Tumor necrosis factor-alpha

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In medicine, tumor necrosis factor-alpha is a "serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to tnf-beta (lymphotoxin), but they share TNF receptors.[1]

Tumor necrosis factor inhibitors

There are several inhibitors of TNF-a. [2]

Use in rheumatoid arthritis

In the United States, five TNF inhibitors are approved for the treatment of rheumatoid arthritis: adalimumab (Humira), certolizumab (Cimzia), etanercept (Enbrel) and infliximab (Remicade). One expert, Stephen Paget, Professor of Medicine, Weill Cornell Medical College, New York, NY; Physician-in-Chief, Center for Rheumatology, Hospital for Special Surgery, New York, NY, discussed criteria for selecting an agent in the group, changing to another agent in the group, and when to abandon therapy with this class and go to a different mechanism. They have generally similar indications and side effect profiles, and all are expensive. When successful, the drugs are very successful. Paget's criteria are:[6]

  1. Track record and time since approval: these agents were approved from 1998 to 2009. Greater experience might seem to lower risk, but the decision is more complex.
  2. Molecular structure and clinical specificity Not all work in exactly the same way, and the mode of one drug may invoke molecular mechanisms not fully understood. Some of the drugs are ineffective for off-label indications. "Etanercept is a fusion protein that connects 2 TNF-binding molecules to the Fc component of an IgG1 molecule and works as a decoy, binding free TNF and stopping it from attaching to a mononuclear cell's TNF receptor; the other four molecules are monoclonal proteins that bind circulating and/or cell-bound TNF. Infliximab is a chimera, one-fourth mouse protein, and three-fourths human. The question you might ask is whether these varied constructs make a difference in how these drugs are used clinically. The answer seems to be yes. All have basically equal clinical effects in patients with RA and SpAs. However, for some reason, etanercept is ineffective in the treatment of inflammatory bowel disease and uveitis, and perhaps sarcoidosis (the latter 2 disorders not being approved uses of anti-TNFs). Etanercept is an effective drug in the treatment of the peripheral joint or spine/sacroiliac inflammation associated with the SpAs, but because it is not helpful in prevent or treating uveitis or possible inflammatory bowel disease, rheumatologists sometimes avoid its use in the treatment of SpAs and use a monoclonal anti-TNF. Infiliximab is the only anti-TNF that needs to be given intravenously; the others are given via the subcutaneous route. Also, infliximab has a greater incidence of allergic reactions because of its mouse component. Of interest is the fact that Medicare patients must get infliximab for various Centers for Medicare & Medicaid Services administrative reasons."
  3. Frequency of dosing and route of administration: All are injectable, but need various frequencys and modes of administration. "After initial intravenous loading doses, infiliximab is given intravenously every 8 weeks. While patients like not having to inject themselves, the bother of going to an infusion center, as opposed to injections at home, is a turn off. Medicare patients must get infliximab, but others have a choice. So, if the patients had their druthers, they would like to take a drug that is subcutaneously injected monthly. Golimumab has monthly dosing; certolizumab has every 2-week loading dosing initially and eventually is given every month. However, with the latter, the patient must have 2 injections at the same time."
  4. Rheumatologist preference: " older rheumatologists will likely choose the drugs that have been around the longest because that is what they were "raised on.""
  5. Cost: "Because all of the anti-TNFs are equally massively expensive $15-$20,000/year or more) and they are usually paid for by insurance companies, rheumatologists usually don't factor cost into their equation. However, those doctors who run their own infusion centers may preferentially use infliximab because they are likely to personally profit from the use of this medication plus the infusion costs. It is of note that infliximab has a wide range of possible doses from 3 to 10 mg/kg and, at the higher doses, patients may have a co-payment.

Changing drugs

So how many anti-TNFs should be used before moving on to a drug with an alternative mode of action (ie, costimulation blockade/T-cell suppression with abatacept [Orencia®], B-cell suppression with rituximab [Rituxan®] or IL-6-receptor blockade with tocilizumab [Actemra®])?Most rheumatologists give each anti-TNF medication about 3 months to work. If the first anti-TNF doesn't lead to significant clinical improvement (defined by using a disease activity score such as the DAS28, CDAI, SDAI or HAQ) or if side effects occur, they usually try one more before moving on to a drug with an alternative mode of action. Approximately 50% of patients who did not respond to a first anti-TNF or had a side effect will respond nicely to a second anti-TNF.

Common adverse effects

Tumor necrosis factor inhibitors increase susceptibility to serious infections.[7] Infections remain the most common serious side effect, and the anti-TNFs have similair profiles. Rheumatologists tend to use antibiotics more aggressively with RA patients treated with anti-TNF. "hImmunizations should be kept up to date and hepatitis B and C screening is needed. Tuberculosis is surprisingly very uncommon, probably because of the effectiveness of tuberculosis screening with 5-TU PPD and quantiferon assays, and chest radiographs when needed."[6]

References

  1. Anonymous (2015), Tumor necrosis factor-alpha (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Dentener MA, Wouters EF (2006). "Tumor necrosis factor inhibitors for rheumatoid arthritis.". N Engl J Med 355 (19): 2047-8; author reply 2048. PMID 17099951[e]
  3. The most up-to-date information about Etanercept and other drugs can be found at the following sites.
  4. Gorman JD, Sack KE, Davis JC (May 2002). "Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha". N. Engl. J. Med. 346 (18): 1349–56. DOI:10.1056/NEJMoa012664. PMID 11986408. Research Blogging.
  5. The most up-to-date information about Infliximab and other drugs can be found at the following sites.
  6. 6.0 6.1 Stephen Paget (15 July 2010), How To Choose An Anti-TNF Agent in RA, Medscape Rheumatology
  7. Anonymous (2008). FDA MedWatch - 2008 Safety Alerts for Human Medical Products. U.S. Food and Drug Administration.