Review of long-term immunogenicity following HPV vaccination: Gaps in current knowledge.

The licensed HPV vaccines are highly efficacious and induce high levels of neutralizing antibody levels, the assumed mediators of protection. However, a correlate of protection against HPV is lacking, and the evidence is still limited as to long-term persistence of antibodies, especially following reduced dosing schedules. The World Health Organization (WHO) urges immunization of young girls as part of the strategy to eliminate cervical cancer, thus long-lasting protection is required. The current review describes long-term follow-up regarding vaccine-induced seropositivity and antibody level development following the different vaccines and dosing schedules. Implications and opportunities of long-term vaccine-induced immune responses are discussed, such as the gaps in monitoring of long-term immunogenicity, the possibilities of reduced dosing schedules, and the importance of evidence for durable immunity.

Measuring vaccine effectiveness against persistent HPV infections: a comparison of different statistical approaches.

BACKGROUND: Persistent high-risk human papillomavirus (HPV) infection is endorsed by the World Health Organization as an intermediate endpoint for evaluating HPV vaccine effectiveness/efficacy. There are different approaches to estimate the vaccine effectiveness/efficacy against persistent HPV infections. METHODS: We performed a systematic literature search in Pubmed to identify statistical approaches that have been used to estimate the vaccine effectiveness/efficacy against persistent HPV infections. We applied these methods to data of a longitudinal observational study to assess their performance and compare the obtained vaccine effectiveness (VE) estimates. RESULTS: Our literature search identified four approaches: the conditional exact test for comparing two independent Poisson rates using a binomial distribution, Generalized Estimating Equations for Poisson regression, Prentice Williams and Peterson total time (PWP-TT) and Cox proportional hazards regression. These approaches differ regarding underlying assumptions and provide different effect measures. However, they provided similar effectiveness estimates against HPV16/18 and HPV31/33/45 persistent infections in a cohort of young women eligible for routine HPV vaccination (range VE 93.7-95.1% and 60.4-67.7%, respectively) and seemed robust to violations of underlying assumptions. CONCLUSIONS: As the rate of subsequent infections increased in our observational cohort, we recommend PWP-TT as the optimal approach to estimate the vaccine effectiveness against persistent HPV infections in young women. Confirmation of our findings should be undertaken by applying these methods after longer follow-up in our study, as well as in different populations.

Comparison of antibody response between boys and girls after infant and childhood vaccinations in the Netherlands.

BACKGROUND: Infectious diseases can differ by sex in their incidence, prevalence, or severity of disease. These differences may be induced by sex-dependent immune responses and resulting protection, for example after vaccination. Therefore, this study aims to assess possible sex-differences in immunoglobulin levels (IgG) after infant and childhood vaccination. METHODS: Data from a national cross-sectional serosurvey conducted in 2006/2007 were used (Pienter 2). We compared IgG levels against measles, mumps, rubella, diphtheria, tetanus, poliomyelitis, pertussis, Haemophilus influenzae type b (Hib), and Neisseria meningitidis serogroup C (MenC) between girls and boys both short term (1 month to 1 year) and long term (1-3 year) after infant and childhood vaccinations, using linear regression analysis. Proportions of boys and girls reaching a protective IgG level were compared using Fishers exact test. RESULTS: Differences in IgG were found at specific time points after vaccination against measles, mumps, rubella, MenC, and polio. The geometric mean concentration or titer (GMC/T) girls:boys ratios ranged between 1.10 for polio type 1 <1 year after the first childhood booster to 1.90 for MenC <1 year after infant vaccination, indicating higher antibody levels in girls. No significant differences were found between boys and girls for diphtheria, tetanus, pertussis, and Hib at either time point. Proportions with protective levels differed only at 1-3 years after infant vaccination for mumps (82.5% boys vs. 91.9% girls, p = 0.046), and at the same time point for MenC (7.0% boys vs. 18.2% girls, p = 0.015), and polio type 1 (87.8% boys vs. 95.9% girls, p = 0.047). CONCLUSION: Differences in IgG between boys and girls were generally small and not consistent, neither between pathogens nor within pathogens. If differences were observed, girls were favored over boys. On the whole, the results suggest that there are no major sex differences in protection from the studied pathogens in the Netherlands.

Severe underestimation of pertussis related hospitalizations and deaths in the Netherlands: A capture-recapture analysis.

OJECTIVE: Despite vaccination, pertussis has remained endemic, sometimes leading to severe disease. We aimed to quantify the completeness of reporting (CoR) of pertussis hospitalizations and deaths in the Netherlands. STUDY DESIGN: CoR was estimated using capture-recapture analyses. Hospitalizations (2007-2014) from the National Registration Hospital Care (hospital data) were matched to the notifiable Infectious Disease case registry (notifications) providing (month and) year of birth, gender and postal code. Deaths (1996-2014) from Statistics Netherlands (death registry) were matched to notifications using gender, age, year of death and notification date. Cases <2years (y) and ≥2y were analysed separately. Chao's estimator estimated the total population, which was used to calculate CoR. RESULTS: Using strict matching criteria, we found 461 matches among 876 (hospital data) and 757 (notifications) hospitalizations <2y. The population estimate of hospitalized infants was 1446, resulting in CoR between 52% and 61%. For hospitalizations ≥2y (246; hospital data and 264; notifications) 43 matches were found, with a population estimate of 1512 and CoR between 16.5% and 22%. Among thirteen (death registry) and eight (notifications) deaths <2y, seven cases overlapped. The population estimate was 16. CoR of the two sources was 50-81%. With two (death registry) and eight (notifications) deaths ≥2y without overlap, the population estimate was 26 and CoR 8-31%. CONCLUSION: Results showed substantial underestimation of pertussis hospitalizations and deaths. This has to be taken into account in evaluation of current and future immunization programs.

Identifying factors hampering physical activity in longstanding rheumatoid arthritis: what is the role of glucocorticoid therapy?

OBJECTIVES: To identify factors hampering the level of physical activity in longstanding rheumatoid arthritis (RA) patients, and to evaluate the effects of glucocorticoid therapy on physical activity. METHODS: Patient characteristics, disease characteristics and cardiovascular parameters were recorded in 170 patients, who participated in a study about glucose metabolism in longstanding RA treated with or without glucocorticoids. Disease activity scores (DAS28) were calculated and x-rays of hands and feet were taken and scored according to the Sharp van der Heijde score (SHS). Participants completed the health assessment questionnaire and short questionnaire to assess health-enhancing physical activity (SQUASH), which reflect physical disability and physical activity, respectively. Adherence rates to recommendations on physical activity were calculated, and patients were categorised as fully adhering, insufficiently adhering (adherence on less than the recommended number of days per week) or inactive (adherence on none of the days). RESULTS: Forty-four percent of the patients showed adherence to the recommended minimum level of physical activity, and 22% were classified as inactive. Higher DAS28 and SHS, glucocorticoid therapy, and presence of cardiovascular risk factors were associated with lower total SQUASH physical activity scores univariately. In a multivariate model, higher age, higher body mass index (BMI), higher DAS28, and higher SHS negatively influenced the score significantly; cardiovascular risk factors and glucocorticoid therapy were no longer significantly influencing physical activity. CONCLUSIONS: Physical activity in longstanding RA is hampered by higher age, higher BMI, higher disease activity, and more radiographic joint damage. Glucocorticoid therapy was not identified as independent risk factor in multivariate analyses.

Glucose tolerance, insulin sensitivity and ß-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids.

OBJECTIVES: To compare glucose tolerance and parameters of insulin sensitivity and ß-cell function between chronic glucocorticoid (GC)-using and GC-naive patients with rheumatoid arthritis (RA). METHODS: Frequently sampled 75 g oral glucose tolerance tests were performed in 58 chronic GC-using and 82 GC-naive patients with RA with established disease, with no known type 2 diabetes mellitus (T2DM), and 50 control subjects of comparable age with normal glucose tolerance. The associations between cumulative GC dose and disease characteristics and glucose tolerance state, insulin sensitivity and ß-cell function were tested using multivariate linear and logistic regression models, correcting for patient characteristics. RESULTS: Glucose tolerance state, insulin sensitivity and ß-cell function did not differ between the two RA populations; de novo T2DM was detected in 11% and impaired glucose metabolism in 35% of patients with RA. In patients with RA, cumulative GC dose was associated with T2DM, which seemed mostly driven by the effects of cumulative GC dose on insulin resistance; however, the association decreased when corrected for current disease activity. Patients with RA had decreased insulin sensitivity and impaired ß-cell function compared with controls, and multivariate regression analyses showed a negative association between the presence of RA and insulin sensitivity. CONCLUSIONS: GC-using and GC-naive patients with RA had comparable metabolic parameters, and had decreased insulin sensitivity and ß-cell function as compared with healthy controls. Although cumulative GC dose was shown to have a negative impact on glucose tolerance state and insulin sensitivity, confounding by indication remains the main challenge in this cross-sectional analysis.

Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis.

OBJECTIVES: To systematically analyse the literature on reported adverse events of low- to medium-dose glucocorticoids during >or=1 month for inflammatory diseases. METHODS: Data were systematically retrieved and selected from PUBMED, EMBASE and CINAHL databases (6097 hits). RESULTS: A total of 28 studies (2382 patients) met the inclusion criteria. The risk of adverse events over all studies was 150 per 100 patient-years (95% confidence interval (CI) 132 to 169). Psychological and behavioural adverse events (eg, minor mood disturbances) were most frequently reported, followed by gastrointestinal events (eg, dyspepsia, dysphagia). In 14 studies comprising 796 patients with rheumatoid arthritis the risk of adverse events was 43/100 patient-years (95% CI 30 to 55), in 4 studies of 167 patients with polymyalgia rheumatica the risk of adverse events was 80/100 patient-years (95% CI 15 to 146), and in 10 studies of 1419 patients with inflammatory bowel disease the risk of adverse events was 555/100 patient-years (95% CI 391 to 718). High rates of adverse events were reported in high-quality studies with short follow-up, notably in studies of patients with inflammatory bowel disease. CONCLUSIONS: The risk of adverse events depends on study design and disease. Studies on inflammatory bowel disease were often of short duration with frequent documentation of adverse events which resulted in higher adverse event rates whereas, in studies of rheumatoid arthritis, the longer follow-up may have resulted in lower adverse event rates. In most studies aimed at efficacy of glucocorticoids or other drugs, adverse events were not systematically assessed. Clear guidelines on assessment of adverse events are lacking.

EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases.

OBJECTIVE: To develop evidence-based recommendations for the management of systemic glucocorticoid (GC) therapy in rheumatic diseases. METHODS: The multidisciplinary guideline development group from 11 European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist-epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference. RESULTS: The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy (ie, non-steroidal anti-inflammatory drugs, gastroprotection and cyclo-oxygenase-2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice (ie, adrenal insufficiency, pregnancy, growth impairment). CONCLUSION: Ten key recommendations for the management of systemic GC-therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence (ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC-replacement) and need further research; therefore also a research agenda was composed.

Joint surgery in the Utrecht Rheumatoid Arthritis Cohort: the effect of treatment strategy.

OBJECTIVE: To investigate the prevalence and prognostic factors of joint surgery in a large cohort of patients with rheumatoid arthritis, whose treatment, clinical and radiographic data have been assessed at predefined points in time since disease onset. METHODS: Data on surgical interventions were retrospectively obtained from 482 patients with rheumatoid arthritis whose follow-up data for at least 2 years were available, including treatment and response to treatment during the first 2 years. Survival time until the first surgical intervention and until the first major surgical intervention was determined for the total study population by Kaplan-Meier survival curves. Three separate Cox regression analyses were carried out to determine which variables measured at baseline, during the first year and during the first 2 years were predictors for joint surgery. RESULTS: 27% of the patients underwent surgical interventions. Mean survival time until the first surgical intervention was 10.4 years. The percentage of patients with a surgical intervention was 10% lower in the group with response to treatment when compared with the non-response group. Next to a delayed start with disease-modifying antirheumatic drugs, fast radiographic progression during the first year and first 2 years was a predictor of joint surgery in the multivariate regression analyses. CONCLUSION: Treatment with disease-modifying antirheumatic drugs immediately after diagnosis results in less joint surgery when compared with a delayed start. Furthermore, joint surgery is carried out more often in patients who do not respond to treatment.