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ORIGINAL ARTICLE
Increased Serum Interleukin-6 and Tumor Necrosis Factor Alpha Levels in Fabry Disease: Correlation with Disease Burden
Nilton Salles Rosa Neto
Corresponding author
nsalles@yahoo.com

Corresponding author.
, Judith Campos de Barros Bento, Valéria de Falco Caparbo, Rosa Maria Rodrigues Pereira
Divisao de Reumatologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR.
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    "titulo" => "Increased Serum Interleukin-6 and Tumor Necrosis Factor Alpha Levels in Fabry Disease&#58; Correlation with Disease Burden"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Fabry disease &#40;FD&#41; is an X-linked lysosomal disease caused by pathogenic variants of the <span class="elsevierStyleItalic">GLA</span> gene&#44; which encode a defective alpha-galactosidase A enzyme&#44; contributing to substrate accumulation in several organs&#44; with varying degrees of severity and subsequent loss of organ function &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">The natural role of lysosomes includes not only substrate degradation&#44; but also the exocytosis of proteins and vesicles&#44; plasma membrane repair&#44; remodeling and growth&#44; inter-organelle and inter-cellular signaling&#44; metabolic sensing&#44; lipid metabolism&#44; and response to cell injury &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46; Moreover&#44; as regulators of the immune system&#44; lysosomes are also active players in antigenic presentation and processing&#44; secretion of perforins&#44; phagocytosis&#44; and release of pro-inflammatory mediators &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; Progressive Gb3 accumulation inside lysosomes is not sufficient to explain all aspects of FD pathology&#46; Nevertheless&#44; it is the starting point for a cascade of cellular events that ultimately disrupts the normal functioning of cells &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib4">4-6</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">After the initial trigger&#44; it is thought that energetic metabolism becomes impaired&#44; oxidative stress attains a pro-oxidative status&#44; and autophagosomes fail to mature efficiently&#46; Eventually&#44; dysfunction of the ionic membrane channels ensues&#46; In due course&#44; injury of small vessels results in tissue ischemia&#44; cell death&#44; and development of irreversible tissue fibrosis&#44; most prominently affecting the heart and kidneys &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib7">7-12</a>&#41;&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">In this context&#44; chronic inflammation is thought to contribute to organ damage in patients with FD&#46; Previous reports have evaluated the plasma levels of pro-inflammatory cytokines &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib13">13-16</a>&#41;&#44; peripheral blood mononuclear cell &#40;PBMC&#41; levels of pro-inflammatory cytokines &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#44;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#44; and functional polymorphisms of pro-inflammatory cytokine-encoding genes in patients with FD &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">This study aimed to evaluate the levels of serum inflammatory cytokines in patients with FD&#44; compared to those in healthy controls&#44; and to ascertain their correlations with the Mainz Severity Score Index &#40;MSSI&#41;&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">METHODS</span><p id="para60" class="elsevierStylePara elsevierViewall">This is a sub-analysis of the laboratory findings from the protocol &#8220;Assessment of Parameters of Bone Metabolism in patients with Fabry Disease&#44;&#8221; which was undertaken at the Rheumatology Division&#44; Faculdade de Medicina&#44; Universidade de S&#227;o Paulo&#44; S&#227;o Paulo&#44; Brazil&#46; This work was approved by the Faculdade de Medicina da Universidade de S&#227;o Paulo Ethics Review Board &#40;number 1&#46;464&#46;841&#41; on March 24&#44; 2016&#46; Written informed consent was obtained from all patients&#46; All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975&#44; as revised in 1983&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">Thirty-six genotype-confirmed classic FD patients - 15 men and 21 women &#40;variants&#58; C142R&#44; A156D&#44; L180F&#44; R227X&#44; W262X&#44; G271A&#44; P293S&#44; and Y264SX&#41; - and 25 age-matched healthy controls &#40;20 men and 8 women&#41; were assessed&#46; The MSSI &#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#41; was established after interviews with the patients and chart review&#46; Because this is a transverse study&#44; it is not possible to have a trend of MSSI values&#46; Data regarding the age at symptom onset&#44; age at diagnosis&#44; and age at treatment initiation have been previously published &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46; In summary&#44; the median age at symptom onset was 12&#46;0 years &#40;range&#44; 5-55 years&#41; and 16&#46;5 years &#40;range&#44; 9-66 years&#41; for men and women&#44; respectively&#46; The mean age at diagnosis was 35&#46;5 years for men &#40;range&#44; 8-55 years&#41; and 35&#46;9 years for women &#40;range&#44; 4-71 years&#41;&#46; The median time to diagnosis after symptom onset was 20&#46;5 years &#40;range&#44; 1-42 years&#41; for men and 14&#46;0 years &#40;range&#44; 0-52 years&#41; for women &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">Serum interleukin &#40;IL&#41;-6&#44; IL-1&#946;&#44; and tumor necrosis factor &#40;TNF&#41;-&#945; levels were evaluated using the HBNMAG-51K-13 kit&#46; The human Milliplex&#174; assay was performed using the Luminex&#174; technology kit &#40;Millipore Corporation&#44; Billerica&#44; MA&#44; USA&#41;&#44; which is a multi-analyte panel used for bone metabolism research and measures the IL-6&#44; IL-1&#946;&#44; and TNF-&#945; levels&#46;</p><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Statistical analysis</span><p id="para90" class="elsevierStylePara elsevierViewall">Results are presented as the mean and standard deviation for continuous variables and percentages for categorical variables&#46; Correlations between continuous variables were measured using Pearson&#39;s correlation coefficient&#46; Statistical significance was set at <span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#46;</p></span></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">RESULTS</span><p id="para100" class="elsevierStylePara elsevierViewall">The mean age &#40;years&#41; of the FD patients was 43&#46;1&#177;15&#46;4 and that of the control subjects was 47&#46;4&#177;12&#46;2 &#40;<span class="elsevierStyleItalic">p</span>&#62;0&#46;05&#41;&#46; Twenty-two patients &#40;59&#46;5&#37;&#41; were treated with enzyme replacement therapy &#40;ERT&#41; and no patients were treated with chaperone therapy during the assessment period&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">When all patients were included in the analysis&#44; the serum levels of IL-6 and TNF-&#945; were significantly higher than those in the healthy controls&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#46; There was no difference in the levels of IL-1&#946; between FD patients and the controls&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><p id="para120" class="elsevierStylePara elsevierViewall">When patients were separated based on sex&#44; women with FD had significantly higher serum levels of TNF-&#945; than the healthy female controls &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2</a>&#41;&#46; In contrast&#44; men with FD had significantly higher serum levels of IL-6 and TNF-&#945; than the healthy male controls &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia><elsevierMultimedia ident="fig3"></elsevierMultimedia><p id="para130" class="elsevierStylePara elsevierViewall">Patients treated with ERT exhibited higher serum IL-6 and TNF-&#945; levels than those not treated with ERT&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig4">Figure 4</a>&#46; No difference was found between the serum IL-1&#946; levels of patients treated with ERT and those that were not&#46; Cytokine levels in patients treated with and without ERT separated based on sex are available in the Appendix&#46;</p><elsevierMultimedia ident="fig4"></elsevierMultimedia><p id="para140" class="elsevierStylePara elsevierViewall">The MSSI separates patients into three categories based on severity&#58; low&#44; moderate&#44; or severe&#46; Six patients showed severe FD &#40;1 women&#47;5 men&#41;&#59; 14 patients showed moderate FD &#40;8 women&#47;6 men&#41;&#44; and 17 patients showed low-severity FD &#40;12 women&#47;5 men&#41;&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">The mean MSSI score in men with FD who were treated with ERT was not different from that of patients not treated with ERT &#40;29&#46;0&#177;11&#46;1 <span class="elsevierStyleItalic">versus</span> 26&#46;7&#177;14&#46;9&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;78&#41;&#46; In contrast&#44; in women with FD&#44; the mean score was 25&#46;8&#177;8&#46;2 for those treated with ERT and 10&#46;3&#177;7&#46;1 for those not treated with ERT &#40;<span class="elsevierStyleItalic">p</span>&#61;0&#46;0003&#41;&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">In all patients&#44; the MSSI score correlated with the serum levels of IL-6 &#40;r&#61;0&#46;60&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41; and TNF-&#945; levels &#40;r&#61;0&#46;45&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41;&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig5">Figure 5</a>&#46; However&#44; the serum IL-1&#946; levels did not correlate with the severity score &#40;r&#61;0&#46;02&#41;&#46; When separated based on sex&#44; a correlation with the MSSI score was observed only for TNF-&#945; levels &#40;r&#61;0&#46;48&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41; in women with FD and only for IL-6 levels &#40;r&#61;0&#46;77&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41; in men with FD&#46;</p><elsevierMultimedia ident="fig5"></elsevierMultimedia></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">DISCUSSION</span><p id="para170" class="elsevierStylePara elsevierViewall">The evidence presented in this study reinforces the fact that FD patients have elevated serum levels of pro-inflammatory cytokines&#46; The disease burden&#44; as estimated by the MSSI score&#44; is clearly related to higher levels of IL-6 and TNF-&#945;&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">The pro-inflammatory state has previously been described in FD&#46; There is an accumulation of Gb3 in leukocytes and subsequent changes in the subpopulations and expression of surface molecules &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#44;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#44;<a class="elsevierStyleCrossRef" href="#bib21">21</a>&#41;&#46; Invariant natural killer T cells &#40;iNKT&#41; recognize the glycosphingolipid Gb3 as an antigen presented by antigen-presenting cells and promote the release of inflammatory cytokines &#40;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#44;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#41;&#46; In addition&#44; Gb3 may work as an activator of Toll-like receptor 4 &#40;TLR4&#41; and contribute to the deregulation of the activity of both iNKT cells and dendritic cells &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#44;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#41;&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">Lysosomal deposits of Gb3 may function as damage-associated molecular patterns &#40;DAMPs&#41; or induce the production of DAMPs by damaged cells and induce pro-oxidative and pro-apoptotic patterns &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#44;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#41;&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">De Francesco et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41; reported that unstimulated PBMC from FD patients had higher levels of both IL-1&#946; and TNF-&#945;&#44; whereas IL-6 levels were not different from those of controls&#46; After 24h of cell culture&#44; these authors found the elevated production of IL-1&#946; and IL-6&#44; but not TNF-&#945;&#46; Gb3 was associated with the release of the cytokines IL-1&#946; and TNF-&#945;&#44; but not IL-6&#44; and enhanced the activity of dendritic cells and monocytes&#46; When a TLR4 inhibitor was used&#44; the inflammatory response was blocked&#44; suggesting an interaction between Gb3 and this receptor&#46; The participation of the innate immune system in this response has been highlighted&#46; Our results show elevated serum IL-6 and TNF-&#945; levels in classic FD patients&#44; while the IL-1&#946; levels were unchanged&#46; It is not possible to directly compare cellular expression <span class="elsevierStyleItalic">in vitro</span> to the serum levels <span class="elsevierStyleItalic">in vivo</span> because cytokines are released in a paracrine manner and serum levels may vary depending on several factors&#44; such as receptor binding&#44; temperature-associated degradation&#44; and breakdown within reacting cells when the subject&#39;&#180;s blood sample is drawn &#40;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#41;&#46;</p><p id="para210" class="elsevierStylePara elsevierViewall">Recently&#44; &#220;&#231;eyler et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41; found the increased expression of TNF&#44; IL-1&#946;&#44; and TLR4 in PBMCs from men with FD&#46; However&#44; the secreted TNF levels were only increased in PBMCs from men with FD with pain and classical variants and not in those without pain&#46; Nevertheless&#44; it was demonstrated that heat and lipopolysaccharide stimuli enhance TNF secretion and Gb3 accumulation&#44; linking typical triggers with FD pain&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">Biancini et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#44; using a multi-analyte panel similar to that presented herein&#44; evaluated 14 FD patients being treated with ERT and found elevated plasma levels of IL-6 and TNF-&#945; compared to those in controls&#44; and also advocated for the role of Gb3 as a promoter of inflammation&#46; However&#44; the IL-1&#946; levels were not measured in their study&#46; Similarly&#44; we found elevated serum levels of IL-6 and TNF-&#945;&#44; but not IL-1&#946;&#44; in patients with FD&#46; It is noteworthy that both the study by Biancini et al&#46; and our present study included patients being treated with ERT&#44; which may have influenced the observed results&#46; Notably&#44; the elevated levels of IL-6 found in the patients studied herein was largely due to the results from men with FD&#44; but when comparing patients undergoing ERT to those that were not&#44; the elevated IL-6 levels were driven by the women with FD&#46; Sex-associated differences in plasma IL-6 levels are not well understood&#46; The same cut-off value is typically used for both sexes&#46; Pooling of data for men and women with FD may not be accurate&#44; and reference values may require different cut-off values &#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#41;&#46; Thus&#44; data from our study were presented as both a pooled analysis and separated based on sex&#46; Overall&#44; our results suggest that patients with more severe disease&#44; and thus&#44; receiving ERT&#44; have higher serum IL-6 and TNF-&#945; levels than untreated patients&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">The MSSI score is a marker of disease severity&#46; The original work of Whybra et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#41; showed that FD patients undergoing ERT showed reduced MSSI scores after one year of treatment with agalsidase alfa&#44; particularly on account of general&#44; neurological&#44; and cardiovascular sub-scores&#46; The present study was a transverse assessment of FD patients at different disease time points&#46; The majority of the patients enrolled in this study were cared for by outside providers&#59; they had different access to healthcare and data acquisition at regular time points was not possible for many patients&#46; Although the results for the 24-hour urine protein or microalbumin measurements and echocardiograms were obtained for most patients&#44; we only collected information on broadly defined parameters&#44; as required to calculate the MSSI scores&#46; Thus&#44; it was not possible to assess the trend of how the MSSI scores changed over time&#44; nor to compare the parameters to calculate the Fabry Stabilization Index &#40;FASTEX&#41;&#44; a marker of the clinical stabilization of the disease &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">With regard to only women with FD&#44; those undergoing ERT had higher MSSI scores&#44; which reflects the current treatment guidelines&#44; which state that women with FD who are symptomatic or present with organ dysfunction are more likely to be prescribed specific treatment&#46; Therefore&#44; higher serum cytokine levels in this group may be related to a higher disease burden&#44; illustrating the indication for targeted treatment &#40;<a class="elsevierStyleCrossRef" href="#fig6">Figure S1</a>&#44; refer to Appendix&#41;&#46; Moreover&#44; the average MSSI scores and serum cytokine levels in men with FD treated with and without ERT were similar&#46; However&#44; only three men with FD were not being treated with ERT&#44; precluding proper analysis &#40;<a class="elsevierStyleCrossRef" href="#fig6">Figure S2</a>&#44; Appendix&#41;&#46;</p><elsevierMultimedia ident="fig6"></elsevierMultimedia><p id="para250" class="elsevierStylePara elsevierViewall">Interestingly&#44; Safyan et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41; studied polymorphisms of key pro- and anti-inflammatory cytokine-encoding genes in FD&#44; namely&#44; <span class="elsevierStyleItalic">IL-1&#946;</span>&#44; <span class="elsevierStyleItalic">IL-1&#945;</span>&#44; <span class="elsevierStyleItalic">TNF-&#945;</span>&#44; and IL-10&#46; These authors found that most patients had low TNF-&#945; levels and high levels of IL-10&#44; IL-1&#946;&#44; and IL-1&#945;&#46; They described a correlation between the MSSI renal and neurological sub-scores and TNF-&#945; levels &#40;<span class="elsevierStyleItalic">p</span>&#61;0&#46;06&#41; and the MSSI neurological sub-score and IL-10 levels &#40;<span class="elsevierStyleItalic">p</span>&#61;0&#46;03&#41;&#59; however&#44; the levels of none of the cytokines were correlated with alpha-galactosidase A levels&#46; Our results indicate the opposite&#44; with patients having elevated serum TNF-&#945; levels and a positive correlation of the levels of this cytokine with higher MSSI scores&#46;</p><p id="para260" class="elsevierStylePara elsevierViewall">Given that patients being treated with ERT in our study presented with elevated levels of pro-inflammatory cytokines&#44; an observation that has not been consistently reported&#44; this raises several questions&#58; a&#41; whether ERT alone fails to adequately suppress the inflammatory process&#59; b&#41; whether ERT itself contributes to the inflammatory process&#59; c&#41; whether specialists should research the possible use of anti-inflammatory or immunomodulatory drugs in the care of patients with FD&#59; and d&#41; whether there is a point of no return after which ERT is no longer beneficial for a specific target organ and the degree of tissue damage &#40;or fibrosis&#41; may contribute to persistent inflammation and lead to organ failure regardless of the treatment&#46; As reviewed by Rozenfeld and Feriozzi &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#44; fibrosis is a common finding in the heart and kidney of FD patients&#59; it is driven by TGF-&#946;1 and TLR4 activation&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">This study also has a few limitations&#46; We evaluated the serum levels of these cytokines&#44; while previous publications reported their plasma or PBMC levels&#59; therefore&#44; these values are not directly comparable&#46; As a transverse study&#44; the measurement of cytokine levels was performed only once&#44; and the cytokine levels prior to ERT or at the time of FD diagnosis were not measured&#46; Similarly&#44; the MSSI scores were assessed only once&#44; and it is not possible to evaluate the impact of ERT on these results&#44; to establish a trend of MSSI scores&#44; or to calculate the FASTEX scores&#46; Interpretation of the correlations between the cytokine levels and MSSI scores reported in this study should consider all these aspects&#46; In addition&#44; the low number of untreated men with FD hampered additional comparisons&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">Nevertheless&#44; a thorough review was performed to ensure the validity of the MSSI scores at the time of assessment&#46; The patients showed different degrees of kidney and heart damage&#44; and several parameters&#44; including hemodialysis&#44; patient status post kidney transplantation&#44; treatment with different immunosuppressive regimens&#44; delayed time to adequate diagnosis&#44; and specific treatment initiation&#44; were considered in this review&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">CONCLUSION</span><p id="para290" class="elsevierStylePara elsevierViewall">In the patient cohort studied herein&#44; FD was associated with elevated serum levels of IL-6 and TNF-&#945;&#46; Patients with FD that received ERT&#44; particularly&#44; women&#44; showed higher levels of serum IL-6 and TNF-&#945; than those that did not receive ERT&#59; the levels of serum IL-6 and TNF-&#945; were correlated with the MSSI scores reflecting a greater disease burden&#46; Further studies assessing the levels of inflammatory cytokines pre- and post-infusion in treatment-na&#239;ve patients and comparisons to migalastat-treated patients prior to therapy initiation and after determined timepoints may provide additional information regarding this topic&#46;</p><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Conflicts of Interests</span><p id="para300" class="elsevierStylePara elsevierViewall">NSRN declares having received speaker&#39;s and advisory board fees from Shire HGT&#44; now Takeda Pharmaceuticals&#46; JCBB declares that their spouse received speaker&#39;s and advisory board fees from Shire HGT&#44; now Takeda Pharmaceuticals&#46;</p></span></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">AUTHOR CONTRIBUTIONS</span><p id="para310" class="elsevierStylePara elsevierViewall">Rosa Neto NS designed the study&#44; collected&#44; analyzed&#44; interpreted the data and wrote the manuscript&#46; Bento JCB collected the data&#46; Caparbo VF collected the data&#46; Pereira RMR analyzed and interpreted the data and reviewed the manuscript&#46; All of the authors have read and approved the final version of the manuscript&#46;</p></span></span>"
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            0 => "Fabry Disease"
            1 => "<span class="elsevierStyleItalic">GLA</span> Gene"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">Fabry disease &#40;FD&#41; is an X-linked lysosomal disease caused by variants of the <span class="elsevierStyleItalic">GLA</span> gene&#59; the formation of defective alpha-galactosidase A contributes to the accumulation of substrates in several organs&#46; Chronic inflammation is thought to contribute to organ damage in FD patients&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">In total&#44; 36 classic FD patients &#40;15 men&#47;21 women&#41; and 25 healthy controls &#40;20 men&#47;8 women&#41; were assessed&#46; The Mainz Severity Score Index &#40;MSSI&#41; was established after conducting interviews with the patients and chart review&#46; Serum IL-6&#44; IL-1&#946;&#44; and TNF-&#945; levels were evaluated in both groups&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">The mean age &#40;years&#41; for FD patients was 43&#46;1&#177;15&#46;4 and that for the controls was 47&#46;4&#177;12&#46;2 &#40;<span class="elsevierStyleItalic">p</span>&#62;0&#46;05&#41;&#46; Twenty-two patients &#40;59&#46;5&#37;&#41; were treated with enzyme replacement therapy &#40;ERT&#41;&#46; Serum IL-6 and TNF-&#945; levels were significantly higher in FD patients than in the controls&#46; Patients treated with ERT had higher serum IL-6 and TNF-&#945; levels than those not treated with ERT&#46; There was no difference in the serum IL-1&#946; levels between patients treated with ERT and those who were not&#46; The MSSI scores in the patients were correlated with serum levels of IL-6 &#40;r&#61;0&#46;60&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41; and TNF-&#945; &#40;r&#61;0&#46;45&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">FD was associated with elevated serum levels of IL-6 and TNF-&#945; in this cohort&#46; The FD patients treated with ERT&#44; particularly&#44; women&#44; exhibited higher levels of serum IL-6 and TNF-&#945; than those not treated with ERT&#59; the serum IL-6 and TNF-&#945; levels were correlated with the MSSI scores reflecting greater disease burden&#46;</p></span>"
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        "texto" => "<p id="para320" class="elsevierStylePara elsevierViewall">The authors would like to acknowledge Rachel Sayuri Honjo Kawahira&#44; Jaelson Guilhem Gomes&#44; Ana Carolina de Paula&#44; and Rosiane Lacerda for the referral of the FD patients&#46; This study was funded by the Brazilian Society of Rheumatology Research Fund&#46; The Brazilian Society of Rheumatology had no role in the design of the study&#44; collection&#44; analysis&#44; and interpretation of data&#44; or in writing the manuscript&#46;</p>"
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Article information
ISSN: 18075932
Original language: English
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