Travel and TNF-Alpha Inhibitors
Travel and TNF-Alpha Inhibitors
ABSTRACT & COMMENTARY
By Mary-Louise Scully, MD
Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA
Dr. Scully reports no consultant, stockholder, speaker'
s bureau, research, or other financial relationship with companies having ties to this field of study.
Synopsis: Patients with chronic inflammatory conditions such as rheumatoid arthritis and psoriatic arthritis are experiencing significant clinical improvement due to increasing use of TNF-alpha inhibitors. However, the use of such agents associated with their potential immunosuppressive effects, create new challenges for travel medicine providers.
Source: Orenstein R. Travel in Patients Receiving TNF-Alpha Inhibitors. Trav Med Infect Dis. 2005;3:105-109.
An article by dr. robert orenstein addresses the challenging area of travel-related illnesses and their prevention for patients receiving TNF-alpha inhibitors. Tumor Necrosis Factor-alpha (TNF-alpha) is a proinflammatory cytokine that plays an important role in the pathogenesis of rheumatoid arthritis, psoriasis, and other inflammatory conditions. TNF-alpha inhibitors include: etanercept (Enbrel), a fusion protein that consists of the TNF-alpha receptor and a human immunoglobulin heavy chain, infliximab (Remicade), a chimeric human/mouse monoclonal antibody that binds TNF-alpha, and adalimumab (Humira), a fully human anti-TNF monoclonal antibody. It is estimated that currently over a half million patients receive treatment with one of these 3 agents which are approved by United States Food and Drug Administration (FDA). Clinical responses to these agents have lead to more active lifestyles and increasing travel for these patients, prompting concern for the specific risks of travel-related illnesses.
TNF-alpha plays several important roles in the modulation of our host responses to infectious agents, including the recognition of pathogens by dendritic cells, macrophage activation, granuloma formation and maintenance, and recruitment of other inflammatory mediators- all of which are important components of our host defenses against intracellular pathogens.1 The importance of TNF-alpha as a defense against infection with intracellular pathogens such as Salmonella, Listeria, Mycobacteria, and fungi has been demonstrated in both animal and human studies.
The risks of upper respiratory infections, traveler'
s diarrhea, and other serious infections in patients on TNF-alpha inhibitors should be addressed. These patients may be on other immunosuppressives such as corticosteroids or methotrexate, complicating matters
further. Travel vaccinations should be provided, but based upon experience in other immunocompromised
hosts, it is recommended that one avoid the use of live bacterial or viral vaccines. Yellow fever vaccine is not
recommended for patients receiving TNF-alpha inhibitors, and many providers would advise patients to avoid travel to endemic areas. Travelers at risk for typhoid fever should receive a parenteral nonliving Salmonella typhi vaccine, rather than the live oral typhoid vaccine. Similarly, inactivated injectable influenza vaccine is appropriate, but the live nasal influenza vaccine (FluMist) would best be avoided. Pneumococcal and meningococcal vaccinations are considered safe, yet concerns about efficacy and adequate response to vaccination exist. Most likely, immunization prior to initiation of treatment with TNF-alpha inhibitors would provide the best efficacy.
Other preventative strategies should be stressed in these patients, including food and water precautions, good hand hygiene, and both DEET and permethrin-containing products to decrease insect-borne diseases. Specifically, these patients should be reminded to avoid unpasteurized foods, soft cheeses, hot dogs, and cold cuts. Early use of antibacterial treatment of traveler'
s diarrhea might prevent disseminated disease and antibiotics for early treatment of respiratory, and skin infections should be available to the traveler on TNF-alpha inhibitors. Avoidance of high-risk activities for exposure to Histoplasma infections, such as spelunking or excavating, is appropriate as well.
Commentary
A new patient of mine related her past medical history regarding yellow fever vaccination and etanercept. Two years earlier, prior to travel to Africa, she had been given yellow fever vaccine by a nurse in a different travel clinic. Only after vaccination did the nurse ask about medications, and the patient stated she was on etanercept for rheumatoid arthritis. She said the nurse' s face turned "white as a ghost" and she ran out of the room to get the doctor in charge. The patient states that for the next 10-14 days she was a "very popular woman" with daily calls from the nurse or the doctor to check on her. Luckily, she did fine, with no adverse events. Neither the manufacturer of etanercept or infliximab has any available data regarding similar experiences in other patients.
On the ISTM listserv, a physician recently reported having received verbal information from the manufacturer that, 3½ to 4 weeks after discontinuation of etanercept, most of the drug would be gone and, at that point, a provider could make a judgment about whether live yellow fever vaccine could be safely administered. Having contacted the manufacturer, I feel this pharmacology is technically valid, although their policy statement remains that live vaccines are not recommended for patients on etanercept. The patient being discussed had been on etanercept for psoriasis and was planning travel to Ghana for an extended time. It is unlikely that most patients on biologic agents for inflammatory arthritis would tolerate discontinuation of their medication prior to travel, as their disease symptoms would likely flare. Also, etanercept has the shortest half-life (4 days) of the 3 agents (infliximab has a half life of 8-10 days, adalimumab of 10-14 days), making it unlikely that this would be a practical approach for these patients. Certainly, the recent information on yellow fever vaccine-associated viscerotropic disease (YF-AVD) would only heighten one' s concern about giving yellow fever vaccine to any patient with immune defects.2 Most travel medicine clinicians would likely provide a yellow fever waiver letter if the actual risk of yellow fever is low, stressing the importance of personal protection measures against mosquitoes, or advise a patient to consider altering their travel plans if the risk of yellow fever were high.
Now, after several years of post marketing experience, the association of increased risk for granulomatous diseases in patients on TNF-alpha inhibitors is well known. Mycobacterium tuberculosis was the most frequently reported granulomatous infection, with ~144 cases per 100,000 infliximab-treated patients and ~35 cases per 100,000 etanercept-treated patients.3 The higher risk seen with infliximab may relate to the fact that infliximab readily binds transmembrane TNF, which may lead to cell lysis via complement-dependent cytolysis and antibody-dependent cell-mediated cytotoxicity.4 In vivo, infliximab has been shown to induce apoptosis of monocytes.5 This added defect in host immunity results in cell death and may explain the greater efficacy of infliximab in treating granulomatous chronic inflammatory conditions such as Crohn' s disease and sarcoidosis where etanercept is not effective. The FDA has, therefore, required that the package inserts for infliximab and adalimumab carry black box (high level) warnings about the risk of tuberculosis and the recommendation that patients undergo skin testing for latent tuberculosis, and that treatment of latent tuberculosis infection be initiated prior to use of infliximab or adalimumab. Many rheumatologists and dermatologists extend this caution and evaluate a PPD response on any patient under serious consideration for use of any of the TNF-alpha inhibitors.
A growing number of patients are being offered biologic therapy for a variety of inflammatory disorders. This, coupled with the increasing mobility of these patients and their desire to travel, leads to many questions about risk and prevention of travel related illnesses. At the present time, there is are little data on the efficacy of vaccines, such as the new conjugate vaccines, for patients on these biologics. In terms of guidelines and safety issues with live vaccines, we are left with extrapolating the existing data and recommendations for other groups of immunosuppressed patients, such as those who are HIV-infected or are transplant recipients. As more biologic agents like as the TNF-alpha inhibitors receive FDA approval for use in a variety of diseases, this topic will require ongoing investigation and surveillance.
References
1. Ehlers S. Role of Tumour Necrosis Factor (TNF) in Host Defense Against Tuberculosis: Implications for Immunotherapies Targeting TNF. Ann Rheum Dis. 2003;62:ii37-42.
2. Barwick R, et al. History of Thymoma and Yellow Fever Vaccination. Lancet. 2004:364:936.
3. Wallis RS, et al. Granulomatous Infectious Diseases Associated with Tumor Necrosis Factor Antagonists. Clin Infect Dis. 2004:38:1261-1265.
4. Scallon BJ, et al. Chimeric Anti-TNF-Alpha Monoclonal Antibody cA2 Binds Recombinant Transmembrane TNF-Alpha and Activates Immune Effector Functions. Cytokine. 1995;7:251-259.
5. Lugering A, et al. Infliximab Induces Apoptosis in Monocytes from Patients with Chronic Active Crohn's Disease By Using a Caspase-Dependent Pathway. Gastroenterology. 2001;121:1145-1157.
By Mary-Louise Scully, MD Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA Dr. Scully reports no consultant, stockholder, speaker's bureau, research, or other financial relationship with companies having ties to this field of study.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.