How To Choose An Anti-TNF Agent in RA

Stephen Paget, MD


July 15, 2010


Which anti-TNF agent should I choose in my patients with rheumatoid arthritis?

Response from Stephen Paget, MD
Professor of Medicine, Weill Cornell Medical College, New York, NY; Physician-in-Chief, Center for Rheumatology, Hospital for Special Surgery, New York, NY

There are currently 5 tumor necrosis factor-alpha (anti-TNF) antagonists available for the treatment of rheumatoid arthritis (RA) and spondyloarthropathies (SpAs). In alphabetical order, they are adalimumab (Humira®), certolizumab (Cimzia®), etanercept (Enbrel®), infliximab (Remicade®), and golimumab (Simponi™).

When one asks whether they are all created equal, it depends on what you mean by equal. Despite having different proposed mechanisms of action, all 5 of the current anti-TNFs are basically interchangeable with regard to clinical and radiologic effectiveness, side effect profile, and cost in the treatment of patients with RA. So, how should a physician and a patient choose the "right" one to use in a specific clinical situation? The following are the facts that should be used in making a decision:

1. Track record and time since approval: US Food and Drug Administration (FDA) approval for the use of anti-TNFs in the treatment of RA occurred in the following order: etanercept (1998), infliximab (1999), adalimumab (2002), certolizumab, and golimumab (2009). If one likes to choose a drug because it has been around longer and its initial effectiveness and safety profile has remained pretty much the same over the years, you would use a drug that is more "tried and true." So, what might be a reason for not choosing a drug that has been around for 12 years as opposed to one that was approved only 1 year ago? Read on.

2. Molecular structure and clinical specificity: 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: Given the fact that all anti-TNFs seems to have basically the same effectiveness and safety profile, most patients would rather get the same positive effect with fewer injections/month. If they had diabetes, they would inject themselves 3 times a day if that were needed. They don't see RA as a similar threat, even though it is. 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: Rheumatologists, as with most physicians, will likely choose a drug that has the best and longest track record and the one with which they have the most positive experience, regardless of the dosing interval and route of administration. While more recently trained rheumatologists might choose any of the anti-TNFs because they have no particular anti-TNF "loyalty" or experience, 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.

6. Side effect profile: Infections, both viral and bacterial, continue to be the most significant and common side effects with all anti-TNFs and they share a similar infection profile. Rheumatologists let their patients know that they need to hold their anti-TNF in the setting of an infection and also call immediately for guidance. Their threshold for using antibiotics is probably lower in this group of patients. Immunizations 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.

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.

Finally, how does one optimally balance steps 1-6 when making a decision about which anti-TNF to choose? In those patients who do respond to anti-TNFs, the improvement is impressive, profoundly life-enhancing and sustained. Luckily, they all work equally well and the choice is an individual one with help from the facts described above.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: