TNF inhibitor

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections (especially reactivation of latent tuberculosis), congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.^[1]

The global market for TNF inhibitors in 2008 was $13.5 billion^[2] and $22 billion in 2009.^[3]

History of anti-TNF treatments

Early experiments associated TNF with the pathogenesis of bacterial sepsis. Thus, the first preclinical studies using anti-TNF antibodies were performed in animal models of sepsis^[4] and showed that anti-TNF antibodies protected mice from sepsis. However, subsequent clinical trials in patients with sepsis showed no significant benefit. It wasn't until 1991 that studies in a transgenic mouse model of overexpressed human TNF provided the pre-clinical rationale for a causal role of TNF in the development of polyarthritis and that anti-TNF treatments could be effective against human arthritides.^[5] This was later confirmed in clinical trials^[6] and led to the development of the first biological therapies for rheumatoid arthritis.

Examples

Inhibition of TNF effects can be achieved with a monoclonal antibody such as infliximab^[7] (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or with a circulating receptor fusion protein such as etanercept (Enbrel).

Thalidomide (Immunoprin) and its derivatives lenalidomide (Revlimid) and pomalidomide (Pomalyst, Imnovid) are also active against TNF.

While most clinically useful TNF inhibitors are monoclonal antibodies, some are simple molecules such as xanthine derivatives^[8] (e.g. pentoxifylline)^[9] and bupropion.^[10] Bupropion is the active ingredient in the smoking cessation aid Zyban and the antidepressants Wellbutrin and Aplenzin.

Several 5-HT_2A agonist hallucinogens including (R)-DOI, TCB-2, LSD and LA-SS-Az have unexpectedly also been found to act as potent inhibitors of TNF, with DOI being the most active, showing TNF inhibition in the picomolar range, an order of magnitude more potent than its action as a hallucinogen.^[11][12][13]

Therapeutic applications

Rheumatoid arthritis

The role of TNF as a key player in the development of rheumatoid arthritis was originally demonstrated by Kollias and colleagues in proof of principle studies in transgenic animal models.^[14][15]

TNF levels have been shown to be raised in both the synovial fluid and synovium of patients with rheumatoid arthritis. This leads to local inflammation through the signalling of synovial cells to produce metalloproteinases and collagenase^[16]

Clinical application of anti-TNF drugs in rheumatoid arthritis was demonstrated by Marc Feldmann and Ravinder N. Maini, who won the 2003 Lasker Award for their work.^[17] Anti-TNF compounds help eliminate abnormal B cell activity.^[18][19]

Therapy which combines certain anti-TNF agents such as ertanercept with DMARDs such as methotrexate has been shown to be more effective at restoring quality of life to sufferers of rheumatoid arthritis than using either drug alone.^[16]

Skin disease

Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are ongoing.^[20]

The National Institute of Clinical Excellence (NICE) has issued guidelines for the treatment of severe psoriasis using the anti-TNF drugs etanercept (Enbrel) and adalimumab (Humira) as well as the anti-IL12/23 biological treatment ustekinumab (Stelara). In cases where more conventional systemic treatments such as psoralen combined with ultraviolet A treatment (PUVA), methotrexate, and ciclosporin have failed or can not be tolerated, these newer biological agents may be prescribed. Infliximab (Remicade) may be used to treat severe plaque psoriasis if aforementioned treatments fail or can not be tolerated.^[21]

Gastrointestinal Disease

In 2010 The National Institute of Clinical Excellence (NICE) in the UK issues guidelines for the treatment of severe Crohn's Disease with Infliximab and adalimumab. ^[22]

Other uses

It's worth noting that TNF-Alpha inhibitors are being considered for more and more disease, particularly those affecting the immune system and inflammation. ^[23]

Side effects

Cancer

The U.S. Food and Drug Administration continues to receive reports of a rare cancer of white blood cells (known as hepatosplenic T-cell lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with TNF blockers, as well as with azathioprine, and/or mercaptopurine.^[24]

Opportunistic infections

TNF inhibitors put patients at increased risk of certain opportunistic infections. The FDA has warned about the risk of infection from two bacterial pathogens, Legionella and Listeria. People taking TNF blockers are at increased risk for developing serious infections that may lead to hospitalization or death due to certain bacterial, mycobacterial, fungal, viral, and parasitic opportunistic pathogens.^[25]

Tuberculosis

In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab.^[26] Before prescribing a TNF inhibitor, physicians should screen patients for latent tuberculosis. The anti-TNF monoclonal antibody biologics infliximab, golimumab, certolizumab and adalimumab, and the fusion protein etanercept, which are all currently approved by the FDA for human use, have warnings which state that patients should be evaluated for latent TB infection, and if it is detected, preventive treatment should be initiated prior to starting therapy with these medications.

Fungal infections

The FDA issued a warning on September 4, 2008, that patients on TNF inhibitors are at increased risk of opportunistic fungal infections such as pulmonary and disseminated histoplasmosis, coccidioidomycosis, and blastomycosis. They encourage clinicians to consider empiric antifungal therapy in certain circumstances to all patients at risk until the pathogen is identified.^[27] A recent review showed that anti-TNFα agents associate with increased infection risks for both endemic and opportunistic invasive fungal infections, particularly when given late in the overall course of treatment of the underlying disease, and in young patients receiving concomitant cytotoxic or augmented immunosuppressive therapy.^[28]

Anti-TNF agents in nature

TNF or its effects are inhibited by several natural compounds, including curcumin^{[29][30][31][32]} (a compound present in turmeric), and catechins (in green tea). Activation of cannabinoid CB₁ or CB₂ receptors by cannabis or Echinacea purpurea also seems to have anti-inflammatory properties through TNF inhibition.^[33]

References