Vasculitis-like herpes zoster in the course of treatment with tofacitinib in ulcerative colitis: An assessment of local viral distribution by RNA in situ hybridization.

A 67-year-old man had taken the janus kinase (JAK) inhibitor, tofacitinib, for ulcerative colitis. He was referred to our department for a refractory ulcer on his lower leg. We suspected vasculitis and performed skin biopsy. Histopathological examination showed multinucleated giant cells in the epidermis and fibrinoid degeneration of small vessels in the upper dermis. Varicella zoster virus (VZV) DNA was detected by polymerase chain reaction and we diagnosed the patient with atypical vasculitis-like herpes zoster. The patient was treated with oral valacyclovir, but the rash persisted and took 2 months to heal. Immunostaining using anti-VZV antibody was positive mainly in epidermal keratinocytes, but was also observed to be positive in cells in the dermis. We further performed RNA in situ hybridization using a VZV ORF9 mRNA probe and clearly showed that the distribution of VZV mRNA extended into the dermis, including the dermal vessel walls and the eccrine sweat glands as well as the epidermis. The internal administration of JAK inhibitors may induce regional widespread VZV infection including vessels and involved in the formation of prolonged vasculitis-like manifestation. RNA in situ hybridization can be a potent tool for detecting the spread of VZV infection in the skin.

Risk of herpes zoster infection in men with varicocele.

PURPOSE: Several diseases have been identified as stressful factors for herpes zoster (HZ) infection. In this study, we investigated the risk of HZ infection in men with varicocele. METHODS: We enlisted the data of patients with newly diagnosed varicocele between 2000 and 2012 from the Taiwanese National Health Insurance Research Database as case cohort. Four control patients were matched as per age and index year to a case patient. HZ diagnosis was the primary end point, and the follow-up period was considered as the time interval from the index date to the main outcome, withdrawal from the National Health Insurance program, or end of the study (31 December 2013). RESULTS: In total, 8720 patients were recruited (1744 with varicocele and 6976 controls); the overall mean age was 36 years. Majority (85%) of the participants were 20-49 years old. HZ incidence was higher in patients with varicocele (5.60 per 1,000 person-years) than in the control group (4.01 per 1,000 person years). Patients with varicocele were 1.37 times more likely to develop HZ than the controls after adjustment. Compared with the control cohort, the adjusted hazards ratio (HR) of the varicocele cohort was higher in patients younger than 49 years old (adjusted HR = 1.60). CONCLUSION: Men with varicocele had a higher risk of HZ development than those without varicocele, particularly those aged ≤49 years. Thus, stress from varicocele cannot be ignored in young men.

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme.

BACKGROUND AND AIMS: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes. METHODS: Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event]. RESULTS: In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death. CONCLUSIONS: During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

Biological treatment for psoriasis and the risk of herpes zoster: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Purpose: To describe the risk of herpes zoster (HZ) in patients with psoriasis and its relation to non-biologic systemic therapies or biologic treatment. Materials and methods: Psoriasis Longitudinal Assessment and Registry (PSOLAR) is an international, prospective, registry that follows adult patients with psoriasis eligible to receive non-biologic systemic therapies or biologic therapies. Mutually exclusive therapy cohorts were defined. HZ incident rates were calculated for each therapy cohort and rates between cohorts were compared using hazard ratios (HR) adjusted for potential confounders, in new users and prevalent-exposure patients. Results: A total of 55 HZ events were identified in 10,469 patients in PSOLAR. The adjusted hazard ratio in the overall study population (new user and prevalent-exposed patients) was 2.22 (95% CI: 0.82-5.97; p = .116) for tumor necrosis factor-α (TNF) inhibitors, 2.73 (0.98-7.58; p = .054) for ustekinumab, and 1.04 (0.20-5.41; p = .966) for methotrexate versus reference (combined phototherapy, systemic steroids, topical therapy, and immunomodulators other than methotrexate). Conclusions: Exposure to ustekinumab, TNF-α inhibitors, and methotrexate was not associated with a statistically significant increased risk of HZ. However, HRs were elevated for ustekinumab and TNF-α inhibitors; a larger number of HZ events would be needed to assess the presence or absence of risk.

Acute herpes zoster and post herpetic neuralgia in primary care: a study of diagnosis, treatment and cost.

Acute herpes zoster and its complication post herpetic neuralgia represent a significant challenge to primary care physicians in their care of an ageing population of patients. This was a cross-sectional observational study by means of a quantitative survey of 1,000 general practitioners registered in Ireland exploring the frequency of diagnosis, methods of treatment and cost of AHZ and PHN in primary care. We recorded an 18% response rate (n = 184) with an 83% completion rate (n = 152/184). 80% of cases of AHZ occurred in patients aged 50 years or more with 81% of study participants encountering cases at a rate of 1-3 patients per month. Famciclovir (37%) and valaciclovir (36%) were the most commonly prescribed antiviral agents. Mild opioids (32%) were the most common analgesic agents used for first line AHZ pain, and pregabalin (37%) the most commonly prescribed analgesic agent for second line AHZ pain. Pregabalin was also the most commonly prescribed analgesic for both first and second line PHN pain (29% and 24%, respectively). The mean per-case direct cost (medication and GP visits) of treating AHZ and PHN in primary care was €195 (range €153-€236) and €201 (range €140-€313), respectively. Based on national sentinel data the estimated annual direct costs of treating AHZ and PHN in primary care is €2,278,196 (range €1,793,399-€2, 763,445). The treatment of AHZ and PHN represents both a significant care and cost burden on primary care resources in Ireland in keeping with other European based studies.

Mimicking rashes: Use of moulage technique in undergraduate assessment at the aga khan university, Karachi.

BACKGROUND: The use of simulated patients in student assessment is supported by the Best Evidence Medical Education and U.S. Agency for Healthcare Research and Quality, and it provides a safe and effective alternative to real patients in many situations. To assess the validity and feasibility of moulage technique-where a cosmetically constructed rash is used on simulated patients-two dermatologic rashes were developed using moulage simulation on standardized patients at Aga Khan University Hospital for 3rd year medical summative Objective Structured Clinical Examination (OSCE). METHODS: Checklists for cases that focused on history taking of a skin rash were developed. These also included a description and identification of lesions, differential diagnosis, and basic management. Cases were first reviewed and approved by the Educational Committee and a dermatologist content expert. Stations were piloted to assess validity and feasibility. Simple nontoxic materials were used to develop the rash by faculty familiar with moulage simulation. RESULTS: Sixty-four students were assessed on a Herpes Zoster case and 32 students on a Herpes Simplex case in morning and afternoon sessions. The total mean score obtained at all OSCE stations was 64.82 ± 10.22. Mean scores on the morning and afternoon dermatology stations were 62.72 ± 9.74 and 69.03 ± 9.98, respectively. Face validity for both stations was established through input of content experts. The internal reliability as measured by Cronbach's alpha between the checklist items on the morning and afternoon stations was acceptable at 0.60 (20 items) and 0.65 (18 items), respectively. DISCUSSION: The use of moulage technique to develop dermatologic lesions on simulated patients may be utilized for student assessment.

Pain, Itch, Quality of Life, and Costs after Herpes Zoster.

BACKGROUND: Herpes zoster (HZ) and postherpetic neuralgia are known to have a profound effect on the patient's quality of life, but the incidence and severity of itch and its relation with pain and quality of life in the long term are still relatively unknown. OBJECTIVE: The aim of this study was to measure the presence and severity of pain and itch and impact on quality of life in patients over 50 years old with HZ. METHODS: We enrolled 661 patients with HZ in this 12-month observational study. Patient data were collected via a web-based questionnaire. Outcomes were pain, itch, burden of illness, impact on patient's daily life, impact on quality of life, and healthcare costs. RESULTS: At inclusion, 94% of patients reported any pain, 74.3% significant pain, and 26% severe pain. After 3 months, 18.8% of patients suffered from postherpetic neuralgia. At inclusion, 70.8% of patients had any itch, 39.2% significant itch, and 7.3% severe itch. The occurrence of pain increases costs and has a high impact on the quality of life, lowering EQ-5D scores by an average of 18%. In contrast, itch has little effect on the quality of life. CONCLUSIONS: Pain and itch are highly prevalent months after HZ. Pain caused by HZ has a large impact on quality of life, burden of illness, impact on daily life, and health care costs for these patients. The impact of itch on quality of life is relatively small.

Impact of Underlying Conditions on Zoster-Related Pain and on Quality of Life Following Zoster.

BACKGROUND: Chronic conditions have been investigated as risk factors for developing zoster, but in patients suffering from zoster, the impact of underlying conditions in zoster-related pain and quality of life (QOL) remains unclear. METHODS: We performed a post hoc analysis of a prospective cohort study in immunocompetent zoster patients aged 50 years or older, conducted by general practitioners in Italy between 2009 and 2010. Zoster symptoms, pain intensity and characteristics, and physical and mental health scores were assessed at baseline (zoster diagnosis) and at 1, 3, and 6 months of follow-up. RESULTS: Among 413 patients enrolled in the study, 73% (303/413) suffered from underlying conditions of which 69% (209/303) were aged 65 or older. Cardiovascular diseases (75%), diabetes (24%), and respiratory diseases (17%) were most frequent. One to three months after onset, zoster patients with underlying conditions experienced more intense zoster-related pain than those without. QOL scores were significantly lower in patients with underlying conditions, and age-adjusted difference in QOL scores between the groups increased over time, demonstrating a slower recovery for patients with underlying conditions. CONCLUSIONS: In addition to age, the main risk factor of zoster occurrence and severity, the presence of underlying conditions results in more painful and impactful zoster episodes, creating a significant burden for these patients.

Short-term dipeptidyl peptidase-4 inhibitor use increases the risk of herpes zoster infection in Asian patients with diabetes.

BACKGROUND: We aimed to evaluate whether patients with diabetes who use dipeptidyl peptidase (DPP)-4 inhibitors are at a higher risk of developing a herpes zoster (HZ) infection. METHODS: We used a subset of the Longitudinal Health Insurance Database 2000 containing all inpatient and outpatient medical claims of ∼1 million people who were randomly sampled from the National Health Insurance Research Database. Patients who were newly diagnosed with Type 2 diabetes International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM 250.x0 and 250.x2) who used antidiabetic medications were divided into two cohorts based on their use of DPP-4 inhibitors between 2009 and 2011. Cox proportion hazard regression models were used to assess the effects of DPP-4 inhibitors on the incidence of HZ compared with the non-DPP-4-inhibitor-exposed cohort. RESULTS: Patients in DPP-4-inhibitor-exposed cohort with diabetes and HZ infections revealed an incidence density of 4.20 per 1000 person-years compared with 3.50 per 1000 person-years for the non-DPP-4-inhibitor-exposed cohort (adjusted hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.70-1.99). Furthermore, high-dose DPP-4-inhibitor treatment was associated with a significantly higher risk of HZ (adjusted HR = 2.46, 95% CI = 1.16-5.19 for a defined daily dose [DDD] ≥ 360). In addition, short-term DPP-4-inhibitor treatment was associated with a significantly higher risk of HZ (adjusted HR = 2.04, 95% CI = 1.03-4.04 for a DDD ≥ 360 days). CONCLUSION: These results suggest that Asian patients with diabetes who use short-term DPP-4 inhibitors might be at a higher risk of developing HZ.

Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease-modifying therapy.

OBJECTIVE: To evaluate whether the risks of herpes zoster (HZ) differed by biologic agents with different mechanisms of action (MOAs) in older rheumatoid arthritis (RA) patients. METHODS: Using Medicare data from 2006-2011, among RA patients with prior biologic agent use and no history of cancer or other autoimmune diseases, this retrospective cohort study identified new treatment episodes of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Followup started on initiation of the new biologic agent and ended at any of the following: first incidence of HZ, a 30-day gap in current exposure, death, a diagnosis of other autoimmune disease or cancer, loss of insurance coverage, or December 31, 2011. We calculated the proportion of RA patients vaccinated for HZ in each calendar year prior to biologic agent initiation and HZ incidence rate for each biologic agent. We compared HZ risks among therapies using Cox regression adjusted for potential confounders. RESULTS: Of 29,129 new biologic treatment episodes, 28.7% used abatacept, 15.9% adalimumab, 14.8% rituximab, 12.4% infliximab, 12.2% etanercept, 6.1% tocilizumab, 5.8% certolizumab, and 4.4% golimumab. The proportion of RA patients vaccinated for HZ prior to biologic agent initiation ranged from 0.4% in 2007 to 4.1% in 2011. We identified 423 HZ diagnoses with the highest HZ incidence rate for certolizumab (2.45 per 100 person-years) and the lowest for golimumab (1.61 per 100 person-years). Neither the crude incidence rate nor the adjusted hazard ratio differed significantly among biologic agents. Glucocorticoid use had a significant association with HZ. CONCLUSION: Among older patients with RA, the HZ risk was similar across biologic agents, including those with different MOAs.

Molecular detection of varicella zoster virus while keeping an eye on the budget.

Varicella zoster virus (VZV) PCR is highly sensitive compared to traditional detection methods like culture and direct fluorescent antibody testing (DFA); however, the high cost of commercial assays prohibits their use in many clinical laboratories. Major contributors to cost are the nucleic acid extraction and the PCR reagents. This study evaluated an "in-house" qualitative real-time PCR where the nucleic acid extraction was replaced by a crude extraction, homogenization and heat treatment. Three methods were compared: virus culture and DFA and real-time PCR following each extraction methods. The real-time PCR was highly specific for VZV, and the analytical sensitivity was equivalent following both extraction methods. In contrast, virus culture and DFA was approximately 10,000-fold less sensitive. Using 200 clinical specimens, the sensitivity for the real-time PCR following nucleic acid extraction or homogenization and heat treatment was essentially equivalent at 100% and 97.2%, respectively; whereas, virus culture and DFA was significantly less sensitive at 54.8%. Overall, homogenization and heat treatment combined with a qualitative in-house real-time PCR is a rapid, accurate and cost effective method for the detection of VZV.

Vaccination to prevent varicella: Goldman and King's response to Myers' interpretation of Varicella Active Surveillance Project data.

BACKGROUND: There is increasing evidence that herpes zoster (HZ) incidence rates among children and adults (aged <60 years) with a history of natural varicella are influenced primarily by the frequency of exogenous exposures, while asymptomatic endogenous reactivations help to cap the rate at approximately 550 cases/100,000 person-years when exogenous boosting becomes rare. The Antelope Valley Varicella Active Surveillance Project was funded by the Centers for Disease Control and Prevention in 1995 to monitor the effects of varicella vaccination in one of the three representative regions of the United States. The stability in the data collection and number of reporting sites under varicella surveillance from 1995-2002 and HZ surveillance during 2000-2001 and 2006-2007 contributed to the robustness of the discerned trends. DISCUSSION: Varicella vaccination may be useful for leukemic children; however, the target population in the United States is all children. Since the varicella vaccine inoculates its recipients with live, attenuated varicella-zoster virus (VZV), clinical varicella cases have dramatically declined. Declining exogenous exposures (boosts) from children shedding natural VZV have caused waning cell-mediated immunity. Thus, the protection provided by varicella vaccination is neither lifelong nor complete. Moreover, dramatic increases in the incidence of adult shingles cases have been observed since HZ was added to the surveillance in 2000. In 2013, this topic is still debated and remains controversial in the United States. SUMMARY: When the costs of the booster dose for varicella and the increased shingles recurrences are included, the universal varicella vaccination program is neither effective nor cost-effective.

Assessment of skin test with varicella-zoster virus antigen for predicting the risk of herpes zoster.

The Shozu Herpes Zoster (SHEZ) Study was designed to clarify the incidence of and predictive and immunological factors for herpes zoster in a defined community-based Japanese population. As part of this series, a total of 5683 residents aged ≥50 years received a varicella-zoster virus (VZV) skin test with VZV antigen, and 48 h later, the erythema and oedema were assessed by measuring the longest diameter. The diameters of both the erythema and oedema decreased with the increasing age of the subject. Sixty-three subjects contracted herpes zoster within a year after receiving the VZV skin test. Analysis of the herpes zoster incidence rate vs. the skin test reaction revealed that the shorter the diameter of erythema or oedema, the greater the likelihood of herpes zoster. These results demonstrated that the VZV skin test is an excellent surrogate marker for predicting the risk of herpes zoster.

Measuring the burden of herpes zoster and post herpetic neuralgia within primary care in rural Crete, Greece.

BACKGROUND: Research has indicated that general practitioners (GPs) have good clinical judgment in regards to diagnosing and managing herpes zoster (HZ) within clinical practice in a country with limited resources for primary care and general practice. The objective of the current study was to assess the burden of HZ and post herpetic neuralgia (PHN) within rural general practices in Crete, Greece. METHODS: The current study took place within a rural setting in Crete, Greece during the period of November 2007 to November 2009 within the catchment area in which the Cretan Rural Practice-based Research Network is operating. In total 19 GP's from 14 health care units in rural Crete were invited to participate, covering a total turnover patient population of approximately 25, 000 subjects. For the purpose of this study an electronic record database was constructed and used as the main tool for monitoring HZ and PHN incidence. Stress related data was also collected with the use of the Short Anxiety Screening Test (SAST). RESULTS: The crude incidence rate of HZ was 1.4/1000 patients/year throughout the entire network of health centers and satellite practices, while among satellite practices alone it was calculated at 1.3/1000 patients/year. Additionally, the standardised incidence density within satellite practices was calculated at 1.6/1000 patients/year. In regards to the stress associated with HZ and PHN, the latter were found to have lower levels of anxiety, as assessed through the SAST score (17.4 ± 3.9 vs. 21.1 ± 5.7; p = 0.029). CONCLUSIONS: The implementation of an electronic surveillance system was feasible so as to measure the burden of HZ and PHN within the rural general practice setting in Crete.

Herpes zoster and postherpetic neuralgia: prevention and management.

Herpes zoster (shingles) is diagnosed clinically by recognition of the distinctive, painful vesicular rash appearing in a unilateral, dermatomal distribution. An estimated 1 million cases occur in the United States each year, and increasing age is the primary risk factor. Laboratory testing, including polymerase chain reaction, can confirm atypical cases. Treatment with acyclovir, famciclovir, or valacyclovir decreases the duration of the rash. Adjunct medications, including opioid analgesics, tricyclic antidepressants, or corticosteroids, may relieve the pain associated with acute herpes zoster. There is conflicting evidence that antiviral therapy during the acute phase prevents postherpetic neuralgia. Postherpetic neuralgia in the cutaneous nerve distribution may last from 30 days to more than six months after the lesions have healed. Evidence supports treating postherpetic neuralgia with tricyclic antidepressants, gabapentin, pregabalin, long-acting opioids, or tramadol; moderate evidence supports the use of capsaicin cream or a lidocaine patch as a second-line agent. Immunization to prevent herpes zoster and postherpetic neuralgia is recommended for most adults 60 years and older.

In the clinic. Herpes zoster.

This issue provides a clinical overview of herpes zoster focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic.