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<span class="elsevierStyleItalic">tocilizumab</span>&#44; inhibits IL-6&#44; which participates in the inflammatory mechanisms and joint destruction&#59; <span class="elsevierStyleItalic">anakinra</span>&#44; which blocks the activity of IL-1 by competitively inhibiting its binding to the receptor IL-1R1&#59; and <span class="elsevierStyleItalic">ustekinumab</span> &#40;IgG1kappa monoclonal antibody&#44; that inhibits IL-12&#47;IL-23&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Drugs that interfere with the activity of certain cell lines&#58; <span class="elsevierStyleItalic">abatacept</span> &#40;which inhibits binding of CD28 and CD80&#44; blocking the costimulatory signal of T cells&#41;&#59; <span class="elsevierStyleItalic">rituximab</span> &#40;depletion of CD20-positive B cells&#41;&#46;</p></li></ul></p><p id="par0045" class="elsevierStylePara elsevierViewall">In this review&#44; 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has a major role in the pathogenesis of multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a> It is a proinflammatory cytokine that participates in the acute phase of the disease and in the demyelinating process&#46; On the other hand&#44; TNF&#945; also has immunosuppressive properties in the second phase of the disease&#46; These properties are related to the TNF&#945; receptors &#40;TNFR1 and TNFR2&#41;&#44; which measure different biological responses to TNF&#945; itself&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In the central nervous system&#44; TNF&#945; is produced by microglia&#44; astrocytes and other cells&#44; such as the monomer precursor transmembrane protein &#40;tmTNF&#41;&#46; The TNF&#945; converting enzyme disassociates from the cytoplasmic tail and releases soluble forms of TNF&#945; &#40;sTNF&#41;&#46; To carry out its biological functions&#44; the monomeric forms of tmTNF and sTNF should aggregate and form homodimers&#46; Both TNF &#40;tmTNF and sTNF&#41; can bind to both TNFR1 and TNFR2&#59; sTNF has a greater affinity to TNFR1&#44; producing the inflammatory response and apoptosis&#46; tmTNF binds mostly to TNFR2 and promotes cell activation and survival&#46; Transgenic mice have been used to study how the isolated expression of tmTNF can avoid and suppress the progression of experimental autoimmune encephalitis&#44; as it also maintains self-tolerance and resistance to infection&#46; Thus&#44; selective inhibition of the sTNF&#47;TNFR1 signal could be used as a strategy to prevent relapses in multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Taking this theory into account&#44; 4 major hypotheses have been postulated to explain a potential biological relationship between TNF antagonists and demyelinating disease&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">a&#41;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Anti-TNF&#945; do not cross the blood-brain barrier&#44; but they enhance the activity through an increase in the autoreactive peripheral T cells&#44; that can penetrate the central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">12</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">b&#41;</span><p id="par0110" class="elsevierStylePara elsevierViewall">The necessarily reduced regulation of TNFR2 for the proliferation of oligodendrocytes and repair of the damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">12&#44;13</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">c&#41;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Reduced regulation and production of cytokines like IL-10&#44; and overproduction and regulation of IL-12 and interferon &#947; &#40;IFN-&#947;&#41; associated with the demyelinating process&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">14&#44;15</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">d&#41;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Anti-TNF&#945; could camouflage a latent infection that&#44; in turn&#44; could be critical to initiate a demyelinating autoimmune process&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">16</span></a></p></li></ul></p><p id="par0125" class="elsevierStylePara elsevierViewall">Kaltsonoudis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> conducted a prospective study in 77 patients with inflammatory rheumatic disease &#40;36 patients with rheumatoid arthritis&#44; 24 patients with psoriatic arthritis and 17 patients with ankylosing spondylitis&#41; who began with anti-TNF&#945; &#40;infliximab&#44; adalimumab&#44; etanercept&#41;&#46; All underwent a complete neurological examination&#44; nuclear magnetic resonance of the brain and the entire spine&#44; and a neurophysiology study before and more than 18 months after starting the biological therapy&#46; In the initial scrutiny&#44; they detected lesions compatible with demyelinating disease in magnetic resonance in 2 patients and&#44; thus&#44; decided against the biological treatment&#46; At the end of the study&#44; 4&#37; of the patients &#40;3&#47;75&#41; showed evidence of neurological involvement&#58; peripheral demyelinating neuropathy &#40;2 patients&#41; and optic neuritis&#46; In each case&#44; the biological therapy was interrupted and the neurological disease was treated&#46; The neurological symptoms remitted in all the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> The authors stress the importance of magnetic resonance and the neurophysiological study for the early detection of neurological involvement in these patients&#59; however&#44; to perform these ancillary tests in every patient who begins biological therapy would significantly increase the expense and would probably not be cost-effective&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Types of Neurological Involvement and Care Review</span><p id="par0130" class="elsevierStylePara elsevierViewall">Nanau et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> carried out a systematic review of the safety of TNF&#945; inhibitors in patients with inflammatory rheumatic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> They included the publication of clinical trials and case reports published between 2010 and 2014&#46; The majority of the neurological adverse events were observed in patients with rheumatoid arthritis&#59; 50&#46;9&#37; over a 10-year period&#44; according to the authors&#46; The most common finding was the involvement of the central nervous system&#44; the spectrum of demyelinating diseases&#44; optic neuritis and sensory and&#47;or motor demyelinating peripheral neuropathy&#46; The remainder of the neurological events&#44; such as transverse myelitis or progressive multifocal leukoencephalopathy&#44; were less common&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">5&#44;17</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In a French cohort&#44; 33 patients with inflammatory rheumatic disease revealed evidence of demyelinating disease on magnetic resonance&#46; They were treated with anti-TNF&#945; for 3 years&#44; and 2&#47;3 of the patients developed involvement of the central nervous system &#40;encephalitis&#44; transverse myelitis and optic neuritis&#41;&#44; and 1&#47;3 showed peripheral involvement &#40;chronic demyelinating polyneuropathy&#44; Guillain-Barr&#233; syndrome&#41;&#46; The examination of the cerebrospinal fluid showed raised protein levels in 4 cases&#44; oligoclonal bands in 11 and pleocytosis in 4&#46; It was normal in 6 patients&#44; despite central nervous system involvement&#46; In 90&#37; of the cases of peripheral nervous system involvement&#44; the study of the cerebrospinal fluid revealed raised protein levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">5&#44;25</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">On the other hand&#44; if we take into account the number of times that the images from nuclear magnetic resonance were suggestive of demyelination&#44; the diagnosis of multiple sclerosis itself is not so common&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">26&#8211;28</span></a> In many cases&#44; the patient did not meet the diagnostic criteria for multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a> In a Danish series involving 550 patients receiving biological therapy&#44; 6 developed symptoms suggestive of demyelinating disease and 4 met the diagnostic criteria once the study had been completed&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> In short&#44; not all demyelinating involvement will be a manifestation of multiple sclerosis&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Progressive multifocal leukoencephalopathy is a subacute infection of the central nervous system associated with oligodendrocyte destruction by John Cunningham virus &#40;JC virus&#41;&#46; Reactivation of JC virus occurs under conditions of immunosuppression&#46; The symptoms include confusion&#44; motor impairment&#44; impaired coordination&#44; speech disorders and visual disturbances&#46; Seizures are not very common&#46; The areas of demyelination can be seen in the occipital and parietal regions&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">30&#44;31</span></a> The confirmation of the diagnosis is obtained when the virus is identified in cerebrospinal fluid culture or in a brain biopsy&#46; As the incidence of JC virus is somewhat greater in patients treated with rituximab&#44; in patients with anti-TNF&#945; it is low&#44; and is comparable to that of the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a> A total of 15 cases of JC virus have been reported in the <span class="elsevierStyleItalic">Food and Drug Administration Adverse Event Reporting System</span> database&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> Infliximab and adalimumab have been more closely related to JC virus reactivation&#44; according to the Health Canada Drug Product Database and the World Health Organization &#40;WHO&#41; adverse effects database&#46; However&#44; there are also cases with other anti-TNF&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> The association between rituximab and progressive multifocal leukoencephalopathy is better known&#44; with the majority of the reported cases occurring in patients with rheumatoid arthritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">23&#44;24</span></a> Nevertheless&#44; it should be taken into account that rituximab&#44; in contrast to other biological drugs&#44; is used to treat other nonrheumatic diseases&#44; like hematological and neurological disorders&#59; thus&#44; this other group of diseases would also contribute to increasing the prevalence of progressive multifocal leukoencephalopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">22&#44;33&#8211;36</span></a> Other adverse effects related to rituximab are&#58; enterovirus myofasciitis&#44; infectious polyneuropathy &#40;West Nile virus&#41; and encephalitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">34&#8211;36</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Finally&#44; bradykinetic syndromes are rare&#46; There is only 1 case reported in the literature&#44; in a patient with Parkinson&#39;s disease&#44; which was rapidly established 1 year after treatment was begun with anti-TNF&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a> Nevertheless&#44; the database of the Spanish Pharmacovigilance System locates a number of cases relating anti-TNF&#945; with parkinsonian syndromes&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">2</span></a> The Who database provides more than 70 cases that relate anti-TNF&#945; with parkinsonism&#46; However&#44; since the data cannot be accessed&#44; it is impossible to determine whether or not there is a clear causal relationship&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Paradoxically&#44; there may be a relationship between the family of TNF&#945; receptors and <span class="elsevierStyleItalic">caspases</span>&#44; which participate in the pathogenesis of Parkinson&#39;s disease&#46; It has been reported that TNF&#945; could be toxic for midbrain dopaminergic neurons&#44; which are also involved in the development of the disease&#46; If this hypothesis were to be true&#44; TNF&#945; inhibitors would be beneficial&#44; rather than harmful&#46; Belarbi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> carried out an experimental study in rats that demonstrated that inhibiting the synthesis of TNF&#945; reestablished the neuronal function and the cognitive deficits induced by chronic inflammation of the nervous tissue&#46; These authors concluded that the inhibition of TNF&#945; could be a future therapeutic target in the spectrum of neurodegenerative diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> Nonetheless&#44; the results are contradictory and&#44; thus&#44; additional studies will be necessary to shed light on this question&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> is included to summarize the cases reported in the literature over the last 10 years&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">We should not forget the secondary manifestations of the underlying rheumatic disease&#46; Taking into account the fact that most rheumatic diseases have a more or less important systemic component&#44; the differential diagnosis is essential and indispensable&#46; At times&#44; it may be difficult to distinguish whether the neurological involvement is produced by the treatment or is due to the disease itself&#44; even after doing the appropriate ancillary tests&#46; Moreover&#44; the heterogeneity of the series of cases and of the isolated cases reported in the literature makes it difficult to establish a causal relationship between the anti-TNF&#945; drug and the neurological involvement&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Recommendations and Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">The interruption of the biological treatment should be considered if there is any reservation about the diagnosis&#46; This decision must be made by the clinician&#44; taking into account the risk-benefit of discontinuing biological therapy in each patient on an individualized basis&#46; When the neurological involvement is serious&#44; the standard treatment is the administration of glucocorticoids&#46; Immunoglobulins have not often been necessary&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">5&#44;25</span></a> The remission of the neurological signs is not always complete in all the patients&#44; even when the biological therapy has been interrupted&#46; The decision to restore it depends on neurological concerns and on whether a cause&#8211;effect relationship has been established&#46; In clear terms&#44; &#8220;not everything that happens to the patient will be due to the biological therapy&#8221;&#46; Nevertheless&#44; if the doubt exists&#44; the best approach is to discontinue the drug and&#44; if the patient&#39;s disease is still active&#44; the therapeutic target should be changed&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">In conclusion&#44; as rheumatologists&#44; we must be aware of and be familiarized with the adverse effects of the therapies we administer in our routine clinical practice&#44; although some may be infrequent&#46; It is of the utmost importance that they be reported&#44; even if we cannot be sure of a cause-and-effect relationship&#46; Spanish rheumatologists are fortunate to count on the BIOBADASER registry&#44; which facilitates our work when we need to review the effects that we must bear in mind and their distribution among the Spanish population&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Disclosures</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0225" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0230" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Biological therapy has changed the course of inflammatory rheumatic diseases&#46; The safety is well documented in national and international studies&#46; Neurological manifestations are uncommon and it is difficult to establish a clear causal relationship&#46; The neurological signs and symptoms that may appear are multiple and sometimes mimic demyelinating neurological diseases and&#47;or neurodegenerative diseases&#46; Knowledge and disclosure of these cases is essential for a comprehensive management of biological therapy in our patients&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La terapia biol&#243;gica ha cambiado el curso de las enfermedades reum&#225;ticas inflamatorias&#46; La seguridad de la misma est&#225; m&#225;s que documentada en diferentes estudios nacionales e internacionales&#46; La baja frecuencia de las manifestaciones neurol&#243;gicas dificulta en muchas ocasiones el establecer una relaci&#243;n causal clara entre el tratamiento biol&#243;gico y la cl&#237;nica neurol&#243;gica propiamente dicha&#46; Los s&#237;ntomas y signos neurol&#243;gicos que pueden aparecer son m&#250;ltiples&#44; y en ocasiones simulan enfermedades neurol&#243;gicas desmielinizantes y&#47;o neurodegenerativas&#46; El conocimiento y el reporte de los mismos es fundamental para realizar un manejo exhaustivo de la terapia biol&#243;gica en nuestros pacientes&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Tejera-Segura B&#44; Ferraz-Amaro I&#46; Terapias biol&#243;gicas y manifestaciones neurol&#243;gicas&#46; &#191;Qu&#233; sabemos&#63; 2017&#59;13&#58;102&#8211;106&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">ADA&#44; adalimumab&#59; CNS&#44; central nervous system&#59; CSF&#44; cerebrospinal fluid&#59; ETN&#44; etanercept&#59; IFX&#44; infliximab&#59; JIA&#44; juvenile idiopathic arthritis&#59; NMR&#44; nuclear magnetic resonance&#59; PML&#44; progressive multifocal leukoencephalopathy&#59; RTX&#44; rituximab&#59; TNF&#44; tumor necrosis factor&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Series&#47;review of cases over the last 10 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rheumatic disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Neurological manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Nanau et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> &#40;review of all their cases 2010&#8211;2014&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#41;<br>Spondyloarthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;<br>JIA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Rhupus &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>Total &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;<br>ETN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;<br>IFX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Demyelinating and&#47;or chronic&#47;acute inflammatory neuropathies &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;<br>PML &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41;<br>Multiple sclerosis-like disease &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;<br>Encephalitis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;<br><span class="elsevierStyleItalic">De novo</span> demyelination of no known cause &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;<br>Optic neuritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Transverse myelitis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>Cervical myelopathy &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="10" align="left" valign="top">Depending on the diagnosis&#44; the patients underwent&#58; NMR&#44; electrophysiological study&#44; screening for infection &#40;serological and CSF study&#41;<br></td><td class="td" title="table-entry  " rowspan="10" align="left" valign="top">Discontinuation of TNF&#945;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>glucocorticoids&#44; immunosuppressive therapy &#40;depending on whether or not the neurological involvement was reversible&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fern&#225;ndez-Espartero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> &#40;series of 21&#44;425<br>patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown<br>Total &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>ETN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;<br>IFX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Demyelinating disease of no known cause &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;<br>Optic neuritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Multiple sclerosis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Kaltsonoudis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> &#40;series of 77 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>Spondyloarthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>ETN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>IFX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sensory&#47;motor demyelinating neuropathy &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Optic neuritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Theibich et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> &#40;series of 550 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple sclerosis-like disease &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;<br>Demyelinating<br>neuropathy &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fromont et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a> &#40;case reports&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS demyelination &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Winkelmann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a> &#40;case reports&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spondyloarthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS demyelination &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Bendsouda et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a><br>&#40;1 case report&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple sclerosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Healy et al&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Enterovirus-associated fasciitis&#44; meningitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Clifford et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PML&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fleischmann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PML&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Summary of the Series of Patients With Rheumatic Diseases Reported Over the Past 10 Years&#46;</p>"
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Review article
Biological Therapy and Neurological Manifestations. What do We Know?
Terapias biológicas y manifestaciones neurológicas. ¿Qué sabemos?
Beatriz Tejera-Segura
Corresponding author
btejerasegura@gmail.com

Corresponding author.
, Iván Ferraz-Amaro
Servicio de Reumatología, Hospital Universitario de Canarias, Tenerife, Spain
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      "titulo" => "Vitamin D Insufficiency and Deficiency in Mexican Patients With Systemic Lupus Erythematosus&#58; Prevalence and Relationship With Disease Activity"
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    "titulo" => "Biological Therapy and Neurological Manifestations&#46; What do We Know&#63;"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Since the commencement of the age of biological treatments&#44; the prognosis of most inflammatory rheumatic diseases has improved significantly&#46; Both the drugs that inhibit the proinflammatory cytokine&#44; tumor necrosis factor alpha &#40;TNF&#945;&#41;&#44; and those that inhibit other interleukins &#40;IL&#41; and cells that participate in the mechanism of inflammation&#44; have definitively changed the course of many chronic rheumatic diseases&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">At present&#44; the safety of these drugs over the intermediate and long term is well-documented in different national and international studies&#44; based mostly on patient registries that are followed prospectively&#46; The outcomes in some of them are divergent&#44; since the sample to be studied&#44; the data collection and even the analysis&#44; are far from being similar&#46; However&#44; in general&#44; all coincide in that infections and hypersensitivity reactions are the most common adverse effects&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The biological drugs currently available in Spain are as follows<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">1&#44;2</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Drugs that act as TNF&#945; inhibitors and can block the molecule itself <span class="elsevierStyleItalic">&#40;infliximab&#44; adalimumab</span>&#44; <span class="elsevierStyleItalic">golimumab</span>&#44; <span class="elsevierStyleItalic">certolizumab&#41;</span> or its receptor <span class="elsevierStyleItalic">&#40;etanercept&#41;</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Drugs that inhibit other IL&#58; <span class="elsevierStyleItalic">tocilizumab</span>&#44; inhibits IL-6&#44; which participates in the inflammatory mechanisms and joint destruction&#59; <span class="elsevierStyleItalic">anakinra</span>&#44; which blocks the activity of IL-1 by competitively inhibiting its binding to the receptor IL-1R1&#59; and <span class="elsevierStyleItalic">ustekinumab</span> &#40;IgG1kappa monoclonal antibody&#44; that inhibits IL-12&#47;IL-23&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Drugs that interfere with the activity of certain cell lines&#58; <span class="elsevierStyleItalic">abatacept</span> &#40;which inhibits binding of CD28 and CD80&#44; blocking the costimulatory signal of T cells&#41;&#59; <span class="elsevierStyleItalic">rituximab</span> &#40;depletion of CD20-positive B cells&#41;&#46;</p></li></ul></p><p id="par0045" class="elsevierStylePara elsevierViewall">In this review&#44; we will focus mainly on <span class="elsevierStyleItalic">anti-TNF&#945; drugs</span> since there are nearly no cases of neurological involvement with the remainder&#44; probably&#44; among other things&#44; because they have been available for less time&#46; These neurological manifestations are uncommon during treatment with biological drugs&#44; but this does not mean that they are less important&#46; They can also be irreversible&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Since these agents are being utilized&#44; a number of isolated events and series of cases have been published&#44; although it is still hard to establish a definite cause-and-effect relationship&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">3&#8211;5</span></a> The neurological finding most widely described in the literature is the demyelination of the central and&#47;or peripheral nervous system&#44; but others have also been reported&#58; optic neuritis&#44; acute&#47;chronic inflammatory polyneuropathy&#44; mononeuritis multiplex and Guillain-Barr&#233; syndrome&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">6&#8211;9</span></a> All of the guidelines on the use of biological therapy contraindicate their administration to patients with multiple sclerosis&#44; and precaution when there is a family history of the disease&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">However&#44; the debate on whether biological treatment can disguise the development of a preexisting demyelinating disease&#44; such as multiple sclerosis or&#44; on the other hand&#44; is responsible for inducing <span class="elsevierStyleItalic">de novo</span> demyelination in the central and&#47;or peripheral nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0060" class="elsevierStylePara elsevierViewall">In initial studies&#44; it was reported that the risk of developing a demyelinating disease increased by 30&#37; with the use of biological therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a> According to the Spanish registry of adverse events in biological therapies in rheumatic diseases &#40;BIOBADASER&#41;&#44; the incidence is low&#44; between 0&#46;3 and 0&#46;6 for each 1&#44;000 person-years of exposure&#46; In BIOBADASER&#44; after a follow-up of 9256 patients &#40;21&#44;425 person-years&#41;&#44; 9 cases were reported&#44; meaning that the rate of demyelinating disease in patients treated with anti-TNF&#945; was not greater than that expected in the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a> The cases of demyelinating disease were more frequent among patients of more advanced age&#44; men and those diagnosed as having psoriatic arthritis&#44; although in no case were the differences statistically significant&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis</span><p id="par0070" class="elsevierStylePara elsevierViewall">The mechanism that leads a patient to be predisposed to develop a demyelinating disease or experience an exacerbation of that disease once the biological treatment has begun is unknown&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">A number of hypotheses that have been proposed suggest that TNF&#945; has a major role in the pathogenesis of multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a> It is a proinflammatory cytokine that participates in the acute phase of the disease and in the demyelinating process&#46; On the other hand&#44; TNF&#945; also has immunosuppressive properties in the second phase of the disease&#46; These properties are related to the TNF&#945; receptors &#40;TNFR1 and TNFR2&#41;&#44; which measure different biological responses to TNF&#945; itself&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In the central nervous system&#44; TNF&#945; is produced by microglia&#44; astrocytes and other cells&#44; such as the monomer precursor transmembrane protein &#40;tmTNF&#41;&#46; The TNF&#945; converting enzyme disassociates from the cytoplasmic tail and releases soluble forms of TNF&#945; &#40;sTNF&#41;&#46; To carry out its biological functions&#44; the monomeric forms of tmTNF and sTNF should aggregate and form homodimers&#46; Both TNF &#40;tmTNF and sTNF&#41; can bind to both TNFR1 and TNFR2&#59; sTNF has a greater affinity to TNFR1&#44; producing the inflammatory response and apoptosis&#46; tmTNF binds mostly to TNFR2 and promotes cell activation and survival&#46; Transgenic mice have been used to study how the isolated expression of tmTNF can avoid and suppress the progression of experimental autoimmune encephalitis&#44; as it also maintains self-tolerance and resistance to infection&#46; Thus&#44; selective inhibition of the sTNF&#47;TNFR1 signal could be used as a strategy to prevent relapses in multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Taking this theory into account&#44; 4 major hypotheses have been postulated to explain a potential biological relationship between TNF antagonists and demyelinating disease&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">a&#41;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Anti-TNF&#945; do not cross the blood-brain barrier&#44; but they enhance the activity through an increase in the autoreactive peripheral T cells&#44; that can penetrate the central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">12</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">b&#41;</span><p id="par0110" class="elsevierStylePara elsevierViewall">The necessarily reduced regulation of TNFR2 for the proliferation of oligodendrocytes and repair of the damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">12&#44;13</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">c&#41;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Reduced regulation and production of cytokines like IL-10&#44; and overproduction and regulation of IL-12 and interferon &#947; &#40;IFN-&#947;&#41; associated with the demyelinating process&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">14&#44;15</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">d&#41;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Anti-TNF&#945; could camouflage a latent infection that&#44; in turn&#44; could be critical to initiate a demyelinating autoimmune process&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">16</span></a></p></li></ul></p><p id="par0125" class="elsevierStylePara elsevierViewall">Kaltsonoudis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> conducted a prospective study in 77 patients with inflammatory rheumatic disease &#40;36 patients with rheumatoid arthritis&#44; 24 patients with psoriatic arthritis and 17 patients with ankylosing spondylitis&#41; who began with anti-TNF&#945; &#40;infliximab&#44; adalimumab&#44; etanercept&#41;&#46; All underwent a complete neurological examination&#44; nuclear magnetic resonance of the brain and the entire spine&#44; and a neurophysiology study before and more than 18 months after starting the biological therapy&#46; In the initial scrutiny&#44; they detected lesions compatible with demyelinating disease in magnetic resonance in 2 patients and&#44; thus&#44; decided against the biological treatment&#46; At the end of the study&#44; 4&#37; of the patients &#40;3&#47;75&#41; showed evidence of neurological involvement&#58; peripheral demyelinating neuropathy &#40;2 patients&#41; and optic neuritis&#46; In each case&#44; the biological therapy was interrupted and the neurological disease was treated&#46; The neurological symptoms remitted in all the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> The authors stress the importance of magnetic resonance and the neurophysiological study for the early detection of neurological involvement in these patients&#59; however&#44; to perform these ancillary tests in every patient who begins biological therapy would significantly increase the expense and would probably not be cost-effective&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Types of Neurological Involvement and Care Review</span><p id="par0130" class="elsevierStylePara elsevierViewall">Nanau et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> carried out a systematic review of the safety of TNF&#945; inhibitors in patients with inflammatory rheumatic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> They included the publication of clinical trials and case reports published between 2010 and 2014&#46; The majority of the neurological adverse events were observed in patients with rheumatoid arthritis&#59; 50&#46;9&#37; over a 10-year period&#44; according to the authors&#46; The most common finding was the involvement of the central nervous system&#44; the spectrum of demyelinating diseases&#44; optic neuritis and sensory and&#47;or motor demyelinating peripheral neuropathy&#46; The remainder of the neurological events&#44; such as transverse myelitis or progressive multifocal leukoencephalopathy&#44; were less common&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">5&#44;17</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In a French cohort&#44; 33 patients with inflammatory rheumatic disease revealed evidence of demyelinating disease on magnetic resonance&#46; They were treated with anti-TNF&#945; for 3 years&#44; and 2&#47;3 of the patients developed involvement of the central nervous system &#40;encephalitis&#44; transverse myelitis and optic neuritis&#41;&#44; and 1&#47;3 showed peripheral involvement &#40;chronic demyelinating polyneuropathy&#44; Guillain-Barr&#233; syndrome&#41;&#46; The examination of the cerebrospinal fluid showed raised protein levels in 4 cases&#44; oligoclonal bands in 11 and pleocytosis in 4&#46; It was normal in 6 patients&#44; despite central nervous system involvement&#46; In 90&#37; of the cases of peripheral nervous system involvement&#44; the study of the cerebrospinal fluid revealed raised protein levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">5&#44;25</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">On the other hand&#44; if we take into account the number of times that the images from nuclear magnetic resonance were suggestive of demyelination&#44; the diagnosis of multiple sclerosis itself is not so common&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">26&#8211;28</span></a> In many cases&#44; the patient did not meet the diagnostic criteria for multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a> In a Danish series involving 550 patients receiving biological therapy&#44; 6 developed symptoms suggestive of demyelinating disease and 4 met the diagnostic criteria once the study had been completed&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> In short&#44; not all demyelinating involvement will be a manifestation of multiple sclerosis&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Progressive multifocal leukoencephalopathy is a subacute infection of the central nervous system associated with oligodendrocyte destruction by John Cunningham virus &#40;JC virus&#41;&#46; Reactivation of JC virus occurs under conditions of immunosuppression&#46; The symptoms include confusion&#44; motor impairment&#44; impaired coordination&#44; speech disorders and visual disturbances&#46; Seizures are not very common&#46; The areas of demyelination can be seen in the occipital and parietal regions&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">30&#44;31</span></a> The confirmation of the diagnosis is obtained when the virus is identified in cerebrospinal fluid culture or in a brain biopsy&#46; As the incidence of JC virus is somewhat greater in patients treated with rituximab&#44; in patients with anti-TNF&#945; it is low&#44; and is comparable to that of the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a> A total of 15 cases of JC virus have been reported in the <span class="elsevierStyleItalic">Food and Drug Administration Adverse Event Reporting System</span> database&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> Infliximab and adalimumab have been more closely related to JC virus reactivation&#44; according to the Health Canada Drug Product Database and the World Health Organization &#40;WHO&#41; adverse effects database&#46; However&#44; there are also cases with other anti-TNF&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> The association between rituximab and progressive multifocal leukoencephalopathy is better known&#44; with the majority of the reported cases occurring in patients with rheumatoid arthritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">23&#44;24</span></a> Nevertheless&#44; it should be taken into account that rituximab&#44; in contrast to other biological drugs&#44; is used to treat other nonrheumatic diseases&#44; like hematological and neurological disorders&#59; thus&#44; this other group of diseases would also contribute to increasing the prevalence of progressive multifocal leukoencephalopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">22&#44;33&#8211;36</span></a> Other adverse effects related to rituximab are&#58; enterovirus myofasciitis&#44; infectious polyneuropathy &#40;West Nile virus&#41; and encephalitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">34&#8211;36</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Finally&#44; bradykinetic syndromes are rare&#46; There is only 1 case reported in the literature&#44; in a patient with Parkinson&#39;s disease&#44; which was rapidly established 1 year after treatment was begun with anti-TNF&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a> Nevertheless&#44; the database of the Spanish Pharmacovigilance System locates a number of cases relating anti-TNF&#945; with parkinsonian syndromes&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">2</span></a> The Who database provides more than 70 cases that relate anti-TNF&#945; with parkinsonism&#46; However&#44; since the data cannot be accessed&#44; it is impossible to determine whether or not there is a clear causal relationship&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Paradoxically&#44; there may be a relationship between the family of TNF&#945; receptors and <span class="elsevierStyleItalic">caspases</span>&#44; which participate in the pathogenesis of Parkinson&#39;s disease&#46; It has been reported that TNF&#945; could be toxic for midbrain dopaminergic neurons&#44; which are also involved in the development of the disease&#46; If this hypothesis were to be true&#44; TNF&#945; inhibitors would be beneficial&#44; rather than harmful&#46; Belarbi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> carried out an experimental study in rats that demonstrated that inhibiting the synthesis of TNF&#945; reestablished the neuronal function and the cognitive deficits induced by chronic inflammation of the nervous tissue&#46; These authors concluded that the inhibition of TNF&#945; could be a future therapeutic target in the spectrum of neurodegenerative diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> Nonetheless&#44; the results are contradictory and&#44; thus&#44; additional studies will be necessary to shed light on this question&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> is included to summarize the cases reported in the literature over the last 10 years&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">We should not forget the secondary manifestations of the underlying rheumatic disease&#46; Taking into account the fact that most rheumatic diseases have a more or less important systemic component&#44; the differential diagnosis is essential and indispensable&#46; At times&#44; it may be difficult to distinguish whether the neurological involvement is produced by the treatment or is due to the disease itself&#44; even after doing the appropriate ancillary tests&#46; Moreover&#44; the heterogeneity of the series of cases and of the isolated cases reported in the literature makes it difficult to establish a causal relationship between the anti-TNF&#945; drug and the neurological involvement&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Recommendations and Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">The interruption of the biological treatment should be considered if there is any reservation about the diagnosis&#46; This decision must be made by the clinician&#44; taking into account the risk-benefit of discontinuing biological therapy in each patient on an individualized basis&#46; When the neurological involvement is serious&#44; the standard treatment is the administration of glucocorticoids&#46; Immunoglobulins have not often been necessary&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">5&#44;25</span></a> The remission of the neurological signs is not always complete in all the patients&#44; even when the biological therapy has been interrupted&#46; The decision to restore it depends on neurological concerns and on whether a cause&#8211;effect relationship has been established&#46; In clear terms&#44; &#8220;not everything that happens to the patient will be due to the biological therapy&#8221;&#46; Nevertheless&#44; if the doubt exists&#44; the best approach is to discontinue the drug and&#44; if the patient&#39;s disease is still active&#44; the therapeutic target should be changed&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">In conclusion&#44; as rheumatologists&#44; we must be aware of and be familiarized with the adverse effects of the therapies we administer in our routine clinical practice&#44; although some may be infrequent&#46; It is of the utmost importance that they be reported&#44; even if we cannot be sure of a cause-and-effect relationship&#46; Spanish rheumatologists are fortunate to count on the BIOBADASER registry&#44; which facilitates our work when we need to review the effects that we must bear in mind and their distribution among the Spanish population&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Disclosures</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0225" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0230" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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    "fechaRecibido" => "2016-02-07"
    "fechaAceptado" => "2016-04-28"
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            0 => "Biological therapy"
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            0 => "Terapia biol&#243;gica"
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            2 => "Manifestaciones neurol&#243;gicas"
            3 => "Enfermedades reum&#225;ticas inflamatorias"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Biological therapy has changed the course of inflammatory rheumatic diseases&#46; The safety is well documented in national and international studies&#46; Neurological manifestations are uncommon and it is difficult to establish a clear causal relationship&#46; The neurological signs and symptoms that may appear are multiple and sometimes mimic demyelinating neurological diseases and&#47;or neurodegenerative diseases&#46; Knowledge and disclosure of these cases is essential for a comprehensive management of biological therapy in our patients&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La terapia biol&#243;gica ha cambiado el curso de las enfermedades reum&#225;ticas inflamatorias&#46; La seguridad de la misma est&#225; m&#225;s que documentada en diferentes estudios nacionales e internacionales&#46; La baja frecuencia de las manifestaciones neurol&#243;gicas dificulta en muchas ocasiones el establecer una relaci&#243;n causal clara entre el tratamiento biol&#243;gico y la cl&#237;nica neurol&#243;gica propiamente dicha&#46; Los s&#237;ntomas y signos neurol&#243;gicos que pueden aparecer son m&#250;ltiples&#44; y en ocasiones simulan enfermedades neurol&#243;gicas desmielinizantes y&#47;o neurodegenerativas&#46; El conocimiento y el reporte de los mismos es fundamental para realizar un manejo exhaustivo de la terapia biol&#243;gica en nuestros pacientes&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Tejera-Segura B&#44; Ferraz-Amaro I&#46; Terapias biol&#243;gicas y manifestaciones neurol&#243;gicas&#46; &#191;Qu&#233; sabemos&#63; 2017&#59;13&#58;102&#8211;106&#46;</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">ADA&#44; adalimumab&#59; CNS&#44; central nervous system&#59; CSF&#44; cerebrospinal fluid&#59; ETN&#44; etanercept&#59; IFX&#44; infliximab&#59; JIA&#44; juvenile idiopathic arthritis&#59; NMR&#44; nuclear magnetic resonance&#59; PML&#44; progressive multifocal leukoencephalopathy&#59; RTX&#44; rituximab&#59; TNF&#44; tumor necrosis factor&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Series&#47;review of cases over the last 10 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rheumatic disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Neurological manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Nanau et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> &#40;review of all their cases 2010&#8211;2014&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#41;<br>Spondyloarthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;<br>JIA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Rhupus &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>Total &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;<br>ETN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;<br>IFX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Demyelinating and&#47;or chronic&#47;acute inflammatory neuropathies &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;<br>PML &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41;<br>Multiple sclerosis-like disease &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;<br>Encephalitis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;<br><span class="elsevierStyleItalic">De novo</span> demyelination of no known cause &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;<br>Optic neuritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Transverse myelitis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>Cervical myelopathy &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="10" align="left" valign="top">Depending on the diagnosis&#44; the patients underwent&#58; NMR&#44; electrophysiological study&#44; screening for infection &#40;serological and CSF study&#41;<br></td><td class="td" title="table-entry  " rowspan="10" align="left" valign="top">Discontinuation of TNF&#945;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>glucocorticoids&#44; immunosuppressive therapy &#40;depending on whether or not the neurological involvement was reversible&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fern&#225;ndez-Espartero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> &#40;series of 21&#44;425<br>patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown<br>Total &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>ETN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;<br>IFX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Demyelinating disease of no known cause &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;<br>Optic neuritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Multiple sclerosis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Kaltsonoudis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> &#40;series of 77 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>Spondyloarthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>ETN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;<br>IFX &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sensory&#47;motor demyelinating neuropathy &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;<br>Optic neuritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Theibich et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> &#40;series of 550 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple sclerosis-like disease &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;<br>Demyelinating<br>neuropathy &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fromont et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a> &#40;case reports&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS demyelination &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Winkelmann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a> &#40;case reports&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spondyloarthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS demyelination &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Bendsouda et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a><br>&#40;1 case report&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple sclerosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Healy et al&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Enterovirus-associated fasciitis&#44; meningitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Clifford et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PML&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fleischmann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rheumatoid arthritis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PML&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information
ISSN: 21735743
Original language: English
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Idiomas
Reumatología Clínica (English Edition)
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