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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">After more than 50 years&#8217; experience with methotrexate and despite the lack of appropriate trials&#44; the efficacy of this drug for treating psoriasis is unquestioned&#46; However&#44; the numerous guidelines and reviews on the use of methotrexate<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;12</span></a> have not erased practitioners&#8217; uneasiness about unforeseen potential side effects&#44; resulting in considerable variation in the prescribing practices among physicians&#46; One difference in practice is the use or not of a so-called &#8216;test dose&#8217; &#40;a lower initial dose given to assess the likelihood of an unexpected acute adverse event&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Aminopterin was first used empirically for psoriasis and rheumatoid arthritis in 1951 by Gubner&#44; an internist&#44; and coworkers&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and in 1958 this drug was specifically mentioned as a treatment for psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In 1972&#44; the US Food and Drug Administration approved methotrexate for this indication&#46; Dermatologists promptly began to assess the use of both aminopterin and methotrexate in this disease&#44; testing twice weekly parenteral doses of 50&#8211;75<span class="elsevierStyleHsp" style=""></span>mg&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> very small daily doses for several consecutive days a month &#40;0&#46;5&#8211;0&#46;6<span class="elsevierStyleHsp" style=""></span>mg every 4&#8211;6<span class="elsevierStyleHsp" style=""></span>h for 10<span class="elsevierStyleHsp" style=""></span>d&#47;mo&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and topical application for psoriatic plaques&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> After this initial stage&#44; in 1969 the usefulness of a weekly dose was established&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and in 1971&#44; the possibility of dividing the weekly dose into 3 doses administered at 12-h intervals &#40;Weinstein&#39;s regimen&#41; was suggested&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> These prescription practices were an attempt to base dosing on the pharmacokinetics of methotrexate&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> on studies of cell kinetics&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and on the unproven assumption that adverse gastrointestinal events would thereby be prevented or attenuated&#46; Although minimum and maximum doses have not been universally established&#44; the weekly administration of 7&#46;5&#8211;25<span class="elsevierStyleHsp" style=""></span>mg is recommended as an effective therapeutic range in psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The toxicity of methotrexate depends on the extracellular concentration of the drug and the period of exposure&#59; toxicity for a given dose will therefore be proportional to the period of exposure to it&#46; In theory&#44; a toxic event can be anticipated by measuring blood levels of the drug &#40;levels higher than 0&#46;01<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L after intramuscular injection of 10<span class="elsevierStyleHsp" style=""></span>mg should lead to suspicion of toxicity&#41;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#59; however&#44; we do not measure concentrations routinely&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Most adverse reactions related to low-dose methotrexate &#40;gastrointestinal and mucocutaneous&#41; are mild&#44; appear in the first 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h after administration&#44; and do not usually require interruption of the treatment&#46; In some cases reactions can be attenuated by regulating or dividing the dose&#44; by administering the drug intravenously at night&#44; or by having the patient take folic acid supplements&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Gastrointestinal toxicity presents in 60&#37; of patients as stomatitis&#44; nausea&#44; vomiting&#44; indigestion&#44; abdominal pain&#44; dyspepsia&#44; diarrhea&#44; anorexia&#44; and weight loss&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Aphthous stomatitis is associated with higher doses of methotrexate but folate supplements improve tolerance of the course of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The most severe toxicity associated with methotrexate is specific to certain organs and tissues&#44; affecting the blood&#44; liver&#44; and lung&#59; related mortality rates decrease in that order&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The development of toxicity is often associated with concomitant factors&#44; accumulation of drugs or overdose&#44; which are not fully understood&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> These factors must be remembered when selecting patients for treatment with methotrexate&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; a similar profile of adverse effects can also be seen with other drugs for which we do not consider test doses&#46; For most dermatologists the test dose was handed down to us as clinical practice when we were residents&#44; and we accepted it uncritically&#44; presumably because it was a matter of prudence in the prescription of medication and out of respect for our superiors&#59; that was the case for me and I believe my experience was typical&#46; Why then do we not start with test doses of cyclosporin&#44; nonsteroidal anti-inflammatory drugs &#40;which&#44; incidentally&#44; cause more frequent adverse effects&#41;&#44; tetracyclines&#44; or any other drug we use routinely&#63; Is it perhaps because hypersensitivity reactions to methotrexate&#44; but not to cyclosporin&#44; began to be reported at a certain historical moment&#63; The initial trials and reports based on large patient series do not mention hypersensitivity reactions but rather toxicity associated with high doses and&#47;or renal failure&#44; and&#44; in most cases&#44; transitory transaminase elevation not requiring suspension of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;15&#44;16&#44;18&#44;26</span></a> The test dose nonetheless continues to be recommended in most published guidelines&#44; although I have found no documented account of its utility or trial evidence supporting it&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In my opinion&#44; none of the toxicities associated with methotrexate can be considered hypersensitivity reactions&#44; except for methotrexate-associated pneumonitis&#44; which normally appears several weeks after treatment begins &#40;nearly always after the full dose is reached&#41;&#46; The test dose can therefore not be used as an excuse for preventing this serious&#44; though unusual&#44; toxic event&#46; From a theoretical standpoint&#44; assessing a test dose is more relevant in cases where methotrexate is being reintroduced&#44; as allergic hypersensitivity could be expected then rather than at the start of treatment&#46; Interestingly&#44; the general assumption on reintroducing the drug is that the previous experience is sufficient indication of safety and no test dose is needed&#46; However&#44; the literature offers mainly reports of anaphylactoid reactions after high doses in patients who had previously been exposed to methotrexate&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Acute hypersensitivity reactions&#8212;though we have no accurate catalog of exactly what to look for&#44; whether anaphylaxis&#44; urticaria&#44; toxic hepatitis&#44; bone marrow aplasia&#44; or toxic epidermal necrolysis&#8212;have been sporadically described in the literature almost exclusively in oncology or rheumatology patients who are taking concomitant medications and high doses of parenteral methotrexate&#59; the vast majority of these patients had been previously exposed to the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#8211;30</span></a> Very few cases of these reactions have been described after the initial dose and this is also true for patients with a severe underlying disease other than psoriasis and who are taking other medications&#46; &#40;We do note&#44; however&#44; a report of mild&#44; transient purpura after a test dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46;&#41; The available evidence therefore suggests that hypersensitivity reactions have mostly been described in patients who have previously taken high doses of methotrexate and have oncologic and&#47;or rheumatologic disorders&#46; This is not the situation for our patients taking low doses of methotrexate for psoriasis&#44; however&#46; Similarly&#44; leukopenia or pancytopenia are reactions that have been described mainly in patients with underlying conditions &#40;especially those with associated renal failure and in hemodialysis&#41; or in cases of overdose&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">What then is the purpose of a test dose&#63; Solely for the sake of argument&#44; we note that a test dose is indicated for the prevention of a possible non-dose-dependent hypersensitivity reaction&#44; which might be severe and which could be watched for&#59; or we might attenuate a reaction&#39;s seriousness by administering a small dose&#46; Next&#44; my understanding is that we must abandon claiming that the prevention of possible adverse events related to drug accumulation is a criterion for deciding to use a test dose&#44; given that a test occurs at the start of treatment&#46; A survey of the Spanish Psoriasis Group of the Spanish Academy of Dermatology &#40;AEDV&#41;&#44; carried out when the association&#39;s guidelines on methotrexate use in psoriasis<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> were being drafted&#44; included a question about the respondents&#8217; experience with test dosing&#46; The answers we received were extremely varied&#58; some respondents did not use one while others did&#8212;expressing fear of bone marrow aplasia&#44; acute hepatitis&#44; acute urticarial reaction&#8212;or &#8220;just in case of any unexpected reaction&#46;&#8221; None of the respondents had ever witnessed such a reaction among their patients&#44; however&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The only unexpected reaction to methotrexate in psoriasis I have seen was plaque erosion after the first few doses of the drug &#40;hypersensitivity&#63;&#41;&#46; This reaction is certainly not serious and is only remarkable because of the need to recognize it as what it really is in order to avoid interpreting it as a lack of response to methotrexate and then try raising the dose&#44; thereby leading to acute toxicity due to overdose &#40;a practice error&#44; as a higher dose would not be indicated&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">What constitutes a test dose&#63; That there is also variation in what practitioners consider to be a test dose was also evident in the survey mentioned above&#44; in which respondents chose 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; and 10<span class="elsevierStyleHsp" style=""></span>mg for such doses&#46; Several guidelines suggest a test dose of 5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#44; or a lower one of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg in a &#8216;susceptible patient&#8217;&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> The prescribing information for oral and injectable forms of methotrexate recommends an initial dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg and 10<span class="elsevierStyleHsp" style=""></span>mg&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> respectively&#44; without explicitly defining it as a test dose&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Still&#44; doses of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg and higher are already within the therapeutic range &#40;7&#46;5&#8211;25<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#41; for psoriasis&#46; Is 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg the test dose when wanting to prescribe 15 or 20<span class="elsevierStyleHsp" style=""></span>mg&#63; And what if I want to administer a 7&#46;5-mg dose directly&#63; What is&#44; in principle&#44; the dose I eventually want to reach&#63; No studies give guidance on a theoretically optimal dose&#44; and methotrexate is not prescribed according to weight&#46; The precautionary measure of administering low doses would be more valid for patients with underlying risks &#40;due to comorbidity&#44; age&#44; or concomitant medication&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A lower initial dose must not be confused with a test dose&#46; The intention in the first instance is to discover the minimum effective dose rather than to prevent toxic reactions&#58; the minimum effective dose and the test dose are not one and the same&#46; The purpose of the test dose is to prevent an immediate acute adverse reaction that could be severe&#46; If the reaction is idiosyncratic or the result of hypersensitivity&#44; I believe it will matter little whether the dose is of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; or 15<span class="elsevierStyleHsp" style=""></span>mg&#44; since the problem stems from an individual&#39;s genetic makeup and metabolism of a drug and on the molecular structure of the drug itself&#46; Moreover&#44; any of these doses is far lower than those that had been administered in the reported cases of hypersensitivity reactions&#46; If the intention of a test is to prevent dose-dependent toxicity&#44; then indeed&#44; establishing the minimum effective dose could be considered&#46; How can we be sure that a single dose of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg will be safe and that a reaction will not develop after the second&#44; third&#44; or ninth dose&#63; Rather than accepting the test dose as a routine practice&#44; it would be more reasonable to maintain a low dose divided into several weekly intakes and to speak of a test or induction phase rather than a test dose&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Personally&#44; I do not prescribe test doses&#44; instead starting patients on an initial dose of 15<span class="elsevierStyleHsp" style=""></span>mg if they have no comorbidities associated with increased risk when taking this drug&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> I have observed no severe acute toxicity from this initial dose<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> and consider it the optimal one for predicting the efficacy that can be expected from continuing treatment&#46; This dose has been suggested on the basis of findings from trials that compared biologic agents to methotrexate&#44; according to Dr Kristian Reich&#44; speaking at the 2010 annual congress of the European Academy of Dermatology and Venereology in Gothenburg&#44; Sweden&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In my opinion the main issue in the management of methotrexate therapy is not about dosing regimens&#59; rather&#44; we should be concerned with evaluating patients before starting treatment and following them closely &#40;including monitoring laboratory test results&#41;&#44; as we have recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Early reviews of the use of aminopterin and methotrexate in psoriasis indicated that the possible adverse reactions encountered were related to renal or hepatic failure and rarely to hypersensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> When the use of methotrexate is considered&#44; contraindications and special precautions for this drug must be carefully assessed&#46; Any previous relative contraindication experienced by the patient will certainly influence the choice of dose&#44; follow-up&#44; and safety regimens&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; this presupposes a standardized management of methotrexate similar to that of other antipsoriatic drugs&#44; with no resort to a test dose based on uneasiness which neither experience nor evidence justifies&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Perhaps the reason for ongoing debate lies in the lack of randomized clinical trials&#46; Methotrexate is an old drug that appeared in another era&#46; The lack of appropriate clinical trials was denounced decades ago&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> yet trials have not been widely or systematically performed for this drug as they have been for cyclosporin and biologic agents&#44; drugs for which a test dose has not been suggested even though their potential to cause very serious adverse events is acknowledged&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Methotrexate has been the target of myths and groundless fears &#40;high risk of pulmonary and hepatic toxicity&#44; mutagenic potential&#44; etc&#46;&#41;&#44; which have gradually faded or diminished after decades of experience&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In any case&#44; discussions about the initial dose are not as important as the need for prompt patient evaluation and later clinical vigilance once methotrexate has been prescribed&#44; irrespective of the initial dose&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In summary&#44; I believe that when prescribing methotrexate in psoriasis we should consider therapeutic range&#59; patient selection&#59; the so-called attack&#44; or loading&#44; dose as well as the maintenance dose&#59; and follow-up&#46; A test dose&#44; on the other hand&#44; should not be used for fear of the unknown or figments of our imagination&#46; Methotrexate should receive the same medical&#44; pharmacologic&#44; and pharmacovigilance treatment as any other drug and not be subjected to a verdict of guilty without trial&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of Interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The author declares that he has no conflicts of interest with regard to this opinion article&#46; However&#44; he has received fees for speaking at conferences&#44; conducting clinical trials&#44; or otherwise serving as a consultant from the following laboratories&#58; Novartis&#44; Leo-Pharma&#44; MSD&#44; Abbott&#44; Pfizer&#44; and Janssen-Cilag&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Carretero-Hern&#225;ndez G&#46; Metotrexato en psoriasis&#58; &#191;es necesaria una dosis de prueba&#63;&#46; Actas Dermosifiliogr&#46;2012&#59;103&#58;1-4&#46;</p>"
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Opinion Article
Methotrexate in Psoriasis: Do We Need to Give a Test Dose?
Metotrexato en psoriasis: ¿es necesaria una dosis de prueba?
G. Carretero-Hernández
Servicio de Dermatología, Hospital Universitario de Gran Canaria, Las Palmas de Gran Canaria, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">After more than 50 years&#8217; experience with methotrexate and despite the lack of appropriate trials&#44; the efficacy of this drug for treating psoriasis is unquestioned&#46; However&#44; the numerous guidelines and reviews on the use of methotrexate<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;12</span></a> have not erased practitioners&#8217; uneasiness about unforeseen potential side effects&#44; resulting in considerable variation in the prescribing practices among physicians&#46; One difference in practice is the use or not of a so-called &#8216;test dose&#8217; &#40;a lower initial dose given to assess the likelihood of an unexpected acute adverse event&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Aminopterin was first used empirically for psoriasis and rheumatoid arthritis in 1951 by Gubner&#44; an internist&#44; and coworkers&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and in 1958 this drug was specifically mentioned as a treatment for psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In 1972&#44; the US Food and Drug Administration approved methotrexate for this indication&#46; Dermatologists promptly began to assess the use of both aminopterin and methotrexate in this disease&#44; testing twice weekly parenteral doses of 50&#8211;75<span class="elsevierStyleHsp" style=""></span>mg&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> very small daily doses for several consecutive days a month &#40;0&#46;5&#8211;0&#46;6<span class="elsevierStyleHsp" style=""></span>mg every 4&#8211;6<span class="elsevierStyleHsp" style=""></span>h for 10<span class="elsevierStyleHsp" style=""></span>d&#47;mo&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and topical application for psoriatic plaques&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> After this initial stage&#44; in 1969 the usefulness of a weekly dose was established&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and in 1971&#44; the possibility of dividing the weekly dose into 3 doses administered at 12-h intervals &#40;Weinstein&#39;s regimen&#41; was suggested&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> These prescription practices were an attempt to base dosing on the pharmacokinetics of methotrexate&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> on studies of cell kinetics&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and on the unproven assumption that adverse gastrointestinal events would thereby be prevented or attenuated&#46; Although minimum and maximum doses have not been universally established&#44; the weekly administration of 7&#46;5&#8211;25<span class="elsevierStyleHsp" style=""></span>mg is recommended as an effective therapeutic range in psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The toxicity of methotrexate depends on the extracellular concentration of the drug and the period of exposure&#59; toxicity for a given dose will therefore be proportional to the period of exposure to it&#46; In theory&#44; a toxic event can be anticipated by measuring blood levels of the drug &#40;levels higher than 0&#46;01<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L after intramuscular injection of 10<span class="elsevierStyleHsp" style=""></span>mg should lead to suspicion of toxicity&#41;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#59; however&#44; we do not measure concentrations routinely&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Most adverse reactions related to low-dose methotrexate &#40;gastrointestinal and mucocutaneous&#41; are mild&#44; appear in the first 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h after administration&#44; and do not usually require interruption of the treatment&#46; In some cases reactions can be attenuated by regulating or dividing the dose&#44; by administering the drug intravenously at night&#44; or by having the patient take folic acid supplements&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Gastrointestinal toxicity presents in 60&#37; of patients as stomatitis&#44; nausea&#44; vomiting&#44; indigestion&#44; abdominal pain&#44; dyspepsia&#44; diarrhea&#44; anorexia&#44; and weight loss&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Aphthous stomatitis is associated with higher doses of methotrexate but folate supplements improve tolerance of the course of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The most severe toxicity associated with methotrexate is specific to certain organs and tissues&#44; affecting the blood&#44; liver&#44; and lung&#59; related mortality rates decrease in that order&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The development of toxicity is often associated with concomitant factors&#44; accumulation of drugs or overdose&#44; which are not fully understood&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> These factors must be remembered when selecting patients for treatment with methotrexate&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; a similar profile of adverse effects can also be seen with other drugs for which we do not consider test doses&#46; For most dermatologists the test dose was handed down to us as clinical practice when we were residents&#44; and we accepted it uncritically&#44; presumably because it was a matter of prudence in the prescription of medication and out of respect for our superiors&#59; that was the case for me and I believe my experience was typical&#46; Why then do we not start with test doses of cyclosporin&#44; nonsteroidal anti-inflammatory drugs &#40;which&#44; incidentally&#44; cause more frequent adverse effects&#41;&#44; tetracyclines&#44; or any other drug we use routinely&#63; Is it perhaps because hypersensitivity reactions to methotrexate&#44; but not to cyclosporin&#44; began to be reported at a certain historical moment&#63; The initial trials and reports based on large patient series do not mention hypersensitivity reactions but rather toxicity associated with high doses and&#47;or renal failure&#44; and&#44; in most cases&#44; transitory transaminase elevation not requiring suspension of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;15&#44;16&#44;18&#44;26</span></a> The test dose nonetheless continues to be recommended in most published guidelines&#44; although I have found no documented account of its utility or trial evidence supporting it&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In my opinion&#44; none of the toxicities associated with methotrexate can be considered hypersensitivity reactions&#44; except for methotrexate-associated pneumonitis&#44; which normally appears several weeks after treatment begins &#40;nearly always after the full dose is reached&#41;&#46; The test dose can therefore not be used as an excuse for preventing this serious&#44; though unusual&#44; toxic event&#46; From a theoretical standpoint&#44; assessing a test dose is more relevant in cases where methotrexate is being reintroduced&#44; as allergic hypersensitivity could be expected then rather than at the start of treatment&#46; Interestingly&#44; the general assumption on reintroducing the drug is that the previous experience is sufficient indication of safety and no test dose is needed&#46; However&#44; the literature offers mainly reports of anaphylactoid reactions after high doses in patients who had previously been exposed to methotrexate&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Acute hypersensitivity reactions&#8212;though we have no accurate catalog of exactly what to look for&#44; whether anaphylaxis&#44; urticaria&#44; toxic hepatitis&#44; bone marrow aplasia&#44; or toxic epidermal necrolysis&#8212;have been sporadically described in the literature almost exclusively in oncology or rheumatology patients who are taking concomitant medications and high doses of parenteral methotrexate&#59; the vast majority of these patients had been previously exposed to the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#8211;30</span></a> Very few cases of these reactions have been described after the initial dose and this is also true for patients with a severe underlying disease other than psoriasis and who are taking other medications&#46; &#40;We do note&#44; however&#44; a report of mild&#44; transient purpura after a test dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46;&#41; The available evidence therefore suggests that hypersensitivity reactions have mostly been described in patients who have previously taken high doses of methotrexate and have oncologic and&#47;or rheumatologic disorders&#46; This is not the situation for our patients taking low doses of methotrexate for psoriasis&#44; however&#46; Similarly&#44; leukopenia or pancytopenia are reactions that have been described mainly in patients with underlying conditions &#40;especially those with associated renal failure and in hemodialysis&#41; or in cases of overdose&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">What then is the purpose of a test dose&#63; Solely for the sake of argument&#44; we note that a test dose is indicated for the prevention of a possible non-dose-dependent hypersensitivity reaction&#44; which might be severe and which could be watched for&#59; or we might attenuate a reaction&#39;s seriousness by administering a small dose&#46; Next&#44; my understanding is that we must abandon claiming that the prevention of possible adverse events related to drug accumulation is a criterion for deciding to use a test dose&#44; given that a test occurs at the start of treatment&#46; A survey of the Spanish Psoriasis Group of the Spanish Academy of Dermatology &#40;AEDV&#41;&#44; carried out when the association&#39;s guidelines on methotrexate use in psoriasis<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> were being drafted&#44; included a question about the respondents&#8217; experience with test dosing&#46; The answers we received were extremely varied&#58; some respondents did not use one while others did&#8212;expressing fear of bone marrow aplasia&#44; acute hepatitis&#44; acute urticarial reaction&#8212;or &#8220;just in case of any unexpected reaction&#46;&#8221; None of the respondents had ever witnessed such a reaction among their patients&#44; however&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The only unexpected reaction to methotrexate in psoriasis I have seen was plaque erosion after the first few doses of the drug &#40;hypersensitivity&#63;&#41;&#46; This reaction is certainly not serious and is only remarkable because of the need to recognize it as what it really is in order to avoid interpreting it as a lack of response to methotrexate and then try raising the dose&#44; thereby leading to acute toxicity due to overdose &#40;a practice error&#44; as a higher dose would not be indicated&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">What constitutes a test dose&#63; That there is also variation in what practitioners consider to be a test dose was also evident in the survey mentioned above&#44; in which respondents chose 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; and 10<span class="elsevierStyleHsp" style=""></span>mg for such doses&#46; Several guidelines suggest a test dose of 5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#44; or a lower one of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg in a &#8216;susceptible patient&#8217;&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> The prescribing information for oral and injectable forms of methotrexate recommends an initial dose of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg and 10<span class="elsevierStyleHsp" style=""></span>mg&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> respectively&#44; without explicitly defining it as a test dose&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Still&#44; doses of 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg and higher are already within the therapeutic range &#40;7&#46;5&#8211;25<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#41; for psoriasis&#46; Is 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg the test dose when wanting to prescribe 15 or 20<span class="elsevierStyleHsp" style=""></span>mg&#63; And what if I want to administer a 7&#46;5-mg dose directly&#63; What is&#44; in principle&#44; the dose I eventually want to reach&#63; No studies give guidance on a theoretically optimal dose&#44; and methotrexate is not prescribed according to weight&#46; The precautionary measure of administering low doses would be more valid for patients with underlying risks &#40;due to comorbidity&#44; age&#44; or concomitant medication&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A lower initial dose must not be confused with a test dose&#46; The intention in the first instance is to discover the minimum effective dose rather than to prevent toxic reactions&#58; the minimum effective dose and the test dose are not one and the same&#46; The purpose of the test dose is to prevent an immediate acute adverse reaction that could be severe&#46; If the reaction is idiosyncratic or the result of hypersensitivity&#44; I believe it will matter little whether the dose is of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; or 15<span class="elsevierStyleHsp" style=""></span>mg&#44; since the problem stems from an individual&#39;s genetic makeup and metabolism of a drug and on the molecular structure of the drug itself&#46; Moreover&#44; any of these doses is far lower than those that had been administered in the reported cases of hypersensitivity reactions&#46; If the intention of a test is to prevent dose-dependent toxicity&#44; then indeed&#44; establishing the minimum effective dose could be considered&#46; How can we be sure that a single dose of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg will be safe and that a reaction will not develop after the second&#44; third&#44; or ninth dose&#63; Rather than accepting the test dose as a routine practice&#44; it would be more reasonable to maintain a low dose divided into several weekly intakes and to speak of a test or induction phase rather than a test dose&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Personally&#44; I do not prescribe test doses&#44; instead starting patients on an initial dose of 15<span class="elsevierStyleHsp" style=""></span>mg if they have no comorbidities associated with increased risk when taking this drug&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> I have observed no severe acute toxicity from this initial dose<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> and consider it the optimal one for predicting the efficacy that can be expected from continuing treatment&#46; This dose has been suggested on the basis of findings from trials that compared biologic agents to methotrexate&#44; according to Dr Kristian Reich&#44; speaking at the 2010 annual congress of the European Academy of Dermatology and Venereology in Gothenburg&#44; Sweden&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In my opinion the main issue in the management of methotrexate therapy is not about dosing regimens&#59; rather&#44; we should be concerned with evaluating patients before starting treatment and following them closely &#40;including monitoring laboratory test results&#41;&#44; as we have recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Early reviews of the use of aminopterin and methotrexate in psoriasis indicated that the possible adverse reactions encountered were related to renal or hepatic failure and rarely to hypersensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> When the use of methotrexate is considered&#44; contraindications and special precautions for this drug must be carefully assessed&#46; Any previous relative contraindication experienced by the patient will certainly influence the choice of dose&#44; follow-up&#44; and safety regimens&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; this presupposes a standardized management of methotrexate similar to that of other antipsoriatic drugs&#44; with no resort to a test dose based on uneasiness which neither experience nor evidence justifies&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Perhaps the reason for ongoing debate lies in the lack of randomized clinical trials&#46; Methotrexate is an old drug that appeared in another era&#46; The lack of appropriate clinical trials was denounced decades ago&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> yet trials have not been widely or systematically performed for this drug as they have been for cyclosporin and biologic agents&#44; drugs for which a test dose has not been suggested even though their potential to cause very serious adverse events is acknowledged&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Methotrexate has been the target of myths and groundless fears &#40;high risk of pulmonary and hepatic toxicity&#44; mutagenic potential&#44; etc&#46;&#41;&#44; which have gradually faded or diminished after decades of experience&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In any case&#44; discussions about the initial dose are not as important as the need for prompt patient evaluation and later clinical vigilance once methotrexate has been prescribed&#44; irrespective of the initial dose&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In summary&#44; I believe that when prescribing methotrexate in psoriasis we should consider therapeutic range&#59; patient selection&#59; the so-called attack&#44; or loading&#44; dose as well as the maintenance dose&#59; and follow-up&#46; A test dose&#44; on the other hand&#44; should not be used for fear of the unknown or figments of our imagination&#46; Methotrexate should receive the same medical&#44; pharmacologic&#44; and pharmacovigilance treatment as any other drug and not be subjected to a verdict of guilty without trial&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of Interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The author declares that he has no conflicts of interest with regard to this opinion article&#46; However&#44; he has received fees for speaking at conferences&#44; conducting clinical trials&#44; or otherwise serving as a consultant from the following laboratories&#58; Novartis&#44; Leo-Pharma&#44; MSD&#44; Abbott&#44; Pfizer&#44; and Janssen-Cilag&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Carretero-Hern&#225;ndez G&#46; Metotrexato en psoriasis&#58; &#191;es necesaria una dosis de prueba&#63;&#46; Actas Dermosifiliogr&#46;2012&#59;103&#58;1-4&#46;</p>"
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