ChloroquineV1, Pmc, Corpus, bibRecord, 000485

Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis

Identifieur interne : 000485 ( Pmc/Corpus ); précédent : 000484; suivant : 000486

Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis

Auteurs : Katrina Wilcox Hagberg ; Rebecca Persson ; Catherine Vasilakis-Scaramozza ; Steve Niemcryk ; Michael Peng ; Maria Paris ; Anders Lindholm ; Susan Jick

Source :

Clinical Epidemiology [ 1179-1349 ] ; 2020.

RBID : PMC:7024766

Abstract

Purpose

Psoriasis and psoriatic arthritis (PsA) are associated with an increased infection risk. In this cohort study of patients with treated psoriasis or PsA, we used MarketScan (2014–2018) to estimate rates of herpes zoster, hepatitis C (HepC) and tuberculosis (TB) with apremilast compared to other systemic treatments.

Materials and Methods

Patients were exposed from first apremilast [APR], DMARD, TNF-inhibitor [TNF], IL-inhibitor [IL], or corticosteroids [CS] prescription after March 21, 2014. Study exposures were APR, DMARDs only, TNF-only, IL-only, CS-only, DMARDs+CS, TNF+DMARDs and/or CS, IL+DMARDs and/or CS. Cases had treated herpes zoster, HepC, or TB event. We calculated incidence rates (IRs) [95% confidence intervals] per 1000 patient-years.

Results

The study population included 131,604 patients. For herpes zoster (N=2271), IRs were highest for users of DMARDs+CS (12.5 [9.8–15.7]), CS-only (12.5 [10.4–14.1]), and TNF+DMARDs and/or CS (11.9 [10.6–13.4]), compared with DMARDs only (9.9 [8.7–11.2]). IRs were lowest for users of IL-only (6.7 [5.8–7.8]) and APR (7.0 [5.8–8.4]). IRs of HepC (N=150) and TB (N=81) were low and between-treatment differences were not significant.

Conclusion

Rates of herpes zoster varied by treatment: highest among those who received polytherapy, lowest in users of apremilast only. IRs for HepC and TB were low for all exposures.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024766

DOI: 10.2147/CLEP.S239511
PubMed: 32104099
PubMed Central: 7024766

Links to Exploration step

PMC:7024766

Le document en format XML

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<author><name sortKey="Hagberg, Katrina Wilcox" sort="Hagberg, Katrina Wilcox" uniqKey="Hagberg K" first="Katrina Wilcox" last="Hagberg">Katrina Wilcox Hagberg</name>
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<author><name sortKey="Lindholm, Anders" sort="Lindholm, Anders" uniqKey="Lindholm A" first="Anders" last="Lindholm">Anders Lindholm</name>
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<author><name sortKey="Jick, Susan" sort="Jick, Susan" uniqKey="Jick S" first="Susan" last="Jick">Susan Jick</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis</title>
<author><name sortKey="Hagberg, Katrina Wilcox" sort="Hagberg, Katrina Wilcox" uniqKey="Hagberg K" first="Katrina Wilcox" last="Hagberg">Katrina Wilcox Hagberg</name>
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<author><name sortKey="Peng, Michael" sort="Peng, Michael" uniqKey="Peng M" first="Michael" last="Peng">Michael Peng</name>
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<addr-line>07901</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Paris, Maria" sort="Paris, Maria" uniqKey="Paris M" first="Maria" last="Paris">Maria Paris</name>
<affiliation><nlm:aff id="AFF0002"><institution>Celgene Corporation</institution>
,<addr-line>Summit</addr-line>
,<addr-line>NJ</addr-line>
<addr-line>07901</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
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<author><name sortKey="Lindholm, Anders" sort="Lindholm, Anders" uniqKey="Lindholm A" first="Anders" last="Lindholm">Anders Lindholm</name>
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,<addr-line>NJ</addr-line>
<addr-line>07901</addr-line>
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</nlm:aff>
</affiliation>
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<author><name sortKey="Jick, Susan" sort="Jick, Susan" uniqKey="Jick S" first="Susan" last="Jick">Susan Jick</name>
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,<addr-line>Lexington</addr-line>
,<addr-line>MA</addr-line>
<addr-line>02421</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="AFF0003"><institution>Boston University School of Public Health</institution>
,<addr-line>Lexington</addr-line>
,<addr-line>MA</addr-line>
<addr-line>02421</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Clinical Epidemiology</title>
<idno type="eISSN">1179-1349</idno>
<imprint><date when="2020">2020</date>
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<front><div type="abstract" xml:lang="en"><sec id="S2001"><title>Purpose</title>
<p>Psoriasis and psoriatic arthritis (PsA) are associated with an increased infection risk. In this cohort study of patients with treated psoriasis or PsA, we used MarketScan (2014–2018) to estimate rates of herpes zoster, hepatitis C (HepC) and tuberculosis (TB) with apremilast compared to other systemic treatments.</p>
</sec>
<sec id="S2002"><title>Materials and Methods</title>
<p>Patients were exposed from first apremilast [APR], DMARD, TNF-inhibitor [TNF], IL-inhibitor [IL], or corticosteroids [CS] prescription after March 21, 2014. Study exposures were APR, DMARDs only, TNF-only, IL-only, CS-only, DMARDs+CS, TNF+DMARDs and/or CS, IL+DMARDs and/or CS. Cases had treated herpes zoster, HepC, or TB event. We calculated incidence rates (IRs) [95% confidence intervals] per 1000 patient-years.</p>
</sec>
<sec id="S2003"><title>Results</title>
<p>The study population included 131,604 patients. For herpes zoster (N=2271), IRs were highest for users of DMARDs+CS (12.5 [9.8–15.7]), CS-only (12.5 [10.4–14.1]), and TNF+DMARDs and/or CS (11.9 [10.6–13.4]), compared with DMARDs only (9.9 [8.7–11.2]). IRs were lowest for users of IL-only (6.7 [5.8–7.8]) and APR (7.0 [5.8–8.4]). IRs of HepC (N=150) and TB (N=81) were low and between-treatment differences were not significant.</p>
</sec>
<sec id="S2004"><title>Conclusion</title>
<p>Rates of herpes zoster varied by treatment: highest among those who received polytherapy, lowest in users of apremilast only. IRs for HepC and TB were low for all exposures.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Epidemiol</journal-id>
<journal-id journal-id-type="iso-abbrev">Clin Epidemiol</journal-id>
<journal-id journal-id-type="publisher-id">CLEP</journal-id>
<journal-id journal-id-type="pmc">clinepid</journal-id>
<journal-title-group><journal-title>Clinical Epidemiology</journal-title>
</journal-title-group>
<issn pub-type="epub">1179-1349</issn>
<publisher><publisher-name>Dove</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32104099</article-id>
<article-id pub-id-type="pmc">7024766</article-id>
<article-id pub-id-type="publisher-id">239511</article-id>
<article-id pub-id-type="doi">10.2147/CLEP.S239511</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis</article-title>
<alt-title alt-title-type="running-authors">Hagberg et al</alt-title>
<alt-title alt-title-type="running-title">Hagberg et al</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-2407-2995</contrib-id>
<name><surname>Hagberg</surname>
<given-names>Katrina Wilcox</given-names>
</name>
<xref ref-type="aff" rid="AFF0001">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Persson</surname>
<given-names>Rebecca</given-names>
</name>
<xref ref-type="aff" rid="AFF0001">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vasilakis-Scaramozza</surname>
<given-names>Catherine</given-names>
</name>
<xref ref-type="aff" rid="AFF0001">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Niemcryk</surname>
<given-names>Steve</given-names>
</name>
<xref ref-type="aff" rid="AFF0002">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Peng</surname>
<given-names>Michael</given-names>
</name>
<xref ref-type="aff" rid="AFF0002">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Paris</surname>
<given-names>Maria</given-names>
</name>
<xref ref-type="aff" rid="AFF0002">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lindholm</surname>
<given-names>Anders</given-names>
</name>
<xref ref-type="aff" rid="AFF0002">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-2215-1067</contrib-id>
<name><surname>Jick</surname>
<given-names>Susan</given-names>
</name>
<xref ref-type="corresp" rid="AN0001"></xref>
<xref ref-type="aff" rid="AFF0001">1</xref>
<xref ref-type="aff" rid="AFF0003">3</xref>
</contrib>
<aff id="AFF0001"><label>1</label>
<institution>Boston Collaborative Drug Surveillance Program</institution>
,<addr-line>Lexington</addr-line>
,<addr-line>MA</addr-line>
<addr-line>02421</addr-line>
,<country>USA</country>
</aff>
<aff id="AFF0002"><label>2</label>
<institution>Celgene Corporation</institution>
,<addr-line>Summit</addr-line>
,<addr-line>NJ</addr-line>
<addr-line>07901</addr-line>
,<country>USA</country>
</aff>
<aff id="AFF0003"><label>3</label>
<institution>Boston University School of Public Health</institution>
,<addr-line>Lexington</addr-line>
,<addr-line>MA</addr-line>
<addr-line>02421</addr-line>
,<country>USA</country>
</aff>
</contrib-group>
<author-notes><corresp id="AN0001">Correspondence: Susan Jick <institution>Boston Collaborative Drug Surveillance Program</institution>
, <addr-line>11 Muzzey Street</addr-line>
, <addr-line>Lexington</addr-line>
, <addr-line>MA</addr-line>
<addr-line>02421</addr-line>
, <country>USA</country>
<phone>Tel +1-781-862-6660</phone>
<fax>Fax +1-781-862-1680</fax>
 Email sjick@bu.edu</corresp>
</author-notes>
<pub-date pub-type="epub"><day>12</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><year>2020</year>
</pub-date>
<volume>12</volume>
<fpage>153</fpage>
<lpage>161</lpage>
<history><date date-type="received"><day>22</day>
<month>11</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>24</day>
<month>1</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>© 2020 Hagberg et al.</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder>Hagberg et al.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/"><license-p>This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at <ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link>
 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>
). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (<ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link>
).</license-p>
</license>
</permissions>
<abstract><sec id="S2001"><title>Purpose</title>
<p>Psoriasis and psoriatic arthritis (PsA) are associated with an increased infection risk. In this cohort study of patients with treated psoriasis or PsA, we used MarketScan (2014–2018) to estimate rates of herpes zoster, hepatitis C (HepC) and tuberculosis (TB) with apremilast compared to other systemic treatments.</p>
</sec>
<sec id="S2002"><title>Materials and Methods</title>
<p>Patients were exposed from first apremilast [APR], DMARD, TNF-inhibitor [TNF], IL-inhibitor [IL], or corticosteroids [CS] prescription after March 21, 2014. Study exposures were APR, DMARDs only, TNF-only, IL-only, CS-only, DMARDs+CS, TNF+DMARDs and/or CS, IL+DMARDs and/or CS. Cases had treated herpes zoster, HepC, or TB event. We calculated incidence rates (IRs) [95% confidence intervals] per 1000 patient-years.</p>
</sec>
<sec id="S2003"><title>Results</title>
<p>The study population included 131,604 patients. For herpes zoster (N=2271), IRs were highest for users of DMARDs+CS (12.5 [9.8–15.7]), CS-only (12.5 [10.4–14.1]), and TNF+DMARDs and/or CS (11.9 [10.6–13.4]), compared with DMARDs only (9.9 [8.7–11.2]). IRs were lowest for users of IL-only (6.7 [5.8–7.8]) and APR (7.0 [5.8–8.4]). IRs of HepC (N=150) and TB (N=81) were low and between-treatment differences were not significant.</p>
</sec>
<sec id="S2004"><title>Conclusion</title>
<p>Rates of herpes zoster varied by treatment: highest among those who received polytherapy, lowest in users of apremilast only. IRs for HepC and TB were low for all exposures.</p>
</sec>
</abstract>
<kwd-group kwd-group-type="author"><title>Keywords</title>
<kwd>apremilast</kwd>
<kwd>psoriasis</kwd>
<kwd>psoriatic arthritis</kwd>
<kwd>herpes zoster</kwd>
<kwd>hepatitis C</kwd>
<kwd>tuberculosis</kwd>
</kwd-group>
<counts><table-count count="5"></table-count>
<ref-count count="29"></ref-count>
<page-count count="9"></page-count>
</counts>
</article-meta>
</front>
<body><sec sec-type="intro" id="S0001"><title>Introduction</title>
<p>Apremilast is a drug marketed in the United States as of March 2014 for the treatment of psoriasis and psoriatic arthritis (PsA). It is an oral medication that inhibits phosphodiesterase-4, a protein found in immune cells associated with inflammation. In randomized clinical trials of apremilast for the treatment of psoriasis or PsA, serious infections were rare and comparable across the various exposure groups.<xref rid="CIT0001" ref-type="bibr">1</xref>
–<xref rid="CIT0006" ref-type="bibr">6</xref>
 No cases of active tuberculosis, herpes zoster, or reactivation of hepatitis C were reported in trials for apremilast, although active tuberculosis, history of tuberculosis, and/or positive hepatitis C antibodies at screening were the reason for exclusion from some of the studies.<xref rid="CIT0001" ref-type="bibr">1</xref>
–<xref rid="CIT0006" ref-type="bibr">6</xref>
 While the safety profile for apremilast in the clinical trials is reassuring, drugs used to treat autoimmune disorders have been shown to increase the risk of serious infection, though there is no consensus on the magnitude of the risk.<xref rid="CIT0007" ref-type="bibr">7</xref>
–<xref rid="CIT0026" ref-type="bibr">26</xref>
 Hepatitis C and tuberculosis are particularly rare and unlikely to occur in small selected clinical trial populations compared with larger epidemiological studies. Therefore, we conducted a post-marketing safety study to estimate rates of treated herpes zoster, hepatitis C, and tuberculosis in patients with psoriasis or PsA treated with apremilast compared with users of other systemic psoriasis and PsA treatments.</p>
</sec>
<sec id="S0002"><title>Methods</title>
<sec id="S0002-S2001"><title>Study Population</title>
<p>We conducted a cohort study within the IBM MarketScan Commercial Claims and Encounters Database (CCE) with Medicare supplement, a large United States (US)-based claims database containing data on over 50 million patients from over 150 large employers distributed throughout the US that covers employees and their dependent family members. It has been reported that the age, sex, and geographic distribution of patients who participated in an employer-sponsored private insurance survey are similar to the US population.<xref rid="CIT0027" ref-type="bibr">27</xref>
 The database contains basic demographics and information on pharmaceuticals (using National Drug Codes), diagnoses (using International Classification of Diseases (ICD)-9 and 10-CM), and procedures (using Current Procedural Terminology, Fourth Edition and the Healthcare Common Procedure Coding System).</p>
<p>The study population included all patients with a diagnosis of psoriasis and/or PsA who received ≥1 prescription for apremilast, a disease-modifying antirheumatic drug (DMARD), a tumor necrosis factor inhibitor (TNF-i) biologic, an interleukin-17 or −12/23 inhibitor (IL-i) biologic, or systemic corticosteroids between March 21, 2014 (when apremilast was marketed) and October 31, 2018 (end of study) (see <underline><ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/get_supplementary_file.php?f=239511.docx">Supplemental Table 1</ext-link>
</underline>
for a list of all study drugs). Because systemic corticosteroids are not indicated for treatment of psoriasis, patients with psoriasis only (ie, no PsA at any time) whose only study drug was a corticosteroid were not included in the study population. For patients with PsA, we required a PsA diagnosis on the same day as a corticosteroid injection or within 15 days before filling a prescription for oral corticosteroids because corticosteroids have multiple indications for use. Patients diagnosed with rheumatoid arthritis before psoriasis or PsA were excluded from the study population. Patients entered the study at the time of their first study drug prescription after March 21, 2014 (cohort entry date) and were followed through the censor date, defined as record end, date the patient became a case, or October 31, 2018 (end of the study period), whichever came first.</p>
</sec>
<sec id="S0002-S2002"><title>Exposure Definition</title>
<p>The study exposures of interest were apremilast, TNF-i biologics, IL-i biologics, conventional DMARDs, and systemic corticosteroids. Current use of each study drug was calculated using the length of each prescription claim plus 30 days. For those who received the drug by injection or infusion, current use was defined as 60 days (or 120 days for ustekinumab). If a new prescription for the same drug was received before the end of the previous prescription duration, the number of days was truncated and days were accumulated from the date of the new prescription. A patient was considered exposed to multiple study drugs if the duration of different study drug prescriptions overlapped, except for TNF-i and IL-i biologics which were not allowed to overlap. We assigned exposure for each day of follow-up to one of the following mutually exclusive categories: apremilast only, apremilast with other study drugs, TNF-i biologics only, IL-i biologics only, DMARDs only, corticosteroids only, DMARDs + corticosteroids, TNF-i biologics with DMARDs and/or corticosteroids, IL-i biologics with DMARDs and/or corticosteroids, or unexposed (defined as any days after “current use” and before a new study drug prescription).</p>
</sec>
<sec id="S0002-S2003"><title>Case Definition</title>
<p>Cases were treated herpes zoster, treated hepatitis C, or treated tuberculosis, and included both newly diagnosed and reactivated infections. A patient was required to have both a diagnosis and treatment for the study infection within 15 days of each other to be a case, and the infection diagnosis and treatment had to first occur at least 7 days after cohort entry. We further required at least 60 days of treatment for cases of hepatitis C and tuberculosis. See <underline><ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/get_supplementary_file.php?f=239511.docx">Supplemental Table 2</ext-link>
</underline>
 for treatments for herpes zoster, hepatitis C, and tuberculosis included in the study. Patients with active, treated infections at cohort entry (prevalent cases) were not considered as cases; however, they did remain in the study population and were followed forward from their initial diagnosis date to determine if they later qualified to be a reactivated case. To be considered a case of reactivated infection, a 6-month treatment-free period after the initial infection was required before the next episode of treated infection. Cases were censored at the first qualifying diagnosis code or treatment for that outcome, whichever came first. The electronic records of all hepatitis C cases, all tuberculosis cases, and a sample of herpes zoster cases were reviewed manually to confirm case status and index dates.</p>
</sec>
<sec id="S0002-S2004"><title>Covariates</title>
<p>We described the study population according to their exposure at cohort entry with respect to the presence of chronic infection risk factors (<xref rid="T0001" ref-type="table">Table 1</xref>
). We also described the presence of acute infection risk factors within the 60 days before the index date, including other immunosuppressant drugs (azathioprine, chloroquine, cyclophosphamide, hydroxychloroquine, leflunomide, minocycline, and sulfasalazine), fractures, major or minor surgical procedures, ventilator use, urinary catheter use, pressure ulcers, and diagnosis or treatment for malignant neoplasm. Duration of psoriasis or PsA was calculated using the date of the first diagnosis code in the patient record, categorized as <1 year, 1–2.9, 3–4.9, ≥5 years, and unknown (where the first psoriasis or PsA diagnosis was recorded less than 6 months after enrollment in MarketScan).<table-wrap id="T0001" orientation="landscape" position="float"><label>Table 1</label>
<caption><p>Characteristics of Study Population at Cohort Entry Date by Exposure</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="2" colspan="1"></th>
<th rowspan="2" colspan="1">Total, N=131,604 (%)</th>
<th colspan="9" rowspan="1">Exposure on Cohort Entry Date</th>
</tr>
<tr><th rowspan="1" colspan="1">DMARDs Only, N=24,678 (%)</th>
<th rowspan="1" colspan="1">Apremilast Only, N=9422 (%)</th>
<th rowspan="1" colspan="1">Apremilast + Other, N=652 (%)</th>
<th rowspan="1" colspan="1">TNF-I Biologics Only, N=47,361 (%)</th>
<th rowspan="1" colspan="1">IL-i Biologics Only, N=12,438 (%)</th>
<th rowspan="1" colspan="1">CS Only, N=20,692 (%)</th>
<th rowspan="1" colspan="1">DMARDs + CS, N=6318 (%)</th>
<th rowspan="1" colspan="1">TNF-i with DMARDs and/or CS, N=9029 (%)</th>
<th rowspan="1" colspan="1">IL-i with DMARDs and/or CS, N=1014 (%)</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1"><bold>Age at cohort entry</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Less than 40 years</td>
<td rowspan="1" colspan="1">32,024 (24.3)</td>
<td rowspan="1" colspan="1">5305 (21.5)</td>
<td rowspan="1" colspan="1">2286 (24.3)</td>
<td rowspan="1" colspan="1">112 (17.2)</td>
<td rowspan="1" colspan="1">13,067 (27.6)</td>
<td rowspan="1" colspan="1">3928 (31.6)</td>
<td rowspan="1" colspan="1">4336 (21.0)</td>
<td rowspan="1" colspan="1">1107 (17.5)</td>
<td rowspan="1" colspan="1">1694 (18.8)</td>
<td rowspan="1" colspan="1">189 (18.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 40–49 years</td>
<td rowspan="1" colspan="1">30,748 (23.4)</td>
<td rowspan="1" colspan="1">5142 (20.8)</td>
<td rowspan="1" colspan="1">2103 (22.3)</td>
<td rowspan="1" colspan="1">155 (23.8)</td>
<td rowspan="1" colspan="1">11,933 (25.2)</td>
<td rowspan="1" colspan="1">3194 (25.7)</td>
<td rowspan="1" colspan="1">4569 (22.1)</td>
<td rowspan="1" colspan="1">1345 (21.3)</td>
<td rowspan="1" colspan="1">2051 (22.7)</td>
<td rowspan="1" colspan="1">256 (25.3)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 50–59 years</td>
<td rowspan="1" colspan="1">39,376 (29.9)</td>
<td rowspan="1" colspan="1">7484 (30.3)</td>
<td rowspan="1" colspan="1">2896 (30.7)</td>
<td rowspan="1" colspan="1">208 (31.9)</td>
<td rowspan="1" colspan="1">13,601 (28.7)</td>
<td rowspan="1" colspan="1">3381 (27.2)</td>
<td rowspan="1" colspan="1">6410 (31.0)</td>
<td rowspan="1" colspan="1">2034 (32.2)</td>
<td rowspan="1" colspan="1">2995 (33.2)</td>
<td rowspan="1" colspan="1">367 (36.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 60–69 years</td>
<td rowspan="1" colspan="1">23,308 (17.7)</td>
<td rowspan="1" colspan="1">5115 (20.7)</td>
<td rowspan="1" colspan="1">1712 (18.2)</td>
<td rowspan="1" colspan="1">134 (20.6)</td>
<td rowspan="1" colspan="1">7334 (15.5)</td>
<td rowspan="1" colspan="1">1644 (13.2)</td>
<td rowspan="1" colspan="1">3989 (19.3)</td>
<td rowspan="1" colspan="1">1317 (20.9)</td>
<td rowspan="1" colspan="1">1896 (21.0)</td>
<td rowspan="1" colspan="1">167 (16.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> ≥70 years</td>
<td rowspan="1" colspan="1">6148 (4.7)</td>
<td rowspan="1" colspan="1">1632 (6.6)</td>
<td rowspan="1" colspan="1">425 (4.5)</td>
<td rowspan="1" colspan="1">43 (6.6)</td>
<td rowspan="1" colspan="1">1426 (3.0)</td>
<td rowspan="1" colspan="1">291 (2.3)</td>
<td rowspan="1" colspan="1">1388 (6.7)</td>
<td rowspan="1" colspan="1">515 (8.2)</td>
<td rowspan="1" colspan="1">393 (4.4)</td>
<td rowspan="1" colspan="1">35 (3.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Median (years)</td>
<td rowspan="1" colspan="1">50</td>
<td rowspan="1" colspan="1">52</td>
<td rowspan="1" colspan="1">51</td>
<td rowspan="1" colspan="1">53</td>
<td rowspan="1" colspan="1">48</td>
<td rowspan="1" colspan="1">47</td>
<td rowspan="1" colspan="1">52</td>
<td rowspan="1" colspan="1">53</td>
<td rowspan="1" colspan="1">52</td>
<td rowspan="1" colspan="1">51</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Sex</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Female</td>
<td rowspan="1" colspan="1">66,474 (50.5)</td>
<td rowspan="1" colspan="1">13,422 (54.4)</td>
<td rowspan="1" colspan="1">4941 (52.4)</td>
<td rowspan="1" colspan="1">400 (61.4)</td>
<td rowspan="1" colspan="1">20,874 (44.1)</td>
<td rowspan="1" colspan="1">5667 (45.6)</td>
<td rowspan="1" colspan="1">11,790 (57.0)</td>
<td rowspan="1" colspan="1">3828 (60.6)</td>
<td rowspan="1" colspan="1">5018 (55.6)</td>
<td rowspan="1" colspan="1">534 (52.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Male</td>
<td rowspan="1" colspan="1">65,130 (49.5)</td>
<td rowspan="1" colspan="1">11,256 (45.6)</td>
<td rowspan="1" colspan="1">4481 (47.6)</td>
<td rowspan="1" colspan="1">252 (38.7)</td>
<td rowspan="1" colspan="1">26,487 (55.9)</td>
<td rowspan="1" colspan="1">6771 (54.4)</td>
<td rowspan="1" colspan="1">8902 (43.0)</td>
<td rowspan="1" colspan="1">2490 (39.4)</td>
<td rowspan="1" colspan="1">4011 (44.4)</td>
<td rowspan="1" colspan="1">480 (47.3)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Indication for use</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> PsA (with or without psoriasis)</td>
<td rowspan="1" colspan="1">56,549 (43.0)</td>
<td rowspan="1" colspan="1">10,471 (42.4)</td>
<td rowspan="1" colspan="1">1997 (21.2)</td>
<td rowspan="1" colspan="1">197 (30.2)</td>
<td rowspan="1" colspan="1">19,364 (40.9)</td>
<td rowspan="1" colspan="1">2159 (17.4)</td>
<td rowspan="1" colspan="1">12,894 (62.3)</td>
<td rowspan="1" colspan="1">2977 (47.1)</td>
<td rowspan="1" colspan="1">6132 (67.9)</td>
<td rowspan="1" colspan="1">359 (35.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Psoriasis only</td>
<td rowspan="1" colspan="1">75,055 (57.0)</td>
<td rowspan="1" colspan="1">14,207 (57.6)</td>
<td rowspan="1" colspan="1">7425 (78.8)</td>
<td rowspan="1" colspan="1">455 (69.8)</td>
<td rowspan="1" colspan="1">27,998 (59.1)</td>
<td rowspan="1" colspan="1">10,279 (82.6)</td>
<td rowspan="1" colspan="1">7798 (37.7)</td>
<td rowspan="1" colspan="1">3341 (52.9)</td>
<td rowspan="1" colspan="1">2897 (32.1)</td>
<td rowspan="1" colspan="1">655 (65.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Duration of psoriasis/PsA before cohort entry</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> <1 year</td>
<td rowspan="1" colspan="1">33,027 (25.1)</td>
<td rowspan="1" colspan="1">7870 (31.9)</td>
<td rowspan="1" colspan="1">2672 (28.4)</td>
<td rowspan="1" colspan="1">226 (34.7)</td>
<td rowspan="1" colspan="1">7904 (16.7)</td>
<td rowspan="1" colspan="1">1361 (10.9)</td>
<td rowspan="1" colspan="1">8312 (40.2)</td>
<td rowspan="1" colspan="1">2920 (46.2)</td>
<td rowspan="1" colspan="1">1607 (17.8)</td>
<td rowspan="1" colspan="1">155 (15.3)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 1–<3 years</td>
<td rowspan="1" colspan="1">16,723 (12.7)</td>
<td rowspan="1" colspan="1">3131 (12.7)</td>
<td rowspan="1" colspan="1">1203 (12.8)</td>
<td rowspan="1" colspan="1">78 (12.0)</td>
<td rowspan="1" colspan="1">6146 (13.0)</td>
<td rowspan="1" colspan="1">1295 (10.4)</td>
<td rowspan="1" colspan="1">2545 (12.3)</td>
<td rowspan="1" colspan="1">820 (13.0)</td>
<td rowspan="1" colspan="1">1376 (15.2)</td>
<td rowspan="1" colspan="1">129 (0.8)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 3–<5 years</td>
<td rowspan="1" colspan="1">3433 (2.6)</td>
<td rowspan="1" colspan="1">618 (2.5)</td>
<td rowspan="1" colspan="1">691 (7.3)</td>
<td rowspan="1" colspan="1">35 (5.4)</td>
<td rowspan="1" colspan="1">738 (1.6)</td>
<td rowspan="1" colspan="1">240 (1.9)</td>
<td rowspan="1" colspan="1">819 (4.0)</td>
<td rowspan="1" colspan="1">202 (3.2)</td>
<td rowspan="1" colspan="1">76 (0.8)</td>
<td rowspan="1" colspan="1">14 (0.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"> ≥5 years</td>
<td rowspan="1" colspan="1">2634 (2.0)</td>
<td rowspan="1" colspan="1">413 (1.7)</td>
<td rowspan="1" colspan="1">693 (7.4)</td>
<td rowspan="1" colspan="1">33 (5.1)</td>
<td rowspan="1" colspan="1">500 (1.1)</td>
<td rowspan="1" colspan="1">302 (2.4)</td>
<td rowspan="1" colspan="1">515 (2.5)</td>
<td rowspan="1" colspan="1">119 (1.9)</td>
<td rowspan="1" colspan="1">48 (0.5)</td>
<td rowspan="1" colspan="1">11 (0.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Unknown</td>
<td rowspan="1" colspan="1">75,787 (57.6)</td>
<td rowspan="1" colspan="1">12,646 (51.2)</td>
<td rowspan="1" colspan="1">4163 (44.2)</td>
<td rowspan="1" colspan="1">280 (42.9)</td>
<td rowspan="1" colspan="1">32,073 (67.7)</td>
<td rowspan="1" colspan="1">9240 (74.3)</td>
<td rowspan="1" colspan="1">8501 (41.1)</td>
<td rowspan="1" colspan="1">2257 (35.7)</td>
<td rowspan="1" colspan="1">5922 (65.6)</td>
<td rowspan="1" colspan="1">705 (69.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Median (years)<break></break>
(excluding unknown)</td>
<td rowspan="1" colspan="1">0.6</td>
<td rowspan="1" colspan="1">0.3</td>
<td rowspan="1" colspan="1">1.0</td>
<td rowspan="1" colspan="1">0.4</td>
<td rowspan="1" colspan="1">0.9</td>
<td rowspan="1" colspan="1">1.4</td>
<td rowspan="1" colspan="1">0.1</td>
<td rowspan="1" colspan="1">0.1</td>
<td rowspan="1" colspan="1">0.9</td>
<td rowspan="1" colspan="1">1.0</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Chronic infection risk Factors before cohort entry</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Diabetes</td>
<td rowspan="1" colspan="1">19,824 (15.1)</td>
<td rowspan="1" colspan="1">3818 (15.5)</td>
<td rowspan="1" colspan="1">1454 (15.4)</td>
<td rowspan="1" colspan="1">137 (21.0)</td>
<td rowspan="1" colspan="1">6217 (13.1)</td>
<td rowspan="1" colspan="1">1654 (13.3)</td>
<td rowspan="1" colspan="1">3581 (17.3)</td>
<td rowspan="1" colspan="1">1123 (17.8)</td>
<td rowspan="1" colspan="1">1641 (18.2)</td>
<td rowspan="1" colspan="1">199 (19.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Chronic obstructive pulmonary disease and other lung diseases*</td>
<td rowspan="1" colspan="1">15,686 (11.9)</td>
<td rowspan="1" colspan="1">2966 (12.0)</td>
<td rowspan="1" colspan="1">1148 (12.2)</td>
<td rowspan="1" colspan="1">124 (19.0)</td>
<td rowspan="1" colspan="1">4011 (8.5)</td>
<td rowspan="1" colspan="1">990 (8.0)</td>
<td rowspan="1" colspan="1">3698 (17.9)</td>
<td rowspan="1" colspan="1">1232 (19.5)</td>
<td rowspan="1" colspan="1">1359 (15.1)</td>
<td rowspan="1" colspan="1">158 (15.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Heart failure</td>
<td rowspan="1" colspan="1">2771 (2.1)</td>
<td rowspan="1" colspan="1">565 (2.3)</td>
<td rowspan="1" colspan="1">247 (2.6)</td>
<td rowspan="1" colspan="1">22 (3.4)</td>
<td rowspan="1" colspan="1">604 (1.3)</td>
<td rowspan="1" colspan="1">193 (1.6)</td>
<td rowspan="1" colspan="1">657 (3.2)</td>
<td rowspan="1" colspan="1">234 (3.7)</td>
<td rowspan="1" colspan="1">224 (2.5)</td>
<td rowspan="1" colspan="1">25 (2.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Angina</td>
<td rowspan="1" colspan="1">2303 (1.8)</td>
<td rowspan="1" colspan="1">414 (1.7)</td>
<td rowspan="1" colspan="1">179 (1.9)</td>
<td rowspan="1" colspan="1">24 (3.7)</td>
<td rowspan="1" colspan="1">565 (1.2)</td>
<td rowspan="1" colspan="1">154 (1.2)</td>
<td rowspan="1" colspan="1">574 (2.8)</td>
<td rowspan="1" colspan="1">171 (2.7)</td>
<td rowspan="1" colspan="1">206 (2.3)</td>
<td rowspan="1" colspan="1">16 (1.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Gastrointestinal ulcer</td>
<td rowspan="1" colspan="1">1539 (1.2)</td>
<td rowspan="1" colspan="1">267 (1.1)</td>
<td rowspan="1" colspan="1">99 (1.1)</td>
<td rowspan="1" colspan="1">10 (1.5)</td>
<td rowspan="1" colspan="1">420 (0.9)</td>
<td rowspan="1" colspan="1">101 (0.8)</td>
<td rowspan="1" colspan="1">353 (1.7)</td>
<td rowspan="1" colspan="1">125 (2.0)</td>
<td rowspan="1" colspan="1">155 (1.7)</td>
<td rowspan="1" colspan="1">9 (0.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Dementia</td>
<td rowspan="1" colspan="1">224 (0.2)</td>
<td rowspan="1" colspan="1">54 (0.2)</td>
<td rowspan="1" colspan="1">19 (0.2)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
<td rowspan="1" colspan="1">48 (0.1)</td>
<td rowspan="1" colspan="1">15 (0.1)</td>
<td rowspan="1" colspan="1">59 (0.3)</td>
<td rowspan="1" colspan="1">16 (0.3)</td>
<td rowspan="1" colspan="1">12 (0.1)</td>
<td rowspan="1" colspan="1">1 (0.1)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Crohn’s disease</td>
<td rowspan="1" colspan="1">3555 (2.7)</td>
<td rowspan="1" colspan="1">206 (0.8)</td>
<td rowspan="1" colspan="1">40 (0.4)</td>
<td rowspan="1" colspan="1">8 (1.2)</td>
<td rowspan="1" colspan="1">2046 (4.3)</td>
<td rowspan="1" colspan="1">114 (0.9)</td>
<td rowspan="1" colspan="1">249 (1.2)</td>
<td rowspan="1" colspan="1">95 (1.5)</td>
<td rowspan="1" colspan="1">779 (8.6)</td>
<td rowspan="1" colspan="1">18 (1.8)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Ulcerative colitis</td>
<td rowspan="1" colspan="1">2388 (1.8)</td>
<td rowspan="1" colspan="1">173 (0.7)</td>
<td rowspan="1" colspan="1">61 (0.7)</td>
<td rowspan="1" colspan="1">9 (1.4)</td>
<td rowspan="1" colspan="1">1155 (2.4)</td>
<td rowspan="1" colspan="1">79 (0.6)</td>
<td rowspan="1" colspan="1">296 (1.4)</td>
<td rowspan="1" colspan="1">86 (1.4)</td>
<td rowspan="1" colspan="1">522 (5.8)</td>
<td rowspan="1" colspan="1">7 (0.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Diffuse diseases of connective tissue*</td>
<td rowspan="1" colspan="1">4028 (3.1)</td>
<td rowspan="1" colspan="1">938 (3.8)</td>
<td rowspan="1" colspan="1">191 (2.0)</td>
<td rowspan="1" colspan="1">23 (3.5)</td>
<td rowspan="1" colspan="1">792 (1.7)</td>
<td rowspan="1" colspan="1">90 (0.7)</td>
<td rowspan="1" colspan="1">1020 (4.9)</td>
<td rowspan="1" colspan="1">556 (8.8)</td>
<td rowspan="1" colspan="1">388 (4.3)</td>
<td rowspan="1" colspan="1">30 (3.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Multiple sclerosis</td>
<td rowspan="1" colspan="1">458 (0.4)</td>
<td rowspan="1" colspan="1">119 (0.5)</td>
<td rowspan="1" colspan="1">46 (0.5)</td>
<td rowspan="1" colspan="1">2 (0.3)</td>
<td rowspan="1" colspan="1">56 (0.1)</td>
<td rowspan="1" colspan="1">42 (0.3)</td>
<td rowspan="1" colspan="1">119 (0.6)</td>
<td rowspan="1" colspan="1">45 (0.7)</td>
<td rowspan="1" colspan="1">23 (0.3)</td>
<td rowspan="1" colspan="1">6 (0.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Rheumatoid arthritis</td>
<td rowspan="1" colspan="1">12,532 (9.5)</td>
<td rowspan="1" colspan="1">2384 (9.7)</td>
<td rowspan="1" colspan="1">289 (3.1)</td>
<td rowspan="1" colspan="1">33 (5.1)</td>
<td rowspan="1" colspan="1">3994 (8.4)</td>
<td rowspan="1" colspan="1">268 (2.2)</td>
<td rowspan="1" colspan="1">2079 (10.1)</td>
<td rowspan="1" colspan="1">1017 (16.1)</td>
<td rowspan="1" colspan="1">2370 (26.3)</td>
<td rowspan="1" colspan="1">98 (9.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Peripheral vascular disease</td>
<td rowspan="1" colspan="1">2667 (2.0)</td>
<td rowspan="1" colspan="1">525 (2.1)</td>
<td rowspan="1" colspan="1">237 (2.5)</td>
<td rowspan="1" colspan="1">24 (3.7)</td>
<td rowspan="1" colspan="1">607 (1.2)</td>
<td rowspan="1" colspan="1">143 (1.2)</td>
<td rowspan="1" colspan="1">672 (3.3)</td>
<td rowspan="1" colspan="1">238 (3.8)</td>
<td rowspan="1" colspan="1">206 (2.3)</td>
<td rowspan="1" colspan="1">15 (1.5)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><bold>Notes:</bold>
 *Chronic obstructive pulmonary disease and other lung diseases included asthma, bronchitis, emphysema, bronchiectasis and pneumoconiosis. Diffuse diseases of connective tissue included systemic lupus erythematosus, dermatopolymyositis, systemic sclerosis and other systemic disorders of connective tissue.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="S0002-S2005"><title>Statistical Analyses</title>
<p>We calculated incidence rates (IRs) with 95% confidence intervals (CIs) of treated herpes zoster, treated hepatitis C, and treated tuberculosis separately for each exposure. For herpes zoster, we calculated incidence rate ratios (IRRs) with 95% CIs and adjusted IRRs controlling for age, sex, calendar year and presence of rheumatoid arthritis for each exposure category compared to DMARDs only using Poisson regression, as well as stratified by indication for use (ie, PsA or psoriasis). There were too few exposed cases of hepatitis C and tuberculosis to calculate crude or adjusted IRRs. Studies using MarketScan are exempt from IRB review because the data is compliant with the Health Insurance Portability and Accountability Act (HIPAA) to protect patient privacy.</p>
</sec>
</sec>
<sec id="S0003"><title>Results</title>
<p>The study population encompassed 131,604 patients with psoriasis or PsA (<xref rid="T0001" ref-type="table">Table 1</xref>
). At cohort entry, 10,074 (7.7%) patients were exposed to apremilast (alone or in combination with other study drugs), while 47,361 (36.0%) were exposed to TNF-i biologics only, 24,678 (18.8%) were exposed to DMARDs only, 12,438 (9.5%) were exposed to IL-i biologics only, 20,692 (15.7%) were exposed to CS only, and 16,361 (12.4%) were exposed to multiple study drugs (DMARDs+CS, or TNF-i with DMARDs and/or CS, or IL-i with DMARDs and/or CS). Half of the population (53.3%) were between 40 and 59 years old at cohort entry, and half (50.5%) were female. At cohort entry, proportionally more apremilast users had an indication of psoriasis rather than PsA compared to users of the other study drugs.</p>
<p>We identified 2271 new or reactivated cases of treated herpes zoster (<xref rid="T0002" ref-type="table">Table 2</xref>
), yielding an IR in the entire study population and regardless of treatment of 8.9 (95% CI 8.5–9.3) per 1000 person-years (PY) (<xref rid="T0003" ref-type="table">Table 3</xref>
). IRs of treated herpes zoster were highest for current users of DMARDs+CS (12.5, 95% CI 9.8–15.7), CS only (12.5, 95% CI 10.4–14.1), TNF-i biologics with DMARDs and/or CS (11.9, 95% CI 10.6–13.4), and IL-i biologics with DMARDs and/or CS (10.3, 95% CI 7.6–13.7) (<xref rid="T0003" ref-type="table">Table 3</xref>
). IRs of treated herpes zoster were lowest for current users of IL-i biologics only (6.7, 95% CI 5.8–7.8) and apremilast alone or in combination (7.0, 95% CI 5.8–8.4). The crude and adjusted IRRs, with DMARDs only as the referent, were around 1.2 for current users of TNF-i biologics with DMARDs and/or CS, CS only, and DMARDs+CS, while the IRRs were close to or below 1.0 for all other exposure categories (<xref rid="T0003" ref-type="table">Table 3</xref>
). Compared to DMARDs only, the adjusted IRR for current use of apremilast only was 0.70 (95% CI 0.54–0.90) and 0.89 (95% CI 0.63–1.25) for current use of apremilast in combination with other study exposures. The results were similar when stratified by indication for use (ie, PsA or psoriasis) (<xref rid="T0003" ref-type="table">Table 3</xref>
).<table-wrap id="T0002" orientation="portrait" position="float"><label>Table 2</label>
<caption><p>Characteristics of Cases at the Index Date</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1">Characteristic</th>
<th rowspan="1" colspan="1">Herpes Zoster Cases, N=2271 (%)</th>
<th rowspan="1" colspan="1">Hepatitis C Cases, N=150 (%)</th>
<th rowspan="1" colspan="1">Tuberculosis Cases, N=81 (%)</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1"><bold>Age at index date</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Less than 40 years</td>
<td rowspan="1" colspan="1">283 (12.5)</td>
<td rowspan="1" colspan="1">7 (4.7)</td>
<td rowspan="1" colspan="1">16 (19.8)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 40–49 years</td>
<td rowspan="1" colspan="1">421 (18.5)</td>
<td rowspan="1" colspan="1">13 (8.7)</td>
<td rowspan="1" colspan="1">18 (22.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 50–59 years</td>
<td rowspan="1" colspan="1">785 (34.6)</td>
<td rowspan="1" colspan="1">63 (42.0)</td>
<td rowspan="1" colspan="1">22 (27.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 60–69 years</td>
<td rowspan="1" colspan="1">580 (25.5)</td>
<td rowspan="1" colspan="1">62 (41.3)</td>
<td rowspan="1" colspan="1">15 (18.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> ≥70 years</td>
<td rowspan="1" colspan="1">202 (8.9)</td>
<td rowspan="1" colspan="1">5 (3.3)</td>
<td rowspan="1" colspan="1">10 (12.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Median (years)</td>
<td rowspan="1" colspan="1">56</td>
<td rowspan="1" colspan="1">58</td>
<td rowspan="1" colspan="1">53</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Sex</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Female</td>
<td rowspan="1" colspan="1">1386 (61.0)</td>
<td rowspan="1" colspan="1">43 (28.7)</td>
<td rowspan="1" colspan="1">39 (48.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Male</td>
<td rowspan="1" colspan="1">885 (39.0)</td>
<td rowspan="1" colspan="1">107 (71.3)</td>
<td rowspan="1" colspan="1">42 (51.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Index year</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> 2014</td>
<td rowspan="1" colspan="1">357 (15.7)</td>
<td rowspan="1" colspan="1">35 (23.3)</td>
<td rowspan="1" colspan="1">14 (17.3)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 2015</td>
<td rowspan="1" colspan="1">472 (20.8)</td>
<td rowspan="1" colspan="1">52 (34.7)</td>
<td rowspan="1" colspan="1">21 (25.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 2016</td>
<td rowspan="1" colspan="1">535 (23.6)</td>
<td rowspan="1" colspan="1">34 (22.7)</td>
<td rowspan="1" colspan="1">19 (23.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 2017</td>
<td rowspan="1" colspan="1">528 (23.2)</td>
<td rowspan="1" colspan="1">20 (13.3)</td>
<td rowspan="1" colspan="1">19 (23.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 2018</td>
<td rowspan="1" colspan="1">379 (16.7)</td>
<td rowspan="1" colspan="1">9 (6.0)</td>
<td rowspan="1" colspan="1">8 (9.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Indication at index date</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> PsA (with or without psoriasis)</td>
<td rowspan="1" colspan="1">1268 (55.8)</td>
<td rowspan="1" colspan="1">73 (48.7)</td>
<td rowspan="1" colspan="1">43 (53.1)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Psoriasis</td>
<td rowspan="1" colspan="1">1003 (44.2)</td>
<td rowspan="1" colspan="1">77 (51.3)</td>
<td rowspan="1" colspan="1">38 (46.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Psoriasis/PsA disease duration before index date</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> <1 year</td>
<td rowspan="1" colspan="1">148 (6.5)</td>
<td rowspan="1" colspan="1">11 (7.3)</td>
<td rowspan="1" colspan="1">9 (11.1)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 1–<3 years</td>
<td rowspan="1" colspan="1">336 (14.8)</td>
<td rowspan="1" colspan="1">12 (8.0)</td>
<td rowspan="1" colspan="1">6 (7.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"> 3–<5 years</td>
<td rowspan="1" colspan="1">266 (11.7)</td>
<td rowspan="1" colspan="1">12 (8.0)</td>
<td rowspan="1" colspan="1">6 (7.4)</td>
</tr>
<tr><td rowspan="1" colspan="1"> ≥5 years</td>
<td rowspan="1" colspan="1">423 (18.6)</td>
<td rowspan="1" colspan="1">18 (12.0)</td>
<td rowspan="1" colspan="1">15 (18.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Unknown</td>
<td rowspan="1" colspan="1">1098 (48.4)</td>
<td rowspan="1" colspan="1">97 (64.7)</td>
<td rowspan="1" colspan="1">45 (55.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Median (years), excluding unknown</td>
<td rowspan="1" colspan="1">3.1</td>
<td rowspan="1" colspan="1">2.6</td>
<td rowspan="1" colspan="1">7.3</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Infection risk factors before index date</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Diabetes</td>
<td rowspan="1" colspan="1">532 (23.4)</td>
<td rowspan="1" colspan="1">30 (20.0)</td>
<td rowspan="1" colspan="1">22 (27.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Chronic obstructive pulmonary disease and other lung diseases*</td>
<td rowspan="1" colspan="1">522 (23.0)</td>
<td rowspan="1" colspan="1">25 (16.7)</td>
<td rowspan="1" colspan="1">17 (21.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Heart failure</td>
<td rowspan="1" colspan="1">116 (5.1)</td>
<td rowspan="1" colspan="1">9 (6.0)</td>
<td rowspan="1" colspan="1">5 (6.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Angina</td>
<td rowspan="1" colspan="1">82 (3.6)</td>
<td rowspan="1" colspan="1">5 (3.3)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Gastrointestinal ulcer</td>
<td rowspan="1" colspan="1">59 (2.6)</td>
<td rowspan="1" colspan="1">4 (2.7)</td>
<td rowspan="1" colspan="1">2 (2.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Dementia</td>
<td rowspan="1" colspan="1">5 (0.2)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Crohn’s disease</td>
<td rowspan="1" colspan="1">127 (5.6)</td>
<td rowspan="1" colspan="1">8 (5.3)</td>
<td rowspan="1" colspan="1">8 (9.9)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Ulcerative colitis</td>
<td rowspan="1" colspan="1">96 (4.2)</td>
<td rowspan="1" colspan="1">4 (2.7)</td>
<td rowspan="1" colspan="1">3 (3.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Diffuse diseases of connective tissue*</td>
<td rowspan="1" colspan="1">157 (6.9)</td>
<td rowspan="1" colspan="1">5 (3.3)</td>
<td rowspan="1" colspan="1">1 (1.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Multiple sclerosis</td>
<td rowspan="1" colspan="1">19 (0.8)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Rheumatoid arthritis</td>
<td rowspan="1" colspan="1">484 (21.3)</td>
<td rowspan="1" colspan="1">16 (10.7)</td>
<td rowspan="1" colspan="1">15 (18.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Peripheral vascular disease</td>
<td rowspan="1" colspan="1">108 (4.8)</td>
<td rowspan="1" colspan="1">2 (1.3)</td>
<td rowspan="1" colspan="1">2 (2.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>Infection risk factors within 60 days before index date</bold>
</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr><td rowspan="1" colspan="1"> Other immunosuppressant use</td>
<td rowspan="1" colspan="1">127 (5.6)</td>
<td rowspan="1" colspan="1">3 (2.0)</td>
<td rowspan="1" colspan="1">3 (3.7)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Any fracture</td>
<td rowspan="1" colspan="1">21 (0.9)</td>
<td rowspan="1" colspan="1">2 (1.3)</td>
<td rowspan="1" colspan="1">2 (2.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Surgical procedures (major or minor) **</td>
<td rowspan="1" colspan="1">526 (23.2)</td>
<td rowspan="1" colspan="1">51 (34.0)</td>
<td rowspan="1" colspan="1">32 (29.5)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Ventilator use</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Urinary catheter use</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Pressure ulcer</td>
<td rowspan="1" colspan="1">4 (0.2)</td>
<td rowspan="1" colspan="1">1 (0.7)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Diagnosis or treatment for malignant neoplasm</td>
<td rowspan="1" colspan="1">75 (3.3)</td>
<td rowspan="1" colspan="1">7 (4.7)</td>
<td rowspan="1" colspan="1">0 (0.0)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><bold>Notes:</bold>
 *Chronic obstructive pulmonary disease and other lung diseases included asthma, bronchitis, emphysema, bronchiectasis and pneumoconiosis. Diffuse diseases of connective tissue included systemic lupus erythematosus, dermatopolymyositis, systemic sclerosis and other systemic disorders of connective tissue. **Includes all major and minor surgical procedures CPT codes 100021–69990, excluding venous and capillary blood specimen collection CPT codes 36415 and 36416.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T0003" orientation="portrait" position="float"><label>Table 3</label>
<caption><p>Incidence Rates (IR) and Incidence Rate Ratios (IRR) for Treated Herpes Zoster by Exposure in Patients with Psoriasis or PsA</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1">Exposure at Index Date</th>
<th rowspan="1" colspan="1">Cases</th>
<th rowspan="1" colspan="1">Person-Years</th>
<th rowspan="1" colspan="1">IR per 1000 PY (95% CI)</th>
<th rowspan="1" colspan="1">Crude IRR (95% CI)</th>
<th rowspan="1" colspan="1">Adjusted IRR (95% CI) *</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1"><bold>All Patients</bold>
</td>
<td rowspan="1" colspan="1"><bold>N=2271</bold>
</td>
<td rowspan="1" colspan="1"><bold>Total=255,451</bold>
</td>
<td rowspan="1" colspan="1"><bold>8.9 (8.5–9.3)</bold>
</td>
<td rowspan="1" colspan="1">–</td>
<td rowspan="1" colspan="1">–</td>
</tr>
<tr><td rowspan="1" colspan="1"> DMARDs only</td>
<td rowspan="1" colspan="1">256</td>
<td rowspan="1" colspan="1">25,865</td>
<td rowspan="1" colspan="1">9.9 (8.7–11.2)</td>
<td rowspan="1" colspan="1">Reference</td>
<td rowspan="1" colspan="1">Reference</td>
</tr>
<tr><td rowspan="1" colspan="1"> Apremilast</td>
<td rowspan="1" colspan="1">120</td>
<td rowspan="1" colspan="1">17,180</td>
<td rowspan="1" colspan="1">7.0 (5.8–8.4)</td>
<td rowspan="1" colspan="1">0.71 (0.57–0.88)</td>
<td rowspan="1" colspan="1">0.75 (0.60–0.94)</td>
</tr>
<tr><td rowspan="1" colspan="1">  Apremilast only</td>
<td rowspan="1" colspan="1">82</td>
<td rowspan="1" colspan="1">12,842</td>
<td rowspan="1" colspan="1">6.4 (5.1–7.9)</td>
<td rowspan="1" colspan="1">0.65 (0.50–0.83)</td>
<td rowspan="1" colspan="1">0.70 (0.54–0.90)</td>
</tr>
<tr><td rowspan="1" colspan="1">  Apremilast + other</td>
<td rowspan="1" colspan="1">38</td>
<td rowspan="1" colspan="1">4338</td>
<td rowspan="1" colspan="1">8.8 (6.2–12.0)</td>
<td rowspan="1" colspan="1">0.89 (0.63–1.24)</td>
<td rowspan="1" colspan="1">0.89 (0.63–1.25)</td>
</tr>
<tr><td rowspan="1" colspan="1"> TNF-i biologics only</td>
<td rowspan="1" colspan="1">712</td>
<td rowspan="1" colspan="1">75,547</td>
<td rowspan="1" colspan="1">9.4 (8.7–10.1)</td>
<td rowspan="1" colspan="1">0.95 (0.83–1.10)</td>
<td rowspan="1" colspan="1">1.11 (0.96–1.28)</td>
</tr>
<tr><td rowspan="1" colspan="1"> IL-i biologics only</td>
<td rowspan="1" colspan="1">173</td>
<td rowspan="1" colspan="1">25,654</td>
<td rowspan="1" colspan="1">6.7 (5.8–7.8)</td>
<td rowspan="1" colspan="1">0.68 (0.56–0.83)</td>
<td rowspan="1" colspan="1">0.82 (0.68–1.00)</td>
</tr>
<tr><td rowspan="1" colspan="1"> CS only</td>
<td rowspan="1" colspan="1">169</td>
<td rowspan="1" colspan="1">13,943</td>
<td rowspan="1" colspan="1">12.5 (10.4–14.1)</td>
<td rowspan="1" colspan="1">1.22 (1.01–1.49)</td>
<td rowspan="1" colspan="1">1.22 (1.01–1.49)</td>
</tr>
<tr><td rowspan="1" colspan="1"> DMARDs + CS</td>
<td rowspan="1" colspan="1">75</td>
<td rowspan="1" colspan="1">5990</td>
<td rowspan="1" colspan="1">12.5 (9.8–15.7)</td>
<td rowspan="1" colspan="1">1.27 (0.98–1.64)</td>
<td rowspan="1" colspan="1">1.19 (0.92–1.54)</td>
</tr>
<tr><td rowspan="1" colspan="1"> TNF-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">284</td>
<td rowspan="1" colspan="1">23,806</td>
<td rowspan="1" colspan="1">11.9 (10.6–13.4)</td>
<td rowspan="1" colspan="1">1.21 (1.02–1.43)</td>
<td rowspan="1" colspan="1">1.23 (1.04–1.46)</td>
</tr>
<tr><td rowspan="1" colspan="1"> IL-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">49</td>
<td rowspan="1" colspan="1">4742</td>
<td rowspan="1" colspan="1">10.3 (7.6–13.7)</td>
<td rowspan="1" colspan="1">1.04 (0.77–1.42)</td>
<td rowspan="1" colspan="1">1.12 (0.82–1.52)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Unexposed</td>
<td rowspan="1" colspan="1">433</td>
<td rowspan="1" colspan="1">62,723</td>
<td rowspan="1" colspan="1">6.9 (6.3–7.6)</td>
<td rowspan="1" colspan="1">0.70 (0.60–0.81)</td>
<td rowspan="1" colspan="1">0.77 (0.66–0.90)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>All patients with PsA</bold>
</td>
<td rowspan="1" colspan="1"><bold>N=1268</bold>
</td>
<td rowspan="1" colspan="1"><bold>Total=132,721</bold>
</td>
<td rowspan="1" colspan="1"><bold>9.6 (9.0–10.1)</bold>
</td>
<td rowspan="1" colspan="1">–</td>
<td rowspan="1" colspan="1">–</td>
</tr>
<tr><td rowspan="1" colspan="1"> DMARDs only</td>
<td rowspan="1" colspan="1">141</td>
<td rowspan="1" colspan="1">14,154</td>
<td rowspan="1" colspan="1">10.0 (8.4–11.7)</td>
<td rowspan="1" colspan="1">Reference</td>
<td rowspan="1" colspan="1">Reference</td>
</tr>
<tr><td rowspan="1" colspan="1"> Apremilast</td>
<td rowspan="1" colspan="1">67</td>
<td rowspan="1" colspan="1">7,367</td>
<td rowspan="1" colspan="1">9.1 (7.0–11.5)</td>
<td rowspan="1" colspan="1">0.91 (0.68–1.22)</td>
<td rowspan="1" colspan="1">0.95 (0.71–1.28)</td>
</tr>
<tr><td rowspan="1" colspan="1">  Apremilast only</td>
<td rowspan="1" colspan="1">37</td>
<td rowspan="1" colspan="1">4515</td>
<td rowspan="1" colspan="1">8.2 (5.8–11.3)</td>
<td rowspan="1" colspan="1">0.82 (0.57–1.18)</td>
<td rowspan="1" colspan="1">0.87 (0.61–1.25)</td>
</tr>
<tr><td rowspan="1" colspan="1">  Apremilast + other</td>
<td rowspan="1" colspan="1">30</td>
<td rowspan="1" colspan="1">2852</td>
<td rowspan="1" colspan="1">10.5 (7.1–15.0)</td>
<td rowspan="1" colspan="1">1.06 (0.71–1.20)</td>
<td rowspan="1" colspan="1">1.08 (0.73–1.60)</td>
</tr>
<tr><td rowspan="1" colspan="1"> TNF-i biologics only</td>
<td rowspan="1" colspan="1">392</td>
<td rowspan="1" colspan="1">39,734</td>
<td rowspan="1" colspan="1">9.9 (8.9–10.9)</td>
<td rowspan="1" colspan="1">0.99 (0.82–1.20)</td>
<td rowspan="1" colspan="1">1.13 (0.93–1.38)</td>
</tr>
<tr><td rowspan="1" colspan="1"> IL-i biologics only</td>
<td rowspan="1" colspan="1">59</td>
<td rowspan="1" colspan="1">8068</td>
<td rowspan="1" colspan="1">7.3 (5.6–9.4)</td>
<td rowspan="1" colspan="1">0.73 (0.54–0.99)</td>
<td rowspan="1" colspan="1">0.86 (0.63–1.16)</td>
</tr>
<tr><td rowspan="1" colspan="1"> CS only</td>
<td rowspan="1" colspan="1">102</td>
<td rowspan="1" colspan="1">8349</td>
<td rowspan="1" colspan="1">12.2 (10.0–14.8)</td>
<td rowspan="1" colspan="1">1.23 (0.95–1.58)</td>
<td rowspan="1" colspan="1">1.22 (0.94–1.57)</td>
</tr>
<tr><td rowspan="1" colspan="1"> DMARDs + CS</td>
<td rowspan="1" colspan="1">44</td>
<td rowspan="1" colspan="1">3668</td>
<td rowspan="1" colspan="1">12.0 (8.7–16.1)</td>
<td rowspan="1" colspan="1">1.20 (0.86–1.69)</td>
<td rowspan="1" colspan="1">1.15 (0.82–1.62)</td>
</tr>
<tr><td rowspan="1" colspan="1"> TNF-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">220</td>
<td rowspan="1" colspan="1">18,477</td>
<td rowspan="1" colspan="1">11.9 (10.4–13.6)</td>
<td rowspan="1" colspan="1">1.20 (0.97–1.48)</td>
<td rowspan="1" colspan="1">1.24 (1.00–1.53)</td>
</tr>
<tr><td rowspan="1" colspan="1"> IL-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">32</td>
<td rowspan="1" colspan="1">2793</td>
<td rowspan="1" colspan="1">11.5 (7.8–16.2)</td>
<td rowspan="1" colspan="1">1.15 (0.78–1.69)</td>
<td rowspan="1" colspan="1">1.23 (0.84–1.82)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Unexposed</td>
<td rowspan="1" colspan="1">211</td>
<td rowspan="1" colspan="1">30,111</td>
<td rowspan="1" colspan="1">7.0 (6.1–8.0)</td>
<td rowspan="1" colspan="1">0.70 (0.57–0.87)</td>
<td rowspan="1" colspan="1">0.75 (0.60–0.93)</td>
</tr>
<tr><td rowspan="1" colspan="1"><bold>All patients with psoriasis only</bold>
</td>
<td rowspan="1" colspan="1"><bold>N=1003</bold>
</td>
<td rowspan="1" colspan="1"><bold>Total=122,730</bold>
</td>
<td rowspan="1" colspan="1"><bold>8.2 (7.7–8.7)</bold>
</td>
<td rowspan="1" colspan="1">–</td>
<td rowspan="1" colspan="1">–</td>
</tr>
<tr><td rowspan="1" colspan="1"> DMARDs only</td>
<td rowspan="1" colspan="1">115</td>
<td rowspan="1" colspan="1">11,711</td>
<td rowspan="1" colspan="1">9.8 (8.1–11.8)</td>
<td rowspan="1" colspan="1">Reference</td>
<td rowspan="1" colspan="1">Reference</td>
</tr>
<tr><td rowspan="1" colspan="1"> Apremilast</td>
<td rowspan="1" colspan="1">53</td>
<td rowspan="1" colspan="1">9813</td>
<td rowspan="1" colspan="1">5.4 (4.0–7.1)</td>
<td rowspan="1" colspan="1">0.55 (0.40–0.76)</td>
<td rowspan="1" colspan="1">0.59 (0.42–0.82)</td>
</tr>
<tr><td rowspan="1" colspan="1">  Apremilast only</td>
<td rowspan="1" colspan="1">45</td>
<td rowspan="1" colspan="1">8327</td>
<td rowspan="1" colspan="1">5.4 (3.9–7.2)</td>
<td rowspan="1" colspan="1">0.55 (0.40–0.78)</td>
<td rowspan="1" colspan="1">0.59 (0.42–0.84)</td>
</tr>
<tr><td rowspan="1" colspan="1">  Apremilast + other</td>
<td rowspan="1" colspan="1">8</td>
<td rowspan="1" colspan="1">1486</td>
<td rowspan="1" colspan="1">5.4 (2.3–10.6)</td>
<td rowspan="1" colspan="1">0.55 (0.27–1.12)</td>
<td rowspan="1" colspan="1">0.56 (0.27–1.15)</td>
</tr>
<tr><td rowspan="1" colspan="1"> TNF-i biologics only</td>
<td rowspan="1" colspan="1">320</td>
<td rowspan="1" colspan="1">35,813</td>
<td rowspan="1" colspan="1">8.9 (8.0–10.0)</td>
<td rowspan="1" colspan="1">0.91 (0.74–1.13)</td>
<td rowspan="1" colspan="1">1.09 (0.88–1.36)</td>
</tr>
<tr><td rowspan="1" colspan="1"> IL-i biologics only</td>
<td rowspan="1" colspan="1">114</td>
<td rowspan="1" colspan="1">17,587</td>
<td rowspan="1" colspan="1">6.5 (5.3–7.8)</td>
<td rowspan="1" colspan="1">0.66 (0.51–0.86)</td>
<td rowspan="1" colspan="1">0.80 (0.61–1.68)</td>
</tr>
<tr><td rowspan="1" colspan="1"> CS only</td>
<td rowspan="1" colspan="1">67</td>
<td rowspan="1" colspan="1">5594</td>
<td rowspan="1" colspan="1">12.0 (9.3–15.2)</td>
<td rowspan="1" colspan="1">1.22 (0.90–1.65)</td>
<td rowspan="1" colspan="1">1.24 (0.84–1.85)</td>
</tr>
<tr><td rowspan="1" colspan="1"> DMARDs + CS</td>
<td rowspan="1" colspan="1">31</td>
<td rowspan="1" colspan="1">2322</td>
<td rowspan="1" colspan="1">13.4 (9.1–19.0)</td>
<td rowspan="1" colspan="1">1.36 (0.91–2.02)</td>
<td rowspan="1" colspan="1">1.24 (0.84–1.85)</td>
</tr>
<tr><td rowspan="1" colspan="1"> TNF-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">64</td>
<td rowspan="1" colspan="1">5330</td>
<td rowspan="1" colspan="1">12.0 (9.2–15.3)</td>
<td rowspan="1" colspan="1">1.22 (0.90–1.66)</td>
<td rowspan="1" colspan="1">1.30 (0.96–1.77)</td>
</tr>
<tr><td rowspan="1" colspan="1"> IL-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">17</td>
<td rowspan="1" colspan="1">1950</td>
<td rowspan="1" colspan="1">8.7 (5.1–14.0)</td>
<td rowspan="1" colspan="1">0.89 (0.53–1.48)</td>
<td rowspan="1" colspan="1">0.97 (0.58–1.61)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Unexposed</td>
<td rowspan="1" colspan="1">222</td>
<td rowspan="1" colspan="1">32,612</td>
<td rowspan="1" colspan="1">6.8 (5.9–7.8)</td>
<td rowspan="1" colspan="1">0.69 (0.55–0.87)</td>
<td rowspan="1" colspan="1">0.78 (0.62–0.98)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><bold>Note:</bold>
 *Adjusted for sex, age, calendar year, and rheumatoid arthritis.</p>
<p><bold>Abbreviations:</bold>
 CI, confidence interval; CS, corticosteroids; DMARDs, disease-modifying antirheumatic drugs; IL-I, interleukin-17, −23 or −12/23 inhibitor biologics; IR, incidence rate; IRR, incidence rate ratio; PY, person-years; TNF-I, tumor necrosis factor inhibitor biologics.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
<p>We identified 150 new or reactivated cases of treated hepatitis C (<xref rid="T0002" ref-type="table">Table 2</xref>
), resulting in an IR for the entire study population, regardless of treatment, of 0.6 (95% CI 0.5–0.7) per 1000 PY (<xref rid="T0004" ref-type="table">Table 4</xref>
). IRs of treated hepatitis C were low for all exposure categories and there were only 12 cases with current exposure to apremilast. Finally, we identified 81 new or reactivated cases of treated tuberculosis (<xref rid="T0002" ref-type="table">Table 2</xref>
), yielding an IR in the entire study population, regardless of treatment, of 0.3 (95% CI 0.2–0.4) per 1000 person-years (PY) (<xref rid="T0005" ref-type="table">Table 5</xref>
). IRs of tuberculosis were low and there were only four cases were exposed to apremilast. The IRs were similar and not statistically different for all exposures. The crude IRRs were all below 1.0 (<xref rid="T0005" ref-type="table">Table 5</xref>
). There were too few exposed cases of hepatitis C and tuberculosis, especially in the reference group, to calculate stable IRRs and all estimates were based on small numbers.<table-wrap id="T0004" orientation="portrait" position="float"><label>Table 4</label>
<caption><p>Incidence Rates (IR) for Treated Hepatitis C by Exposure in Patients with Psoriasis or PsA</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1">Exposure at Index Date</th>
<th rowspan="1" colspan="1">Cases</th>
<th rowspan="1" colspan="1">Person-Years</th>
<th rowspan="1" colspan="1">IR per 1000 PY (95% CI)</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1"><bold>All Patients</bold>
</td>
<td rowspan="1" colspan="1"><bold>N=150</bold>
</td>
<td rowspan="1" colspan="1"><bold>Total=255,451</bold>
</td>
<td rowspan="1" colspan="1"><bold>0.6 (0.5–0.7)</bold>
</td>
</tr>
<tr><td rowspan="1" colspan="1">DMARDs only</td>
<td rowspan="1" colspan="1">13</td>
<td rowspan="1" colspan="1">25,865</td>
<td rowspan="1" colspan="1">0.5 (0.3–0.9)</td>
</tr>
<tr><td rowspan="1" colspan="1">Apremilast</td>
<td rowspan="1" colspan="1">12</td>
<td rowspan="1" colspan="1">17,180</td>
<td rowspan="1" colspan="1">0.7 (0.4–1.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Apremilast only</td>
<td rowspan="1" colspan="1">8</td>
<td rowspan="1" colspan="1">12,842</td>
<td rowspan="1" colspan="1">0.6 (0.3–1.2)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Apremilast + other</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1">4338</td>
<td rowspan="1" colspan="1">0.9 (0.2–2.4)</td>
</tr>
<tr><td rowspan="1" colspan="1">TNF-i biologics only</td>
<td rowspan="1" colspan="1">44</td>
<td rowspan="1" colspan="1">75,547</td>
<td rowspan="1" colspan="1">0.6 (0.4–0.8)</td>
</tr>
<tr><td rowspan="1" colspan="1">IL-i biologics only</td>
<td rowspan="1" colspan="1">14</td>
<td rowspan="1" colspan="1">25,654</td>
<td rowspan="1" colspan="1">0.5 (0.3–0.9)</td>
</tr>
<tr><td rowspan="1" colspan="1">CS only</td>
<td rowspan="1" colspan="1">17</td>
<td rowspan="1" colspan="1">13,943</td>
<td rowspan="1" colspan="1">1.2 (0.7–2.0)</td>
</tr>
<tr><td rowspan="1" colspan="1">DMARDs + CS</td>
<td rowspan="1" colspan="1">0</td>
<td rowspan="1" colspan="1">5990</td>
<td rowspan="1" colspan="1">0.0 (0.0–0.6)</td>
</tr>
<tr><td rowspan="1" colspan="1">TNF-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">14</td>
<td rowspan="1" colspan="1">23,806</td>
<td rowspan="1" colspan="1">0.6 (0.3–1.0)</td>
</tr>
<tr><td rowspan="1" colspan="1">IL-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">2</td>
<td rowspan="1" colspan="1">4742</td>
<td rowspan="1" colspan="1">0.4 (0.0–1.5)</td>
</tr>
<tr><td rowspan="1" colspan="1">Unexposed</td>
<td rowspan="1" colspan="1">34</td>
<td rowspan="1" colspan="1">62,723</td>
<td rowspan="1" colspan="1">0.5 (0.4–0.8)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><bold>Note:</bold>
 Number of cases were too small to calculate stable IRR estimates.</p>
<p><bold>Abbreviations:</bold>
 CI, confidence interval; CS, corticosteroids; DMARDs, disease-modifying antirheumatic drugs; IL-i, interleukin-17, −23 or −12/23 inhibitor biologics; IR, incidence rate; PY, person-years; TNF-i, tumor necrosis factor inhibitor biologics.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T0005" orientation="portrait" position="float"><label>Table 5</label>
<caption><p>Incidence Rates (IR) for Treated Tuberculosis by Exposure in Patients with Psoriasis or PsA</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1">Exposure at Index Date</th>
<th rowspan="1" colspan="1">Cases</th>
<th rowspan="1" colspan="1">Person-Years</th>
<th rowspan="1" colspan="1">IR per 1000 PY (95% CI)</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1"><bold>All Patients</bold>
</td>
<td rowspan="1" colspan="1"><bold>N=81</bold>
</td>
<td rowspan="1" colspan="1"><bold>Total=255,451</bold>
</td>
<td rowspan="1" colspan="1"><bold>0.3 (0.2–0.4)</bold>
</td>
</tr>
<tr><td rowspan="1" colspan="1">DMARDs only</td>
<td rowspan="1" colspan="1">3</td>
<td rowspan="1" colspan="1">25,865</td>
<td rowspan="1" colspan="1">0.1 (0.0–0.3)</td>
</tr>
<tr><td rowspan="1" colspan="1">Apremilast</td>
<td rowspan="1" colspan="1">4</td>
<td rowspan="1" colspan="1">17,180</td>
<td rowspan="1" colspan="1">0.2 (0.1–0.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"><italic> </italic>
Apremilast only</td>
<td rowspan="1" colspan="1">2</td>
<td rowspan="1" colspan="1">12,842</td>
<td rowspan="1" colspan="1">0.2 (0.0–0.6)</td>
</tr>
<tr><td rowspan="1" colspan="1"><italic> </italic>
Apremilast + other</td>
<td rowspan="1" colspan="1">2</td>
<td rowspan="1" colspan="1">4338</td>
<td rowspan="1" colspan="1">0.5 (0.1–1.7)</td>
</tr>
<tr><td rowspan="1" colspan="1">TNF-i biologics only</td>
<td rowspan="1" colspan="1">27</td>
<td rowspan="1" colspan="1">75,547</td>
<td rowspan="1" colspan="1">0.4 (0.2–0.5)</td>
</tr>
<tr><td rowspan="1" colspan="1">IL-i biologics only</td>
<td rowspan="1" colspan="1">6</td>
<td rowspan="1" colspan="1">25,654</td>
<td rowspan="1" colspan="1">0.2 (0.1–0.5)</td>
</tr>
<tr><td rowspan="1" colspan="1">CS only</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1">13,943</td>
<td rowspan="1" colspan="1">0.5 (0.2–1.0)</td>
</tr>
<tr><td rowspan="1" colspan="1">DMARDs + CS</td>
<td rowspan="1" colspan="1">5</td>
<td rowspan="1" colspan="1">5990</td>
<td rowspan="1" colspan="1">0.8 (0.3–1.9)</td>
</tr>
<tr><td rowspan="1" colspan="1">TNF-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">8</td>
<td rowspan="1" colspan="1">23,806</td>
<td rowspan="1" colspan="1">0.3 (0.1–0.7)</td>
</tr>
<tr><td rowspan="1" colspan="1">IL-i with DMARDs and/or CS</td>
<td rowspan="1" colspan="1">1</td>
<td rowspan="1" colspan="1">4742</td>
<td rowspan="1" colspan="1">0.2 (0.0–1.2)</td>
</tr>
<tr><td rowspan="1" colspan="1">Unexposed</td>
<td rowspan="1" colspan="1">20</td>
<td rowspan="1" colspan="1">62,723</td>
<td rowspan="1" colspan="1">0.3 (0.2–0.5)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><bold>Note:</bold>
 Number of cases were too small to calculate stable IRR estimates.</p>
<p><bold>Abbreviations:</bold>
 CI, confidence interval; CS, corticosteroids; DMARDs, disease-modifying antirheumatic drugs; IL-i, interleukin-17, −23 or −12/23 inhibitor biologics; IR, incidence rate; PY, person-years; TNF-i, tumor necrosis factor inhibitor biologics.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="S0004"><title>Discussion</title>
<p>In this large study of patients with psoriasis and PsA, there was no suggestion that patients treated with apremilast were at higher risk of new or recurrent infections of treated herpes zoster, hepatitis C, or tuberculosis compared to patients with psoriasis or PsA treated with DMARDs only. The IRs and IRRs of herpes zoster among apremilast users were slightly lower compared with those of users of other treatments for psoriasis or PsA evaluated in this study, whereas the IRs of hepatitis C and tuberculosis were similar to those of patients treated with DMARDs and/or biologics. The results of this study provide reassurance that apremilast is not likely to be associated with a high risk of herpes zoster, hepatitis C, or tuberculosis in patients with psoriasis or PsA.</p>
<p>The incidence of herpes zoster for users of DMARDs and biologics in our study was similar to those reported in several other studies and systematic reviews.<xref rid="CIT0008" ref-type="bibr">8</xref>
–<xref rid="CIT0017" ref-type="bibr">17</xref>
 This provides confidence in the quality of the data and the ability to detect associations between these exposures and outcomes. This further provides reassurance that the incidence of herpes zoster among patients exposed to apremilast, which was slightly lower than users of DMARDS only, is not elevated compared with users of other psoriasis and PsA treatments.</p>
<p>The available literature describing hepatitis C among patients treated for rheumatoid arthritis, psoriasis or PsA is limited and consists primarily of case reports of hepatitis C reactivation or liver function changes among these patients.<xref rid="CIT0007" ref-type="bibr">7</xref>
,<xref rid="CIT0019" ref-type="bibr">19</xref>
–<xref rid="CIT0022" ref-type="bibr">22</xref>
,<xref rid="CIT0028" ref-type="bibr">28</xref>
 There was one retrospective cohort study that found that biologic treatment in patients with psoriasis increased the risk of reactivation of hepatitis C infection; however, there was no data on apremilast users in particular.<xref rid="CIT0023" ref-type="bibr">23</xref>
 Overall, we identified 150 cases of treated hepatitis C in our entire cohort, only 12 of which were exposed to apremilast (alone or in combination with other study drugs), indicating that hepatitis C is rare in patients with psoriasis or PsA and does not occur more often in apremilast users compared with users of other treatments.</p>
<p>Few studies have been conducted since the implementation of tuberculosis screening to assess the incidence of tuberculosis among patients with rheumatoid arthritis, psoriasis or PsA.<xref rid="CIT0024" ref-type="bibr">24</xref>
–<xref rid="CIT0026" ref-type="bibr">26</xref>
,<xref rid="CIT0029" ref-type="bibr">29</xref>
 We found a few cases of patients with treated tuberculosis in our cohort, four of whom were exposed to apremilast. The IRs for treated tuberculosis among users of DMARDs and biologics in our study fall within the range previously reported.<xref rid="CIT0023" ref-type="bibr">23</xref>
–<xref rid="CIT0026" ref-type="bibr">26</xref>
 Our results provide reassurance that apremilast is not likely to be associated with a high risk of reactivation of latent tuberculosis in patients with psoriasis or PsA.</p>
<p>Our study evaluated a large cohort of more than 10,000 apremilast exposed patients with psoriasis and PsA. We required all cases of herpes zoster, hepatitis C, and tuberculosis to have received treatment for the infection to minimize case misclassification. We were also able to classify all study exposures according to whether or not they were prescribed in combination with other treatments. There were small numbers of cases in some exposure categories, particularly for hepatitis C and tuberculosis, resulting in wide confidence intervals. While due to small numbers we were unable to include all infection risk factors in our adjusted models, there were enough cases of herpes zoster to evaluate the impact of important covariates (sex, age, calendar year, and rheumatoid arthritis) on the association of treatment and infection. Due to the nature of ICD coding in claims data, differentiating between screening, infection, and routine follow-up visits for patients with a history of hepatitis C or tuberculosis is challenging. To minimize case misclassification, we reviewed the records of every case and required each to have received at least 60 days of treatment; however, it remains possible that some of these infection cases may have received chemoprophylaxis and the event was not a true latent infection reactivation. Because the total number of hepatitis C (N=150) and tuberculosis (N=83) cases identified in this study were small, we only presented rates of these infections and did not calculate IRRs between exposure categories; thus, the presented results are not biased by differential case misclassification. Finally, at cohort entry proportionally more users of apremilast had an indication of psoriasis compared with the other study exposures, and due to small numbers, we were unable to adjust our estimates by indication for use. Thus, disease severity should be taken into consideration and the results of this study should be interpreted with caution.</p>
</sec>
<sec id="S0005"><title>Conclusion</title>
<p>These data suggest that rates of hepatitis C and tuberculosis were low among commercially insured US patients for all types of psoriasis and PsA treatment. Rates of herpes zoster varied by treatment and were lowest in users of apremilast only. The results of this study provide reassurance that apremilast is not likely to be associated with a high risk of reactivation of herpes zoster, hepatitis C, or latent tuberculosis in patients with psoriasis or PsA. However, the outcomes evaluated in this study are relatively rare events and some exposure groups had limited numbers of cases; thus, these results should be interpreted with caution.</p>
</sec>
</body>
<back><ack><title>Acknowledgments</title>
<p>This study was supported by Celgene Corporation (Summit, NJ 07901). The abstract entitled “Rates of Herpes Zoster, hepatitis C, and tuberculosis among patients with psoriasis treated with apremilast, biologics, DMARDs, and corticosteroids: a cohort study in the US MarketScan Database” was submitted for presentation at American Academy of Dermatology 2020 Annual Meeting. While related to the paper that we have submitted for publication, this abstract presents preliminary results on a subgroup of patients with psoriasis.</p>
</ack>
<sec id="S0006" sec-type="COI-statement"><title>Disclosure</title>
<p>Ms Katrina Wilcox Hagberg reports grants from Celgene Corp, during the conduct of the study. Ms Rebecca Persson reports grants from Celgene Corporation, during the conduct of the study; grants from Celgene Corporation and AbbVie Inc., outside the submitted work. Dr Catherine Vasilakis-Scaramozza reports grants from Celgene Corporation, during the conduct of the study. Dr Steve Niemcryk is an employee of Celgene Corp, and owns stock in Celgene Corp. Dr Michael Peng, Dr Maria Paris, and Dr Anders Lindholm are employees of Celgene Corp. Dr Susan Jick reports grants from Celgene Corp, during the conduct of the study. The authors report no other conflicts of interest in this work.</p>
</sec>
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Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis

Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis

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