Herpes zoster in psoriasis patients treated with tofacitinib.

BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor. Immunomodulatory therapies can increase the risk for herpes zoster (HZ) in patients with psoriasis. OBJECTIVE: To evaluate the relationship between tofacitinib use and HZ risk. METHODS: We used phases 2 and 3 and long-term extension (LTE) data from the tofacitinib development program in psoriasis to calculate HZ incidence rates (IR; events per 100 patient-years); potential HZ risk factors were evaluated using Cox-proportional hazard models. RESULTS: One hundred thirty (3.6%) patients on tofacitinib (IR 2.55), no patients on placebo, and 2 using etanercept (IR 2.68) developed HZ. Nine patients (7%) were hospitalized, and 8 (6%) had multidermatomal HZ; no encephalitis, visceral involvement, or deaths occurred. In total, 121 (93%) patients on tofacitinib continued or resumed use after HZ. HZ risk factors included Asian descent (hazard ratio [HR] 2.92), using tofacitinib 10 mg twice daily (vs 5 mg twice daily; HR 1.72), prior use of biologics (HR 1.72), and older age (HR 1.30). LIMITATIONS: Generalizability to other psoriasis populations might be limited. The effect of HZ vaccination was not studied. CONCLUSION: Tofacitinib is associated with increased HZ risk relative to placebo. Asian race, increasing age, higher dose, and prior biologic exposure are associated with heightened risk.

Relation between disease modifying anti-rheumatic drugs and herpes zoster in rheumatoid arthritis.

Biologics have revolutionized the treatment of rheumatoid arthritis (RA). However certain amount of the patients cannot achieve goal of therapy. Recently, compounds targeting the intracellular kinase, Janus kinase (JAK) have demonstrated therapeutic effects resembling biologics. Tofacitinib is the only JAK inhibitor approved for RA and during the clinical trial, increased events of herpes zoster (HZ) was observed. Incidence rate was twice as much as patients treated with conventional anti-rheumatic drug and was especially increased in Japan that was four times as much. The risk factors were age and glucocorticoid that is identical to that of common RA patients and there was nothing specific for tofacitinib. Mechanism of increased incidence of HZ and the difference in ethnicity remains unknown. Analysis of clinical trials have identified that HZ do not correlate with further adverse events. Therefore, it is extremely important to accumulate clinical data with considerable amount of patients with long term follow up including the post marketing surveillance in Japan to reveal the significance of increased HZ in RA patients.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Examination of links between herpes zoster incidence and childhood varicella vaccination.

BACKGROUND: Introduction of a universal varicella vaccine program for U.S. children in 1996 sparked concern that less-frequent exposure to varicella would decrease external boosting of immunity to varicella zoster virus and thereby increase incidence of herpes zoster (HZ). OBJECTIVE: To determine whether the varicella vaccination program has influenced trends in HZ incidence in the U.S. population older than 65 years. DESIGN: Retrospective study of Medicare claims. SETTING: Medicare, 1992 through 2010. PARTICIPANTS: 2 848 765 beneficiaries older than 65 years. MEASUREMENTS: Annual HZ incidence from 1992 through 2010; rate ratios (RRs) for HZ incidence by age, sex, and race or ethnicity; and state-level varicella vaccination coverage. RESULTS: 281 317 incident cases of HZ occurred. Age- and sex-standardized HZ incidence increased 39% from 10.0 per 1000 person-years in 1992 to 13.9 per 1000 person-years in 2010 with no evidence of a statistically significant change in the rate of increase after introduction of the varicella vaccination program. Before introduction of this program, HZ incidence was higher in women (RR, 1.21 [95% CI, 1.19 to 1.24]) than men and was lower in black persons (RR, 0.51 [CI, 0.48 to 0.53]) and Hispanic persons (RR, 0.76 [CI, 0.72 to 0.81]) than white persons. In a model adjusted for sex, age, and calendar year from 1997 to 2010, HZ incidence did not vary by state varicella vaccination coverage (RR, 0.9998 [CI, 0.9993 to 1.0003]). LIMITATION: Uncertain level and consistency of health-seeking behavior and access and uncertain accuracy of disease coding. CONCLUSION: Age-specific HZ incidence increased in the U.S. population older than 65 years even before implementation of the childhood varicella vaccination program. Introduction and widespread use of the vaccine did not seem to affect this increase. This information is reassuring for countries considering universal varicella vaccination. PRIMARY FUNDING SOURCE: None.

Herpes zoster knowledge, prevalence, and vaccination rate by race.

OBJECTIVES: To determine the prevalence of self-reported herpes zoster (HZ) disease and vaccination in a geriatric population and to characterize the deciding factors to receive the HZ vaccine. METHODS: This was a cross-sectional survey of patients older than age 60 years at 3 university-based primary care clinics in the southeastern United States. Participants provided information for age, race, sex, education level, history of having "shingles" or knowing someone else who had shingles, past vaccinations, and factors influencing their decision to receive the HZ vaccine. RESULTS: We surveyed 403 patients (49% African American [AA], 47% white). The prevalence of HZ was 12.4% overall and was significantly different among races (8% AA, 17% white; P = .01). Only 29% of patients (16% AA, 42% white; P < .001) were aware that the HZ vaccine was recommended. The HZ vaccination rate was 7.7% (2% AA, 14% white; P < .001). Only 13.7% of all study subjects reported having any communication with their medical providers regarding the HZ vaccine. Physician recommendation and media had the greatest influence on patients who received the vaccine. Of those who had not been vaccinated, 70% had never heard about it and 59% were interested in receiving the vaccine after the survey. CONCLUSION: There is a large difference in self-reported HZ and vaccination rates among races. The HZ vaccination rate was low overall, but most patients were interested in receiving the vaccine after the survey. More public awareness and education is needed to improve rates of HZ vaccination.

Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients.

BACKGROUND: Immunosuppressed patients are at increased risk for herpes zoster (HZ), but incidence in solid organ transplant (SOT) recipients has varied in multiple studies. To assess incidence of HZ, we examined patients who underwent SOT and received follow-up care within the large multicenter US Department of Veteran's Affairs healthcare system. METHODS: Incident cases of HZ were determined using ICD-9 coding from administrative databases. A multivariable Cox proportional hazards model, adjusted for a priori risk factors, was used to assess demographic factors associated with development of HZ. RESULTS: Among the 1077 eligible SOT recipients, the cohort-specific incidence rate of HZ was 22.2 per 1000 patient-years (95% confidence interval [CI], 18.1-27.4). African Americans (37.6 per 1000 [95% CI, 25.0-56.6]) and heart transplants recipients (40.0 per 1000 [95% CI, 23.2-68.9]) had the highest incidence of HZ. Patients transplanted between 2005 and 2007 had the lowest incidence (15.3 per 1000 [95% CI, 8.2-28.3]). In a multivariable model, African Americans (hazard ratio [HR] 1.88; 95% CI: 1.12, 3.17) and older transplant recipients (HR 1.13; 95% CI: 1.01, 1.27 [per 5-year increment]) had increased relative hazards of HZ. CONCLUSIONS: These data demonstrate that HZ is a common infectious complication following SOT. Future studies focused on HZ prevention are needed in this high-risk population.

Varicella-zoster-virus genotypes in East London: a prospective study in patients with herpes zoster.

A total of 298 patients with herpes zoster were recruited as part of 2 community-based studies in East London between 1998 and 2003. Single nucleotide-polymorphism analysis of 4 regions (genes 1, 21, 37, and 60) found that most genotypes were European strains C and B, representing 58% and 21% of all samples collected. No change in the proportion of these European clades has occurred during the past 80 years, strongly supporting the hypothesis that these strains are indigenous to the United Kingdom. White patients almost exclusively had reactivation of genotypes C (66%) and B (21%), whereas patients from Africa, Asia, or the Caribbean mainly had reactivation of genotypes A and J. An increase in BglI-positive A and J genotypes in UK cases of zoster is only partly explained by immigration from endemic regions. The data presented provide a baseline against which to evaluate changes in the molecular epidemiology of varicella-zoster virus and the effect of immunization with the Japanese Oka vaccine strain.

The molecular epidemiology of varicella-zoster virus: evidence for geographic segregation.

Of 75 varicella-zoster virus (VZV) isolates obtained from patients in Africa, Asia, and the Far East, 74 (98.6%) were found to be positive for a BglI restriction site in gene 54. By contrast, <22% of strains from patients in the United Kingdom and in North and South America were positive for the BglI restriction site. Viruses positive for BglI were significantly more common in zoster occurring in patients of nonwhite origin (P<.05). Irrespective of the country in which the sample was obtained, 98% of strains positive for BglI clustered within a single phylogenetic group, which we termed "group A"; the exception was 1 strain that appeared to be recombinant genotype C/A. We used the BglI site to examine both the spread of type A viruses in the United Kingdom and the patterns of VZV infections within persons from different ethnic groups who grew up in the United Kingdom or abroad.

Incidence and hospitalization rates of varicella and herpes zoster before varicella vaccine introduction: a baseline assessment of the shifting epidemiology of varicella disease.

BACKGROUND: A 15-year postmarketing evaluation of the impact of varicella vaccine on the age distribution of varicella disease is being conducted at Kaiser Permanente Medical Care Program, Northern California (KPMCP). We report on a baseline assessment of the age-specific incidence and hospitalization rates of varicella and herpes zoster that was conducted before vaccine introduction. METHODS: To assess the annual incidence of varicella, a telephone survey was conducted in a random sample of approximately 8,000 youths 5 to 19 years of age. The annual incidence of hospitalizations for varicella and herpes zoster in 1994 was assessed with the use of the computerized database at KPMCP. RESULTS: Varicella annual incidence was 10.3% in 5- to 9-year-olds, 1.9% in 10- to 14-year-olds and 1.2% in the 15- to 19-year age groups, respectively. Hospitalization rates among the entire KPMCP membership were 2.6 and 2.1 per 100,000 person years for varicella and zoster, respectively. Varicella incidence in the 15- to 19-year age group was higher among African-Americans than among Caucasians. CONCLUSIONS: Varicella rates were similar in the 5- to 9- and 10- to 14-year age groups to rates from other published studies conducted in 1972 to 1978, 1980 to 1988 and 1990 to 1992; however, the rate in 15- to 19-year-olds was 2 to 4 times higher than published rates in the same age category.

Epidemiology of primary varicella and herpes zoster hospitalizations: the pre-varicella vaccine era.

To determine the epidemiology and costs of hospitalization with primary varicella and herpes zoster in the prevaccine era and the usefulness of hospital discharge data to determine the population impact of vaccination on these conditions, statewide hospital discharge data in Connecticut from 1986 to 1995 were analyzed. Annual hospitalizations for herpes zoster were 4-fold higher than for primary varicella (16.1 vs. 4.1/100,000). Overall, 69% and 83%, respectively, had no underlying immunosuppressive conditions. Regarding primary varicella, 53% of patients were aged <15 years, there was a marked winter-spring seasonality, and Hispanics and blacks were 4.1 and 2.6 times more likely than whites to be hospitalized. Regarding herpes zoster, 66.9% of patients were aged >64 years, and there was no seasonality. The mean patient charges in 1995 were $12,819 for primary varicella and $15,583 for herpes zoster. Analysis of population-based hospital discharge data is a feasible means of monitoring the impact of varicella immunization on severe morbidity due to primary varicella and herpes zoster.

Race and stress in the incidence of herpes zoster in older adults.

OBJECTIVES: To examine the effect of black race and acute (negative life events) and chronic (lack of social support) psychological stress on the risk of herpes zoster in late life. DESIGN: A population-based, prospective cohort study. SETTING: Central North Carolina. PARTICIPANTS: Duke Established Populations for Epidemiological Studies of the Elderly, a stratified probability sample of community-dwelling persons more than 65 years of age. MEASUREMENTS: Interviewers administered a comprehensive health survey to the participants in 1986-1987 (P1, n = 4162), 1989-1990 (P2, n = 3336), and 1992-1994 (P3, n = 2568). Incident cases of zoster between P1 and P2 and P2 and P3 served as the dependent variable. Hypothesis-testing variables included race, negative life events, and five measures of social support. Control variables included age, sex, education, cancer, chronic diseases, basic ADLs, instrumental ADLs, depression, self-rated health, hospitalization, and cigarette smoking. Statistical analyses employed chi-square tests and proportional hazards model. RESULTS: At baseline, the sample had a mean age of 73.6 years and was 55% black, 45% white, and 65% female. There were 65 cases of zoster between P1 and P2 and 102 cases of zoster between P2 and P3. From P1 to P2, 1.4% of blacks and 3.4% of whites developed zoster (P < .001). From P2 to P3, 2.9% of blacks and 7.5% of whites developed zoster (P < .001). After controlling for the above variables, blacks were significantly less likely to develop zoster (adjusted risk ratio = 0.35; 95% confidence interval (CI), 0.24-0.51; P < .001). Negative life events increased the risk of zoster, but the result was borderline for statistical significance (adjusted RR = 1.38, 95% CI 0.96-1.97; P = .078). No measures of social support were significantly associated with zoster. CONCLUSION: Black race decreased the risk of zoster in late life significantly. Measures of stress were not significantly related to zoster, but study limitations preclude definitive conclusions. Future research should focus on these factors in larger samples and different populations.

Common infectious diseases in a population with low multiple sclerosis and varicella occurrence.

A previous study revealed the rarity of varicella zoster virus (VZV) diseases among 5601 Hutterite Brethren living in a high-risk area for these diseases. The current study was established to determine the frequency of other common infectious diseases. The information was gathered from a population-based study of a unique group of Manitoba citizens and compared with an equal number of their age and sex-matched neighbors. The data were contained in the records of the Manitoba Health Services Commission (MHSC). The MHSC, the sole paying agency for medical diseases in Manitoba, contained 94,383,972 records for all of Manitoba for the years 1985 to 1991 inclusive. From these, the records of a cohort of 5601 Hutterites and an equal number of non-Hutterite age- and sex-matched controls were examined for the frequency of 14 diseases of interest. To be eligible a Hutterite subject must have one of the 22 unique family names and live on a Colony with the precise address. A control must be age (within 10 years) and sex-matched, live in the same or a contiguous postal code, and use the same medical practitioners. There were no interventions or identification of any member of the study. Mumps, acute coryza, and rubella are of the same frequency among the two groups. Only herpes simplex and cellulitis are more common among the Hutterites. All of the other nine common infectious diseases are significantly more common among the controls. The VZV diseases are not exclusively less common among the Hutterite Brethren. Nine other common infectious diseases are also less common but the degree of significant difference does not reach the level of the VZV diseases. The reduction in numbers of these diseases among the Hutterites is not related to the vaccination habits of the group and is not due to physical isolation. The Hutterites appear to have a more effective immune system relative to their neighbors.

Varicella zoster virus and multiple sclerosis in a Hutterite population.

There are similarities between multiple sclerosis and varicella. They are common in the same parts of the world and both are scarce in other areas. Immigration studies suggest the environmental cause of multiple sclerosis (MS) must be contracted prior to age 15 years and will usually remain dormant for years. At age 10 years varicella has occurred in greater than 95% of children living in the high-risk areas for both of these diseases. The varicella zoster virus (VZV) could be etiologically important in multiple sclerosis. The known host containment of the virus for decades with recrudescence and the variable cell-mediated immunity of the host, which can wax and wane without clinical manifestations, all lend themselves to the natural history of multiple sclerosis. A population-based study of the medical records of 5601 Hutterite Brethren was performed to determine the occurrence of multiple sclerosis, varicella, and herpes zoster. Compared to their matched non-Hutterite neighbors who acted as controls, these events were significantly less common among the Hutterites. Included in the study was an assessment of other common neurological diseases and "autoimmune" diseases among the Hutterites and the controls. There is evidence of a relationship between MS and VZV that may not be coincidental.

Racial differences in the occurrence of herpes zoster.

The purpose of this study was to determine if there are racial differences in the occurrence of herpes zoster (shingles). The study population was the Duke Established Populations for Epidemiologic Studies of the Elderly, a probability sample of community-dwelling persons > 64 years old in North Carolina. Interviewers administered a comprehensive health survey to the participants that included questions about lifetime occurrence of shingles. Of the 3206 subjects, 316 (9.9%) had had zoster: 81 (4.5%) of 1754 blacks and 235 (16.1%) of 1452 whites had had shingles (P < .0001). After controlling for age, cancer, and demographic factors, blacks remained one-fourth as likely as whites (adjusted odds ratio 0.25, 95% confidence interval 0.18-0.35; P = .0001) to have experienced zoster. In summary, blacks had a significantly lower risk of developing herpes zoster than whites, a new finding in herpes zoster epidemiology.