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Anti-TNF drugs

Tumor necrosis factor-alpha or TNF-alpha is a cytokine critical for effective immune surveillance and is required for proper proliferation and function of natural killer cells, T cells, B cells, macrophages, and dendritic cells.1 Anti-TNF drugs, also known as TNF blockers, are drugs which interfere with the body's production of TNF-alpha.2

Anti-TNF drugs are expensive, ineffective at treating chronic disease and have a number of adverse effects. Also, anti-TNF inhibitors can make a patient feel temporarily less symptomatic, because they reduce immunopathology, the bacterial die-off reaction.

Types of anti-TNF drugs

  • adalimumab (Humira)
  • etanercept (Enbrel)
  • infliximab (Remicade)
  • pentoxyfyllene (Trental)

Molecular actions

During immunopathology, cytokines, are elevated. Although cytokines are usually associated with an inflammatory process, it has been demonstrated that TNF, interleukin-6 (IL-6) and IL-8 are involved in the immunopathological reaction, each peaking at different times throughout the response: TNF elevates first, shortly after antibiotic administration, followed by IL-6 at the onset of symptoms and finally IL-8.

The release of cytokines appears to be essential for recovery after an infection. One study found that the cytokine TNF-alpha is necessary for the proper expression of acquired specific resistance following infection with Mycobacterium tuberculosis.3 4 5 Another effect of the use of TNF blockers is to break or reduce the formation of granuloma, one of the body's mechanisms to control bacterial pathogens.6

For these reasons among others, TNF-alpha inhibitors, drugs which suppress the cytokine, are contraindicated for MP patients.

Olmesartan (Benicar) vs. TNF-alpha blockers

Related article: Olmesartan safety

While the Marshall Protocol medication olmesartan also reduces levels of TNF-alpha, it does so by blocking the generation of the substance in the first place. This is in contrast to TNF-alpha blockers, which bind and disable free-floating TNF-alpha after the cytokine has been produced. This distinction is significant enough to be responsible for the vastly different safety profiles between olmesartan and the anti-TNF drugs. In contrast to drugs like Remicade, olmesartan enjoys one of the safest reputations of any prescription medication.

Weaning from infliximab (Remicade)

The half life of Remicade is 9.5 days. The excretion rate is unknown. Patients who are starting the Marshall Protocol may take olmesartan (Benicar) to dampen inflammatory symptoms that may flare as Remicade leaves the system. Wait three weeks to begin minocycline so the body will be accustomed to the absence of Remicade's immunosuppression before inducing immunopathology with minocycline.

Increased risk of infection

One recent systematic review of the adverse effects of anti-TNF therapies as they were used in rheumatoid arthritis concluded that patients taking the drugs are at 2.0 times higher risk for serious infections.7 The study's authors concluded that these side effects were dose-dependent.

According to Centocor, the company which manufactures Remicade, patients taking the drug put themselves at increased risk for opportunistic infection.

Serious infections, including sepsis and pneumonia, have been reported in patients receiving TNF-blocking agents. Some of these infections have been fatal.

U.S. Food and Drug Administration, 2006 statement

M. tuberculosis is one such infection.8

Cases of active tuberculosis have been reported worldwide with the use of therapeutic agents that inhibit tumour necrosis factor (TNF) alpha. TNF-alpha has a central role in mycobacterial infection and disease. Accordingly, progression of recently acquired tuberculosis infection or reactivation of remotely acquired infection should be expected with the use of anti-TNF agents.

Michael A. Gardam, et al. 9

To reduce the likelihood of contracting or exacerbating tuberculosis, prospective patients are routinely tested for infection via a skin test. However, as some researchers have noted, TB skin tests on patients treated with immunosupressants, which are routinely used on rheumatoid arthritis patients, are not reliable, because they result in false negatives.10

“Exaggerated Borreliosis infections” have been noted11 as have been fatal fungal infections. In 2008, the FDA ordered stronger warnings on Enbrel, Remicade, Humira and Cimzia due to increased risk of fungal infections.

Researchers have also observed reactivation of latent viral infections, namely hepatitis B in patients who are chronic carriers of the virus.

For these reasons, physicians are strongly advised by the FDA not to prescribe TNF blockers to patients who suffer from active or latent infections and to discontinue therapy in the event of serious infection. Yet, this advisory is strikingly incomplete. In fact, all patients who suffer from diseases for which an anti-TNF agent could possibly indicated suffer from a chronic bacterial infection, a fact which underscores the importance of not taking such drugs.

Other adverse effects

  • Allergic reaction – Some patients report an allergic response to Remicade. One possible reason may be that the chimeric monoclonal antibody in Remicade is part human, part mouse. Exposed to purely mouse (murine) antibodies, human immune systems naturally develop human antibodies to the foreign mouse proteins, a process which can trigger an allergic-like response.
  • Congestive heart failure – Exacerbation of CHF is a major side effect of Remicade use in patients with moderate to severe CHF. This is especially problematic in that many sarcoidosis patients do not know that they have cardiac involvement.
  • Liver problemsAccording to the FDA, patients taking Remicade can (but rarely) experience severe hepatic reactions including acute liver failure, jaundice, hepatitis and cholestasis.
  • Skin problems – In one prospective trial, 25% of patients on TNF-alpha-blocking therapy suffered from a dermatological condition that led them to visit a skin specialist. In a control group of patients who were not undergoing TNF-alpha blocking therapy and had less severe disease only 13% visited a dermatologist during the same period of time.12
  • Cancer – One recent systematic review of the adverse effects of anti-TNF therapies as they were used in rheumatoid arthritis concluded that patients taking the drugs are at 3.3 times higher risk for “malignancies.”13 The study's authors concluded that these side effects were dose-dependent. Since then, the FDA has issued an early communication about an ongoing investigation of approximately 30 reports of cancer in children and young adults. More recently, a study of over 20,000 US military veterans show that nonmelanoma skin cancer risk is about one third higher for patients with rheumatoid arthritis treated with TNF inhibitors than for similar patients treated with nonbiologic disease-modifying antirheumatic drugs (DMARDs).14

Economic motives for ongoing use

Considering that Abbott’s Humira was the company’s best-selling product in 2007 with over $3 billion in sales, and Remicade also topped Schering-Plough’s portfolio with sales of $1.65 billion, there is minimal hope that such companies will be willing to embrace a true understanding of how their drugs foster the development of chronic disease.

Insurance coverage and baseline cost of anti-TNF drugs varies, but patients in the United States and Canada have reported being charged $4,600 or more for a single treatment of Remicade. According to one estimate, $1,000 of the $4,600 goes to pay the prescribing physician's clinical group.

One citizen watchdog group, the New Jersey Citizen Action (NJCA), filed a lawsuit to stop Remicade from being promoted by promising doctors windfall profits when they prescribe the drug.

References

1 Aggarwal BB, Shishodia S, Takada Y, Jackson-Bernitsas D, Ahn KS, Sethi G, Ichikawa H TNF blockade: an inflammatory issue. Ernst Schering Res Found Workshop. 2006;:161-86.
3 Allie N, Alexopoulou L, Quesniaux VJ, Fick L, Kranidioti K, Kollias G, Ryffel B, Jacobs M Protective role of membrane tumour necrosis factor in the host's resistance to mycobacterial infection. Immunology. 2008;125:522-34.
4 Arend SM, Breedveld FC, van Dissel JT TNF-alpha blockade and tuberculosis: better look before you leap. Neth J Med. 2003;61:111-9.
5 Islam N, Kanost AR, Teixeira L, Johnson J, Hejal R, Aung H, Wilkinson RJ, Hirsch CS, Toossi Z Role of cellular activation and tumor necrosis factor-alpha in the early expression of Mycobacterium tuberculosis 85B mRNA in human alveolar macrophages. J Infect Dis. 2004;190:341-51.
6 Hamilton CD Immunosuppression related to collagen-vascular disease or its treatment. Proc Am Thorac Soc. 2005;2:456-60.
8 Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lortholary O, Mariette X Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009;60:1884-94.
9 , 10 Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55.
11 Molin S, Ruzicka T, Prinz JC Borreliosis mimicking lupus-like syndrome during infliximab treatment. Clin Exp Dermatol. 2010;:.
12 Flendrie M, Vissers WH, Creemers MC, de Jong EM, van de Kerkhof PC, van Riel PL Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2005;7:R666-76.
14 Amari W, Zeringue AL, McDonald JR, Caplan L, Eisen SA, Ranganathan P Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis. Rheumatology (Oxford). 2011;50:1431-9.
Last modified: 08.29.2012
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