CASE AND RESEARCH LETTERS
Systemic Absorption of Topical Tacrolimus in Metastatic Crohn Disease With Skin Ulcers
Absorción sistémica de tacrolimus tópico en enfermedad de Crohn metastásica con úlceras cutáneas
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García-Delgado, E. Escario-Travesedo, A. Sánchez-Romero" "autores" => array:3 [ 0 => array:4 [ "nombre" => "R." "apellidos" => "García-Delgado" "email" => array:1 [ 0 => "rfcog@sescam.jccm.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "E." "apellidos" => "Escario-Travesedo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "A." "apellidos" => "Sánchez-Romero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Farmacología Clínica, Complejo Hospitalario Universitario de Albacete, Albacete, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Dermatología, Complejo Hospitalario Universitario de Albacete, Albacete, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Absorción sistémica de tacrolimus tópico en enfermedad de Crohn metastásica con úlceras cutáneas" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We present the case of a 54-year-old woman with colonic Crohn disease with metastatic Crohn lesions affecting the perianal region and skin folds. During an exacerbation she presented ulcerated intertrigo in the intergluteal, inguinal, and abdominal folds (measured surface area of ulceration of 155<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span>, done with ImageJ software). After the administration of fentanyl and lorazepam for analgesia and anxiolysis, daily lavage was performed with soap and water and normal saline, and 60<span class="elsevierStyleHsp" style=""></span>g of topical 0.1% tacrolimus was applied using an impregnated swab. After 15 days, the nursing staff developed a new method for the daily application of the cream, emptying the contents of the tube into a pressure-lavage syringe and applying the preparation directly to the ulcers. Ten days later a moderate kidney failure was detected (elevation of creatinine from 1.4<span class="elsevierStyleHsp" style=""></span>mg/dL to 2.4<span class="elsevierStyleHsp" style=""></span>mg/dL and of urea from 69<span class="elsevierStyleHsp" style=""></span>mg/dL to 110<span class="elsevierStyleHsp" style=""></span>mg/dL). This was interpreted as prerenal failure and was treated by increasing fluid intake and intravenous fluids administration. However, suspecting the possible implication of tacrolimus in the deterioration of renal function, blood tests were performed and tacrolimus levels of 9.7<span class="elsevierStyleHsp" style=""></span>ng/mL were detected in whole blood (the therapeutic range after solid organ transplant is 5-20<span class="elsevierStyleHsp" style=""></span>ng/mL). The application of the cream was interrupted for 24<span class="elsevierStyleHsp" style=""></span>hours, and the level fell to 5.3<span class="elsevierStyleHsp" style=""></span>ng/mL. The concentration of the topical tacrolimus formulation was then reduced to 0.03%. Subsequent controls showed almost undetectable tacrolimus concentrations, and the serum creatinine fell to previous values.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Discussion</span><p id="par0010" class="elsevierStylePara elsevierViewall">Cutaneous manifestations of CD occur in 9% to 23% of patients.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> Perianal fissures and fistulas are probably the most common lesions (17%-43% of patients).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a> Metastatic CD is defined as the presence of compatible granulomatous lesions in skin that is not contiguous with the digestive tract.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Topical tacrolimus administered once a day has shown a limited effect on the clinical course of fistulas and ulcers, achieving remission in 36% of patients and some response in 29%.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> Regarding its side effects, Shah et al.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a>considered the most common to be mild pruritus at the site of application; they added that absorption through skin lacking the epidermal barrier or through the mucosas is usually low, giving rise to low or undetectable blood levels. Other authors have described elevated blood concentrations of tacrolimus after its application to the skin. Faisal<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> reported a level of 14.7<span class="elsevierStyleHsp" style=""></span>ng/mL associated with nausea, paresthesia, and dizziness, which he attributed to absorption through the gastrointestinal mucosa in a case of perianal CD. Russell et al.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a>described a patient with orofacial involvement in whom the application of 0.05% tacrolimus to an area of 1-2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span> produced blood concentrations of 9<span class="elsevierStyleHsp" style=""></span>ng/mL and the patient developed thoracolumbar herpes zoster. Olson et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> defined a series of risk factors for increased transcutaneous absorption of tacrolimus: the surface area involved, the absence of the skin barrier, and the use of occlusive dressings. Neuman et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a> added a further 2 factors: young age and warm skin due to increased circulation. They recommended monitoring tacrolimus blood levels in patients with 1 or more of these factors.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In our patient, the application of topical tacrolimus directly over the skin fold ulcers coincided temporaly matched with a deterioration in her renal function. Other causative factors may be implicated, but tacrolimus blood concentrations of 9.7<span class="elsevierStyleHsp" style=""></span>ng/mL could certainly have contributed to this deterioration; the effect may have been more intense in this patient as she had underlying kidney disease (serum creatinine, 1.4<span class="elsevierStyleHsp" style=""></span>mg/dL). Dose adjustment and the falling blood levels coincided with the improvement in renal function.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In our patient, absorption of the topical preparation was high as it was applied to ulcers (absent stratum corneum) and to skin folds (occlusive dressing). The progressive fall in tacrolimus blood levels in our patient may be explained not only by the dose reduction (topical 0.03% tacrolimus), but also by the improvement in the lesions and in the barrier properties of the skin.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In summary, we have presented a case of systemic absorption of tacrolimus after topical application, with a deterioration of renal function (a common adverse effect of this drug). This coincided with the direct application of tacrolimus to ulcerated areas (altered skin barrier) and the use of occlusive dressings (skin folds and moist areas). Monitoring tacrolimus blood levels is recommended to avoid side effects associated with unexpectedly high concentrations, particularly in patients with underlying kidney disease. A rational regimen would be to monitor levels weekly for the first month and every 2 weeks or every month thereafter, and at any time that complications are detected.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of Interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Discussion" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of Interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: García-Delgado R, Escario-Travesedo E, Sánchez-Romero A. Absorción sistémica de tacrolimus tópico en enfermedad de Crohn metastásica con úlceras cutáneas. 2016;107:868–869.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Manifestaciones cutáneas de la enfermedad inflamatoria intestinal" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P. Zaballos Diego" 1 => "M. Ara Martín" 2 => "E. Salsench Serrano" 3 => "F. Lafuente Urrez" 4 => "J. Alcedo González" 5 => "F.J. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 6 | 8 | 14 |
| 2024 Octubre | 70 | 36 | 106 |
| 2024 Septiembre | 71 | 23 | 94 |
| 2024 Agosto | 84 | 54 | 138 |
| 2024 Julio | 78 | 32 | 110 |
| 2024 Junio | 74 | 44 | 118 |
| 2024 Mayo | 68 | 31 | 99 |
| 2024 Abril | 77 | 25 | 102 |
| 2024 Marzo | 75 | 28 | 103 |
| 2024 Febrero | 68 | 36 | 104 |
| 2024 Enero | 48 | 27 | 75 |
| 2023 Diciembre | 67 | 14 | 81 |
| 2023 Noviembre | 63 | 29 | 92 |
| 2023 Octubre | 43 | 24 | 67 |
| 2023 Septiembre | 51 | 32 | 83 |
| 2023 Agosto | 33 | 19 | 52 |
| 2023 Julio | 33 | 22 | 55 |
| 2023 Junio | 76 | 28 | 104 |
| 2023 Mayo | 49 | 28 | 77 |
| 2023 Abril | 42 | 22 | 64 |
| 2023 Marzo | 71 | 33 | 104 |
| 2023 Febrero | 47 | 24 | 71 |
| 2023 Enero | 44 | 24 | 68 |
| 2022 Diciembre | 47 | 43 | 90 |
| 2022 Noviembre | 31 | 20 | 51 |
| 2022 Octubre | 20 | 30 | 50 |
| 2022 Septiembre | 17 | 41 | 58 |
| 2022 Agosto | 29 | 26 | 55 |
| 2022 Julio | 20 | 30 | 50 |
| 2022 Junio | 15 | 22 | 37 |
| 2022 Mayo | 32 | 31 | 63 |
| 2022 Abril | 36 | 30 | 66 |
| 2022 Marzo | 31 | 44 | 75 |
| 2022 Febrero | 21 | 31 | 52 |
| 2022 Enero | 30 | 28 | 58 |
| 2021 Diciembre | 19 | 31 | 50 |
| 2021 Noviembre | 41 | 55 | 96 |
| 2021 Octubre | 28 | 48 | 76 |
| 2021 Septiembre | 25 | 36 | 61 |
| 2021 Agosto | 28 | 57 | 85 |
| 2021 Julio | 24 | 28 | 52 |
| 2021 Junio | 22 | 18 | 40 |
| 2021 Mayo | 28 | 39 | 67 |
| 2021 Abril | 124 | 55 | 179 |
| 2021 Marzo | 39 | 37 | 76 |
| 2021 Febrero | 39 | 26 | 65 |
| 2021 Enero | 33 | 20 | 53 |
| 2020 Diciembre | 43 | 15 | 58 |
| 2020 Noviembre | 19 | 18 | 37 |
| 2020 Octubre | 20 | 5 | 25 |
| 2020 Septiembre | 20 | 18 | 38 |
| 2020 Agosto | 24 | 21 | 45 |
| 2020 Julio | 19 | 16 | 35 |
| 2020 Junio | 27 | 32 | 59 |
| 2020 Mayo | 19 | 12 | 31 |
| 2020 Abril | 33 | 17 | 50 |
| 2020 Marzo | 32 | 14 | 46 |
| 2020 Febrero | 6 | 2 | 8 |
| 2020 Enero | 2 | 0 | 2 |
| 2019 Diciembre | 9 | 0 | 9 |
| 2019 Noviembre | 4 | 0 | 4 |
| 2019 Septiembre | 13 | 0 | 13 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 4 | 0 | 4 |
| 2019 Junio | 6 | 0 | 6 |
| 2019 Mayo | 4 | 0 | 4 |
| 2019 Abril | 2 | 3 | 5 |
| 2019 Marzo | 4 | 0 | 4 |
| 2019 Febrero | 5 | 0 | 5 |
| 2019 Enero | 2 | 0 | 2 |
| 2018 Diciembre | 4 | 0 | 4 |
| 2018 Noviembre | 3 | 0 | 3 |
| 2018 Octubre | 3 | 0 | 3 |
| 2018 Septiembre | 1 | 0 | 1 |
| 2018 Febrero | 47 | 2 | 49 |
| 2018 Enero | 64 | 15 | 79 |
| 2017 Diciembre | 80 | 9 | 89 |
| 2017 Noviembre | 29 | 15 | 44 |
| 2017 Octubre | 28 | 11 | 39 |
| 2017 Septiembre | 19 | 6 | 25 |
| 2017 Agosto | 28 | 23 | 51 |
| 2017 Julio | 21 | 3 | 24 |
| 2017 Junio | 27 | 15 | 42 |
| 2017 Mayo | 25 | 9 | 34 |
| 2017 Abril | 38 | 17 | 55 |
| 2017 Marzo | 29 | 9 | 38 |
| 2017 Febrero | 24 | 7 | 31 |
| 2017 Enero | 17 | 10 | 27 |
| 2016 Diciembre | 58 | 40 | 98 |
| 2016 Noviembre | 17 | 28 | 45 |
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