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Original article
Adverse reactions to Janus kinase inhibitors: Study of their incidence and predictive factors in patients with rheumatoid arthritis
Reacciones adversas a inhibidores de quinasa Janus: estudio de su incidencia y de factores predictivos en los pacientes con artritis reumatoide
Cristina Martinez-Molinaa,b, Jose Maria Guardiola Teyb,c, Jesus Ruiz-Ramosa, Anna Feliua, Mireia Puig-Campmanyb,c, Silvia Vidalb,d, Hèctor Corominasb,e,
Corresponding author
hcorominas@santpau.cat

Corresponding author.
a Servicio de Farmacia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
b Departamento de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
c Servicio de Urgencias, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
d Grupo de Enfermedades Inflamatorias, Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
e Servicio de Reumatología y de Enfermedades Autoinmunes Sistémicas, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Adverse drug events&#44; including adverse drug reactions&#44; are a major public health problem for healthcare systems worldwide&#46; It is estimated that around 5&#37;&#8211;10&#37; of hospital admissions and 10&#37;&#8211;30&#37; of hospital emergency department &#40;ED&#41; visits are due to this problem&#44; most of which are preventable&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> Because they are available 24&#8239;h a day&#44; 365 days a year&#44; easily accessible and highly frequented&#44; EDs are considered a good observatory of the health system&#44; playing a crucial role in the rapid detection and therapeutic management of adverse drug reactions&#44; as well as in optimising treatment and preventing revisits to the emergency department&#46; It is estimated that 70&#37; of the adverse reactions identified in the ED are considered avoidable&#44; so it is advisable to establish measures to prevent their occurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis &#40;RA&#41; is an autoimmune disease&#44; characterised by chronic inflammation leading to joint damage&#44; disability&#44; decreased quality of life&#44; as well as various cardiovascular complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> Pharmacological treatment is currently the main approach to disease management&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> The recommendations of the <span class="elsevierStyleItalic">European League Against Rheumatism</span> &#40;EULAR&#41; and the treatment guidelines of the <span class="elsevierStyleItalic">American College of Rheumatology</span> &#40;ACR&#41; emphasise the importance of initiating drug treatment from the time of diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a> Over the last few decades&#44; the therapeutic armamentarium for moderate to severe RA has undergone considerable development&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Significant progress in disease management has been observed&#44; from the extensive use of conventional synthetic &#40;cs&#41; disease-modifying antirheumatic drugs &#40;DMARDs&#41; to the regular use of targeted synthetic DMARDs&#44; i&#46;e&#46; Janus kinase &#40;JAK&#41; inhibitors&#46; Recently&#44; in some patients&#44; JAK inhibitors have been associated with the occurrence of adverse reactions&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> It is hypothesised that reduced selectivity towards the JAK-1 isoform leads to reduced safety&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> Tofacitinib and baricitinib differ from upadacitinib and filgotinib in that they lack JAK-1 selectivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The aim of this study is to analyse adverse reactions related to the use of tofacitinib&#44; baricitinib&#44; upadacitinib and filgotinib in patients with RA&#44; including the identification of predictive factors related to their occurrence&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0020" class="elsevierStylePara elsevierViewall">A retrospective observational study was conducted based on a review of the medical records of RA patients treated with tofacitinib&#44; baricitinib&#44; upadacitinib or filgotinib at a reference community university hospital&#46; The study was approved by the Hospital Clinical Research Ethics Committee &#40;N&#46;&#176; Ref&#58; IIBSP-JAG-2023-168&#41;&#46; The study was conducted in accordance with the Declaration of Helsinki and related ethical standards&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">Participation in the study was proposed to those adult patients &#40;&#8805;18 years&#41; in follow-up for RA&#44; according to ACR-EULAR diagnostic criteria&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> on JAK inhibitor treatment between September 2017 and January 2024&#46; Patients were recruited from the rheumatology department between January 2023 and January 2024&#46; Patients were enrolled in 2 study groups based on the presence or absence of a JAK inhibitor-related adverse events that motivated ED visits&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Data collection</span><p id="par0030" class="elsevierStylePara elsevierViewall">Data related to sociodemographic &#40;age and sex&#41; and clinical variables of the patients were collected&#58; RA treatment &#40;JAK inhibitor&#44; concomitant use of csDMARDs&#44; concomitant use of glucocorticoid &#91;GC&#93;&#44; prednisone &#91;PDN&#93; daily dose equivalent&#44; seropositive RA&#44; rheumatoid factor &#91;RF&#93;&#44; anti-cyclic citrullinated peptide &#91;anti-CCP&#93;&#44; RA progression&#44; cardiovascular risk factors &#40;smoking&#44; obesity&#44; type II diabetes mellitus &#91;DM2&#93;&#44; hypercholesterolemia&#44; hypertriglyceridemia&#44; hypertension&#44; heart failure&#44; cardiac arrhythmia&#41;&#44; laboratory parameters prior to starting on JAK inhibitors &#40;renal and hepatic functions&#44; blood parameter counts &#91;haemoglobin&#44; platelets&#44; leukocytes&#44; lymphocytes&#44; neutrophils&#93;&#41;&#44; vaccination against varicella-zoster virus &#40;VZV&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">From ED visit episodes we collected&#58; date of episode&#44; clinical diagnosis&#44; patient history&#44; JAK inhibitor &#40;tofacitinib and baricitinib&#44; JAK-1 non-selectivity&#59; upadacitinib and filgotinib&#44; JAK-1 selectivity&#41;&#44; concomitant medication with JAK inhibitor use &#40;treatments for RA&#44; treatments for comorbidities&#41;&#44; diagnostic tests &#40;recording of physiological constants&#44; blood tests&#44; microbiological studies&#44; imaging tests&#41;&#44; action regarding the JAK inhibitor &#40;maintenance or temporary discontinuation of treatment&#41;&#44; clinical course during hospitalisation &#40;clinical resolution or non-resolution of adverse reaction&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">From the rheumatology outpatient episodes&#44; the following were collected&#58; blood tests prior to initiation of JAK inhibitor treatment&#44; date of initiation of JAK inhibitor treatment&#44; other RA treatment &#40;concomitant use of csDMARDs&#44; concomitant use of GC&#44; equivalent daily dose of PDN&#41;&#44; clinical course after the ED episode &#40;clinical resolution or non-resolution of the adverse reaction&#41;&#44; action on JAK inhibitor &#40;maintenance or definitive discontinuation of treatment&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Evaluations and statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Sociodemographic and clinical characteristics of the patients were described separately by presence or absence of adverse reaction to JAK inhibitor&#46; Differences were assessed using Fisher&#8217;s exact test for categorical variables and the Mann&#8211;Whitney test for quantitative variables&#46; Categorical variables were expressed as median and interquartile range &#40;IQR&#41;&#46; Quantitative variables were presented as absolute numbers &#40;n&#41; and percentages &#40;&#37;&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The primary endpoint under study was the cumulative incidence of adverse drug reaction to JAK inhibitor prompting patient ED visit from September 2017 to January 2024&#46; The cumulative incidence was attributed using the adverse drug reaction probability scale&#44; also known as the Naranjo et al&#46; scale&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Only those with definite&#44; probable or possible likelihoods were attributed adverse reactions&#46; The secondary variable was the identification of predictors of adverse drug reaction to JAK inhibitors&#46; The analysis was conducted using logistic regression&#44; including in the multivariate analysis those variables with a value of P&#8239;&#60;&#8239;0&#46;1 in the bivariate analysis&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">A value of P&#8239;&#60;&#8239;0&#46;05 was considered statistically significant&#46; Statistical analyses were performed using STATA&#174; software version 12&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Study population</span><p id="par0060" class="elsevierStylePara elsevierViewall">A total of 223 patients with RA on JAK inhibitor treatment were included in the study&#46; Adverse reactions to JAK inhibitors that led to an ED visit occurred in 28&#46;7&#37; &#40;64&#47;223&#41; of patients&#46; 5&#46;4&#37; &#40;12&#47;223&#41; required discontinuation of JAK inhibitor treatment in order to manage drug-related adverse events&#46; The socio-demographic and clinical characteristics of the patients enrolled are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Cumulative incidences of adverse reactions to Janus kinase inhibitor</span><p id="par0065" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the cumulative incidences of adverse reactions to JAK inhibitors for the study period&#44; based on the Naranjo et al&#46; scale&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Infections and gastrointestinal disorders describe the highest percentages of calculated cumulative incidence&#46; The infection reported with the highest cumulative incidence was upper respiratory tract infection &#40;4&#46;5&#37;&#41;&#44; followed by cellulitis &#40;3&#46;1&#37;&#41;&#44; urinary tract infection &#40;2&#46;7&#37;&#41;&#44; herpes zoster &#40;1&#46;8&#37;&#41;&#46; Regarding gastrointestinal disorders&#44; from highest to lowest cumulative incidence&#44; the following were found&#58; abdominal pain &#40;4&#46;0&#37;&#41;&#44; diarrhoea &#40;3&#46;6&#37;&#41;&#44; nausea and vomiting &#40;3&#46;6&#37;&#41;&#44; gastrointestinal perforation &#40;1&#46;3&#37;&#41; and diverticulitis &#40;0&#46;9&#37;&#41;&#46; With lower cumulative incidences&#44; all 0&#46;5&#37;&#44; the following were identified&#58; headache&#44; paraesthesia&#44; rash&#44; severe neutropenia&#44; insomnia&#44; dyspnoea and hypertensive crisis&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Factors predictive of an adverse reaction to Janus kinase inhibitors</span><p id="par0070" class="elsevierStylePara elsevierViewall">The main results of the logistic regression analysis are shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; Older age of the patient was identified as a potential risk predictor for adverse reaction to JAK inhibitor &#40;<span class="elsevierStyleItalic">odds ratio</span> &#91;OR&#93;&#58; 1&#46;03&#59; 95&#37; confidence interval &#91;CI&#93;&#58; 1&#46;01&#8211;1&#46;06&#59; P&#8239;&#61;&#8239;0&#46;017&#41;&#46; So were non-selective JAK inhibitor treatment &#40;OR&#58; 4&#46;16&#59; 95&#37; CI&#58; 1&#46;21&#8211;14&#46;24&#59; P&#8239;&#61;&#8239;0&#46;023&#41;&#44; DM2 &#40;OR&#58; 2&#46;86&#59; 95&#37; CI&#58; 1&#46;25&#8211;6&#46;58&#59; P&#8239;&#61;&#8239;0&#46;013&#41; and obesity &#40;OR&#58; 1&#46;74&#59; 95&#37; CI&#58; 0&#46;90&#8211;3&#46;33&#59; P&#8239;&#61;&#8239;0&#46;098&#41;&#46; On multivariate analysis&#44; the following were found to be predictive risk factors&#58; older age of the patient&#44; with an adjusted OR of 1&#46;03 &#40;95&#37; CI&#58; 1&#46;00&#8211;1&#46;05&#59; P&#8239;&#61;&#8239;0&#46;036&#41;&#44; and treatment with a non-selective JAK inhibitor&#44; with an OR of 4&#46;03 &#40;95&#37; CI&#58; 1&#46;15&#8211;14&#46;10&#59; P&#8239;&#61;&#8239;0&#46;029&#41;&#46; The following factors were not identified as predictive of either risk or protection&#58; DM2&#44; obesity&#44; hypertension&#44; hypercholesterolemia&#44; hypertriglyceridemia&#44; smoking&#44; VZV vaccination&#44; heart failure&#44; arrhythmia&#44; female sex&#44; years of RA progression&#44; seropositive RA &#40;RF and&#47;or anti-CCP&#41;&#44; concomitant csDMARD use&#44; concomitant GC use&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Our study analysed adverse reactions related to the use of tofacitinib&#44; baricitinib&#44; upadacitinib and filgotinib in patients with RA&#44; including the identification of predictive factors related to their occurrence&#46; Understanding the comprehensive safety profile of JAK inhibitors&#44; as well as their specificities&#44; is essential as several post-marketing adverse reactions have been reported&#46; Based on the available literature reviewed&#44; this is the first safety registry of JAK inhibitors developed in routine clinical practice through patient visits to EDs&#44; considered a good observatory of the healthcare system&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The results show that infections are among the most common side effects of JAK inhibitors&#44; in line with expectations from clinical trial data&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> From highest to lowest incidence&#44; upper respiratory tract infections&#44; cellulitis&#44; urinary tract infections and herpes zoster were identified in our study&#46; Upper respiratory tract infection was described as the most common adverse reaction to JAK inhibitors&#44; classified as &#8220;very common&#8221; &#40;&#8805;1&#47;10&#41; among targeted therapies for RA&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The pattern of infection is thought to be related to the inhibitory selectivity profile of the drug<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and may include other common infections such as urinary tract infections&#44; cellulitis and herpes zoster&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> An increased risk of herpes zoster infection has been associated with tofacitinib and baricitinib treatment<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#59; its incidence may be reduced by vaccination against varicella-zoster virus prior to initiation of JAK inhibitor treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In addition to infections&#44; gastrointestinal disorders were the most common adverse reactions in our study&#44; with abdominal pain&#44; diarrhoea&#44; nausea and vomiting&#44; gastrointestinal perforation and diverticulitis&#46; Baricitinib&#44; a JAK-1 and JAK-2 inhibitor&#44; has received a warning for the risk of diverticulitis and gastrointestinal perforation&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> JAK-1 and JAK-2 signal through interleukin &#40;IL&#41;-6&#44; the receptor which has been prominently linked to intestinal homeostasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> Thus&#44; a higher selectivity towards JAK-1 suggests a lower risk of gastrointestinal disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In terms of JAK-1 inhibition selectivity&#44; Traves et al&#46; combined clinical and in vitro pharmacokinetics to differentiate the inhibition selectivity of tofacitinib&#44; baricitinib&#44; upadacitinib and filgotinib&#44; and concluded that differences in selectivity towards JAK-1 may explain the observed differences in adverse reactions among JAK inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In relation&#44; our results suggest treatment with a non-selective JAK inhibitor as a predictive risk factor for adverse reaction &#40;OR&#58; 4&#46;03&#59; 95&#37; CI&#58; 1&#46;15&#8211;14&#46;10&#59; P&#8239;&#61;&#8239;0&#46;029&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The other predictive risk factor identified in our study is the older age of the patient &#40;OR&#58; 1&#46;03&#59; 95&#37; CI&#58; 1&#46;00&#8211;1&#46;05&#59; P&#8239;&#61;&#8239;0&#46;036&#41;&#46; An age &#8805;65 years has been associated with an increased risk of discontinuation of JAK inhibitor treatment due to adverse events&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> with cardiovascular events and malignancies being associated with tofacitinib treatment in a study &#40;<span class="elsevierStyleItalic">ORAL Surveillance&#41;</span> conducted in subpopulations with cardiovascular risk factors and compared with tumour necrosis factor-alpha &#40;TNF-&#945; &#41; inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Consequently&#44; and following the recommendations of the European Medicines Agency &#40;EMA&#41;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> and EULAR&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> special caution should be exercised when prescribing the JAK inhibitor to patients aged &#8805;65 years&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Regarding gender&#44; it has been suggested that it does not influence the safety of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;26</span></a> According to our findings&#44; being female is not associated with the development of adverse reactions to JAK inhibitors&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Regarding concomitant GC use&#44; PDN doses &#8239;&#62;&#8239;7&#46;5&#8239;mg&#47;day in patients treated with tofacitinib have been associated with an increased risk of serious infection&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Low doses of GC &#40;&#60;7&#46;5&#8239;mg&#47;day of PDN&#41; in short periods of time are recommended by both EULAR<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and ACR&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> with clinical benefit observed in patients aged &#62;65 years&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> 59&#46;2&#37; of patients in our study were on GC treatment at a PDN dose of 5 &#91;0&#8211;5&#93; mg&#47;day&#46; As described above&#44; the use of low-dose GC &#40;&#60;7&#46;5&#8239;mg&#47;day&#41; was not associated with the development of adverse reactions to JAK inhibitors&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding concomitant use of csDMARDs&#44; EULAR recommends reducing their dose to convey the additional benefit of the combination versus monotherapy and&#44; at the same time&#44; mitigate the risk of adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> According to recent literature<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;29</span></a> and the results of our study&#44; where 26&#46;5&#37; of patients maintained treatment with csDMARDs&#44; including 13&#46;5&#37; with methotrexate&#44; the use of csDMARDs was not associated with a risk factor for adverse reaction to JAK inhibitors&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Regarding RA seropositivity &#40;RF or anti-CCP&#41;&#44; the evidence supports that it does not influence the safety of JAK inhibitor treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;26&#44;30</span></a> Similarly&#44; neither does disease progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;26&#44;29</span></a> Our study did not identify seropositivity or RA progression as predictors of adverse reactions to JAK inhibitors&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">With regard to cardiovascular risk factors &#40;CVRFs&#41;&#44; our study did not identify them as a risk factor for the adverse reactions described&#46; It is noteworthy that&#44; despite this&#44; JAK inhibitors have been associated with an increased risk of cardiovascular events in patients with CVRFs&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The data from our study suggest that&#44; as recommended by the EMA<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> and EULAR&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> special caution has been exercised in prescribing the drug for this group of patients&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">This study has limitations&#46; Firstly&#44; the size of the population and the fact that it was conducted in a single centre&#44; which must be taken into account when extrapolating the results obtained&#46; Secondly&#44; this is a retrospective observational study&#44; so the findings should be considered hypothesis-generating&#46; Nevertheless&#44; the results obtained are in line with previously published evidence&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The main strength of the study lies in the originality and appropriateness of analysing the safety of JAK inhibitors through patient visits to the emergency department&#44; which is a good observatory of clinically relevant adverse reactions&#44; easily accessible and available&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In conclusion&#44; 28&#46;7&#37; of JAK inhibitor patients visited the ED for adverse reactions related to these drugs&#46; Infections &#40;upper respiratory tract&#44; cellulitis&#44; urinary tract&#44; herpes zoster&#41; and gastrointestinal disorders &#40;abdominal pain&#44; diarrhoea&#44; nausea and vomiting&#44; gastrointestinal perforation&#44; diverticulitis&#41; represent the most common adverse reactions to JAK inhibitors&#44; with non-selective JAK inhibitor treatment and older age being risk factors for their occurrence&#46; These findings&#44; which are derived from routine clinical practice&#44; may significantly complement the currently available evidence on the safety of JAK inhibitors&#44; improving the detection and therapeutic management of adverse reactions related to these drugs&#44; and thus optimising decision-making and the prevention of ED re-visits&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ethical considerations</span><p id="par0140" class="elsevierStylePara elsevierViewall">The study was approved by the Clinical Research Ethics Committee of the Hospital de la Santa Creu i Sant Pau &#40;N&#46;&#176; Ref&#58; IIBSP-JAG-2023-168&#41;&#46; The study was conducted in accordance with the Declaration of Helsinki and related ethical standards&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that there is no specific research grant reported from any public&#44; private or non-profit funding agency&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflict of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that there is no conflict of interest that could bias or influence the impartiality of this research study&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The safety profile of Janus kinase &#40;JAK&#41; inhibitors has acquired attention due to post-marketing observed adverse drug reactions&#46; The study focuses on the analysis of adverse reactions related to tofacitinib&#44; baricitinib&#44; upadacitinib&#44; and filgotinib in rheumatoid arthritis patients&#44; including identifying predictive factors linked to their occurrence&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Observational retrospective study&#46; Adult patients with rheumatoid arthritis from a university hospital receiving JAK inhibitor treatment between September 2017 and January 2024 were included&#46; The cumulative incidence of each adverse reaction was calculated using the Naranjo scale&#46; Risk factors for developing adverse reactions were identified through logistic regression analyses&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Two hundred twenty-three patients were included&#44; with 28&#46;7&#37; presenting adverse reaction related to JAK inhibitor treatment&#46; The adverse drug reactions with the highest cumulative incidence were infections and gastrointestinal disorders&#46; Infections included&#58; upper respiratory tract &#40;4&#46;5&#37;&#41;&#44; cellulitis &#40;3&#46;1&#37;&#41;&#44; urinary tract &#40;2&#46;7&#37;&#41;&#44; herpes zoster &#40;1&#46;8&#37;&#41;&#46; Gastrointestinal disorders comprised&#58; abdominal pain &#40;4&#46;0&#37;&#41;&#44; diarrhea &#40;3&#46;6&#37;&#41;&#44; nausea and vomiting &#40;3&#46;6&#37;&#41;&#44; gastrointestinal perforation &#40;1&#46;3&#37;&#41;&#44; diverticulitis &#40;0&#46;9&#37;&#41;&#46; Classified at 0&#46;5&#37; were&#58; headache&#44; paresthesias&#44; skin rash&#44; severe neutropenia&#44; insomnia&#44; dyspnea&#44; hypertensive crisis&#46; As risk factors&#44; were identified&#58; the treatment with a non-selective JAK inhibitor &#40;OR adjusted&#58; 4&#46;03&#59; 95&#37; CI&#58; 1&#46;15&#8211;14&#46;10&#59; <span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;0&#46;029&#41; and older age &#40;OR adjusted&#58; 1&#46;03&#59; 95&#37; CI&#58; 1&#46;00&#8211;1&#46;05&#59; <span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;0&#46;036&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Infections and gastrointestinal disorders represented the adverse reactions related to JAK inhibitor treatment with the highest cumulative incidence&#44; with risk factors for their occurrence being non-selective JAK inhibitor treatment and older age of the patient&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objective"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Patients and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivo</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">La seguridad de los inhibidores de quinasa Janus &#40;JAK&#41; ha ganado atenci&#243;n debido a reacciones adversas observadas poscomercializaci&#243;n&#46; El estudio se centra en el an&#225;lisis de reacciones adversas relacionadas con tofacitinib&#44; baricitinib&#44; upadacitinib y filgotinib en pacientes con artritis reumatoide&#44; incluyendo la identificaci&#243;n de factores predictivos relacionados con su aparici&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Estudio retrospectivo observacional&#46; Se incluyeron pacientes adultos en seguimiento por artritis reumatoide en un hospital universitario&#44; en tratamiento con inhibidor de JAK entre septiembre 2017 y enero 2024&#46; Se calcul&#243; la incidencia acumulada de cada reacci&#243;n adversa mediante la escala de Naranjo&#46; Se identificaron los factores predictivos para la aparici&#243;n de reacciones adversas mediante an&#225;lisis de regresi&#243;n log&#237;stica&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 223 pacientes&#44; el 28&#44;7&#37; present&#243; reacci&#243;n adversa a inhibidor de JAK&#46; Las reacciones adversas con mayor incidencia acumulada fueron infecciones y trastornos gastrointestinales&#46; Las infecciones comprendieron&#58; tracto respiratorio superior &#40;4&#44;5&#37;&#41;&#44; celulitis &#40;3&#44;1&#37;&#41;&#44; tracto urinario &#40;2&#44;7&#37;&#41;&#44; herpes z&#243;ster &#40;1&#44;8&#37;&#41;&#46; Los trastornos gastrointestinales englobaron&#58; dolor abdominal &#40;4&#44;0&#37;&#41;&#44; diarrea &#40;3&#44;6&#37;&#41;&#44; n&#225;useas y v&#243;mitos &#40;3&#44;6&#37;&#41;&#44; perforaci&#243;n gastrointestinal &#40;1&#44;3&#37;&#41; y diverticulitis &#40;0&#44;9&#37;&#41;&#46; Con un 0&#44;5&#37; se clasificaron&#58; cefalea&#44; parestesias&#44; erupci&#243;n cut&#225;nea&#44; neutropenia severa&#44; insomnio&#44; disnea y crisis hipertensiva&#46; Como factores de riesgo&#44; se identificaron&#58; el tratamiento con inhibidor de JAK no selectivo &#40;OR ajustado&#58; 4&#44;03&#59; IC 95&#37;&#58; 1&#44;15&#8211;14&#44;10&#59;P&#8239;&#61;&#8239;0&#44;029&#41; y una mayor edad &#40;OR ajustado&#58; 1&#44;03&#59; IC 95&#37;&#58; 1&#44;00&#8211;1&#44;05&#59;P&#8239;&#61;&#8239;0&#44;036&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Infecciones y trastornos gastrointestinales representaron las reacciones adversas a inhibidor de JAK con mayor incidencia acumulada&#44; siendo los factores de riesgo para su aparici&#243;n el tratamiento con inhibidor de JAK no selectivo y una mayor edad del paciente&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Antecedentes y objetivo"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Pacientes y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "multimedia" => array:3 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Differences between groups were assessed using Fisher&#8217;s exact test or the Mann&#8211;Whitney test&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">ADR&#58; adverse drug reaction&#59; ALT&#58; alanine aminotransferase&#59; anti-CCP&#58; anti-cyclic citrullinated peptide&#59; AST&#58; aspartate transaminase&#59; CV&#58; cardiovascular&#59; CVRF&#58; cardiovascular risk factors&#59; csDMARD&#58; conventional synthetic disease-modifying antirheumatic drug&#59; DM2&#58; diabetes mellitus type II&#59; eGFR&#58; estimated glomerular filtration rate&#59; GC&#58; glucocorticoid&#59; Hb&#58; haemoglobin&#59; IQR&#58; interquartile range &#91;P25&#8211;P75&#93;&#59; JAK&#58; Janus kinase&#59; MTX&#58; methotrexate&#59; PDN&#58; prednisone&#59; RA&#58; rheumatoid arthritis&#59; RF&#58; rheumatoid factor&#59; VZV&#58; varicella-zoster virus&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients without ADR &#40;n&#8239;&#61;&#8239;159&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients with ADR &#40;n&#8239;&#61;&#8239;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P Value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total patients &#40;n&#8239;&#61;&#8239;223&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Sociodemographics</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Age &#40;years&#41;&#44; median &#91;IQR&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65 &#91;52&#8211;71&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71 &#91;60&#8211;75&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66 &#91;53&#8211;73&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sex &#40;female&#41;&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">136 &#40;85&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58 &#40;90&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;382&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">194 &#40;87&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Clinical features</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RA treatment</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>JAK inhibitor &#40;non-selective&#41;&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">132 &#40;83&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61 &#40;95&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">193 &#40;86&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Concomitant GC&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96 &#40;60&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;56&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;652&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">132 &#40;59&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PDN &#40;mg&#47;day&#41;&#44; median &#91;IQR&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#91;0&#8211;5&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#91;0&#8211;5&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;753&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#91;0&#8211;5&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Concomitant csDMARDs&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42 &#40;26&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;26&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59 &#40;26&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;15&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;9&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;288&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">30 &#40;13&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Other csDMARDs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">20 &#40;12&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11 &#40;17&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;395&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">31 &#40;13&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Seropositivity for RA&#44; n &#40;&#37;&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">96 &#40;60&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39 &#40;60&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">135 &#40;60&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-CCP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">120 &#40;75&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">41 &#40;64&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;099&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">161 &#40;72&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Change in RA &#40;years&#41;&#44; median &#91;IQR&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">14 &#91;6&#8211;25&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">17 &#91;7&#46;5&#8211;20&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;708&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">14 &#91;6&#8211;21&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>CVRF</span>&#44; n &#40;&#37;&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Smoking&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">26 &#40;16&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;20&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;559&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39 &#40;17&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Obesity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">33 &#40;20&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20 &#40;31&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;117&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">53 &#40;23&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>DM2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;20&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;019&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">26 &#40;11&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hypercholesterolemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">101 &#40;63&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">28 &#40;43&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;012&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">129 &#40;57&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hypertriglyceridemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">38 &#40;23&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">10 &#40;15&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;274&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">48 &#40;19&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CV disease</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hypertension&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">81 &#40;50&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">26 &#40;40&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;184&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">107 &#40;48&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">7 &#40;4&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">2 &#40;3&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">9 &#40;4&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cardiac arrhythmia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">15 &#40;9&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5 &#40;7&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;801&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20 &#40;9&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Parameters prior to JAK inhibitor initiation</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">129 &#91;123&#8211;139&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;667&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">129 &#91;121&#8211;140&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1&#46;9 &#91;1&#46;4&#8211;2&#46;5&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;9 &#91;1&#46;5&#8211;2&#46;6&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Neutrophils &#40;&#215;109 &#47;l&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Vaccination against ZVV&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">21 &#40;32&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cellulite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Urinary tract&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Herpes zoster&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Gastrointestinal disorder</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Abdominal pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diarrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Nausea and vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Gastrointestinal perforation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diverticulitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Nervous system disorder</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Paresthesia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Skin disorder</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Skin rash&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Blood disorder</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Severe neutropenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sleep disorder</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Insomnia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">All variables statistically significant &#40;P&#8239;&#60;&#8239;0&#46;05&#41; or borderline significant &#40;P&#8239;&#60;&#8239;0&#46;1 and &#62;&#8239;0&#46;05&#41; in the bivariate analysis were included in the multivariate analysis&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">aOR&#58; adjusted odds ratio&#59; CI&#58; confidence interval&#59; csDMARD&#58; conventional synthetic disease-modifying antirheumatic drug&#59; DM2&#58; diabetes mellitus type II&#59; JAK&#58; Janus kinase&#59; OR&#58; odds ratio&#59; RA&#58; rheumatoid arthritis&#59; VZV&#58; varicella-zoster virus&#46;</p>"
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                  \t\t\t\t">1&#46;88 &#91;0&#46;76&#8211;4&#46;66&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;174&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">0&#46;017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1&#46;03 &#91;1&#46;00&#8211;1&#46;05&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;036&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK inhibitor &#40;non-selective&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">4&#46;16 &#91;1&#46;21&#8211;14&#46;24&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;023&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;03 &#91;1&#46;15&#8211;14&#46;10&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;029&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Obesity &#40;presence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;74 &#91;0&#46;90&#8211;3&#46;33&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;098&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;57 &#91;0&#46;77&#8211;3&#46;21&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;218&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High blood pressure &#40;presence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;66 &#91;0&#46;37&#8211;1&#46;19&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;164&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VZV vaccination &#40;presence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;80 &#91;0&#46;65&#8211;4&#46;99&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;262&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypercholesterolemia &#40;presence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;45 &#91;0&#46;25&#8211;1&#46;83&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;268&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypertriglyceridemia &#40;presence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;61 &#91;0&#46;28&#8211;1&#46;31&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;202&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex &#40;female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;63 &#91;0&#46;63&#8211;4&#46;23&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;310&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Seropositivity for RA &#40;RF and&#47;or anti-CCP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;86 &#91;0&#46;61&#8211;1&#46;21&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;383&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smoking &#40;current&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;30 &#91;0&#46;62&#8211;2&#46;73&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;482&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Concomitant GC &#40;use&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;84 &#91;0&#46;47&#8211;1&#46;52&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;571&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heart failure &#40;presence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;70 &#91;0&#46;14&#8211;3&#46;47&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;663&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cardiac arrhythmia &#40;presence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;81 &#91;0&#46;28-2&#46;34&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;702&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Change in RA &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;00 &#91;0&#46;97&#8211;1&#46;03&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;952&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Concomitant csDMARD &#40;use&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;01 &#91;0&#46;52&#8211;1&#46;94&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;982&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab3699811.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Logistic regression analysis of predictive factors for adverse reactions to JAK inhibitors&#46;</p>"
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      ]
    ]
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
              "identificador" => "bib0005"
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                  "contribucion" => array:1 [
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                      "titulo" => "Drug-related visits to the emergency department&#58; how big is the problem&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "P&#46; Patel"
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                      "Revista" => array:6 [
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                            "web" => "Medline"
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            1 => array:3 [
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                    0 => array:2 [
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                      "autores" => array:1 [
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                          "etal" => false
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                            0 => "J&#46; Ruiz-Ramos"
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                  ]
                  "host" => array:1 [
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                      "doi" => "10.1093/ijpp/riad022"
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                          "etal" => true
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                            1 => "M&#46;J&#46; Faus"
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                            4 => "F&#46; Sierra"
                            5 => "J&#46; Martinez-Olmos"
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                      "doi" => "10.1007/s00228-006-0116-0"
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            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "EVADUR&#58; eventos adversos ligados a la asistencia en los servicios de urgencias de hospitales espa&#241;oles"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46; Tom&#225;s Vecina"
                            1 => "M&#46; Chanovas Borr&#224;s"
                            2 => "F&#46; Roqueta"
                            3 => "J&#46; Alcaraz"
                            4 => "T&#46; Toranzo"
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Emergencias"
                        "fecha" => "2010"
                        "volumen" => "22"
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              "etiqueta" => "5"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnosis and management of rheumatoid arthritis&#58; a review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46; Aletaha"
                            1 => "J&#46;S&#46; Smolen"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.2018.13103"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2018"
                        "volumen" => "320"
                        "paginaInicial" => "1360"
                        "paginaFinal" => "1372"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30285183"
                            "web" => "Medline"
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            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The pathogenesis of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "I&#46;B&#46; McInnes"
                            1 => "G&#46; Schett"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra1004965"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2011"
                        "volumen" => "365"
                        "paginaInicial" => "2205"
                        "paginaFinal" => "2219"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22150039"
                            "web" => "Medline"
                          ]
                        ]
                      ]
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                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs&#58; 2022 update"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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ISSN: 23870206
Original language: English
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