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Questions and answers on immunization.

QUESTION: Does regular topical use of tacrolimus or pimecrolimus alter the antibody response to immunization? 
 
COMMENT: Atopic dermatitis (AD) is a common chronic inflammatory skin disease that causes significant suffering and has limited treatment options. Because of a perception by physicians and patients that topical tacrolimus (Protopic, Astellas Pharma Canada) and pimecrolimus (Elidel, Novartis Pharmaceuticals Canada Inc) are safer than steroid preparations, abetted by heavy direct-to-consumer advertising, these topical immunomodulators (TIMs) have been increasingly used as first-line therapy in paediatrics. 
 
TIMs are indicated for children two years and older with refractory AD, or those who have experienced local or systemic side effects with topical steroids. TIMs act by suppressing T cell and mast cell activation, inhibiting inflammatory cytokine release and downregulating aberrant expression of high-affinity immunoglobulin E receptors on Langerhans cells. In early 2005, public attention was focused on these new medications when the United States Food and Drug Administration posted an advisory warning of a potential cancer risk from the use of TIMs (1,2). This advisory was based on animal studies, case reports in a small number of patients and mechanisms of action of the drugs. Beyond the possible cancer risk, many other questions are now being raised concerning these new medications, including whether TIMs have any effect on the immune response following immunization. 
 
Two recent studies have addressed this question directly. The first, by Stiehm et al (3), examined seroconversion after vaccination with the pneumococcal polysaccharide vaccine (Pneumovax 23, Merck Frosst Canada Ltd) in children treated with tacrolimus ointment. Children aged two to 12 years with moderate to severe AD were treated twice daily for six weeks with tacrolimus 0.03%. After the third week of treatment, they were immunized using the 23-valent polysaccharide vaccine, and all subjects developed protective antibody titres to the majority of pneumococcal serotypes examined. This was not a rigorous test of immune function because responses to this vaccine involve only B lymphocytes and in some instances only involve boosting naturally acquired immunity to the common types. 
 
The second study, by Papp et al (4), examined the impact of pimecrolimus on the development of protective antibodies following the primary vaccination series. Subjects used pimecrolimus intermittently, twice daily for one to two years, starting at the first sign of a flare and continuing until clearance. Serum concentrations of antibodies against tetanus, diphtheria, measles and rubella were measured at months 18 and 24. The seropositivity rates were comparable with those reported in the general population. Importantly, seropositivity was not significantly affected by the use of pimecrolimus at the time of vaccination. While these data provide some assurance that long-term treatment with pimecrolimus in children does not interfere with antibody production after primary vaccinations, the final word awaits a properly controlled study. 
 
In conclusion, treatment of AD with TIMs does not appear to interfere with antibody production following vaccination, based on limited data. However, it is important to stress that TIMs should only be used as a second-line therapy in patients two years of age or older who are unresponsive to or intolerant of conventional steroid therapies. 
 
 
The Upshots column in Paediatrics & Child Health is meant to address practical questions without ready answers in standard references such as the Red Book or the Canadian Immunization Guide. Readers are invited to submit questions to the journal office. A timely response will be provided, whenever possible, from one member of a panel of experts. The most interesting exchanges will be selected for publication. Submitters should identify themselves, but will be given the option of anonymity in the published version. Submitted questions may be edited for clarity and brevity. 
 
David Scheifele, MD 
 
Associate Editor, Paediatrics & Child Health