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Spanish consensus on the use of natalizumab (Tysabri®) – 2011
Consenso español sobre la utilización de natalizumab (Tysabri®) – 2011
O. Fernándeza,
Corresponding author
, J.A. García-Merinob, R. Arroyoc, J.C. Álvarez-Cermeñod, T. Arbizue, G. Izquierdof, A. Saizg, J. Olascoagah, A. Rodríguez-Antigüedadi, J.M. Prietoj, C. Oreja-Guevarak, M.A. Hernándezl, X. Montalbánm
a Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Regional Universitario Carlos Haya, IMABIS, Málaga, Spain
b Servicio de Neurología, Hospital Universitario Puerta de Hierro, Madrid, Spain
c Servicio de Neurología, Hospital Clínico Universitario San Carlos, Madrid, Spain
d Servicio de Neurología, Hospital Universitario Ramón y Cajal, Madrid, Spain
e Servicio de Neurología, Hospital Universitario de Bellvitge, Barcelona, Spain
f Servicio de Neurología, Hospital Universitario Virgen Macarena, Sevilla, Spain
g Servicio de Neurología, Hospital Clinic, IDIBAPS, Barcelona, Spain
h Servicio de Neurología, Hospital Donostia, San Sebastián, Spain
i Servicio de Neurología, Hospital de Basurto, Bilbao, Spain
j Servicio de Neurología, Hospital Clínico Universitario Santiago de Compostela, Santiago de Compostela, Spain
k Servicio de Neurología, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
l Servicio de Neurología, Hospital Universitario Ntra. Sra. de la Candelaria, Tenerife, Spain
m Centre d’Esclerosi Múltiple de Catalunya (CEMCAT), Hospital Universitari Vall d’Hebron, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Natalizumab &#40;Tysabri<span class="elsevierStyleSup">&#174;</span>&#41; is a recombinant humanised monoclonal antibody that binds to the &#945;4 subunit of &#945;4&#946;1 integrin &#40;VLA-4&#41; on the surface of lymphocytes&#46; This action blocks the binding of the subunit to its receptor &#40;VCAM-1&#41;&#44; which is present in the endothelium&#46; This prevents lymphocytes from entering the central nervous system&#44; thereby reducing the pathological process of MS&#46; In initial drug trials&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> natalizumab was shown to be highly effective in patients with relapsing-remitting multiple sclerosis &#40;RRMS&#41;&#46; However&#44; 2 cases of progressive multifocal leukoencephalopathy &#40;PML&#41; were reported in the SENTINAL study which compared natalizumab plus interferon beta-1a with interferon beta-1a monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">For the reason listed above&#44; natalizumab is indicated as a RRMS disease modifying agent that is very effective in the following patient groups&#58; patients with high disease activity despite interferon beta treatment&#44; and patients with severe and rapidly progressing RRMS&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Patients with treatment failure following a complete course of interferon beta were defined as those who experienced at least 1 relapse in the past year while on treatment and had at least 9 hyperintense lesions in T2-weighted brain MRI sequences&#44; or at least 1 gadolinium-enhancing lesion&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Patients with severe&#44; rapidly progressing RRMS were defined as those who experienced 2 or more disabling relapses in a year and had 1 or more gadolinium-enhancing lesions in the brain MRI&#44; or a significant increase in lesions in T2-weighted sequences compared to an earlier MRI&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Our knowledge of treatment risks and benefits has increased considerably since the first cases of PML were reported&#44; and continues to grow thanks to the efforts of researchers&#46; Today&#44; given the new information which is available&#44; the patient and the neurologist can make decisions that are tailored to the patient&#39;s individual case&#46; In this consensus statement&#44; we will present a survey of current knowledge to be used as a guide when making decisions concerning natalizumab treatment&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">We must point out that although this document lists the most recent general recommendations for managing patients treated with natalizumab&#44; neurologists must use their best judgement when prescribing treatment and monitoring patients&#46; This is all the more true due to the rapidity of changes in this field&#44; and the tendency to make use of increasingly personalised treatments&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">Spanish experts in MS&#44; the authors of this article&#44; held a meeting to identify the relevant topics to be addressed in this consensus document&#46; Chosen topics were as follows&#58; how to evaluate risks and benefits in general&#44; PML risk stratification&#44; how to inform patients regarding treatment risks and benefits&#44; and how to monitor patients during treatment or after discontinuing the drug&#44; if applicable&#46; Each of the topics was assigned to the expert in the group who would write that section&#46; Those responsible for each topic reviewed all available literature and any relevant presentations from international congresses&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Randomised trials of natalizumab were carried out in patients whose MS was less severe than in the patient population described in the drug information leaflet&#46; Given the lack of available randomised clinical trials &#40;CTs&#41; conducted with this type of patient&#44; it was not possible to create a hierarchy of evidence such as would normally appear in a consensus statement&#46; Nevertheless&#44; we should clarify that this document covers all relevant articles about natalizumab &#40;phase II and III studies and observational studies&#41;&#44; in addition to data&#44; both published and unpublished&#44; that has been presented at international congresses&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">During the initial meeting&#44; we designated a coordinator &#40;O&#46;F&#46;&#41; who gathered the texts and prepared a first draft which we then reviewed in the second meeting&#46; After receiving comments&#44; a new version was drafted and presented once again to the group of experts&#46; Once we had reached an agreement concerning the document&#39;s content and format&#44; and following several meetings and review sessions&#44; the finished document was sent to the Spanish Society of Neurology&#39;s panel on demyelinating diseases for review&#46; Once comments from the review had been taken on board&#44; the final draft of the consensus statement was completed&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">The concept of benefit&#8211;risk balance</span><p id="par0050" class="elsevierStylePara elsevierViewall">When establishing a benefit&#8211;risk balance&#44; doctors should be aware of information from CTs testing the drug in question&#46; We should also consider continued exposure to the drug and both short-term and long-term results in the areas of efficacy and safety&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">When evaluating benefits&#44; consider that the primary efficacy objectives of CTs are just one of several types of results perceived by patients&#46; We must also evaluate treatment feasibility&#44; and any changes in quality of life caused by use of this treatment&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Benefit was calculated using the statistic &#8216;number needed to treat&#8217; &#40;NNT&#41; to attain a specific objective&#44; such as number of relapses&#44; progression of disability&#44; or variables determined by MRI&#46; NNT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#47;ARR &#40;ARR&#58; absolute risk reduction&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Damage level was determined by closely scrutinising severe adverse events&#44; significant changes in laboratory results&#44; treatment discontinuation&#44; and unknown future risks &#40;for example&#44; the possibility that a patient will suffer infections or neoplasia in the future&#41;&#46; These variables are used to calculate the number needed to harm &#40;NNH&#41; in a process similar to that for determining benefit&#46; NNH<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#47;AHD &#40;AHD&#58; absolute harm reduction&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Once both statistical measurements have been calculated&#44; we can determine the difference between them provided that both benefits and adverse effects have clinically comparable levels of importance&#46; This will be determined by both the doctor and the patient&#44; and perhaps also by health authorities responsible for assigning resources and considering relevant aspects of the case&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Risk levels considered assumable or acceptable should factor in the risk of the disease being treated in addition to the risks associated with the drug&#46; If the disease does not cause disability or may only produce minor disability&#44; the assumable risk should be low &#40;1&#47;10<span class="elsevierStyleHsp" style=""></span>000 or lower&#41;&#59; on the other hand&#44; if the disease can result in major disability&#44; the assumable risk may be higher &#40;1&#47;1000 to 10<span class="elsevierStyleHsp" style=""></span>000&#41;&#44; and if the disease entails grave clinical risks &#40;risk of death&#44; for example&#41;&#44; the assumable risk for adverse effects may be even higher &#40;1&#47;100 or greater&#41;&#46; The patient must be informed of any risks&#44; and the final decision must be made between the two parties &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">In a risk&#47;benefit analysis&#44; low NNT indicates a good treatment response &#40;few patients are required in order to obtain a response to treatment&#41;&#46; High NNH indicates a good safety profile &#40;a high number of patients must be treated before an adverse event occurs&#41;&#46; The measurement can be expressed as a quotient or as a difference&#46; The first approach delivers a benefit&#47;risk ratio or risk-benefit probability&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Risk difference or absolute risk reduction is the simple difference between adverse event rates &#40;40&#37;<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>30&#37;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#37;&#59; NNT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#46; The difference in relative risk in this case is 25&#37;&#46; Keep in mind that if the relative effect of the treatment is the same&#44; absolute risk reduction may be different despite the fact that the relative risk reduction is similar in both cases&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">When it comes to evaluating benefits against harm or risk&#44; quotients may be misleading if we do not know the baseline risk&#46; It is therefore preferable to use statistics that account for differences in risk&#44; and this is why we must always consider absolute benefit or absolute risk&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#8211;8</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In MS&#44; the efficacy measures for NNT calculations include relapse prevention&#44; keeping a patient progression-free&#44; and absence of MRI findings suggesting activity&#47;progression&#46; NNH factors include the presence of severe adverse events and treatment discontinuation due to such events&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">MS is a chronic disease with a risk of progression&#46; In cases of this disease&#44; the goal is for a treatment to benefit a specific patient by reducing the number of relapses and slowing or stopping disease progression&#44; while itself causing the least possible harm&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Although patients have different wishes regarding the sharing of information&#44; a growing number of patients prefer to be fully informed and make shared decisions with their doctors&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">We can help patients understand the process by using NNT and analysing gains in disease-free periods&#46; However&#44; explaining the concept of benefit&#8211;risk balance is an art&#44; and when providing explanations&#44; we must allow for ample participation by the patient and evaluate his&#47;her preferences regarding information&#44; plus the patient&#39;s expectations&#44; concerns&#44; and capacity for assuming risks&#46; Lastly&#44; we must determine how the final decision will affect the patient&#39;s quality of life&#44; which will enable the patient and the doctor to make a joint decision regarding treatment and follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> We must always be aware of which treatment alternatives are available to a specific patient&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In any case&#44; the benefit&#8211;risk balance depends on both the drug and the disease being treated&#46; The NNT&#47;NNH figures are important for informing patients about benefits and adverse effects that have been demonstrated by CTs&#46; We must define the right process for informing each patient&#44; considering the fact that although patients generally prefer to be informed&#44; they tend to trust their doctor&#39;s final decision&#44; which should ideally be supported by both parties&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Information on the benefits associated with the treatment</span><p id="par0120" class="elsevierStylePara elsevierViewall">In the phase III AFFIRM study&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> treatment with natalizumab in MS patients reduced the risk of steady disability progression by 42&#37;&#8211;54&#37; over 2 years&#44; the relapse rate decreased by 68&#37; in 1 year&#44; the number of new or worsening lesions in T2-weighted MRI sequences decreased by 83&#37;&#44; and the number of gadolinium-enhancing lesions fell by 92&#37;&#46; The number of patients who remained relapse-free after 2 years increased by 57&#37;&#46; NNTs for these variables are as follows&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">NNT for relapses &#40;per year&#41;&#58; 2&#46;0</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0130" class="elsevierStylePara elsevierViewall">NNT for being relapse-free &#40;2 years&#41;&#58; 4</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0135" class="elsevierStylePara elsevierViewall">NNT for being progression-free &#40;2 years&#41;&#58; 8</p></li></ul></p><p id="par0140" class="elsevierStylePara elsevierViewall">Later observational studies of patients who responded poorly to conventional interferon and&#47;or glatiramer acetate showed natalizumab to be highly effective&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Information on the risks associated with the treatment</span><p id="par0145" class="elsevierStylePara elsevierViewall">In the AFFIRM study&#44; patients in the natalizumab group experienced more adverse effects than those in the placebo group&#59; these were mostly fatigue and allergic reactions&#46; Hypersensitivity reactions of different types appeared in 4&#37; of the patients&#44; and were serious in 1&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In the SENTINEL study&#44; adverse reactions caused by combination therapy with IM interferon beta 1a were anxiety&#44; pharyngitis&#44; sinus congestion and peripheral oedema&#46; There were 2 cases of PML in the natalizumab group&#44; and 1 was fatal&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In addition&#44; another CT reported a case of PML in a patient with Crohn&#39;s disease previously treated with immunosuppressants &#40;IS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">PML is a subacute form of encephalitis caused by the JC virus&#46; It is listed as an opportunistic infection since it occurs almost exclusively in patients whose immune systems are severely compromised&#44; whether due to HIV&#44; immunosuppressant agents&#44; different types of cancer&#44; or certain autoimmune diseases&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">After the drug began to be marketed and used in monotherapy&#44; this complication continued to occur in a small number of patients&#46; However&#44; their number has increased alongside the number of patients treated with the drug&#46; Different analyses have shown that the overall risk of developing PML is estimated to be about 1 per 1000 treated cases&#46; They have also shown that risk increases with years of treatment&#59; the effect is more noticeable after 2 years&#44; and it is greater still in patients with a prior history of treatment with IS&#46; NNH for these variables are as follows&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0160" class="elsevierStylePara elsevierViewall">NNH for discontinuing treatment due to adverse effects&#58; 50</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0165" class="elsevierStylePara elsevierViewall">NNH for a case of PML to occur &#40;de novo treatment&#44; treatment duration &#62;2 years and no prior IS&#41;&#58; 1&#47;3000&#46;</p></li></ul></p><p id="par0170" class="elsevierStylePara elsevierViewall">Treatment duration is one of the main risk factors for PML&#46; Data from patients who developed PML reveal that it rarely appears prior to 1 year of treatment&#44; and that the mean time before onset in most cases is about 2 years in patients with treatment durations of up to 4 years&#46; We do not know if risk continues to increase after this time period or if it remains stable&#44; given that the number of patients being treated is still low&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Prior immunosuppression treatment is another of the fundamental factors involved in risk of PML&#59; it was present in nearly half of the cases that developed this complication&#46; The recorded types of IS vary greatly&#44; and there are no specific patterns related to drug type or posology&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Data derived from the TYGRIS study suggest that regarding the 2 factors listed above&#44; patients with no prior history of IS treatment and less than 2 years on natalizumab are at low risk&#44; while those with a prior history of IS use and a treatment duration of more than 2 years are at high risk&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Stratifying risk and beginning treatment</span><p id="par0185" class="elsevierStylePara elsevierViewall">At present&#44; there is no single tool capable of predicting the individual risk of PML in an MS patient beginning treatment with natalizumab&#46; Proper patient selection and follow-up will make it possible to achieve a favourable benefit&#8211;risk balance in the patients in whom the treatment is indicated&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">When selecting patients&#44; doctors should consider different sections of each candidate&#39;s medical history&#44; including confirmed diagnosis of MS&#44; disease activity&#44; presence of comorbidities&#44; prior history of IS treatment&#44; and the baseline values from laboratory analyses&#46; Natalizumab is contraindicated in patients who are HIV positive or have a history of immunodeficiency or lymphoproliferative disease&#46; Although the drug information leaflet does not list pregnancy&#44; trying to conceive&#44; or breastfeeding as contraindications&#44; some consensus statements discourage use of the drug by patients in these situations&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> An MRI should be taken before beginning treatment and scans should be repeated periodically&#46; MRI periodicity will depend on the patient&#39;s risk group&#44;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a> but it normally ranges from 6 to 12 months&#46; Natalizumab must always be used in monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">We must inform the patient of any risks entailed by starting treatment&#46; Measuring antinatalizumab antibodies after 6 months of treatment is recommendable&#44; since when these antibodies do appear&#44; they do so within this period in nearly all cases&#46; If the patient is positive for antibodies&#44; the test should be repeated in 4 weeks&#59; if the antibodies persist&#44; treatment should be discontinued&#44; because presence of antibodies is linked to decreased effectiveness of the drug&#46; This enables us to avoid unnecessary exposure to the drug and reduce risk&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Recently&#44; implementation of a 2-step ELISA procedure with high sensitivity and specificity for detecting anti-JC virus antibodies has brought up the possibility of being able to stratify that risk&#46; There is a Europe-wide programme that analyses samples from MS patients in a central laboratory &#40;Unilabs&#44; Denmark&#41;&#46; Individual health centres must register with that programme if they wish to participate&#46; This test&#44; which has a high negative predictive value&#44; confirms prior exposure to the virus or primary infection&#44; which is present in 53&#46;6&#37; of patients with MS&#59; a negative result rules out exposure&#46; In addition&#44; antibodies were detected in previously obtained samples in the 25 cases of confirmed PML which were studied&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#8211;22</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">If studies currently underway&#44; specifically STRATIFY-1 &#40;clinicaltrials&#46;gov identifier&#58; <a href="ctgov:NCT01070823">NCT01070823</a>&#41; and STRATIFY-2 &#40;clinicaltrials&#46;gov identifier&#58; <a href="ctgov:NCT01070836">NCT01070836</a>&#41; confirm the hypothesis that a negative test for anti-JC antibodies rules out prior contact with the JC virus&#44; this detection process added to the 2 factors mentioned before &#8211; history of immunosuppression and treatment duration &#8211; could serve as tools for stratifying PML risk clearly&#46; An additional recommendation would be to complete a serology study annually&#44; since there is a 2&#37; annual seroconversion rate among patients testing negative for antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">If all these data are confirmed definitively&#44; this will constitute a fundamental step towards providing personalised natalizumab treatment in MS&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Before beginning treatment&#44; neurologists must inform patients of the benefits and risks of natalizumab treatment and explain the benefit&#8211;risk balance for each individual patient as clearly as possible&#46; The patient&#39;s medical history should contain a record of the information that was provided&#44; especially that regarding PML&#46; Likewise&#44; doctors should inform patients of the risks of discontinuing the drug and record that information&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Doctors should provide patients with treatment warning cards&#59; it is also considered useful&#44; while not mandatory&#44; to have them sign an informed consent form prior to treatment&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Throughout the entire treatment process&#44; we continue informing the patient about the drug&#39;s benefits and risks of complications&#44; especially the appearance of PML&#44; according to that patient&#39;s situation&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">We recommend completing both an analytical and MRI study&#44; plus a neuropsychological study where possible&#44; prior to starting treatment&#46; This allows us to compare values if PML is suspected at some point in the future&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">On a practical level&#44; we are currently attempting to stratify risk of PML based on 3 variables&#58; presence&#47;absence of anti-JC virus antibodies&#44; presence&#47;absence of previous IS treatment&#44; and treatment duration in months &#40;greater than or less than 24 months&#41;&#46; Using these variables&#44; we can create a risk&#47;benefit algorithm that lets us stratify risk in 3 groups&#58; minimum to low risk&#44; &#8804;1&#47;10<span class="elsevierStyleHsp" style=""></span>000&#8211;1&#47;3000&#59; moderate risk&#44; 1&#47;833&#8211;1&#47;400&#59; and high risk&#44; 1&#47;128&#46; This enables us to provide patients with more precise information about the benefit&#8211;risk balance&#46; These data are still being polished&#44; but this is the best numerical approximation available at this time &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Monitoring treatment</span><p id="par0240" class="elsevierStylePara elsevierViewall">Monitoring the patients undergoing treatment is the way to ensure an early diagnosis of potential complications and a rapid response that will minimise consequences&#46; This is achieved through clinical vigilance and the use of MRI and laboratory findings&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The neurologist&#39;s expertise and clinical abilities are the best tools for monitoring patients and detecting PML development as early as possible&#46; The specialist must consider the onset&#44; development and type of symptoms presented by a patient in order to distinguish PML from an MS relapse&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">The patient and the family members must also be informed so that they will be able to help detect new symptoms and signs&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">If clinical data are not sufficient&#44; an MRI study is used to visualise suspected PML lesions which can then be distinguished from typical MS lesions based on such characteristics as location&#44; borders&#44; and the type of change&#46; This technique is very sensitive&#44; but not very specific&#44; particularly when dealing with the initial PML lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Although cerebrospinal fluid &#40;CSF&#41; analysis to check for JC virus DNA is very specific for diagnosing PML&#44; it often gives negative results during early stages of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> As a result&#44; it is not a good tool for screening patients&#44; and it is only used in patients with suspicious clinical or MRI findings&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Scientific evidence of the efficacy of measuring viraemia and viruria is insufficient&#46; One study describes an increase in JC viral count in the plasma and urine of patients undergoing treatment&#44; which could prove useful for monitoring patients at a greater risk of developing PML&#44;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> but this has not been observed in other larger cohorts&#44; probably due to differences in methodology&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#8211;32</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">The immune response to the JC virus has also been the subject of scrutiny&#46; Some researchers have found no changes in immune response&#44; while others point to a decrease in T-cell activity during treatment with the drug&#44; and still others claim that T-cell activity increases&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Lastly&#44; the RESTORE study is being carried out in order to research immunological function and disease activity in periods during which treatment has been discontinued&#46; It analyses objectives following suspension of natalizumab treatment during 6 months&#44; and contains 3 arms&#58; no treatment&#44; treatment with corticosteroids at high monthly doses&#44; or treatment with interferon beta or glatiramer acetate &#40;clinicaltrials&#46;gov identifier&#58; <a href="ctgov:NCT01071083">NCT01071083</a>&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Practical advice for monitoring treatment<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;33&#8211;36</span></a></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical monitoring</span><p id="par0280" class="elsevierStylePara elsevierViewall">Doctors and nurses should be well-acquainted with the patient and have special training in the use of natalizumab&#46; They should be able to recognise the potential complications of treatment with that drug&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Nurses or doctors should be present during every infusion to watch for any reactions to the drug &#40;fatigue&#44; dizziness&#44; headache&#44; asthenia&#44; nausea&#44; etc&#46;&#41; and be able to distinguish them from allergic reactions or hypersensitivity &#40;urticaria with or without systemic repercussions&#41;&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">During each infusion &#40;every 4 weeks&#41;&#44; specialist doctors or nurses should be near the patient so as to monitor clinical activity and quickly detect potential medication-related complications&#44; especially PML&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">During treatment with natalizumab&#44; the patient&#39;s clinical course should be monitored with periodic examinations by a neurologist every 3 to 6 months&#44; especially if new symptoms appear&#59; ruling out PML is the main concern &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">MRI monitoring</span><p id="par0300" class="elsevierStylePara elsevierViewall">A brain MRI must be taken in the 3 months prior to starting natalizumab treatment&#46; After that&#44; some authors propose taking brain MRI scans in order to detect potential cases of PML in their early stages&#44; establishing MRI periodicity according to the patient&#39;s risk group&#59; patients at high risk for PML would have scans every 6 months&#44; and those at moderate to low risk&#44; every 12 months&#46; This proposal may reflect a lack of experience with MS patients treated with natalizumab&#46; &#40;There is no evidence demonstrating that MRI is an effective tool for detecting PML in a subclinical stage&#44; and we cannot therefore recommend use of this technique for early diagnosis of the complication in that stage&#46;&#41;</p><p id="par0305" class="elsevierStylePara elsevierViewall">An emergency brain MRI must be performed if any neurological symptoms or signs appear that would raise doubts as to whether the patient was undergoing a relapse or PML&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">MRI should be performed in radiology units by staff members who are knowledgeable about MS and the complications of MS treatment&#46; We recommend that subsequent studies of the patient be taken using similar machines &#40;the same units&#44; if possible&#41; and following standard protocols&#44; including T2-weighted FLAIR images and T1-weighted images with and without contrast&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Laboratory monitoring</span><p id="par0315" class="elsevierStylePara elsevierViewall">An analytical study including a haemogram and a basic biochemical assessment &#40;including liver function&#41; should be completed at treatment onset and at least every 3 months thereafter&#46; While liver alterations are uncommon&#44; we recommend discontinuing the treatment temporarily until liver enzymes normalise&#44; and resuming treatment at a later date&#46; If the patient is suspected to be immunocompromised at treatment onset&#44; measure the neutrophil&#44; CD4&#44; and CD8 counts and the CD4&#47;CD8 ratio&#46; In areas with a high incidence of HIV infection&#44; HIV testing is recommended prior to starting treatment&#46; If there is a risk of tuberculosis&#44; we recommend a chest radiography and a tuberculin test&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Measuring antinatalizumab antibodies</span><p id="par0320" class="elsevierStylePara elsevierViewall">Approximately 9&#37; of patients on natalizumab treatment have persistent neutralising antibodies in their serum which appear during the first 6 months&#46; Most of these neutralising antibodies are associated with allergic reactions or hypersensitivity&#44; especially at the time of the second infusion&#46; Testing for antinatalizumab antibodies is probably recommendable for all patients&#44; but it should be mandatory in the following cases&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0325" class="elsevierStylePara elsevierViewall">Patients with allergic reactions or hypersensitivity to the drug&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0330" class="elsevierStylePara elsevierViewall">Clinical relapse or MRI findings indicative of radiological activity&#46;</p></li></ul></p><p id="par0335" class="elsevierStylePara elsevierViewall">If a patient&#39;s sample reveals neutralising antibodies&#44; the analysis should be repeated again in 4 weeks&#46; If the patient should test positive again &#40;persistent antibodies&#41;&#44; discontinuing treatment is recommended&#46; Presence of antibodies is linked to loss of clinical efficacy of natalizumab and increased incidence of hypersensitivity reactions&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;13</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Information for the patient</span><p id="par0340" class="elsevierStylePara elsevierViewall">At 24 months of treatment&#44; all patients should be informed once more about the natalizumab risks and benefits known at that time&#46; The patient should reiterate his or her consent to continue treatment&#44; and this should be reflected in writing in the section of the medical history that includes information provided to the patient&#46; This information should be updated every year and every time new information about the risks of treatment becomes available &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment discontinuation and follow-up</span><p id="par0345" class="elsevierStylePara elsevierViewall">Discontinuation of natalizumab has been associated with the reappearance of disease activity&#59; the clinical effects of the drug last about 3 months&#44; while the biological effect lasts between 6 and 12 months&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> After discontinuing natalizumab&#44; we therefore recommend immediately starting treatment with an immunomodulator &#40;interferon beta or glatiramer acetate&#41; or corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> As its drug information leaflet states&#44; natalizumab remains in the blood during approximately 12 weeks after the last dose is administered&#46; Therefore&#44; beginning other treatments during that period will result in concomitant exposure to both drugs&#44; and extreme caution must be exercised&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">If the patient began natalizumab treatment because an immunomodulator proved to be ineffective&#44; the logical step would be to treat the patient with another drug to which he or she has had no prior exposure&#46; We do not know what role the forthcoming oral drugs might play in this area&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">Appearance of PML is a severe complication with high mortality &#40;20&#37;&#41; and morbidity rates&#46; The best treatment is prevention&#44; but this strategy is complex as there are no simple&#44; reliable diagnostic procedures that would allow us to anticipate PML development&#46; As a result&#44; we recommend extreme vigilance and following currently available recommendations&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;12&#8211;16</span></a> Suspected diagnosis is based on clinical and MRI findings&#44; and the disease is confirmed when the JC virus is detected in CSF&#46;</p><p id="par0360" class="elsevierStylePara elsevierViewall">Treatment for cases of PML associated with natalizumab aims to rapidly eliminate the drug from the bloodstream&#44; fight the virus&#44; and prevent the neurological damage caused by immune reconstitution inflammatory syndrome &#40;IRIS&#41;&#46; Since PML is attributed to lymphocytes being prevented from entering the inner CNS as a result of natalizumab&#39;s action mechanism&#44; the main priority is removing that mechanism&#46; Approaches include plasmapheresis and immunoabsorption in different dosing regimens&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">Numerous different antiviral or immunomodulating agents and 5-HT2A receptor antagonists&#44; including psychoactive drugs &#40;mirtazapine&#41;&#44; have been tested as treatments but their results have been unclear&#46; The efficacy of the antimalarial drug mefloquine is also unclear&#44; but it has been used in a number of cases of PML&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">IRIS&#44; which appears several weeks after plasmapheresis or immunoabsorption treatment&#44; may cause extremely severe neurological damage or death&#46; It is characterised by the onset of neurological deterioration with signs of inflammation appearing in neuroimaging studies&#46; Although there is no consensus regarding IRIS prevention and treatment&#44; abundant clinical evidence&#44; most of which comes from experience with patients with HIV&#44; suggests that high doses of intravenous corticosteroids may be useful in both prevention and treatment&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">Lastly&#44; there is no evidence identifying the best &#8216;detox&#8217; duration after discontinuing natalizumab and prior to starting other immunosuppressant agents&#46; We could speculate that 3 to 6 months might be sufficient&#44; but this will have to be confirmed&#46; Likewise&#44; we are unaware of the risks involved in starting another immunosuppressant directly&#44; and in particular&#44; how that action may affect risk of PML&#46; These matters will have to be strictly monitored in the future&#44; especially once the new oral drugs have become available&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0380" class="elsevierStylePara elsevierViewall">In conclusion&#44; we are currently witnessing very important advances in the treatment of MS with natalizumab as we move towards personalised medicine&#46; We have access to sufficient data regarding treatment benefits and possess a better understanding of its risks now that a very large number of patients have been treated worldwide&#46;</p><p id="par0385" class="elsevierStylePara elsevierViewall">This situation allows us to establish a fairly realistic quantitative approximation of the benefit&#8211;risk balance&#44; stratify risks&#44; and inform patients of their risk level at any time in the treatment process&#44; whether at the beginning or during follow-up&#44; based on 3 variables&#58; anti-JC virus antibodies&#44; history of immunosuppression&#44; and treatment duration&#46;</p><p id="par0390" class="elsevierStylePara elsevierViewall">Recommendations for treatment monitoring are beginning to become available&#46;</p><p id="par0395" class="elsevierStylePara elsevierViewall">Our knowledge of the consequences of discontinuing treatment and the steps to take in this case is growing&#46; This enables us to prevent relapses&#44; and can even prevent the appearance of IRIS&#44; which can be devastating&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">These advances mean that we can proceed with more confidence in treating MS with natalizumab&#44; which has considerable benefits&#44; since we can now also reduce the risks associated with its use&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0405" class="elsevierStylePara elsevierViewall">Oscar Fern&#225;ndez has received fees as a consultant to committees and as a moderator or speaker at medical congresses and symposia&#46; He has also participated in clinical trials and other research projects promoted by Biogen-Idec&#44; Bayer-Schering&#44; Merck-Serono&#44; Teva&#44; and Novartis&#46;</p><p id="par0410" class="elsevierStylePara elsevierViewall">Xavier Montalb&#225;n has received fees and travel expenses for attending meetings as a speaker&#46; He has acted on the steering committees of clinical trials&#44; and has also recently collaborated with clinical trial committees as a consultant with Bayer Schering Pharma&#44; Biogen Idec&#44; EMD Merck Serono&#44; Genentech&#44; Genzyme&#44; Novartis&#44; Sanofi-Aventis&#44; Teva Pharmaceuticals&#44; and Almirall&#46;</p></span></span>"
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    "fechaAceptado" => "2011-09-05"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Natalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis &#40;RRMS&#41;&#46; However&#44; treatment has also been associated with a risk of progressive multifocal leukoencephalopathy &#40;PML&#41;&#46; The aim of this article is to provide a consensus view on the assessment and stratification of these risks&#44; and to improve the management of natalizumab-treated patients&#46;</p> <span class="elsevierStyleSectionTitle">Development</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">At an initial meeting of experts on multiple sclerosis &#40;MS&#41; &#40;the authors of this consensus&#41;&#44; the relevant topics of the consensus were decided and assigned for development&#46; Topics included how to establish benefit and risk in general&#44; stratification for risk of PML&#44; informing patients of benefit&#47;risk&#44; monitoring treatment&#44; and treatment withdrawal and follow-up&#46; During the drafting phase&#44; all available information published or presented at international meetings was reviewed&#46; After a series of review rounds and meetings&#44; the final draft was produced&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Although natalizumab is a very effective drug&#44; its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular&#46; The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand&#46; Before starting treatment&#44; baseline laboratory test and magnetic resonance imaging &#40;MRI&#41; should be available for comparison purposes in the event of suspected PML&#46; The risk of PML should be stratified into high&#44; medium and low risk groups according to antibodies against JC virus status&#44; prior immunosuppressive therapy&#44; and treatment duration&#46; The follow-up&#44; in particular&#44; the frequency of MRI scans&#44; should depend on the risk group to which patient belongs&#46; As our understanding of the risk factors for PML develops&#44; it should be possible to offer patients increasingly individualised therapy&#46; This is a consensus that establishes general recommendations&#44; but neurologists must use their clinical expertise to treat and follow individual patients&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introducci&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Natalizumab es un tratamiento que ha demostrado ser muy eficaz en los pacientes con esclerosis m&#250;ltiple recurrente-remitente &#40;EMRR&#41; en cuanto a la reducci&#243;n del n&#250;mero de brotes y al enlentecimiento de la progresi&#243;n de la enfermedad&#46; Sin embargo&#44; el f&#225;rmaco se ha asociado con el riesgo de desarrollar leucoencefalopat&#237;a multifocal progresiva &#40;LMP&#41;&#46; El objetivo de este art&#237;culo es proporcionar una posici&#243;n consensuada sobre la valoraci&#243;n y estratificaci&#243;n de este riesgo y mejorar el manejo de los pacientes tratados con natalizumab&#46;</p> <span class="elsevierStyleSectionTitle">Desarrollo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En una reuni&#243;n inicial de expertos en EM &#40;los autores de este consenso&#41;&#44; se perfilaron los temas de inter&#233;s que fueron asignados a los asistentes para su desarrollo ulterior&#46; Los temas inclu&#237;an c&#243;mo establecer el beneficio y el riesgo en general&#44; la estratificaci&#243;n para el riesgo de LMP&#44; c&#243;mo informar a los pacientes de los beneficios y riesgos&#44; c&#243;mo realizar el seguimiento del paciente en tratamiento y tras la suspensi&#243;n del f&#225;rmaco&#46; Durante la fase de redacci&#243;n&#44; se revis&#243; toda la informaci&#243;n disponible&#44; publicada o presentada en reuniones internacionales&#46; Despu&#233;s de varios ciclos de revisi&#243;n y de reuniones&#44; se produjo el borrador final&#46;</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A pesar de ser un f&#225;rmaco muy eficaz&#44; la decisi&#243;n de prescribir natalizumab debe ser tomada con cuidado por los posibles efectos adversos y en particular&#44; el riesgo de LMP&#46; El neur&#243;logo debe explicar al paciente en detalle los riesgos y beneficios del tratamiento&#44; en t&#233;rminos comprensibles para el paciente&#46; Antes de empezar el tratamiento&#44; deben estar disponibles las pruebas de laboratorio y las im&#225;genes de resonancia magn&#233;tica &#40;RM&#41; que permitan comparaciones en el futuro&#44; en caso de sospecha de LMP&#46; El riesgo de LMP debe estratificarse en alto&#44; medio y bajo de acuerdo con la presencia o ausencia de anticuerpos frente al virus JC&#44; antecedente de tratamiento inmunosupresor y duraci&#243;n del tratamiento&#46; El seguimiento cl&#237;nico y la frecuencia de la RM depender&#225; del grupo de riesgo al que pertenece el paciente&#46; A medida que mejore nuestra comprensi&#243;n de los factores de riesgo&#44; ser&#225; posible ofrecer a los pacientes una terapia cada vez m&#225;s personalizada&#46; El presente consenso establece unas recomendaciones generales&#44; pero los neur&#243;logos deben aplicar su experiencia cl&#237;nica para hacer un seguimiento individualizado de los pacientes&#46;</p>"
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        "texto" => "<p id="par0415" class="elsevierStylePara elsevierViewall">We would like to acknowledge the valuable comments made by A&#46; Miralles&#44; C&#46; de Andr&#233;s&#44; A&#46; Rovira&#44; L&#46; Landete&#44; F&#46;J&#46; Hern&#225;ndez&#44; J&#46; Meca&#44; B&#46; Casanova&#44; C&#46; Arnal&#44; and V&#46; P&#233;rez de Colos&#237;a&#44; and G&#46; Morley&#39;s contribution to the drafting of this text&#46;</p>"
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Article information
ISSN: 21735808
Original language: English
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