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Cervical cancer and premalignant lesions are more prevalent in patients with. SLE. .... called Squamous Intra-epithelial Lesions (SIL), can be divided.
JOURNAL OF CLINICAL RHEUMATOLOGY & MUSCULOSKELETAL MEDICINE

REVIEW ARTICLE

Systemic Lupus Erythematosus, Immunosuppression, and Vaccinations: Focus on Human Papillomavirus Vaccination Noortje Groot, Marloes W. Heijstek and Nico M. Wulffraat Affiliation: Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, The Netherlands

A B S T R A C T Patients with systemic lupus erythematosus (SLE) may be at higher risk of infections, due to the underlying disease or immunosuppressive treatment. Vaccinations against several pathogens may prevent these infections. The vaccine against human papillomavirus (HPV) serotype 16 and 18 has been developed to prevent chronic HPV infections, one of the causative agents for cervical cancer and its premalignant lesions. The purpose of this study is to review the safety and efficacy of vaccination in SLE patients, especially the pneumococcal and influenza vaccines. In addition, we wanted to assess whether vaccination against HPV in women with SLE prevents cervical cancer and premalignant lesions. A literature search in Medline (PubMed) was performed. We pound that nonlive vaccines can be used safely in SLE, but several drugs used for control of the disease can reduce the immunogenicity. Cervical cancer and premalignant lesions are more prevalent in patients with SLE. This underlines the necessity of prevention of chronic HPV infections in these patients. The HPV vaccine has proven to be immunogenic and safe in the general population, although long-term efficacy in preventing cancer is still unknown. No studies have been performed on HPV vaccination in SLE patients. Circumstantial evidence in favor of HPV vaccination is that most nonlive composite vaccines appear to be immunogenic and safe in patients with quiescent SLE in conclusion. Vaccination of SLE patients with the HPV vaccine may be recommended. Studies on short-term safety and immunogenicity of the HPV vaccine in SLE patients are necessary. Subsequently, a longterm cohort study has to prove whether the HPV vaccine actually reduces the incidence of cervical cancer and premalignant lesions in patients with SLE. Keywords: vaccination, systemic lupus erythematosus, human papillomavirus, cervical cancer Correspondence: N. M. Wulffraat, associate professor pediatric immunology, Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Room number KC 03.063.0, PO BOX 85090, 3508 AB, Utrecht, The Netherlands. Tel: 31-(0)887554003; Fax: 31-(0)887555350; e-mail: [email protected]

The HPV vaccines are of particular interest in systemic lupus erythematosus (SLE) patients, as there are indications that cervical cancer and its premalignant stages are more common in SLE patients than in the healthy population.1719 Due to the underlying disease and the immunosuppressive treatment, it can be questioned whether SLE patients respond properly to the HPV vaccine and are indeed protected after vaccination, preventing chronic infections, and thereby reducing the incidence of cervical carcinomas.

INTRODUCTION The relation between autoimmune diseases and vaccines is controversial. Several case studies have reported that vaccination triggered or aggravated autoimmune disease.14 Despite these case reports, no study so far has established a definite relation between vaccinations and the development of autoimmune diseases.58 In addition, the safety and efficacy of vaccinations in patients with established autoimmune disease is a matter of debate. Most nonlive composite vaccines, however, do not seem to aggravate established autoimmune diseases. The immunogenicity of vaccines may be impaired when the immune system is suppressed by medication, depending on the type and dose of the immunosuppressive drug.4,5,9 Significant developments in the treatment with these immunosuppressive drugs in patients with autoimmune diseases have greatly improved their outcome. One of the obvious downsides of such treatments is the elevated risk of bacterial and viral infections due to therapy-induced immunosuppression.1013 Of course, some of these infections can be prevented through vaccination.

OBJECTIVES To review the safety and efficacy of vaccination in SLE patients especially the pneumococcal and influenza vaccines. The association between HPV infection and cervical cancer, specifically in SLE patients, was also assessed, as well as the rationale for HPV vaccination in these patients. A high occurrence of chronic HPV infections or cervical cancer in SLE patients would support the necessity of vaccination against HPV in SLE patients.

This review focuses on published evidence of vaccination in SLE patients with special interest to the recently developed human papillomavirus (HPV) vaccines, which have been developed to prevent cervical cancer and/or genital warts.1416 www.slm-rheumatology.com

METHODS A literature search in Medline (PubMed) was used. First, published studies on vaccination of SLE patients were 45

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reviewed. Secondly, we looked for studies focusing on the relation between chronic HPV infections and cervical cancer and its premalignant lesions in healthy individuals and in SLE patients. Lastly, we searched the topic of prevention of cervical cancer in SLE patients through vaccination against HPV, based on the currently available literature on safety and efficacy of nonlive composite vaccinates in SLE patients.

response compared to healthy controls, although this response was higher than the patients receiving treatment.22,23 Special attention needs to be paid to one of the newer therapies for SLE: rituximab or anti-CD20, which causes Bcell depletion. Of course, B-cells are responsible for the humoral immune response and, therefore, important in vaccination. Studies have shown an impairment of the immune system until 6 months after treatment of rituximab.30 Since SLE patients may already have a decreased response to vaccines, this may result in an even poorer response. Because of this, it may be advisable to administer vaccinations before starting treatment with rituximab. By depleting the humoral branch of the immune system, protective antibodies may also diminish. Studies show that the effect of rituximab on protective antibodies is variable. Median levels of protective antibodies did not seem to change significantly from baseline.31,32

RESULTS Vaccination of SLE Patients Several studies have given an extensive overview on the issue of vaccination of patients under immunosuppression. In adults, pneumococcal, influenza, and hepatitis B vaccines are used most often. Pneumococcal vaccines have been studied in several trials. None of these studies found an association between pneumococcal vaccination and exacerbations of SLE or any increase in laboratory parameters of disease activity.2024 Almost all studies show that there are some patients who show a poor response, although the majority still produced protective antibody levels. A significant connection between disease severity or medication and the response to vaccination has not been found.2024

It stands to reason that the immunization of patients using anti-CD20 will have little use. However, vaccinating these patients before they start this therapy might be useful in preventing subsequent infections. Of note, the European League Against Rheumatism (EULAR) has proposed general recommendations for the use of vaccines in SLE.33 The HPV vaccines, which are also nonlive composite vaccines, are currently being tested in immunocompromised patients. Three studies on HPV vaccination and SLE are currently recruiting.34 The quadrivalent HPV vaccine has already been tested in Human Immunodeficiency Virus type I (HIV-I) positive men.35 All enrolled patients had CD4 levels of at least 250 cells per microliter. The vaccine showed a high immunogenicity in patients naı¨ve to HPV. Patients with preexisting anti-HPV antibodies also showed an increase in these antibodies after vaccination. The immunogenicity of the vaccine in this group was lower than reported in the healthy population.35

Vaccination against influenza in several groups of SLE patients did not cause local adverse effects or exacerbations of the disease.2527 One study reported a transient increase of anti-dsDNA and ANA, although no clinical flares of SLE were observed.25 Although this increase had no clinical consequences, it indicates that vaccinations may lead to autoimmune phenomena.9,25 In general, immunized patients and healthy controls showed a significant increase in antibody titers, although some studies showed a lower seroprotection rate in SLE patients compared to the healthy controls (62 73% in patients vs 9098% in controls).20,25,26,28 One study showed a rapid decline of their protective antibody levels over time compared to the healthy controls.20,25,28

HPV and Cervical Cancer in the Healthy Population There is a causative association between HPV infection and cervical cancer and premalignant lesions.36 The HPV DNA can be detected in 90100% of the cervical cancers. The oncogenic serotypes HPV-16 and HPV-18 are found in respectively 50% and 10% of these cancers. Along with HPV types 31, 33, 35, 45, 51, 52, 58, and 59, they are usually referred to as high risk HPV (HR-HPV).37 The prevalence of HPV infections is age-dependent. It is high at a young age, after which it decreases until 45 years of age. This is usually followed by a plateau level. The point prevalence of HPV infections in younger age groups is strongly related to sexual behavior patterns.37,38

Hepatitis B vaccines have not yet been studied extensively in SLE patients. One prospective study showed the vaccine to be safe in inactive SLE patients. The numbers of disease flares (measured by an increase in SLEDAI) after vaccination was limited in this study, and a direct causal association between vaccination and exacerbation could not be made. Antibody levels comparable to the healthy population were generated.29 Reduced response to vaccination may be caused by the treatment of SLE.26 However, definite statements on this subject are difficult to make, mostly because the majority of studies concerning SLE and vaccinations contain low patient numbers with various treatment schedules. Studies that did analyze the effect of therapy on the immune response to vaccines show different results. The use of azathioprine, cyclophosphamide, and low doses of prednisone resulted in a lower antibody response to vaccines in comparison to healthy controls.22,23,26 However, most studies did not show statistically significant differences in antibody titers. Moreover, SLE patients who received no therapy also showed a lower JCRMM 2011; 2:(1). July 2011

Most HPV infections are cleared spontaneously, usually within a few months. These infections are referred to as incident infections. When the persistence of the virus exceeds 6 months, the HPV infection is considered to be chronic or persistent. The chance to clear the infection then decreases. Occasionally, an infection appears to be cleared, when in fact it has reached a quiescent state. These so-called latent or prevalent infections can be reactivated. Therefore, 46

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differentiating between reactivation of a latent (prevalent) infection or an incident infection can be difficult.19,39 This complicates measuring the prevalence of HPV infection.

Besides the increased occurrence of chronic HPV infections, cervical lesions have been shown to be more common in SLE patients compared to healthy controls.46,5053 Most studies involving SLE and cancer focus solely on the invasive stage of cervical cancer, disregarding the premalignant stages.46,5054 These studies did not find a particularly high occurrence of cervical pathology in SLE patients. Studies that did include patients with SIL and/or carcinoma in situ showed a significantly higher occurrence of cervical lesions.52,55 Abnormal smears and SIL in SLE patients were increased (16.5% respectively 11.8%) compared to controls (5.7% respectively 2.0%).18

The persistence of an oncogenic HPV infection seems to be required for the progression of most premalignant cervical lesions into cervical cancers. Premalignant cervical lesions, called Squamous Intra-epithelial Lesions (SIL), can be divided into different stages. Low grade SIL represents low grade dysplasia of the cervix. High grade SIL corresponds to intermediate or high grade dysplasia.40 If left untreated, progression from low grade dysplasia to cervical cancer takes 1015 years.41 Fortunately, SIL can still resolve when the underlying HR-HPV infection is effectively cleared.42

Based on the above, SLE patients seem to be at higher risk of chronic HPV infection and (pre)malignant cervical lesions. This underlines the necessity of prevention of HPV infections in these patients, possibly through HPV vaccination, given that this vaccine is immunogenic in SLE patients.

Cervical carcinomas are currently prevented through population wide screening, using cervical smears to detect SIL. This screening program has attributed to the early detection and treatment of premalignant lesions, preventing malignant disease to develop.43,44 By preventing HPV infection through vaccination, an additional tool for prevention of cervical cancer has emerged.

HPV Vaccination in Healthy Subjects Two vaccines have been developed to prevent SIL and cervical cancer.15 Gardasil is a vaccine against four types of HPV: 6, 11, 16, 18 and is developed by Merck. HPV 6 and 11 cause condylomata acuminata.16 The bivalent Cervarix vaccine is aimed at HR-HPV types 16 and 18 and developed by GlaxoSmithKline (GSK).14 Both vaccines contain L1-proteins, which are originally found on the viral capsid.39 Both vaccines significantly increase antibody titers against the L1-protein in healthy controls.14,16

HPV Infection, SIL, and Cervical Cancer in SLE Patients Studies on the incidence, persistence, and clearance of HPV infections in SLE patients have shown that the presence of HPV infection is significantly higher compared to healthy controls (ranging from 12% to 54% in SLE patients vs 715% in healthy controls). In addition, the presence of infections with multiple HPV serotypes was higher in patients compared to healthy controls (522% in patients vs 111% in healthy controls).1719,45 Moreover, cervical swabs of SLE patients were more likely to contain HR-HPV types (ranging from 11% to 43%) compared to the control groups (ranging from 4% to 40%).1719,45

Although the immunogenicity for the two vaccines has been proven for up to 5 and 6.4 years, respectively, the effects on the definite endpoint, namely cervical cancer, has yet to be determined. Therefore, trials on efficacy, immunogenicity, and safety of both vaccines are still ongoing.15 The vaccines are primarily meant for HPV-naı¨ve individuals to prevent incident infections. However, high antibody titers may provide protection against reactivation or reinfection of an already encountered virus. Consequently, the vaccines may possibly prevent subsequent incident infections in nonnaı¨ve subjects.56 However, the vaccines do not have a primary therapeutic purpose. A basal epithelial cell already infected with HPV may not be restored to normal after vaccination.57

Persistent infections were more common compared to the general population, although absolute numbers were not mentioned.1719,45 Independent risk factors for both incident and persistent HPV infections in SLE patients were a younger age at first sexual intercourse, more than three lifetime sexual partners, and the damage the disease has caused (independent of drug use). The first two risk factors have also been described in the general population.1719,38,43,45 The damage the disease has caused defined with the SLICC (Systemic Lupus International: Collaborating Clinics/American College of Rheumatology Damage Index) is probably an important factor in the increased risk of SIL and cervical cancer in SLE patients with persistent HPV infection.19,45 In addition, both immunosuppressive therapy and high disease activity have been associated with the persistence of an HPV infection and even cervical pathology.17,18,45 Since the severity of the disease is related to more intense use of immunosuppressive drugs, it is still unclear whether both are associated independently with persistence of an HPV infection. Immunosuppressive drugs could additionally contribute to reactivation of latent HPV infection.1719,4549 More studies are needed to determine whether the higher prevalence of HPV infection is due to an increased acquisition or reduced clearance of the virus. www.slm-rheumatology.com

In the age range 1845 years, the bivalent HPV vaccine has induced a higher increase in specific antibodies than the quadrivalent HPV vaccine. There were also more neutralizing antibodies found in the cervicovaginal mucus in women vaccinated with the bivalent HPV vaccine in comparison to those vaccinated with quadrivalent vaccine. With each vaccine, the immune response in higher age groups was lower than the response in younger women.15,57 In healthy women aged 1626 years old, the quadrivalent HPV vaccine has proven to be well tolerated and effective in preventing premalignant stages of cervical cancer until 3 years after vaccination.58 Healthy women aged 2445 years, who were not naı¨ve to HPV 6, 11, 16, or 18 showed higher antibody titers in comparison to naı¨ve patients for at least 6 months after injection in this age group.59 47

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Initial trials have included women aged 1526 years of age. Since the vaccine will mostly be administered to the population naı¨ve to HPV, efficacy, immunogenicity, and safety data of a younger age group is necessary. Administration of the quadrivalent HPV vaccine in a group of boys and girls aged 1015 years resulted in a higher antibody response than observed in the control group consisting of females 1623 of age. Long-term effects have yet to be determined. No serious adverse events were reported in this study.57,60

rituximab especially, in suppressing antibody response is significant. If the HPV vaccines are also able to induce a sufficient immune response against HPV in SLE patients, the incidence and prevalence of future and persistent infections will be lowered significantly. This may result in a lower incidence and prevalence of cervical cancer. Immunization at a young age, when the subject is naı¨ve to the virus, guarantees an adequate immune response at first contact with the virus. However, SLE occurs mainly in women in the reproductive age, who will most likely already have been in contact with the virus. Therefore, the safety and efficacy of HPV vaccines needs to be studied in (nonnaı¨ve) SLE patients. Ideally, a cohort of women with SLE must be followed in time to determine the prevalence of persistent HPV infections after vaccination. This will prove difficult as SLE is a rare disease, and a large cohort will be needed to assess the long-term efficacy of the vaccines.

The bivalent HPV vaccine has been studied for a period of 6.4 years in healthy young women previously seronegative for HPV-16 and HPV-18 DNA at the start of the study.14 The antibody titers against both HPV types were approximately 12fold higher than in women who cleared the infection naturally and were, thus, considered to be protective. These titers were maintained throughout the study period. Ninety-nine percent of the women remained seropositive after 6.4 years. The vaccine was also effective against persistent infection. None of the women who were vaccinated showed cervical abnormalities during the study period. Cross protection against HPV31 and HPV-45 incident infections was seen. No serious adverse events were reported.14

Despite our lack of knowledge on HPV vaccination in (nonnaı¨ve) SLE patients, we believe that HPV vaccination in SLE patients can be recommended, albeit that vigilance for thromboembolic events after vaccination might be warranted. Since persistent HPV infection is frequent in women with SLE, protection against this virus is vital. Given the fact that other nonlive composite vaccines are generally safe and immunogenic in controlled studies, the vaccines developed against HPV seem promising tools to prevent HPV infection, thereby reducing the risk of cervical cancer and its premalignant stages.

Importantly, thromboembolic events have been described after administration of the quadrivalent HPV vaccine.60 It is still unknown whether these were attributable to HPV vaccination. However, since SLE patients have an increased risk of thromboembolism, it is important to be vigilant to these adverse events after HPV vaccination.61 The immunogenicity of other nonlive vaccines was sufficient in most patients. A booster vaccine may be considered in the patients that show an inadequate response.

Disclosure: NMW received an unrestricted grant from GSK to study HPV vaccination in female adolescents with autoimmune diseases (www.clinicaltrials.gov, number NCT00815282).

CONCLUSIONS

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Will HPV Vaccination in SLE Patients Prevent Cervical Cancer?

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Chronic HPV infections are associated with the development of cervical cancer. Chronic HPV infections are more prevalent in SLE patients. In addition, SIL and cervical cancer are more common in SLE patients compared to healthy controls. Two vaccines against HPV infection have been developed. They are safe and immunogenic in the healthy population and proven to prevent premalignant lesions up until 3 years after vaccination.62 The effect of HPV vaccination in subjects not naı¨ve to the human papillomavirus needs further research. In addition, the preventive effects of the vaccines on the progression of premalignant cervical lesions to cervical cancer need to be established. The HPV vaccine has not yet been studied in SLE patients, although two trials on the safety and efficacy of the quadrivalent HPV vaccine and one trial on the safety and efficacy of the bivalent vaccine are currently in progress.34 Other types of nonlive composite vaccines have shown to be safe, immunogenic, and effective in the majority of SLE patients. The effect of different immunosuppressive therapy, JCRMM 2011; 2:(1). July 2011

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