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which makes correct diagnosis even more complex&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> Unlike some immunosuppressants&#44; where a higher capacity for resulting in oral ulcers has been demonstrated &#40;mTOR inhibitors are most commonly associated with this type of ulcers&#41;&#44; as far as we know&#44; mycophenolate mofetil &#40;MMF&#41; has been noted to rarely cause oral ulcers with only 9 patients reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1&#8211;6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Here we report one new case of MMF-induced oral ulcerations&#46; We also review all patients in the literature with this uncommon side effect&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Report</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 67 year-old man with renal insufficiency due to polycystic kidney disease and arterial hypertension underwent a kidney transplant in 2015&#46; He received immunosupressive treatment with metilprednisolone &#40;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; tacrolimus &#40;16<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; and MMF &#40;2<span class="elsevierStyleHsp" style=""></span>g&#47;d&#41;&#46; Nine months after kidney transplantation 3 painful oral ulcers appeared on both sides of the tongue and on the oral mucosa&#46; He also presented intense odynophagia&#44; difficulty swallowing&#44; decreased intake and weight loss without fever&#46; On examination&#44; 2 major aphthous ulcers&#44; with surrounding edema and erythema were present on his tongue &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; and 1 smaller erosion was observed in his buccal mucosa &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Apart from the immunosupressive treatment&#44; at this moment he was also taking oral valganciclovir because of a CMV infection reactivation&#46; The blood sample test showed leukopenia&#44; anemia and thrombocytopenia with a stable renal function &#40;creatinine 2&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; and a normal hepatic profile&#46; Levels of tacrolimus were correct in relation with the time after kidney transplantation&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Cultures of the oral lesions were negative for herpes simplex virus types 1 and 2&#44; CMV&#44; and fungus&#46; Rapid plasma reagin &#40;RPR&#41; and HIV antibody testing results were nonreactive&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Oral biopsy showed nonspecific inflammatory changes on hematoxylin&#8211;eosin &#40;H&#38;E&#41; staining&#46; Finally MMF was subsequently discontinued&#46; After 4 days&#44; the patient&#39;s oral ulcers decreased considerably in size&#44; with a significant reduction in his oral pain&#44; improving the ability to eat and drink&#46; After 9 days&#44; complete healing of the patient&#39;s ulcers was observed&#46; The patient has since remained off MMF with no recurrences of his ulcerations&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">MMF is a powerful immunosuppressant that is often used to prevent acute rejection in hematopoietic stem cell or solid organ transplant patients as well as in some autoimmune diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">7&#44;8</span></a> Its mechanism of action is based on inhibition of purine synthesis via inhibition of the inosine phosphate dehydrogenase enzyme&#46; This results in a decrease in lymphocyte proliferation that is responsible for the immunosuppressive effects of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">7&#44;8</span></a> Its most common side effects are digestive in the form of diarrhea or vomiting with extremely varied other adverse effects&#46; Among them&#44; oral ulcers are one of the less frequent and therefore less known by dermatologists&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">We searched PubMed with the terms &#8220;mycophenolate mofetil&#8221; and &#8220;oral ulceration&#8221; and found 9 cases in the English-language literature&#46; Characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Since the first case reported in 2001&#44; 9 additional cases of MMF-oral ulcerations have been described &#40;including our patient&#41; presenting as very painful ulcers<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> &#40;2 or more ulcers per patient&#41;&#44; located in the oral mucosa&#46; One case had also anal ulcers and another&#44; edema in gums&#46; To date&#44; all cases published&#44; are in patients who have undergone a solid organ transplant and the dose of MMF that they were receiving&#44; ranged from 1 to 2<span class="elsevierStyleHsp" style=""></span>g&#47;d&#46; In all the cases&#44; the ulcers healed quickly once the drug was stopped&#46; In every reported case improvement of the lesions is observed within the first 4&#8211;10 days and complete healing is seen in 6 weeks at most&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1&#8211;6</span></a> Our patient referred significant improvement only four days after stopping the drug&#46; These lesions are usually not accompanied by other side effects and the interval time between starting the drug and the appearance of the ulcers varies greatly&#44; with described cases ranging from 1 week to 3 years&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">From the microscopic point of view no specific findings are observed&#44; usually showing nonspecific mixed inflammatory infiltrates with a negative immunofluorescence&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Despite of this&#44; in our opinion biopsy should always be performed in order to rule out other common diseases such as fungal infections or CMV&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Regarding the pathogenesis of these lesions&#44; most authors propose their appearance as the result of a direct cytotoxic effect of the drug on the mucosa although this point is not yet fully proven&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion&#44; oral ulcers caused by MMF are a rare cause of oral ulcers that dermatologists should be aware of&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflict of interests</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mouth ulcers are a cutaneous complication that can often affect kidney transplant patients&#44; mostly due to the effect of immunosuppressive treatment&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Even so&#44; before asserting that said complication is indeed secondary to drugs&#44; it is very important to establish a differential diagnosis with other mouth ulcer causes&#44; such as systemic diseases or viral infections&#44; which are also common in these patients&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las &#250;lceras orales son una de las complicaciones cut&#225;neas que pueden afectar con frecuencia a los pacientes trasplantados renales&#44; debido muchas veces al efecto del tratamiento inmunosupresor&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Aun as&#237;&#44; es importante&#44; antes de asegurar que dicha complicaci&#243;n es secundaria a los f&#225;rmacos&#44; establecer el diagn&#243;stico diferencial con otras causas de &#250;lceras orales como pueden ser enfermedades sist&#233;micas o infecciones virales&#44; tambi&#233;n frecuentes en este tipo de pacientes&#46;</p></span>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">MMF&#44; mycophenolate mofetil&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Age&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Transplant type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Time since transplant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Histopathology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MMF dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Concomitant drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Outcome after MMF withdrawal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salik et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 major oral ulcers&#44; sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;16<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 9 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salik et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 major and 1 minor oral ulcers&#44; sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;6<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 4 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salik et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 major and 4 minor oral ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine &#40;200<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;40<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 7 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Philipone et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 major and several minor oral ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;16<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing 4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weng et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Several minor ulcers&#44; gum swelling and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No biopsy was done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Great improvement after 1 week and complete healing after 6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Naranjo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 major oral ulcers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No biopsy was done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus and prednisone &#40;no doses specified&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Naranjo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No specified&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 major oral ulcers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No biopsy was done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine and metilprednisolone &#40;no doses specified&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 1 week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Apostolou et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 major and 3 minor oral ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;4<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Great improvement after 6 days and complete healing after 6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Garrigue<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Several oral and anal ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine &#40;400<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete healing after 3 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Case report
Mycophenolate mofetil-induced mouth ulcers in a kidney transplant patient: Case report and literature review
Úlceras orales secundarias a micofenolato mofetilo en un paciente trasplantado renal: caso clínico y revisión de la literatura
Adrià Plana-Plaa,
Autor para correspondencia
adriplanapla@gmail.com

Corresponding author.
, Laura Cañas Soléb, Aram Boada Garciaa, Ricardo Lauzurica Valdemorosb
a Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
b Department of Nephrology, Hospital Universitari, Germans Trias i Pujol, Badalona, Barcelona, Spain
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which makes correct diagnosis even more complex&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> Unlike some immunosuppressants&#44; where a higher capacity for resulting in oral ulcers has been demonstrated &#40;mTOR inhibitors are most commonly associated with this type of ulcers&#41;&#44; as far as we know&#44; mycophenolate mofetil &#40;MMF&#41; has been noted to rarely cause oral ulcers with only 9 patients reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1&#8211;6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Here we report one new case of MMF-induced oral ulcerations&#46; We also review all patients in the literature with this uncommon side effect&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Report</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 67 year-old man with renal insufficiency due to polycystic kidney disease and arterial hypertension underwent a kidney transplant in 2015&#46; He received immunosupressive treatment with metilprednisolone &#40;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; tacrolimus &#40;16<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; and MMF &#40;2<span class="elsevierStyleHsp" style=""></span>g&#47;d&#41;&#46; Nine months after kidney transplantation 3 painful oral ulcers appeared on both sides of the tongue and on the oral mucosa&#46; He also presented intense odynophagia&#44; difficulty swallowing&#44; decreased intake and weight loss without fever&#46; On examination&#44; 2 major aphthous ulcers&#44; with surrounding edema and erythema were present on his tongue &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; and 1 smaller erosion was observed in his buccal mucosa &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Apart from the immunosupressive treatment&#44; at this moment he was also taking oral valganciclovir because of a CMV infection reactivation&#46; The blood sample test showed leukopenia&#44; anemia and thrombocytopenia with a stable renal function &#40;creatinine 2&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; and a normal hepatic profile&#46; Levels of tacrolimus were correct in relation with the time after kidney transplantation&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Cultures of the oral lesions were negative for herpes simplex virus types 1 and 2&#44; CMV&#44; and fungus&#46; Rapid plasma reagin &#40;RPR&#41; and HIV antibody testing results were nonreactive&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Oral biopsy showed nonspecific inflammatory changes on hematoxylin&#8211;eosin &#40;H&#38;E&#41; staining&#46; Finally MMF was subsequently discontinued&#46; After 4 days&#44; the patient&#39;s oral ulcers decreased considerably in size&#44; with a significant reduction in his oral pain&#44; improving the ability to eat and drink&#46; After 9 days&#44; complete healing of the patient&#39;s ulcers was observed&#46; The patient has since remained off MMF with no recurrences of his ulcerations&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">MMF is a powerful immunosuppressant that is often used to prevent acute rejection in hematopoietic stem cell or solid organ transplant patients as well as in some autoimmune diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">7&#44;8</span></a> Its mechanism of action is based on inhibition of purine synthesis via inhibition of the inosine phosphate dehydrogenase enzyme&#46; This results in a decrease in lymphocyte proliferation that is responsible for the immunosuppressive effects of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">7&#44;8</span></a> Its most common side effects are digestive in the form of diarrhea or vomiting with extremely varied other adverse effects&#46; Among them&#44; oral ulcers are one of the less frequent and therefore less known by dermatologists&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">We searched PubMed with the terms &#8220;mycophenolate mofetil&#8221; and &#8220;oral ulceration&#8221; and found 9 cases in the English-language literature&#46; Characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Since the first case reported in 2001&#44; 9 additional cases of MMF-oral ulcerations have been described &#40;including our patient&#41; presenting as very painful ulcers<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> &#40;2 or more ulcers per patient&#41;&#44; located in the oral mucosa&#46; One case had also anal ulcers and another&#44; edema in gums&#46; To date&#44; all cases published&#44; are in patients who have undergone a solid organ transplant and the dose of MMF that they were receiving&#44; ranged from 1 to 2<span class="elsevierStyleHsp" style=""></span>g&#47;d&#46; In all the cases&#44; the ulcers healed quickly once the drug was stopped&#46; In every reported case improvement of the lesions is observed within the first 4&#8211;10 days and complete healing is seen in 6 weeks at most&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1&#8211;6</span></a> Our patient referred significant improvement only four days after stopping the drug&#46; These lesions are usually not accompanied by other side effects and the interval time between starting the drug and the appearance of the ulcers varies greatly&#44; with described cases ranging from 1 week to 3 years&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">From the microscopic point of view no specific findings are observed&#44; usually showing nonspecific mixed inflammatory infiltrates with a negative immunofluorescence&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Despite of this&#44; in our opinion biopsy should always be performed in order to rule out other common diseases such as fungal infections or CMV&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Regarding the pathogenesis of these lesions&#44; most authors propose their appearance as the result of a direct cytotoxic effect of the drug on the mucosa although this point is not yet fully proven&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion&#44; oral ulcers caused by MMF are a rare cause of oral ulcers that dermatologists should be aware of&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflict of interests</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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        1 => array:2 [
          "identificador" => "xpalclavsec1067018"
          "titulo" => "Keywords"
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          "titulo" => "Resumen"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
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          "titulo" => "Introduction"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Report"
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          "identificador" => "sec0015"
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        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Conflict of interests"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2017-09-19"
    "fechaAceptado" => "2018-05-06"
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      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1067018"
          "palabras" => array:4 [
            0 => "Kidney transplant"
            1 => "Mycophenolate mofetil"
            2 => "Mouth ulcers"
            3 => "Cytomegalovirus"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Trasplante renal"
            1 => "Micofenolato mofetilo"
            2 => "&#218;lceras orales"
            3 => "Citomegalovirus"
          ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mouth ulcers are a cutaneous complication that can often affect kidney transplant patients&#44; mostly due to the effect of immunosuppressive treatment&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Even so&#44; before asserting that said complication is indeed secondary to drugs&#44; it is very important to establish a differential diagnosis with other mouth ulcer causes&#44; such as systemic diseases or viral infections&#44; which are also common in these patients&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las &#250;lceras orales son una de las complicaciones cut&#225;neas que pueden afectar con frecuencia a los pacientes trasplantados renales&#44; debido muchas veces al efecto del tratamiento inmunosupresor&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Aun as&#237;&#44; es importante&#44; antes de asegurar que dicha complicaci&#243;n es secundaria a los f&#225;rmacos&#44; establecer el diagn&#243;stico diferencial con otras causas de &#250;lceras orales como pueden ser enfermedades sist&#233;micas o infecciones virales&#44; tambi&#233;n frecuentes en este tipo de pacientes&#46;</p></span>"
      ]
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinical photograph shows 2 major aphthous ulcers&#44; with surrounding edema and erythema&#44; on the tongue&#46;</p>"
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      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Clinical photograph shows 1 minor aphthous ulcer&#44; on buccal mucosa&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">MMF&#44; mycophenolate mofetil&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Age&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Transplant type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Time since transplant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Histopathology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MMF dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Concomitant drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Outcome after MMF withdrawal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salik et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 major oral ulcers&#44; sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;16<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 9 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salik et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 major and 1 minor oral ulcers&#44; sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;6<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 4 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Salik et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 major and 4 minor oral ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine &#40;200<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;40<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 7 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Philipone et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 major and several minor oral ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;16<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing 4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weng et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Several minor ulcers&#44; gum swelling and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No biopsy was done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Great improvement after 1 week and complete healing after 6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Naranjo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 major oral ulcers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No biopsy was done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus and prednisone &#40;no doses specified&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Naranjo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No specified&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 major oral ulcers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No biopsy was done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine and metilprednisolone &#40;no doses specified&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Healing after 1 week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Apostolou et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 major and 3 minor oral ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tacrolimus &#40;4<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Great improvement after 6 days and complete healing after 6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Garrigue<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Several oral and anal ulcers and sever oral pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonspecific inflammatory changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>g&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ciclosporine &#40;400<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#44; prednisone &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete healing after 3 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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