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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Wilson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr Gastroenterol Nutr" "fecha" => "2001" "volumen" => "32" "paginaInicial" => "207" "paginaFinal" => "208" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11321395" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0085" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Toxic tacrolimus levels after application of topical tacrolimus and use of occlusive dressings in two bone marrow transplant recipients with cutaneous graft-versus-host disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K.A. Olson" 1 => "K. West" 2 => "P.L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 8 | 14 |
| 2024 October | 70 | 36 | 106 |
| 2024 September | 71 | 23 | 94 |
| 2024 August | 84 | 54 | 138 |
| 2024 July | 78 | 32 | 110 |
| 2024 June | 74 | 44 | 118 |
| 2024 May | 68 | 31 | 99 |
| 2024 April | 77 | 25 | 102 |
| 2024 March | 75 | 28 | 103 |
| 2024 February | 68 | 36 | 104 |
| 2024 January | 48 | 27 | 75 |
| 2023 December | 67 | 14 | 81 |
| 2023 November | 63 | 29 | 92 |
| 2023 October | 43 | 24 | 67 |
| 2023 September | 51 | 32 | 83 |
| 2023 August | 33 | 19 | 52 |
| 2023 July | 33 | 22 | 55 |
| 2023 June | 76 | 28 | 104 |
| 2023 May | 49 | 28 | 77 |
| 2023 April | 42 | 22 | 64 |
| 2023 March | 71 | 33 | 104 |
| 2023 February | 47 | 24 | 71 |
| 2023 January | 44 | 24 | 68 |
| 2022 December | 47 | 43 | 90 |
| 2022 November | 31 | 20 | 51 |
| 2022 October | 20 | 30 | 50 |
| 2022 September | 17 | 41 | 58 |
| 2022 August | 29 | 26 | 55 |
| 2022 July | 20 | 30 | 50 |
| 2022 June | 15 | 22 | 37 |
| 2022 May | 32 | 31 | 63 |
| 2022 April | 36 | 30 | 66 |
| 2022 March | 31 | 44 | 75 |
| 2022 February | 21 | 31 | 52 |
| 2022 January | 30 | 28 | 58 |
| 2021 December | 19 | 31 | 50 |
| 2021 November | 41 | 55 | 96 |
| 2021 October | 28 | 48 | 76 |
| 2021 September | 25 | 36 | 61 |
| 2021 August | 28 | 57 | 85 |
| 2021 July | 24 | 28 | 52 |
| 2021 June | 22 | 18 | 40 |
| 2021 May | 28 | 39 | 67 |
| 2021 April | 124 | 55 | 179 |
| 2021 March | 39 | 37 | 76 |
| 2021 February | 39 | 26 | 65 |
| 2021 January | 33 | 20 | 53 |
| 2020 December | 43 | 15 | 58 |
| 2020 November | 19 | 18 | 37 |
| 2020 October | 20 | 5 | 25 |
| 2020 September | 20 | 18 | 38 |
| 2020 August | 24 | 21 | 45 |
| 2020 July | 19 | 16 | 35 |
| 2020 June | 27 | 32 | 59 |
| 2020 May | 19 | 12 | 31 |
| 2020 April | 33 | 17 | 50 |
| 2020 March | 32 | 14 | 46 |
| 2020 February | 6 | 2 | 8 |
| 2020 January | 2 | 0 | 2 |
| 2019 December | 9 | 0 | 9 |
| 2019 November | 4 | 0 | 4 |
| 2019 September | 13 | 0 | 13 |
| 2019 August | 4 | 0 | 4 |
| 2019 July | 4 | 0 | 4 |
| 2019 June | 6 | 0 | 6 |
| 2019 May | 4 | 0 | 4 |
| 2019 April | 2 | 3 | 5 |
| 2019 March | 4 | 0 | 4 |
| 2019 February | 5 | 0 | 5 |
| 2019 January | 2 | 0 | 2 |
| 2018 December | 4 | 0 | 4 |
| 2018 November | 3 | 0 | 3 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 1 | 0 | 1 |
| 2018 February | 47 | 2 | 49 |
| 2018 January | 64 | 15 | 79 |
| 2017 December | 80 | 9 | 89 |
| 2017 November | 29 | 15 | 44 |
| 2017 October | 28 | 11 | 39 |
| 2017 September | 19 | 6 | 25 |
| 2017 August | 28 | 23 | 51 |
| 2017 July | 21 | 3 | 24 |
| 2017 June | 27 | 15 | 42 |
| 2017 May | 25 | 9 | 34 |
| 2017 April | 38 | 17 | 55 |
| 2017 March | 29 | 9 | 38 |
| 2017 February | 24 | 7 | 31 |
| 2017 January | 17 | 10 | 27 |
| 2016 December | 58 | 40 | 98 |
| 2016 November | 17 | 28 | 45 |
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