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Herpes Zoster in Patients Treated with Biologicals

Herpes Zoster in Patients Treated with Biologicals IntroductionThe tumor necrosis factor-α TNF-α antagonists etanercept, adalimumab and infliximab, the anti-CD20 antibody rituximab and the anti-p40 interleukin 12/23 antibody ustekinumab are immunosuppressive biologicals whose adverse effect profiles are linked to their specific mechanisms of action. Among these, an increased propensity to viral infections has been observed, including varicella zoster virus (VZV)-related infections [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. In addition, increased severity and duration of herpes zoster (HZ) infections has been reported [8,16,17,18,19], as well as extensive cutaneous [20,21,22] and systemic VZV infections including interstitial pneumonitis [17] and encephalitis [23]. The reported incidence of HZ during TNF-α antagonist treatment has varied between studies [1,5,12,24]. Clinical data relating to HZ cases in association with TNF-α antagonists have often been incomplete. This study reports on the incidence of HZ during biological therapy and describes its clinical features in a single-center cohort of 1,220 patients receiving etanercept, adalimumab, infliximab, rituximab or ustekinumab.Materials and MethodsThe study was performed in accordance with the Declaration of Helsinki. A computer search was performed over a 5-year period using the university hospital medical record database to retrieve patients receiving either etanercept, adalimumab, infliximab, rituximab or ustekinumab. All these patients were followed on a regular base. Cases were classified as rheumatoid arthritis (RA), spondylarthritis, psoriasis, Crohn’s disease and rectocolitis. Patients with off-label use of biologicals were excluded. This first database was cross-matched with HZ as a key word. All the medical records of this second database were reviewed in order to only include patients having presented HZ. The features of the individual HZ episodes were assessed using the university hospital medical records. The method of diagnosis of HZ and who had made the diagnosis were assessed for every HZ patient. The data analysis comprised age, gender, comedication, varicella or HZ vaccination status, underlying disease, severity, duration, localization, prodromal pains and postherpetic neuralgia (PHN; defined as pain persisting for 6 months or more after resolution of the skin lesions), duration of PHN (as assessed on November 15, 2011; +: ongoing PHN, –: resolution of PHN) and treatment. The time to event, expressed in months, was calculated from the start of the last biological treatment to the HZ event. The severity of HZ was classified as follows: + = 1 dermatome involved; ++ = 2 adjacent dermatomes involved; +++ = 3 or more adjacent dermatomes involved; ++++ = disseminated cutaneous HZ; +++++ = systemic multiorgan VZV disease. In order to complete data that could not be retrieved from the university hospital medical records, both the patients and their general practitioners were contacted. The results were compared to the clinical data of a nonimmunocompromised reference population, previously published by Hope-Simpson [25].The incidence rate (IR) was calculated by dividing the number of incident cases by the number of patient-years. 95% confidence intervals (95% CIs) were also estimated. IR and 95% CIs were calculated for each treatment. The null hypothesis was tested by comparing the crude IRs (CIRs) to confirm potential higher occurrence rates of HZ in any of the treatment groups. Rates were also estimated by age category and then compared to the crude rate in a reference population, previously reported by Hope-Simpson [25].ResultsA total of 1,220 eligible patients with a total of 4,206 patient-years were included in the analysis. Table 1 shows the cohort data including patient-years for the different treatments and indications. The search matching the biologicals and HZ produced 27 hits. Five patients were excluded as HZ appeared before the biological therapy. Twenty-two patients developed HZ during etanercept, adalimumab, infliximab, rituximab or ustekinumab therapy. The CIR per 1,000 patient-years was 5.2 (95% CI: 3.0–7.4). The individual demographics and clinical features of the HZ cases are summarized in table 2. The mean age of patients with HZ was 56.2 years (range: 25–77 years). The gender ratio was 17 females/5 males. All but 1 of the HZ patients were exposed to a single biological and had no previous exposure to other biologicals. Eleven HZ cases occurred during adalimumab treatment (CIR: 7.1 per 1,000 patient-years, 95% CI: 2.9–11.3), 4 during etanercept treatment (CIR: 5.1 per 1,000 patient-years, 95% CI: 0.1–10.0), 4 during infliximab treatment (CIR: 2.4 per 1,000 patient-years, 95% CI: 0.0–4.7), 2 during ustekinumab treatment (CIR: 53.5 per 1,000 patient-years, 95% CI: 0.0–125.6) and 1 during rituximab treatment (CIR: 5.2 per 1,000 patient-years, 95% CI: 0.0–17.6). The age-specific incidence observed in our population is compared to a nonimmunocompromised reference population (fig. 1). The incidence was higher for patients aged over 60 years in our population, compared with the general population, although not statistically significantly so. Fourteen cases of HZ were observed in patients suffering from chronic inflammatory joint disease (14/737 = 1.89%), 5 in psoriasis (5/238 = 2.1%) and 3 in chronic inflammatory intestinal disease (3/360 = 0.83%). No psoriasis and chronic inflammatory intestinal disease patients received any immunosuppressive comedication, but 2 chronic inflammatory joint disease patients received methotrexate at the time of the HZ episode. In all the patients, the readministration of biologicals was delayed until complete healing of HZ skin lesions. None of the patients had been vaccinated previously with the varicella or HZ vaccine. The diagnosis of HZ was initially proposed by the general practitioner in all the patients. In 18/22 patients, the diagnosis was confirmed by a dermatologist on a clinical basis, and in 12/12 cases a positive immunohistochemical identification of VZV on a Tzanck smear was available. The overall mean time to event was 30 months (range: 1.5–108 months). The mean times to event for the individual biologicals were as follows: etanercept 9 months (n = 4), adalimumab 37 months (n = 9), infliximab 53 months (n = 4) and ustekinumab 5 months (n = 2). The dermatomal distribution was as follows: thoracic 15/22 (68%), trigeminal 2/22 (9%), lumbar 2/22 (9%) and sacral 3/22 (14%). Bidermatomal (severity score: ++) and multidermatomal HZ (severity scores: +++, ++++) was observed in 10 (45%) and 7 (32%) patients, respectively. None of the patients showed any signs of systemic VZV disease. Two cases of HZ duplex were identified. Prodromal pains and PHN were observed in 12/20 (60%) and 5/20 (25%) patients, respectively. On November 15, 2011, 4/5 patients still presented ongoing PHN. All patients received antiviral therapy (oral aciclovir 16/20, oral valaciclovir 1/20 or intravenous aciclovir 3/20). All patients responded positively to antiviral treatment. Two patients presented with a protracted course (>4 weeks) of cutaneous VZV infection. Table 1Cohort data: CIRs of HZ events per 1,000 patient-yearsTable 2Demographics and clinical features of the HZ casesFig. 1Incidence of HZ in different age groups.DiscussionThe number of cases and IRs of HZ in patients receiving TNF-α antagonists vary considerably between publications [1,5,12,24]. Among 300 patients receiving TNF-α antagonists for chronic inflammatory joint disease, 9 cases of HZ (3%, 6 women and 3 men, RA n = 7 and spondylarthritis n = 2) were identified [5]. Patients receiving etanercept or adalimumab showed a hazard ratio (HR) for developing HZ of 0.62 and 0.53, respectively [12]. The HR of HZ was increased 2-fold following treatment with TNF-α antagonists as a class, compared with disease-modifying antirheumatic drugs. Among 5,040 patients receiving TNF-α antagonists, 39 HZ cases (CIR: 11.1, 95% CI: 7.9–15.1) occurred with anti-TNF-α antibodies and 23 (CIR: 8.9, 95% CI: 5.6–13.3) with etanercept. Etanercept showed an HR of 1.36, and TNF-α antagonist an HR of 1.63, neither of which was statistically significant [12]. Two of 23 infliximab patients (8.7%) developed HZ [11]. The increased risk of developing non-BK opportunistic infections with anti-TNF antibodies compared to the soluble TNF receptor was confirmed recently [15,26]. The antibodies (rather than the receptor therapy) and steroid use >10 mg/day were independently associated with non-BK opportunistic infections. Risk factors for opportunistic infections were treatment with infliximab [odds ratio (OR) = 17.6; 95% CI: 4.3–72.9; p < 0.0001] or adalimumab (OR = 10.0; 95% CI: 2.3–44.4; p = 0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous bolus injections during the previous year (OR = 6.3; 95% CI: 2.0–20.0; p = 0.002) [15]. More VZV-related hospitalizations have been reported in patients with rheumatic diseases receiving TNF-α antagonists than would be expected in the general population [27]. In our study, incidences of HZ were calculated for each biological treatment. Incidences were compared in pairs and were found to be not statistically significantly different. The particularly high values for ustekinumab were probably related to the small sample size. The risk of HZ in this study seemed higher than in the reference population. Indeed, it appeared that from the age of 60 years, the risk of developing HZ was multiplied by 2.1. Between 60 and 69 years, 6.8 cases per 1,000 patient-years are reported in the reference population [25] whilst 14.02 cases were observed. However, this difference was not statistically significant. In a recent study analyzing the incidence of HZ among 22,330 patients with psoriasis (215,656 patient-years) treated with various therapies, 1,321 HZ cases were diagnosed [26]. The CIR per 1,000 person-years was 13.9 for etanercept (95% CI: 0.3–27.4), 19.3 for infliximab (0–45.8) and 4.6 for controls (4.3–5.0), whereas no cases of HZ were observed among patients treated with alefacept, efalizumab or adalimumab. The association of HZ with infliximab approached statistical significance (HR: 1.77, 95% CI: 0.92–3.43), but none of the other biological drugs were significantly associated with the risk of HZ [28]. Our data are in line with the findings of this study. A recent review of the French RATIO Registry also mentioned an increased HZ risk in patients receiving TNF-α antagonists (etanercept OR: 1, adalimumab OR: 3.25, infliximab OR: 3.94) as well as an increased severity [26].The comparison of our study data is difficult, as several factors may interfere with the interpretation, including the age-related increase in HZ incidence, the presence of any underlying disease, the already increased risk of HZ in RA and systemic lupus patients [1,28], exposure to more than 1 biological agent, the duration of exposure, and any combination therapies, such as TNF-α antagonists and methotrexate for RA. Furthermore, underestimation of HZ frequency could be explained by non-reporting. Severe HZ infections have been observed in randomized controlled trials and open-label follow-up studies in RA patients receiving infliximab or adalimumab [29,30,31,32], but not etanercept [33,34]. This tendency was confirmed by Serac et al. [26] as well as in our series which reported an HZ incidence of 0.89% with etanercept versus 1.83% with adalimumab that is about 2-fold higher. Contrary to literature data, the incidence of HZ with infliximab was lower than with etanercept (0.63 vs. 0.89%). Among 22 RA patients receiving rituximab, 1 case of disseminated HZ was reported [13,14]. In a series of 205 B-cell lymphoma patients treated with rituximab, 17 HZ cases were identified (8.3%). In our series, only 1 patient out of 130 (0.77%) presented with HZ, that is a 10-fold lower rate. There were 19 HZ cases in total, among 357 rituximab patients, representing 5.3%. Two cases of severe HZ were reported during ustekinumab treatment, although only 1 HZ case has been reported in randomized controlled trials [21]. However, more long-term observations will be required to clarify whether the risk and severity of HZ are increased.In our series, the time to event varied from 1.5 to 180 months, with a mean of 30 months. Another study reported a mean time to event of 27 months ranging from 6 to 42 months [12]. A further report showed that 80% of the HZ cases occurred between 6 and 36 months after beginning treatment [33]. The distribution of dermatomes was different from that in reference populations (Hope-Simpson) [25,35,36]: thoracic 68 versus 30–55%, trigeminal 9 versus 17–48%, lumbar 9 versus 3–13% and sacral 14 versus 1–7%. The clinical severity in our series was also significantly higher, as reported by others [12,26]. Bidermatomal and multidermatomal HZ was observed in 45 and 32% of patients, respectively. This confirmed previous data from a study totaling 6,112 patient-years of treatment with TNF-α antagonists in which 1.01% of HZ cases in the treatment group were unusual and 0.25% were severe, compared with 0.56 and 0.09%, respectively, in the control group which comprised 4,291 patient-years [12]. In reference populations, prodromal pain is observed in up to 90% of cases [35,36], but in our series it was only reported in 60%. This fact might indicate that prodromal pain in patients on biologicals does not constitute a reliable clinical marker of HZ or risk factor for PHN. In contrast, PHN persisting for more than 6 months after the healing of the skin lesions was observed in 25% of the patients compared to 2–9% at 3 months in the general population aged over 50 years [37]. These findings are in line with previously published risk factors for PHN, stating that patients with a severe rash have a higher risk (OR: 2.31) for PHN [38,39]. In contrast, other studies present contradictory results. One study reported that only 2.4% of the patients experienced PHN [12]. A retrospective analysis of 206 patients presenting HZ while on TNF-α inhibitors (infliximab, etanercept or adalimumab) also only reported 2 cases of persisting PHN (<1%, pain score >3/10 at 90 days) which is unexpectedly low compared to the incidence reported in the literature [40]. None of the patients showed any signs of systemic VZV disease. The outcome of HZ was favorable in all the patients of our series. In conclusion, the HZ incidence was 2.1-fold higher among patients on biologicals over 60 years, as compared with an age-matched reference population, although not statistically significant. However, the severity, extension and duration of HZ and the risk of PHN are seriously aggravated. This study also suggests that the common clinical predictors of HZ and PHN are less reliable in patients on biologicals. The efficacy of HZ vaccination prior to biological therapy should be evaluated.Disclosure StatementNo conflicts of interest. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Dermatology Karger

Herpes Zoster in Patients Treated with Biologicals

Dermatology , Volume 224 (3): 6 – Jan 1, 2012

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References (40)

Publisher
Karger
Copyright
© 2012 S. Karger AG, Basel
ISSN
1018-8665
eISSN
1421-9832
DOI
10.1159/000338691
Publisher site
See Article on Publisher Site

Abstract

IntroductionThe tumor necrosis factor-α TNF-α antagonists etanercept, adalimumab and infliximab, the anti-CD20 antibody rituximab and the anti-p40 interleukin 12/23 antibody ustekinumab are immunosuppressive biologicals whose adverse effect profiles are linked to their specific mechanisms of action. Among these, an increased propensity to viral infections has been observed, including varicella zoster virus (VZV)-related infections [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. In addition, increased severity and duration of herpes zoster (HZ) infections has been reported [8,16,17,18,19], as well as extensive cutaneous [20,21,22] and systemic VZV infections including interstitial pneumonitis [17] and encephalitis [23]. The reported incidence of HZ during TNF-α antagonist treatment has varied between studies [1,5,12,24]. Clinical data relating to HZ cases in association with TNF-α antagonists have often been incomplete. This study reports on the incidence of HZ during biological therapy and describes its clinical features in a single-center cohort of 1,220 patients receiving etanercept, adalimumab, infliximab, rituximab or ustekinumab.Materials and MethodsThe study was performed in accordance with the Declaration of Helsinki. A computer search was performed over a 5-year period using the university hospital medical record database to retrieve patients receiving either etanercept, adalimumab, infliximab, rituximab or ustekinumab. All these patients were followed on a regular base. Cases were classified as rheumatoid arthritis (RA), spondylarthritis, psoriasis, Crohn’s disease and rectocolitis. Patients with off-label use of biologicals were excluded. This first database was cross-matched with HZ as a key word. All the medical records of this second database were reviewed in order to only include patients having presented HZ. The features of the individual HZ episodes were assessed using the university hospital medical records. The method of diagnosis of HZ and who had made the diagnosis were assessed for every HZ patient. The data analysis comprised age, gender, comedication, varicella or HZ vaccination status, underlying disease, severity, duration, localization, prodromal pains and postherpetic neuralgia (PHN; defined as pain persisting for 6 months or more after resolution of the skin lesions), duration of PHN (as assessed on November 15, 2011; +: ongoing PHN, –: resolution of PHN) and treatment. The time to event, expressed in months, was calculated from the start of the last biological treatment to the HZ event. The severity of HZ was classified as follows: + = 1 dermatome involved; ++ = 2 adjacent dermatomes involved; +++ = 3 or more adjacent dermatomes involved; ++++ = disseminated cutaneous HZ; +++++ = systemic multiorgan VZV disease. In order to complete data that could not be retrieved from the university hospital medical records, both the patients and their general practitioners were contacted. The results were compared to the clinical data of a nonimmunocompromised reference population, previously published by Hope-Simpson [25].The incidence rate (IR) was calculated by dividing the number of incident cases by the number of patient-years. 95% confidence intervals (95% CIs) were also estimated. IR and 95% CIs were calculated for each treatment. The null hypothesis was tested by comparing the crude IRs (CIRs) to confirm potential higher occurrence rates of HZ in any of the treatment groups. Rates were also estimated by age category and then compared to the crude rate in a reference population, previously reported by Hope-Simpson [25].ResultsA total of 1,220 eligible patients with a total of 4,206 patient-years were included in the analysis. Table 1 shows the cohort data including patient-years for the different treatments and indications. The search matching the biologicals and HZ produced 27 hits. Five patients were excluded as HZ appeared before the biological therapy. Twenty-two patients developed HZ during etanercept, adalimumab, infliximab, rituximab or ustekinumab therapy. The CIR per 1,000 patient-years was 5.2 (95% CI: 3.0–7.4). The individual demographics and clinical features of the HZ cases are summarized in table 2. The mean age of patients with HZ was 56.2 years (range: 25–77 years). The gender ratio was 17 females/5 males. All but 1 of the HZ patients were exposed to a single biological and had no previous exposure to other biologicals. Eleven HZ cases occurred during adalimumab treatment (CIR: 7.1 per 1,000 patient-years, 95% CI: 2.9–11.3), 4 during etanercept treatment (CIR: 5.1 per 1,000 patient-years, 95% CI: 0.1–10.0), 4 during infliximab treatment (CIR: 2.4 per 1,000 patient-years, 95% CI: 0.0–4.7), 2 during ustekinumab treatment (CIR: 53.5 per 1,000 patient-years, 95% CI: 0.0–125.6) and 1 during rituximab treatment (CIR: 5.2 per 1,000 patient-years, 95% CI: 0.0–17.6). The age-specific incidence observed in our population is compared to a nonimmunocompromised reference population (fig. 1). The incidence was higher for patients aged over 60 years in our population, compared with the general population, although not statistically significantly so. Fourteen cases of HZ were observed in patients suffering from chronic inflammatory joint disease (14/737 = 1.89%), 5 in psoriasis (5/238 = 2.1%) and 3 in chronic inflammatory intestinal disease (3/360 = 0.83%). No psoriasis and chronic inflammatory intestinal disease patients received any immunosuppressive comedication, but 2 chronic inflammatory joint disease patients received methotrexate at the time of the HZ episode. In all the patients, the readministration of biologicals was delayed until complete healing of HZ skin lesions. None of the patients had been vaccinated previously with the varicella or HZ vaccine. The diagnosis of HZ was initially proposed by the general practitioner in all the patients. In 18/22 patients, the diagnosis was confirmed by a dermatologist on a clinical basis, and in 12/12 cases a positive immunohistochemical identification of VZV on a Tzanck smear was available. The overall mean time to event was 30 months (range: 1.5–108 months). The mean times to event for the individual biologicals were as follows: etanercept 9 months (n = 4), adalimumab 37 months (n = 9), infliximab 53 months (n = 4) and ustekinumab 5 months (n = 2). The dermatomal distribution was as follows: thoracic 15/22 (68%), trigeminal 2/22 (9%), lumbar 2/22 (9%) and sacral 3/22 (14%). Bidermatomal (severity score: ++) and multidermatomal HZ (severity scores: +++, ++++) was observed in 10 (45%) and 7 (32%) patients, respectively. None of the patients showed any signs of systemic VZV disease. Two cases of HZ duplex were identified. Prodromal pains and PHN were observed in 12/20 (60%) and 5/20 (25%) patients, respectively. On November 15, 2011, 4/5 patients still presented ongoing PHN. All patients received antiviral therapy (oral aciclovir 16/20, oral valaciclovir 1/20 or intravenous aciclovir 3/20). All patients responded positively to antiviral treatment. Two patients presented with a protracted course (>4 weeks) of cutaneous VZV infection. Table 1Cohort data: CIRs of HZ events per 1,000 patient-yearsTable 2Demographics and clinical features of the HZ casesFig. 1Incidence of HZ in different age groups.DiscussionThe number of cases and IRs of HZ in patients receiving TNF-α antagonists vary considerably between publications [1,5,12,24]. Among 300 patients receiving TNF-α antagonists for chronic inflammatory joint disease, 9 cases of HZ (3%, 6 women and 3 men, RA n = 7 and spondylarthritis n = 2) were identified [5]. Patients receiving etanercept or adalimumab showed a hazard ratio (HR) for developing HZ of 0.62 and 0.53, respectively [12]. The HR of HZ was increased 2-fold following treatment with TNF-α antagonists as a class, compared with disease-modifying antirheumatic drugs. Among 5,040 patients receiving TNF-α antagonists, 39 HZ cases (CIR: 11.1, 95% CI: 7.9–15.1) occurred with anti-TNF-α antibodies and 23 (CIR: 8.9, 95% CI: 5.6–13.3) with etanercept. Etanercept showed an HR of 1.36, and TNF-α antagonist an HR of 1.63, neither of which was statistically significant [12]. Two of 23 infliximab patients (8.7%) developed HZ [11]. The increased risk of developing non-BK opportunistic infections with anti-TNF antibodies compared to the soluble TNF receptor was confirmed recently [15,26]. The antibodies (rather than the receptor therapy) and steroid use >10 mg/day were independently associated with non-BK opportunistic infections. Risk factors for opportunistic infections were treatment with infliximab [odds ratio (OR) = 17.6; 95% CI: 4.3–72.9; p < 0.0001] or adalimumab (OR = 10.0; 95% CI: 2.3–44.4; p = 0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous bolus injections during the previous year (OR = 6.3; 95% CI: 2.0–20.0; p = 0.002) [15]. More VZV-related hospitalizations have been reported in patients with rheumatic diseases receiving TNF-α antagonists than would be expected in the general population [27]. In our study, incidences of HZ were calculated for each biological treatment. Incidences were compared in pairs and were found to be not statistically significantly different. The particularly high values for ustekinumab were probably related to the small sample size. The risk of HZ in this study seemed higher than in the reference population. Indeed, it appeared that from the age of 60 years, the risk of developing HZ was multiplied by 2.1. Between 60 and 69 years, 6.8 cases per 1,000 patient-years are reported in the reference population [25] whilst 14.02 cases were observed. However, this difference was not statistically significant. In a recent study analyzing the incidence of HZ among 22,330 patients with psoriasis (215,656 patient-years) treated with various therapies, 1,321 HZ cases were diagnosed [26]. The CIR per 1,000 person-years was 13.9 for etanercept (95% CI: 0.3–27.4), 19.3 for infliximab (0–45.8) and 4.6 for controls (4.3–5.0), whereas no cases of HZ were observed among patients treated with alefacept, efalizumab or adalimumab. The association of HZ with infliximab approached statistical significance (HR: 1.77, 95% CI: 0.92–3.43), but none of the other biological drugs were significantly associated with the risk of HZ [28]. Our data are in line with the findings of this study. A recent review of the French RATIO Registry also mentioned an increased HZ risk in patients receiving TNF-α antagonists (etanercept OR: 1, adalimumab OR: 3.25, infliximab OR: 3.94) as well as an increased severity [26].The comparison of our study data is difficult, as several factors may interfere with the interpretation, including the age-related increase in HZ incidence, the presence of any underlying disease, the already increased risk of HZ in RA and systemic lupus patients [1,28], exposure to more than 1 biological agent, the duration of exposure, and any combination therapies, such as TNF-α antagonists and methotrexate for RA. Furthermore, underestimation of HZ frequency could be explained by non-reporting. Severe HZ infections have been observed in randomized controlled trials and open-label follow-up studies in RA patients receiving infliximab or adalimumab [29,30,31,32], but not etanercept [33,34]. This tendency was confirmed by Serac et al. [26] as well as in our series which reported an HZ incidence of 0.89% with etanercept versus 1.83% with adalimumab that is about 2-fold higher. Contrary to literature data, the incidence of HZ with infliximab was lower than with etanercept (0.63 vs. 0.89%). Among 22 RA patients receiving rituximab, 1 case of disseminated HZ was reported [13,14]. In a series of 205 B-cell lymphoma patients treated with rituximab, 17 HZ cases were identified (8.3%). In our series, only 1 patient out of 130 (0.77%) presented with HZ, that is a 10-fold lower rate. There were 19 HZ cases in total, among 357 rituximab patients, representing 5.3%. Two cases of severe HZ were reported during ustekinumab treatment, although only 1 HZ case has been reported in randomized controlled trials [21]. However, more long-term observations will be required to clarify whether the risk and severity of HZ are increased.In our series, the time to event varied from 1.5 to 180 months, with a mean of 30 months. Another study reported a mean time to event of 27 months ranging from 6 to 42 months [12]. A further report showed that 80% of the HZ cases occurred between 6 and 36 months after beginning treatment [33]. The distribution of dermatomes was different from that in reference populations (Hope-Simpson) [25,35,36]: thoracic 68 versus 30–55%, trigeminal 9 versus 17–48%, lumbar 9 versus 3–13% and sacral 14 versus 1–7%. The clinical severity in our series was also significantly higher, as reported by others [12,26]. Bidermatomal and multidermatomal HZ was observed in 45 and 32% of patients, respectively. This confirmed previous data from a study totaling 6,112 patient-years of treatment with TNF-α antagonists in which 1.01% of HZ cases in the treatment group were unusual and 0.25% were severe, compared with 0.56 and 0.09%, respectively, in the control group which comprised 4,291 patient-years [12]. In reference populations, prodromal pain is observed in up to 90% of cases [35,36], but in our series it was only reported in 60%. This fact might indicate that prodromal pain in patients on biologicals does not constitute a reliable clinical marker of HZ or risk factor for PHN. In contrast, PHN persisting for more than 6 months after the healing of the skin lesions was observed in 25% of the patients compared to 2–9% at 3 months in the general population aged over 50 years [37]. These findings are in line with previously published risk factors for PHN, stating that patients with a severe rash have a higher risk (OR: 2.31) for PHN [38,39]. In contrast, other studies present contradictory results. One study reported that only 2.4% of the patients experienced PHN [12]. A retrospective analysis of 206 patients presenting HZ while on TNF-α inhibitors (infliximab, etanercept or adalimumab) also only reported 2 cases of persisting PHN (<1%, pain score >3/10 at 90 days) which is unexpectedly low compared to the incidence reported in the literature [40]. None of the patients showed any signs of systemic VZV disease. The outcome of HZ was favorable in all the patients of our series. In conclusion, the HZ incidence was 2.1-fold higher among patients on biologicals over 60 years, as compared with an age-matched reference population, although not statistically significant. However, the severity, extension and duration of HZ and the risk of PHN are seriously aggravated. This study also suggests that the common clinical predictors of HZ and PHN are less reliable in patients on biologicals. The efficacy of HZ vaccination prior to biological therapy should be evaluated.Disclosure StatementNo conflicts of interest.

Journal

DermatologyKarger

Published: Jan 1, 2012

Keywords: Herpes zoster; Adalimumab; Etanercept; Infliximab; Rituximab; Ustekinumab; Tumor necrosis factor-α antagonists; Anti-CD20; Anti-interleukin 12/23

There are no references for this article.