How does TNF cause inflammation
Immunobiologics for inflammation
TNF antagonists also affect the cardiovascular system and are contraindicated in patients with moderate and severe heart failure (NYHA class III / IV). In clinical studies, symptoms worsened in patients with heart failure, which was associated with increased mortality. Heart failure developed less frequently in patients without existing cardiovascular disease.
Moderately elevated liver enzymes with values up to five times the upper limit of normal are also observed. Generally this is symptom-free and temporary. Progression to severe liver damage is not observed (23).
ADR: antibodies and autoimmune processes
Proteins foreign to the body such as TNF antagonists have an increased allergic potential. Infliximab is a chimeric monoclonal antibody which, due to its mouse component, has a higher immunogenicity than the fully humanized antibodies when given multiple times. Human anti-chimeric antibodies (HACA) occurred in 14 to 40 percent of patients. A concomitant immunosuppressive administration of MTX reduced their occurrence, which increased the effectiveness of infliximab. The administration of higher doses decreased the immunogenicity of infliximab, which may be due to a satiety effect.
Anti-idiotypic antibodies also develop against fully humanized antibodies. Their clinical significance depends on their neutralizing potential. Cross-reactions are also possible; switching from infliximab to adalimumab may also reduce its effectiveness. Infusion-related reactions such as laryngeal or pharyngeal edema, severe bronchospasm, dyspnoea, hypotension, or urticaria are more common in patients with HACA. Patients taking etanercept are less likely to develop antibodies that are also not clinically relevant.
The TNF blockade can also trigger autoimmune processes. Anti-nuclear antibodies or autoantibodies against double-stranded DNA were detected for all TNF antagonists during treatment. Some patients who tested positive developed a lupus-like syndrome.
The adverse events observed in children and adolescents were similar in type and frequency to those in adult patients (5, 6, 24, 25).
Older age, liver or kidney dysfunction have no influence on the kinetics of the TNF blockers. No dose adjustment is necessary. Serum concentrations are lower in younger children than in adults (6). The administration of TNF inhibitors during pregnancy is not recommended. Women of childbearing age should use reliable contraception. The antibodies cross the placenta. They were found in the serum of infants whose mothers were treated for up to six months after birth. The infants should therefore not receive live vaccines during this time (6, 26).
Herbal TNF inhibitors
Interestingly, there are also herbal ingredients that inhibit TNF. This has been shown for curcumin from turmeric rootstock, for resveratrol, a polyphenol in grapes, and for certain catechins from green tea in cell cultures and in animal experiments. Clinical evidence that these plant ingredients are effective in chronic inflammatory diseases is still pending (27–30).
New indications - partly disappointing
In recent years, TNF-α blockers have been clinically tested in various diseases - sometimes with sobering results. The administration of the chimeric antibody infliximab or Lenercept, a recombinant TNF receptor-IgG fusion protein (TNFR1p55), worsened the symptoms in patients with multiple sclerosis. The same applied to therapy with infliximab and etanercept in chronic heart failure. TNF-α antagonists were also not effective in inflammatory diseases of the lungs such as COPD or asthma, but increased the risk of infection.
The results for Behçet's disease, an autoimmune-mediated vasculitis, are more promising. In addition to ulcers of the oral and genital mucosa and arthritic complaints, the disease manifests itself primarily through uveitis, which can lead to loss of vision. Infliximab or etanercept showed rapid resolution of ocular inflammation and other Behçet symptoms that persisted after treatment was discontinued. Both infliximab and etanercept were effective for uveitis due to other conditions, such as rheumatoid arthritis.
TNF antagonists also help with skin diseases such as acne inversa or neutrophilic dermatoses such as pyoderma gangrenosum. Other promising results were found in studies in patients with diabetic macular edema or age-related macular degeneration. Patients with treatment-resistant depression and elevated markers of inflammation such as C-reactive protein benefited from infliximab. Perispinal administration of etanercept rapidly improved cognitive and verbal impairment in Alzheimer's patients.
More than 100 years after the discovery of tumor necrosis factor, TNF antagonists have revolutionized therapy. Optimized therapy schemes that enable therapy-free intervals also improve the quality of life. This also applies to biomarkers that help to select the most effective therapeutic agent for the individual.
New anti-TNF molecules are in clinical trials (31–36). /
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