Continuing Education Activity

This activity discusses the mechanism of action and clinical applications of infliximab, a monoclonal antibody targeting tumor necrosis factor-alpha (TNF-α). This FDA-approved therapy addresses inflammatory conditions, including Crohn disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and severe plaque psoriasis. The program details infliximab's pharmacokinetics, dosing considerations, contraindications, and monitoring protocols, offering healthcare professionals a comprehensive understanding essential for personalized patient care. Highlighting the significance of an interprofessional approach, this initiative emphasizes the collaborative effort necessary to navigate infliximab therapy effectively. This educational endeavor aims to optimize treatment strategies, mitigate adverse events, and enhance clinical outcomes across diverse patient populations by empowering healthcare professionals with evidence-based insights.

Objectives:

• Evaluate the mechanism of action of infliximab.
• Identify the adverse effects of infliximab.
• Identify the precautions that are necessary before administering infliximab.
• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from infliximab therapy.

Indications

Infliximab is a biological, TNF-α-inhibiting monoclonal antibody drug.[1] This drug may be given in combination with methotrexate to avoid possible immunologic responses by the host, which would decrease or blunt the drug's effect. Treatment for rheumatoid arthritis is the indication the FDA requires concurrent methotrexate use.[2]

FDA-Approved Indications

The United States Food and Drug Administration approved infliximab in 1998 for the following indications (with doses mentioned):

• Crohn disease: For moderate to severe, active Crohn disease in adults and children (6 years and older) who have had a non-satisfactory response to conventional therapy, the induction dose is 5 mg/kg, given as intravenous therapy at 0, 2, and 6 weeks, followed by maintenance therapy at the same dosage every 8 weeks. In patients who do not benefit from the lower dose, 10 mg/kg is considered.[3]
• Ulcerative colitis: For moderate to severe, active ulcerative colitis in adult patients with an unsatisfactory response to conventional therapy, the usual dose is 5 mg/kg intravenously (IV) at 0, 2, and 6 weeks as the initial dose, followed by 5 mg/kg every 8 weeks for maintenance.[4]
• Rheumatoid arthritis: For moderate to severe, active rheumatoid arthritis, induction therapy at 3 mg/kg is administered at 0, 2, and 6 weeks, followed by maintenance therapy every 8 weeks.
• Ankylosing spondylitis: With active ankylosing spondylitis, 5 mg/kg IV is given at 0, 2, and 6 weeks, followed by dosing every 6 weeks.
• Psoriatic arthritis: With active psoriatic arthritis, 5 mg/kg IV is given at 0, 2, and 6 weeks, followed by dosing every 8 weeks.
• Plaque psoriasis: For chronic severe plaque psoriasis in adult patients, 5 mg/kg IV is given at 0, 2, and 6 weeks, followed by dosing every 8 weeks.

Off-Label Uses

The non-FDA approved uses for infliximab include:

• Bechet disease [5]
• Relapsing polychondritis
• Juvenile idiopathic arthritis 
• Pyoderma gangrenosum
• Pustular psoriasis 
• Refractory sarcoidosis (adjunct) [6]
• Hidradenitis suppurativa [7]

Mechanism of Action

Infliximab is a biological therapy/immunotherapy medication designed to stimulate the body's immune system and treat certain diseases. Infliximab is a purified, recombinant DNA-derived chimeric IgG monoclonal antibody protein that contains both murine and human components that inhibit tumor necrosis factor-alpha (TNF-α).[8] TNF-α is a signaling protein involved in acute phase reactions and systemic inflammation. Macrophages, CD4⁺ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons produce TNF-α. This TNF-α inhibition inhibits the inflammatory reaction's cascade, leading to improved disease conditions like psoriasis and inflammatory bowel disease.

Infliximab has a high affinity for TNF-α and does not inhibit TNF-β. TNF-α is responsible for several physiological responses, including inducing proinflammatory cytokines (eg, IL-1 and IL-6), increasing adhesion molecule release, and enhancing the migration of leukocytes from blood vessels in the surrounding tissue (via increased endothelial permeability).[9]

Pharmacokinetics

Absorption: A single intravenous infusion of 3 mg/kg to 20 mg/kg demonstrated a linear relationship between the administered dose of infliximab and the maximum serum concentration.

Distribution: The volume of distribution of infliximab at steady state was dose-independent; infliximab primarily distributes within the vascular compartment.

Metabolism: Monoclonal antibodies, such as infliximab, are expected to break down into peptides/amino acids, which can be either recycled for protein synthesis or excreted by the kidneys. The reticuloendothelial system (RES), comprising immune cells like macrophages and monocytes, removes natural IgG antibodies from circulation. Infliximab is likely cleared through opsonization by the RES.[10]

Elimination: As explained, infliximab is eliminated by the reticuloendothelial system. It has been shown to have a half-life of 7 to 12 days in adults.[11]

Administration

Available Dosage Forms and Strengths

Infliximab is administered via an intravenous or subcutaneous route. It is provided as a lyophilized powder for reconstitution, available in 100 mg/vial for intravenous use after reconstitution. It is also available as a solution for subcutaneous (SC) injection, with a concentration of 120 mg/mL in a single-dose prefilled syringe/pen. In the studies conducted, it has been shown to cause type I and type III hypersensitivity reactions.

A variety of strategies are used to prevent infliximab-induced infusion reactions, including the following:

• Administering antihistamine and acetaminophen 90 minutes before the infusion
• Using a test dose of infliximab
• Patients with a prior history of an anaphylactic reaction to infliximab should receive prednisone, antihistamine, and acetaminophen before infusion. The adult dosage and indications have been discussed.

Specific Patient Populations

Hepatic impairment: Exercise caution when using infliximab in patients with liver impairment due to the potential for hepatotoxicity.[12]

Renal impairment: As of this writing, no dosage adjustments for infliximab have been recommended in patients with renal impairment.[13][14]

Pregnancy considerations: Infliximab has been shown to cross the placenta and is present in the serum of babies whose mothers were given infliximab during pregnancy for up to 6 months. Clinicians have reported agranulocytosis and reactions to live vaccines in these infants.[15] Therefore, a wait of 6 or more months is recommended in exposed infants before administering live vaccines.[16]

Breastfeeding considerations: Infliximab is generally not detectable or found at very low levels in breast milk, with minimal absorption by the nursing infant. Studies on infants exposed to the drug in utero and breastfed during maternal infliximab therapy have shown no adverse effects and normal development. Although some women have minimal concentrations in their milk, suggesting potential local immune suppression in the gastrointestinal tract, these levels do not pose concerns about systemic immunosuppression. For mothers who used infliximab during pregnancy, continuing its use while breastfeeding does not prolong the drug's elimination by the infant. Expert consensus and professional guidelines affirm that infliximab has a low risk to the nursing infant and is considered acceptable for use during breastfeeding. To minimize transfer to the infant, it is recommended to wait at least 2 weeks postpartum before resuming therapy.[17]

Pediatric patients: The safety and efficacy of infliximab have been documented in pediatric patients aged 6 to 17 with Crohn disease (CD) and ulcerative colitis (UC). However, there is insufficient evidence to determine the safety and efficacy of infliximab in patients younger than 6 years old with CD or UC. Although there is little supporting data, studies have shown that infliximab is ineffective in young patients. A study published in 2014 showed a remission rate of 36% in 1 year in patients younger than 7 years compared to a remission rate of 88% in older children. The remission achieved in older children is comparable to that achieved in adults.[18]

Older patients: The frequency of serious infections is higher in geriatric patients receiving infliximab than in younger adults. Therefore, it is advisable to monitor geriatric patients closely for the emergence of serious infections.

Heart Failure: No dosage adjustment is necessary for mild heart failure (NYHA class I/II), but caution and monitoring are essential. In severe heart failure (NYHA Class III/IV), the dosage must be less than or equal to 5 mg/kg.

Adverse Effects

Infliximab is a generally safe and well-tolerated medication, but as the dose or the age of the patient (older than 60) increases, there are heightened chances of adverse effects; some of these adverse events can be life-threatening and are common in the TNF-α-inhibitor class of drugs.[19]

• Infusion-related reactions, including fever, pruritus, and anaphylaxis
• Headache
• Nausea
• Abdominal pain
• ALT elevation
• Dyspepsia
• Diarrhea
• Constipation
• Hepatotoxicity (including severe cases leading to fatality and necessitating liver transplant) [12]
• Heart failure
• Hypertension
• Anemia, leukopenia, neutropenia, and thrombocytopenia; patients should seek immediate medical care if they develop symptoms of an infection.
• Demyelination disease
• Paradoxical reaction
• Tuberculosis reactivation
• Malignancy; half of the cases reported are lymphomas.
• Reactivation of hepatitis B
• Psoriasis
• Lupus-like syndrome
• Vitiligo or other autoimmune disorders; antinuclear antibody has been positive in patients taking infliximab with normal baseline levels.
• Transient vision loss due to optic neuritis necessitating discontinuation of the offending drug.[20]

Patients have developed antibodies (human anti-chimeric antibodies) against infliximab, which lowers the drug's efficacy and causes infusion reactions. To reduce this risk, co-administration of other immunosuppressors like methotrexate should be considered.

Drug-Drug Interactions

Caution is advised when combining infliximab with other biological products used for similar conditions due to an increased risk of serious infections observed in clinical studies of other TNF blockers in combination with anakinra or abatacept without added clinical benefit. During the initiation or discontinuation of infliximab, monitoring is recommended for drugs with a significantly narrow therapeutic index, such as cyclosporine, warfarin, or theophylline.[21] Caution is advised against concomitant use of tocilizumab with biological DMARDs, including infliximab, due to the potential for increased immunosuppression and higher infection risk.

Contraindications

Infliximab can be administered with care in certain conditions, but the following conditions are defined as a contraindication to infliximab administration:

• Heart failure (NYHA class III/IV): According to the American Heart Association, TNF inhibitors may cause myocardial toxicity or exacerbate the underlying myocardial dysfunction.
• Previous hypersensitivity reaction to infliximab
• Current severe infection (sepsis, tuberculosis)
• Active infection

Box Warnings

Serious infections: There is an increased risk of severe infections, including tuberculosis, bacterial sepsis, and invasive fungal infections. Discontinue infliximab if a severe infection develops. Test for latent TB before starting treatment, initiating treatment if positive.[22] Monitor all patients for active TB during treatment, regardless of initial test results.

Malignancy: Lymphoma and other malignancies, some fatal, were documented in children and adolescents treated with TNF blockers, including infliximab. Postmarketing cases of fatal hepatosplenic T-cell lymphoma were reported, mostly in patients with inflammatory bowel disease, particularly adolescent or young adult males.[23][24]

Warning and Precautions

• Preexisting demyelinating disease
• Mild to moderate heart failure (NYHA class I/II)
• History of seizures
• Patients older than 65
• Uncontrolled diabetes mellitus
• Moderate to severe COPD

It is known to cause a cross-reaction with some drugs (eg, abatacept, adalimumab, etanercept), so care is administered when the patient is on another medicine. Infliximab is contraindicated in patients who have or will require live vaccines such as cholera vaccine, live virus MMR vaccine, smallpox vaccine (live vaccinia virus), etc. Generally, vaccination should occur more than 4 weeks before or over 3 months following immunosuppressive therapy with infliximab.[25]

Monitoring

Before administering infliximab, it is recommended to obtain the following tests:

Tuberculosis: A thorough screening for tuberculosis (TB) is necessary with: 

A detailed history of previous exposure/infection AND one of the following:

• Negative purified protein derivative (PPD < 5 mm) testing
• Negative interferon-gamma release assay test
• Positive TB screening but negative chest x-ray with infectious disease consultation
• At least 4 weeks post-initiation of isoniazid therapy for latent TB
• Standard drug therapy for active TB with infectious disease consultation

Hepatitis B: A negative hepatitis screen (particularly Hep B surface antigen) is required.

Heart Failure: Careful monitoring is necessary with serial echocardiograms to avoid heart failure exacerbations. Therapy should be immediately discontinued if the patient has frequent or worsening heart failure exacerbations.

Others: A detailed history should be taken to evaluate the patient for any recent or active infection, recent or upcoming surgery, or live virus vaccination. It is recommended that patients taking infliximab not receive live vaccines.

Toxicity

Infliximab is usually administered by healthcare personnel in a medical setting. Toxicity is very rare. Therefore, there is no specific treatment for infliximab toxicity. The best treatment if such an event occurs is supportive treatment.

Enhancing Healthcare Team Outcomes

Infliximab is an effective drug for several chronic inflammatory disorders. Inflammatory bowel disease requires consultation with a gastroenterologist. For rheumatoid arthritis/psoriatic arthritis, consultation with a rheumatologist is needed. However, all interprofessional healthcare team members (clinicians, nurses, pharmacists) should work together to ensure that the patient has had a proper workup for tuberculosis, hepatitis B, and cardiac status evaluated before administering the drug. Close monitoring of the patient by a specialty-trained nurse is necessary, as the drug does have mild to moderate adverse effects. A clinical pharmacist can also provide valuable input on dosing and drug-drug interactions and answer patient questions about the medication.

One retrospective study aimed to evaluate the consequence of an integrated clinical pharmacy team within a tertiary academic inflammatory bowel disease (IBD) center. Over 1 year, 1800 referrals for advanced IBD therapies were received, including medications such as infliximab. Of these referrals, 98% of patients successfully initiated the intended treatment. Despite encountering insurance denials in 17% of cases, the team overturned many through appeals and obtained manufacturer-patient assistance programs for some patients, including those prescribed infliximab. The clinical pharmacy team also conducted over 2000 pharmacist-initiated interventions, primarily focusing on preventing therapy interruptions and providing patient education. These findings underscore the valuable role of clinical pharmacy teams in optimizing patient care and medication access within IBD centers, suggesting their integration as a best practice.[26] An interprofessional team approach and open communication between clinicians (MDs, DOs, NPs, PAs), pharmacists, nurses, and specialists are necessary to optimize patient outcomes with infliximab therapy.

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Disclosure: Rawish Fatima declares no relevant financial relationships with ineligible companies.

Disclosure: Khaled Bittar declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Aziz declares no relevant financial relationships with ineligible companies.