Marta Gentili

On the relationship between human papilloma virus vaccine and autoimmune diseases

The human papilloma virus (HPV) vaccines were introduced to reduce the incidence of cervical cancer. The bivalent vaccine is effective against HPV-16, -18, -31, -33 and -45 while the quadrivalent vaccine is effective against HPV-16, 18, 31, 6 and 11 types. The immunisation, recommended for adolescent females, has led to high vaccine coverage in many countries. Along with the introduction of the HPV vaccines, several cases of onset or exacerbations of autoimmune diseases following the vaccine shot have been reported in the literature and pharmacovigilance databases, triggering concerns about its safety. This vaccination programme, however, has been introduced in a population that is at high risk for the onset of autoimmune diseases, making it difficult to assess the role of HPV vaccine in these cases and no conclusive studies have been reported thus far. We have thus analysed and reviewed comprehensively all case reports and studies dealing with either the onset of an autoimmune disease in vaccinated subject or the safety in patients with autoimmune diseases to define the role of the HPV vaccines in these diseases and hence its safety. A solid evidence of causal relationship was provided in few cases in the examined studies, and the risk vs. benefit of vaccination is still to be solved. The on-going vigilance for the safety of this vaccine remains thus of paramount importance.

On the Association between Human Papillomavirus Vaccine and Primary Ovarian Failure

Dear Sir, We have read the interesting series of case reports recently published by Colafrancesco et al. on your journal. The reports deal with the occurrence of primary ovarian failure occurring in three young girls few days after the vaccination with human papillomavirus vaccine. The reports by Colafrancesco et al., along with a previously reported case, rise an important concern in term of safety for this vaccine. Primary ovarian failure is estimated to affect 1/ 10,000 women under the age of 20 and etiology may include genetic mutations, autoimmune diseases, and environmental causes. However, in a significant amount of cases, no precise cause can be identified. Concerns about supposed adverse effects of vaccine occur regularly, especially after the implementation of a new vaccine in young healthy adolescent. Spontaneous reports of suspected drug reactions represent an important source of new information for monitoring the safety of a newly introduced vaccine, but many of these are simply a coincidence in time with the administration of the vaccine. To define further the association between primary ovarian failure and HPV vaccine, we carried out an analysis using the major national surveillance databases for adverse event following the administration of vaccines or drugs. In this analysis, we considered the adverse event following HPV vaccine coded as ‘premature ovarian failure’, ‘premature ovarian insufficient’, ‘premature menopause’, and ‘primary ovarian failure’. We retrieved four cases from the Vaccine Adverse Event Reporting System (VAERS) database, one case from the Australian database, and two cases from the European database of suspected adverse drug reaction reports. We assessed the reporting rates (RRs) of 0.065/ 1,000,000 doses for this adverse effect considering the number of quadrivalent HPV vaccine doses distributed in United States from June 1, 2006 through July 30, 2012 (46 million) and the VAERS domestic reports in the same time frame (three reports). A similar evaluation of qHPV vaccine doses (7 million of doses) and reports from the Australian TGA database yielded a RRs of 0.14/1,000,000 doses. We also carried out an evaluation of the number of hospital discharges with a diagnosis of premature ovarian failure (ICD-9 code 256.31) or other ovarian failures (ICD-9 code 256.39) using the United States National Inpatient Sample database (NIS). We did not observe any increase in the number of hospital discharge with these diagnoses in patients aged 1–17 years after the introduction of the HPV vaccine. Similarly, we did not observe significant increases in the number of hospital discharges retrieved from the children inpatient database for patients aged 15–17 before and after the introduction of this vaccine. The absence of a significant increase in primary ovarian failure in a population that has been largely exposed to the HPV vaccine, as well as the low number of reports to the regulatory agencies, argues against a causal relationship between the vaccine and this disease. Despite these observations, we cannot exclude that HPV vaccine had a role in the pathogenesis of the condition described by Colafrancesco et al., especially considering the possibility that a rare and unrecognized mutations acted as risk factor in these patients. As correctly stated by the authors, the fact that two of the three patients were blood relatives could indicate the presence of a rare risk factor capable of determining such adverse event following HPV vaccination. Further analysis is required to identify the presence of possible risk factors for this adverse event and define their prevalence among the population exposed to the HPV vaccine.

Human papillomavirus vaccine in patients with systemic lupus erythematosus.

To the Editor: Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide.1 Although usually transient and asymptomatic, HPV infection can result in cervical cancer in some predisposed women,1 and thus, many programs have been developed to foster HPV immunization. People who are at a particularly high risk for cervical cancer include those affected by systemic lupus erythematosus because of intrinsic immunological defiance and immunosuppressive treatments.2 In view of the higher risk of cervical cancer, guidelines urge HPV vaccination of these patients during adolescence.3 One concern about HPV vaccination in patients with systemic lupus erythematosus is the possible reactivation of the disease triggered by viral antigens or adjuvants contained in the vaccine.4 Although a recent case-control study did not find any increased risk of flares in a group of 50 patients,4 factors such as the variability in immunological response5 and the possible presence of genetic predisposing factors may limit the ability of studies to detect rare adverse events.5 Several case reports have described a possible correlation in predisposed patients,6,7 and 100 cases have been reported in pharmacovigilance databases in Europe, United States, and Australia.8–10 In the view of this limited knowledge, we assessed whether the number of hospitalizations for lupus in the United States increased after introduction of the HPV vaccination in 2006, using data from the National Hospital Discharge Survey, the National Inpatient Sample, and the Kids’ Inpatient Sample. We examined data on patients (all ages and ≤17 years of age) with first-line diagnosis of systemic lupus erythematosus at hospitalization or emergency department admission, in accordance with the codes in the International Classification of Disease, 9th

On the possible interaction between vaccines and drugs

Dear Sirs, Reduction in the hepatic cytochrome P450 system activity has been described after a vaccination in previous studies [1, 2]. While the mechanism behind such reduction was explained as the consequence of the activity of inflammatory cytokines on the mRNA level of hepatic cytochromes [3], it is unclear what effect this interaction may have in the clinical practice. To date, only few reports describe significant changes in drug pharmacokinetics after the administration of a vaccine [4, 5], and small cohort studies reported contrasting results in patients treated with drugs that may be influenced by this interaction [6, 7, 10–12]. Moreover, it is unclear how the effects of vaccines on hepatic cytochrome P450 system activity affect patients who present risk factors such as age or genetic predisposition [1, 2]. To explore this issue further, we used the Vaccine Adverse Event Reporting System (VAERS) database, which collects information about adverse events following the administration of vaccines and is useful to detect rare vaccine-related adverse events [8]. We carried out a search of all reports consistent with a vaccine–drug interaction resulting in an adverse drug reaction, in a detectable increase of drug serum level, or in a change of drug-related biomarkers such as the International Normalized Ratio (INR). As the patients were treated with more than a single drug in many of the cases, we considered only those cases in which there was no mention of recent therapy variation, or there was an explicit statement about the absence of variations. As highlighted in Table 1, we retrieved and validated 28 reports. Among these, 12 were related to an increase of INR, and ten described an increase of serum level of phenytoin, carbamazepine and theophylline (Table 1). The remaining six cases described an adverse drug reaction attributed to an interaction between the vaccine and the drugs (Table 1). As expected, considering previous observations [1], we found that most of the cases occurred in elderly patients and within the first weeks after vaccine administration. Aitken et al. recently observed that human CYP2C8, 2C9, 2C18, 2C19, 2B6, and 3A4 mRNA expression is downregulated by inflammatory cytokines [3], which are also released as result of a vaccination [1, 2]. As one or more of these hepatic cytochromes metabolizes phenytoin, theophylline and carbamazepine, a reduction in their expression due to vaccination may explain the increased level of these drugs that we observed after vaccination. In agreement, other studies showed an increase in phenytoin serum level after vaccination with pertussis vaccine [10] and successive studies confirmed this finding in other drugs such as theophylline [11, 12]. The increased INR we observed with warfarin may also be explained by the vaccination. Warfarin is metabolized primarily by CYP2C9, and a reduction in the activity of this hepatic cytochrome may result in an increase of INR [9]. The reduced activity of this enzyme due to genetic polymorphisms [9], as well as the presence of other variants that may affect the cytokines response to vaccination, may create a subgroup of patients at higher risk for this interaction than the ones observed in our analysis. Paolo Pellegrino and Carla Carnovale contributed equally to this work.

Second generation antipsychotics in ‘real-life’ paediatric patients. Adverse drug reactions and clinical outcomes of drug switch

ABSTRACT Objective: Gap in knowledge on benefit/risk ratio of second generation antipsychotics (SGA) in the paediatric population represents a challenge for the scientific community. This study aims to analyse all suspected adverse drug reactions (ADRs) to SGA observed during the study period; compare the safety profiles of risperidone and aripiprazole; evaluate the effect of switching from risperidone to aripiprazole or to a first generation antipsychotic (FGA). Methods: Prospective analysis of spontaneously reported ADRs concerning 184 paediatric outpatients between 2012 and 2014.; clinical outcomes of drug switch were evaluated. Results: Out of the 184 patients, 130 experienced at least one ADR; ADRs were usually not serious and more frequently associated with aripiprazole. Switching to aripiprazole was associated with better results than switching to FGAs in the Clinical Global Impression scale- Efficacy (CGI-E) scores (p = 0.018), Disturbed behaviour checklist-parents (DBC-P) self-absorption subscale (p = 0.010); only a trend for difference between changing to aripiprazole vs FGAs in the DBC-P total score (p = 0.054) and social relating subscale (p = 0.053) was observed. Conclusions: SGAs safety data were consistent with the ones already known; however, there is still a need to improve the knowledge in pharmacovigilance field among clinicians. Switching to aripiprazole may be a valid alternative to risperidone.

A retrospective review of paediatric adverse drug reactions reported in Lombardy and Croatia from 2005 to 2013

ABSTRACT Objective: to characterise the adverse drugs reactions (ADRs) reported in the Lombard and Croatian paediatric population and to compare data to specific paediatric age groups, in terms of trend, pattern and severity of ADRs, increasing understanding of paediatric ADRs. Research design and methods: We selected and analysed all the spontaneous reports in which children were involved (0 < 18 years old) reported in the Lombardy and in Croatian pharmacovigilance databases from 1th March 2005 to 31th December 2013. Results: 9175 ADR reports were reported in the Lombardy, 2457 were included in the Croatian database. The age groups most involved were 2–11 for both countries. The 13.2% and 40.3% of reports retrieved in Lombardy and Croatia were classified as serious, respectively. Fatalities account for 0.09% and 0.12% in Lombardy and Croatia, respectively. Conclusion: Data on serious reports reflect a similar scenario in terms of age range; strikingly different therapeutic subgroups were involved in reporting activity likely due to greater self-medication practices with penicillins and anti-inflammatory, analgesic and antipyretics drugs in Lombardy than in Croatia, highlighting the need to closely monitor this paediatric therapeutic area to ensure a safe use of these drugs.

Persistence in Therapy With Risperidone and Aripiprazole in Pediatric Outpatients: A 2-Year Naturalistic Comparison.

OBJECTIVE The practical effectiveness of second-generation antipsychotics in children and adolescents is an understudied issue. It is a crucial area of study, though, because such patients are often treated for long-lasting disorders. METHODS We carried out a 24-month (March 2012-March 2014) observational study on an unselected population of pediatric outpatients treated with risperidone, aripiprazole, olanzapine, or quetiapine aiming to (1) describe drug use, (2) compare post hoc the discontinuation rates due to specific causes and dose adjustments by Kaplan-Meier analyses between drugs, and (3) analyze predictors influencing these outcomes by Cox multivariate models. RESULTS Among 184 pediatric patients, 77% patients were prescribed risperidone, and 18% were prescribed aripiprazole. Olanzapine or quetiapine were scantly used; therefore, they were excluded from analyses. Risperidone was prevalent in younger, male patients with disruptive behavioral disorders; aripiprazole, in patients with tic disorders. Overall, discontinuations occurred mostly in the first 6 months, and, at 24 months, the discontinuation numbers were similar between users of risperidone and aripiprazole (41.5% vs 39.4%). In univariate analyses, dose reduction was higher for aripiprazole (P = .033). Multivariate analyses yielded the following predictors: for all-cause discontinuation, baseline severity (hazard ratio [HR] = 1.48, P = .001) and dose increase (HR = 3.55, P = .001); for patient-decided discontinuation, dose change (increase: HR = 6.43, P = .004; reduction: HR = 7.89, P = .049) and the presence of concomitant drugs (HR = 4.03, P = .034), while autistic patients discontinued less (HR = 0.23, P = .050); for clinician-decided discontinuation due to adverse drug reactions, baseline severity (HR = 1.96, P = .005) and dose increase (HR = 5.09, P = .016); for clinician-decided discontinuation due to inefficacy, baseline severity (HR = 2.88, P = .014) and the use of aripiprazole (HR = 5.55, P = .013); for dose increase, none; for dose reduction, the occurrence of adverse drug reactions (HR = 4.74, P = .046), while dose reduction was less probable in autistic patients (HR = 0.22, P = .042). CONCLUSIONS The findings of this study show a similarity between the overall effectiveness of risperidone and aripiprazole in a real-life pediatric outpatient setting.

The importance of monitoring adverse drug reactions in elderly patients: the results of a long-term pharmacovigilance programme

ABSTRACT Objective: To recognise and prevent ADRs (including DDIs) in the elderly through a 4-year post-marketing active pharmacovigilance programme. The programme was designed to enhance high quality spontaneous reporting of ADRs in elderly patients by sampling the Italian population and was termed ‘Pharmacovigilance in Geriatry (ViGer)’. Methods: ADRs were collected for adults aged over 65 years of age treated in nursing homes, continuing care retirement communities and territorial health services in Lombardy. ADRs were evaluated using the Adverse Drug Reaction Probability Scale (Naranjo) and analysed with respect to time, sex, category of ADR, seriousness, suspected medicines, notoriety. We analysed all the potential DDIs. Results: We detected 1073 cases reports corresponding to 2110 ADRs. Vaccines, antibacterials for systemic use and antineoplastic agents were the pharmacotherapeutic subgroups most frequently involved. 18% of ADRs reports were classified as serious. In 752 reports patients were described as in polytherapy; in 55 patients (7.3%) the reported ADR were probably preventable because of DDIs involvement. Conclusion: The ViGer project demonstrated that active pos-marketing pharmacovigilance programmes are a valid strategy to increase awareness on geriatrics pharmacology, reduce underreporting and provide important information on previous unknown ADRs and DDIs, resulting in a therapy optimisation in clinical practice in the geriatric setting.

Levetiracetam-induced rhabdomyolysis: Analysis of reports from the Food and Drug Administration's Adverse Event Reporting System database

We thank Dr. Rajabally for his comments on our study regarding the electrophysiological features of POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome compared with monoclonal gammopathy of undetermined significance (MGUS)-related neuropathy. We agree with the comments pointing out that we compared the homogeneous POEMS syndrome with the electrophysiologically heterogeneous MGUS-related neuropathy; nevertheless, we believe that our study provides useful information for physicians who encounter patients with demyelinating neuropathy and monoclonal gammopathy. In our study, we included all types of MGUS-related neuropathies and compared them with the neuropathy seen in POEMS syndrome. We found that electrophysiological features of POEMS syndrome, specifically low compound motor action potential amplitudes (CMAPs), slow motor conduction velocities (MCVs), and high terminal latency indexes (TLIs), can be valuable clues for differentiating POEMS neuropathy from all types of MGUS-related neuropathy including axonal-, DADS (distal acquired demyelinating symmetric)-, and CIDP (chronic inflammatory demyelinating neuropathy)-like neuropathy. As shown in a post-hoc analysis (refer to Table S2 in the Supplementary Material, available online), when compared with IgM MGUS-related neuropathy, the neuropathy of POEMS syndrome becomes more distinct, with additional features, such as less prolonged distal motor latency. A greater reduction in CMAPs and MCVs with higher TLIs were also identified when comparing POEMS neuropathy with IgG/A MGUS-related neuropathy. POEMS patients generally manifest typical clinical characteristics, such extravascular volume overload, endocrinopathy, and organomegaly (refer to Table S1 online). Therefore, POEMS is diagnosed according to clinical criteria. On occasion, the specific pattern of nerve conduction abnormalities can serve as an indicator of POEMS syndrome, particularly early in the course of the syndrome, when obvious clinical features may be lacking. Additional supporting information can be found in the online version of this article.

Enalapril Associated with Furosemide Induced Acute Kidney Injury in an Infant with Heart Failure. A Case Report, a Revision of the Literature and a Pharmacovigilance Database Analysis

The use of angiotensin converting enzyme (ACE) inhibitors in combination with diuretics is a common strategy used for the treatment of patients affected by heart failure. An infant affected by initial congestive cardiac failure, after starting the treatment with enalapril in association with furosemide, developed acute kidney injury (AKI). No underlying renal disease or renal artery stenosis was found. He recovered from kidney injury after the therapy was suspended, thus suggesting that the drug combination is responsible for the onset of the adverse reaction. The present case report, the appraisal of the current knowledge on the onset of AKI and the analysis of available pharmacovigilance databases indicate that particular caution should be exercised when infants affected by heart failure are treated with the enalapril and furosemide combination therapy. Moreover, we strongly suggest an up-to-date revision of the ACE-inhibitor dosing guidelines in pediatric patients to define unambiguously the safe upper limits of this class of drugs.