CHICAGO — Clinicians need to step up their use of vaccinations as part of an overall plan to reduce the risk of infection in patients with rheumatic disease who receive tumor necrosis factor inhibitors, Dr. John J. Cush said at a symposium sponsored by the American College of Rheumatology.
“We are not as good as we should be [about vaccinations], and they can really have a big impact by preventing serious infections, especially in our immunosuppressed patients,” he said.
Data from pivotal trials show that the risk of serious infectious events with the biologics is two times that with placebo. This trend did not reach statistical significance in many of the studies, but in the real world it becomes significant, said Dr. Cush, director of clinical rheumatology for the Baylor Research Institute and a professor of medicine and rheumatology at Baylor College of Medicine in Dallas.
He suggests that patients with rheumatoid arthritis (RA) should receive the yearly influenza vaccine, and that pneumococcal vaccinations should be given once, with a second dose 5 years later.
Vaccines for meningococcal disease, human papillomavirus, and hepatitis B are needed where exposure is likely, but it is important to avoid live attenuated vaccines.
The package inserts for several TNF inhibitors were also revised in 2007-2008, warning that tuberculosis has been observed with their use. Data from the British Society for Rheumatology Biologics Register on 10,403 patients taking anti-TNF agents and 3,106 patients taking only disease-modifying anti-rheumatic drugs identified 35 cases of tuberculosis, all occurring in patients on anti-TNF agents. The TB rate was 110 per 100,000 patient-years in anti-TNF-treated patients, putting them above the rate for the general U.K. and U.S. populations (6 per 100,000 patient-years) and on par with alcoholics and patients with HIV, Dr. Cush said.
Manufacturers of anti-TNF agents advise clinicians to employ tuberculosis skin testing (purified protein derivative tuberculin) prior to initiating therapy; to monitor for signs and symptoms of TB, even if the initial PPD was negative; and to initiate latent tuberculosis infection (LTBI) treatment prior to TNF therapy.
Dr. Cush suggested that patients with a positive skin test (5 mm or more) or a history of LTBI can be treated with TNF inhibitors immediately after TB therapy with isoniazid is initiated. Moreover, this practice is routine in some RA clinical trials.
Arguments for suspending anti-TNF therapy could include the belief that TB treatment confers protection, or that anti-TNF therapy may increase the potential for toxicity or may cause worsening of latent TB infection before treatment with isoniazid can start working. Dr. Cush contends that there are no data to support waiting, and although toxicity may be an issue, it can be identified early on by lab testing and physician observation. Reactivation of LTBI has not been shown to occur in anti-TNF-treated patients.
To drive home his point, Dr. Cush highlighted a study among Africans with HIV-associated TB in which eight doses of etanercept (25 mg) administered twice weekly beginning on day 4 of TB therapy actually improved TB killing and overall responses, compared with control therapy (AIDS 2004;18:257-64).
Dr. Cush acknowledged that he would not use TNF inhibitors in RA patients who have invasive fungal disease or chronic hepatitis B, or in those infected with atypical mycobacteria. Clinicians should have safeguards and reminders in place to do PPD skin tests in all RA patients prior to TNF-inhibitor therapy and during year 2 (or when TNF-inhibitor therapy is changed), as this will occasionally pick up patients with latent TB who were initially anergic, he said.
There is no added yield to further annual testing, but the PPD skin test can be repeated if the patient has had a recent exposure, has traveled to a high-risk or endemic area, or has signs or symptoms of a mycobacterial infection.
PPD results are notoriously variable depending on who conducts the test, but results are good for 1-2 weeks, Dr. Cush said.
“It's better to have a patient come back late than not at all,” he said. “The best PPD is the one done by you and read by you.”
As an alternative—or in addition—to conventional skin tests, clinicians may want to consider using the QuantiFERON TB test, which was approved by the Food and Drug Administration in 2001 and measures the release of interferon-gamma in whole blood in response to stimulation by a purified protein derivative. Roughly 10% of QuantiFERON testing is indeterminate, but in general, clinicians can “hang their hat on the results,” he said, noting that PPD tests may be positive in those with a history of bacille Calmette-Guérin (BCG) vaccination, whereas QuantiFERON is unaffected by BCG and more truly reflects the likelihood of latent TB infection.