Anti-tumor necrosis factor therapy Domina Petric, MD Inflammatory bowel disease (IBD) pharmacology

Topical corticosteroids (proctitis) Surgery Natalizumab Cyclosporine TNF antagonists Iv. corticosteroids Oral corticosteroids Methotrexate Azathioprine 6-Mercaptopurine Budesonide (ileitis) Topical corticosteroids (proctitis) Antibiotics 5-Aminosalicylates Severe disease Refractory Moderate disease Mild disease Responsive

Pharmacokinetics A dysregulation of the helper T cell type 1 (TH1) response and regulatory T cells (Tregs) is present in IBD. One of the key proinflammatory cytokines in IBD is tumor necrosis factor (TNF).

TNF is produced by: innate immune system (dendritic cells, macrophages) adaptive immune system (especially TH1 cells) nonimmune cells (fibroblasts, smooth muscle cells)

Pharmacokinetics TNF exists in two biologically active forms: soluble TNF and membrane-bound TNF. The biologic activity of soluble and membrane-bound TNF is mediated by binding to TNF receptors (TNFR).

Pharmacokinetics TNFR are present on some cells, especially TH1 cells, innate immune cells and fibroblasts. Binding of TNF to TNFR initially activates components including NF-κB that stimulate transcription, growth and expansion.

TNFR activation causes: release of proinflammatory cytokines from macrophages T-cell activation and proliferation fibroblast collagen production up-regulation of endothelial adhesion molecules responsible for leukocyte migration stimulation of hepatic acute phase reactants

Pharmacokinetics Activation of TNFR may later lead to apoptosis-programmed cell death of activated cells. Monoclonal antibodies to human TNF are approved for the treatment of IBD: infliximab, adalimumab and certolizumab.

Pharmacokinetics Infliximab and adalimumab are antibodies of the IgG1 subclass. Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to polyethylene glycol (PEG), but lacks an Fc portion.

Pharmacokinetics Infliximab is administered as intravenous infusion. Therapeutic doses: 5-10 mg/kg. Half-life is 8-10 days. Plasma disappearance of antibodies: over 8-12 weeks.

Half-life: 2 weeks. Pharmacokinetics Adalimumab and certolizumab are administered by subcutaneous injection. Half-life: 2 weeks.

Infliximab Adalimumab Certolizumab Class Monoclonal antibody % Human 75 100 95 Structure IgG1 Fab fragment attached to PEG (lacks Fc portion) Route of administration Intravenous Subcutaneous Half-life 8-10 days 10-20 days 14 days Neutralizes soluble TNF Yes Neutralizes membrane-bound TNF Induces apoptosis of cells expressing membrane-bound TNF No Complement-mediated cytotoxicity of cells expressing membrane-bound TNF Induction dose 5 mg/kg at 0, 2 and 6 weeks 160 mg, 80 mg and 20 mg at 0, 2 and 4 weeks 400 mg at 0, 2 and 4 weeks Maintenance dose 5 mg/kg every 8 weeks 40 mg every 2 weeks 400 mg every 4 weeks

Pharmacodynamics All 3 agents bind to soluble and membrane-bound TNF with high affinity, preventing the cytokine from binding to its receptors. Binding of these drugs to membrane-bound TNF causes reverse signaling that supresses cytokine release.

Pharmacodynamics When infliximab and adalimumab bind to membrane-bound TNF, the Fc portion of the human IgG1 region promotes antibody-mediated apoptosis, complement activation and cellular cytotoxicity of activated T lymphocytes and macrophages.

Clinical uses All three agents are approved for the acute and chronic treatment of patients with moderate to severe Crohn´s disease (second line treatment). Infliximab is approved for the acute and chronic treatment of moderate to severe ulcerative colitis.

Clinical uses Median time to clinical response is two weeks. One-third of patients lose response despite higher doses or more frequent injections, usually due to the development of antibodies to the TNF antibody.

Adverse effects Serious adverse events occur in up to 6% of patients with anti-TNF therapy. The most important is INFECTION due to suppression of the TH1 inflammatory response.

Serious infections may occur: bacterial sepsis, TBC invasive fungal organisms reactivation of hepatitis B listeriosis reactivation of latent TBC with dissemination

Warning! Before administering anti-TNF therapy, all patients must undergo testing with tuberculin skin tests or interferon gamma release assays.

Adverse effects The risk of serious infections is increased markedly in patients taking concomitant corticosteroids.

Adverse effects More common and less serious infections are upper respiratory infections (sinusitis, bronchitis, pneumonia) and cellulitis.

Adverse effects Antibodies to the antibody (ATA) may develop with all 3 agents. ATA may attenuate or eliminate the clinical response. ATA may increase the likelihood of developing acute or delayed infusion or injection reactions.

Adverse effects Antibody formation is much more likely in patients given episodic anti-TNF therapy than regular scheduled injections. Prevalence of ATA in patients on chronic maintenance therapy: infliximab 10%, certolizumab 8% and adalimumab 3%.

Adverse effects Antibody development is less likely in patients who receive concomitant therapy with immunomodulators (6-MP, MTX). Concomitant treatment with anti-TNF agents and immunomodulators may increase the risk of lymphoma.

Adverse effects Infliximab intravenous infusions result in acute adverse infusion reactions in up to 10% of patients. Infusion reactions are more common with the second or subsequent infusions than with the first.

Adverse effects Early mild reactions are fever, headache, dizziness, urticaria and mild cardiopulmonary symptoms (chest pain, dyspnea, hemodynamic instability).

Adverse effects Prophylactic administration of acetaminophen, diphenhydramine or corticosteroids may reduce reactions to subsequent infusions.

Adverse effects Severe acute reactions are significant hypotension, shortness of breath, muscle spasms and chest discomfort. Treatment: oxygen, epinephrine and corticosteroids.

Adverse effects Delayed serum sickness-like reactions may occur 1-2 weeks after anti-TNF therapy in 1% of the patients. Myalgia, arthralgia, jaw tightness, fever, rash, urticaria, edema: usually is necessary discontinuation of that agent.

Adverse effects Positive antinuclear antibodies and anti-double-stranded DNA develop in a small number of patients. Development of a lupus-like syndrome is rare and resolves after discontinuation of the drug.

Rare and serious adverse effects are: severe hepatic reactions leading to acute hepatic failure demyelinating disorders hematologic reactions new or worsened congestive heart failure in patients with underlying heart disease

Adverse effects Anti-TNF agents may cause a variety of psoriatic skin rashes that usually resolve after drug discontinuation. Lymphoma appears to be increased in patients with untreated IBD. Anti-TNF agents may further increase the risk of lymphoma.

Adverse effects An increased number of cases of hepatosplenic T-cell lymphoma have been noted in children and young adults taking combined therapy with immunomodulators, anti-TNF agents or corticosteroids.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.