Patients with rheumatic diseases are at a higher risk for infection as a function of the disease process. The immune system effects of biologic and steroid medications used in treatment can exacerbate this.
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Explore This IssueDecember 2014
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Because of this, the use of vaccines to prevent illness is an important intervention in these individuals. However, there is some concern among physicians that we don’t understand how vaccines, medications and the disease-related impacts on the immune system interact in most cases.
“Several questions remain, including the role of biological agents on hampering the immune response to vaccines, whether this can influence the efficacy of vaccines and more detailed information about the safety profile of vaccines in this particular subgroup of patients,” says Professor David Isenberg, from the Centre for Rheumatology at the University College of London in the United Kingdom. “There are published recommendations on the use of vaccination in patients with rheumatic disease on conventional immunosuppressives. There are no specific recommendations for vaccination in patients treated with biologics.”
To address some of these issues, Prof. Isenberg and Isabel Ferreira, MD, Hospital Prof. Doutor Fernando Fonseca in Amadora, Portugal, published a review of the literature on the subject in the Annals of Rheumatic Diseases.1
Little Available Guidance
“There really wasn’t much guidance available, but I wanted to see exactly how much information existed,” says Dr. Isenberg. “While it isn’t entirely a data-free area, there is still a very restricted amount of information out there, and that is an issue. The more we got into this research, the more holes we found in our knowledge.”
Their research did result in some specific suggestions. One is that it’s important to complete a thorough assessment of vaccination status before beginning the biologic regimen.
Assessment Before Starting “
Prior to administering immunomodulatory therapy, it would probably be best if patients were given any needed vaccinations at least a month prior to the initial dose, especially for live viral vaccines,” says Camille Kotton, MD, clinical director of transplant infectious diseases at Massachusetts General Hospital in Boston.
She further suggests that rheumatologists may want to consider referring their patients for an evaluation by an infectious disease (ID) specialist prior to beginning the medication.
“As an immunocompromised host ID specialist, I believe such an evaluation can be very helpful when patients are about to undergo immunomodulatory therapy,” she says. “When I see such patients, they are assessed for latent infections, such as tuberculosis, and other endemic pathogens and prophylaxis issues are considered. I evaluate their vaccination and serologic status, and then administer the necessary vaccines.”
The Annals article suggested that timing of vaccinations can be important, may change depending on the type of medication being used and should be contemplated only during stable disease.
Vaccines should ideally be given before starting treatment with Rituximab (RTX). If severity of the disease or other variables makes this impossible, vaccines should be given no sooner than six months after the start of the medicine and no less than four weeks before the next course is scheduled.
“Although there is no data, this approach may also apply for other B cell depleting or targeting treatment regimens,” Dr. Isenberg wrote in the article. “Vaccines can be administered during treatment with anti-tumor necrosis factor (anti-TNF) agents.”
The authors’ review of the literature leads them to suggest that the influenza and pneumococcal vaccine should be administered as they are in the general population. They also call for use of tetanus toxoid per normal guidelines. The one exception would be in those who have been treated with RTX within the previous 24 weeks. In this group, passive immunization with tetanus immunoglobulin would be indicated.
One of the most important aspects of the review is that it also points out what we don’t know. Identifying and addressing these areas can be as important as setting out what is known.
There is currently some controversy about the use of live-attenuated vaccines (LAVs). Guidelines now in force suggest that LAVs should not be given to anyone being treated with biologics. Drs. Isenberg and Ferreira suggest that patients on immunomodulators should not receive measles, mumps and rubella vaccines or LAVs for influenza, varicella-zoster, yellow fever, and rotavirus vaccines. For most patients in North America, the main issue would be with protection from shingles via zoster. In most other cases, there are nonattenuated substitutes readily available.
It’s important to complete a thorough assessment of vaccination status before beginning the biologic regimen.
“The edict against live vaccines in this population has no real evidence to support it,” says Jeffrey R. Curtis, MD, William J. Koopman Endowed Professor in Rheumatology and Immunology at the University of Alabama at Birmingham. “The current prohibition is largely the result of the Centers for Disease Control and Prevention [CDC] being appropriately conservative because it could be dangerous.”
Since the CDC statement, there have been multiple studies and a growing evidence base suggesting that this may not be as much of a concern as originally thought. Dr. Curtis points to a trial of HIV patients who were given the zoster vaccine in which no safety concerns were raised. He is involved with a new study funded by the ACR and National Institutes of Health that just began enrolling patients and may help better define these issues in those with rheumatic diseases.
However, until the results of these and other studies are released, Dr. Curtis notes that the guidelines are still in place and should be followed.
Another possible gap in the literature relates to how rheumatic patients on these kinds of therapies may react differently to the vaccines than the general population. For example, does the suppressed immune system mean a different vaccination schedule may be required?
“Perhaps an even more important question would be, ‘How long do these vaccines last?’” says Dr. Curtis. “That is another area with a dearth of evidence. Should we adhere to the general population guidelines or do we need to give [the vaccines] more often?”
There are guidelines and suggestions in place for administering vaccinations in this group of patients. Both the ACR and the European League Against Rheumatism (EULAR) have issued official recommendations on the subject.2 Studies have shown that patients with rheumatic disease are being vaccinated at lower levels than the general population.
“With the increasing complexity of our therapeutic armamentarium for rheumatic diseases, the recommendations for vaccinations have become more complicated when compared to those who are totally healthy,” notes Leonard H. Calabrese, DO, professor of medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. “This can lead to a lack of physician confidence in knowing what their patients actually need. Studies have shown that our efficiency in vaccinating patient populations with rheumatic disease isn’t very good.”
Some of this relates to the split responsibility for the patient. Vaccinology has long been the focus of the primary care physician. On the other hand, the medications causing the problems are in the domain of the specialty physician.
Dr. Calabrese, who is also a member of the Cleveland Clinic’s Department of Rheumatology, suggests that this is where the professional societies need to lend their weight to the discussions. It should be a collaboration between both the specialists and primary care physicians, through their organizations, to develop best practices that get the job done.
“Many questions remain unanswered [because] the necessary large and well-designed studies to confirm safety and the precise incidence of side effects have yet to be performed,” wrote Drs. Isenberg and Ferreira. “There are few studies about the effectiveness of vaccination, [because] most studies used serological responses as primary endpoints. Some may be inadequately protected because of lower vaccine immunogenicity and optimization of vaccine delivery to this specific group of patients.”
Kurt Ullman is a freelance writer based in Indiana.
- Ferreira I, Isenberg D. Vaccines and biologics. Ann Rheum Dis. 2014 Aug;73(8):1446–1454.
- Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625–639.