • Two weeks later (day 29): Start a maintenance dose of 40 mg every other week.
  • For patients with ulcerative colitis only: Continue adalimumab in only the patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.
• Plaque psoriasis or adult uveitis[10][11]:
  • 80 mg initial dose, followed by 40 mg every other week, starting one week after the initial dose.
• Hidradenitis suppurativa[12]:
  • Initial dose (day 1): 160 mg
  • The second dose is two weeks later (day 15): 80 mg
  • Third (day 29) and the subsequent doses: 40 mg every week.

The injection is available as a pre-filled glass syringe or pen or single-use glass vial in doses of 10 mg, 20 mg, 40 mg, or 80 mg. Patients may use the adalimumab pen for self-administration. The vial is for institutional use only.

Following a single 40 mg subcutaneous dose, the pharmacokinetics of adalimumab are as follows:[6]

• Absolute bioavailability: 64%
• Time to peak concentration: 131 +/- 56 h
• Maximum serum concentration: 4.7 +/- 1.6 mcg/ml
• The volume of distribution: 4.7- 6 L
• Steady-state concentration:
  • Without concomitant methotrexate: 5 mcg/ml
  • With concomitant methotrexate: 8 to 9 mcg/ml
• Systemic clearance: 12 ml/hr
• Terminal half-life: 2 weeks

Adverse Effects

The most common adverse effects of adalimumab are:

• Injection site reactions
• Headache
• Rash
• Risk of serious infections, in particular, reactivation of latent tuberculosis.
• Other infections such as deep fungal infections, histoplasmosis, listeriosis, pulmonary aspergillosis, and Pneumocystis jiroveci pneumonia may occur.
• Antibody development to adalimumab
• Elevated creatinine phosphokinase and transaminases
• Worsening or initiation of congestive heart failure
• Lupus-like syndrome
• Lymphoma
• Pancytopenia
• Worsening or initiation of multiple sclerosis/neurological disease.[5]

Contraindications

Although the manufacturers have listed no contraindications, adalimumab has not been adequately studied in patients who are younger than four years of age and weighing less than 15 kg. Clinicians should avoid using it in this age group as a precautionary measure.[13]

Clinicians must also avoid adalimumab in cases of hypersensitivity, patients with underlying foci of infection, congestive cardiac failure, or hepatic dysfunction.

Concomitant administration of live vaccines is contraindicated. Also, the risk of serious infections increases significantly in the co-administration of abatacept and anakinra.

Monitoring

• Complete blood count, liver function tests, serum urea, and electrolytes: At baseline, then monthly for three months, and subsequently every three months
• Screen for latent tuberculosis before initiating therapy with a chest X-ray and Mantoux test
• Screening for viral markers before initiating therapy
• dsDNA- screen yearly
• Signs/symptoms/worsening of heart failure
• Signs and symptoms of hypersensitivity reactions
• Signs/symptoms of malignancy, including periodic skin examination.[14]
• Newer studies recommend maintaining therapeutic drug monitoring for serum concentrations of adalimumab at between 5 to 8 mg/ml and subsequent maintenance and tapering of the drug guided by these levels.[15]

Toxicity

Long-term human or animal studies on adalimumab have not been conducted, leaving the toxicity profile mostly unknown. It has not been demonstrated to be mutagenic in vitro or in vivo studies.[16]

The FDA categorizes adalimumab as a pregnancy category B drug. There is no conclusive published evidence of poor pregnancy outcomes or specific patterns of defects in infants exposed prenatally to adalimumab.[17]

Enhancing Healthcare Team Outcomes

The administration of TNF alpha antagonists such as adalimumab requires an interprofessional healthcare team with thorough knowledge and working experience with these drugs. A few points to be kept in mind are:

• Ensure that the agent is truly indicated in the situation.
• Thorough investigations for fitness at baseline need to be performed, with a complete blood count, liver, and renal function tests. Ensure the patient is not in or at risk of congestive cardiac failure.
• It is essential to rule out any underlying infections, as these are known to flare up after therapy with TNF alpha antagonists. In tuberculosis-endemic countries, the risk of flaring up of a quiescent focus of tuberculosis is very common. Thus a chest X-ray and a Mantoux test is of great value before starting therapy.
• Monitoring the patient throughout treatment to follow up and track the development of any side effects is paramount.

When clinicians prescribe these drugs, including adalimumab, they should coordinate their activity with a clinical pharmacist to cover potential interactions and ensure the patient is a good candidate for tolerating the drug. Both nurses and pharmacists can explain dosing and administration, particularly if the patient will be self-administering the pen. All interprofessional team members need to inform each other of any changes in status, both positive and negative, during the course of therapy. This type of care coordination will result in improved patient outcomes with fewer adverse effects. [Level 5]