Scientific letter
Relationship between ustekinumab trough concentrations and both clinical and biological remission in patients with Crohn's disease
Relación entre las concentraciones mínimas de ustekinumab y la remisión clínica y biológica en pacientes con enfermedad de Crohn
Read
Not available
Timeswas read the article
Total PDF
Total HTML
Share statistics
array:23 [ "pii" => "S2444382423001487" "issn" => "24443824" "doi" => "10.1016/j.gastre.2022.10.017" "estado" => "S300" "fechaPublicacion" => "2023-10-01" "aid" => "2009" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2022" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Gastroenterol Hepatol. 2023;46:631-2" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:18 [ "pii" => "S2444382423001505" "issn" => "24443824" "doi" => "10.1016/j.gastre.2022.11.005" "estado" => "S300" "fechaPublicacion" => "2023-10-01" "aid" => "2020" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Gastroenterol Hepatol. 2023;46:633-4" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Image of the month</span>" "titulo" => "Spontaneous cutaneous fistula secondary to hepatic hydatidosis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "633" "paginaFinal" => "634" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fístula cutánea secundaria a hidatidosis hepática" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 802 "Ancho" => 988 "Tamanyo" => 103220 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Abdominal CT with oral and intravenous contrast with multiple cystic formations in the segment V of the liver with fistulous communication between the abdominal wall and the hydatid vesiculation (red arrow).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Miguel Sogbe, José Luis del Pozo" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Miguel" "apellidos" => "Sogbe" ] 1 => array:2 [ "nombre" => "José Luis" "apellidos" => "del Pozo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2444382423001505?idApp=UINPBA00004N" "url" => "/24443824/0000004600000008/v2_202311101346/S2444382423001505/v2_202311101346/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2444382423001268" "issn" => "24443824" "doi" => "10.1016/j.gastre.2023.07.002" "estado" => "S300" "fechaPublicacion" => "2023-10-01" "aid" => "1977" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Gastroenterol Hepatol. 2023;46:629-30" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Tofacitinib for the treatment of inflammatory condition of the ileoanal pouch refractory to infliximab" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "629" "paginaFinal" => "630" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tofacitinib para el tratamiento de la afección inflamatoria del reservorio refractaria a infliximab" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1620 "Ancho" => 2933 "Tamanyo" => 269388 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Evolution of haemoglobin values (g/dl) in the last two years (January 2020–May-2022).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Marta Fortuny, Laura Gutiérrez-Rios, Eva Vayreda, Míriam Mañosa, Eugeni Domènech" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Marta" "apellidos" => "Fortuny" ] 1 => array:2 [ "nombre" => "Laura" "apellidos" => "Gutiérrez-Rios" ] 2 => array:2 [ "nombre" => "Eva" "apellidos" => "Vayreda" ] 3 => array:2 [ "nombre" => "Míriam" "apellidos" => "Mañosa" ] 4 => array:2 [ "nombre" => "Eugeni" "apellidos" => "Domènech" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0210570522002096" "doi" => "10.1016/j.gastrohep.2022.08.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210570522002096?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2444382423001268?idApp=UINPBA00004N" "url" => "/24443824/0000004600000008/v2_202311101346/S2444382423001268/v2_202311101346/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Relationship between ustekinumab trough concentrations and both clinical and biological remission in patients with Crohn's disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "631" "paginaFinal" => "632" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Francisco Ángel Lao Domínguez, María José Fobelo Lozano, Antonio Gutiérrez Pizarraya, Manuel Castro Fernández" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Francisco Ángel" "apellidos" => "Lao Domínguez" "email" => array:1 [ 0 => "fralaodom@gmail.com" ] "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" => "María José" "apellidos" => "Fobelo Lozano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Antonio" "apellidos" => "Gutiérrez Pizarraya" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Manuel" "apellidos" => "Castro Fernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Hospital Universitario Virgen de Valme, Pharmacy Service, Seville, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Universitario Virgen de Valme, Digestive Medicine Service, Seville, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Relación entre las concentraciones mínimas de ustekinumab y la remisión clínica y biológica en pacientes con enfermedad de Crohn" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1983 "Ancho" => 3174 "Tamanyo" => 209025 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A. Quartile distribution of ustekinumab levels according clinical remission. B. Ustekinumab levels according clinical remission. C. Ustekinumab levels according biological remission. D. Ustekinumab levels according clinical remission in patients without intestinal resection surgery. NS: not significant.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The data about TDM of ustekinumab is still limited despite being a potential drug for it.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">1–4</span></a> Taking into consideration the potential benefits of TDM, the addition of ustekinumab monitoring to clinical practice could improve clinical decisions in the treatment of Crohn disease (CD) for which it is necessary to provide more data in this regard.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We studied patients with CD undergoing maintenance treatment with ustekinumab who underwent at least one determination of serum ustekinumab level to provide further evidence of the correlation between them and both clinical and biological remission.</p><p id="par0015" class="elsevierStylePara elsevierViewall">All samples were classified according to disease activity at the time of level determination. Clinical remission was established through Harvey-Bradshaw index considering no disease activity when it had a value ≤4. Biological remission was based on analytical values of both CRP (<5<span class="elsevierStyleHsp" style=""></span>mg/L) and CAL (<250<span class="elsevierStyleHsp" style=""></span>μg/g). Sample extraction was performed just before the next administration of ustekinumab.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Forty one samples from thirty seven patients were collected. Median age was 43 years (IQR: 35–52.5) and 20 patients were women. CD was located in 62.2% (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>23) in ileum-colon, 27% (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10) in ileum and 10.8% (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4) in colon. The profile of CD was inflammatory in 43.2%, stenosing in 32.4%, penetrating in 10.8% and stenosing-penetrating in 13.5%. Intestinal resection surgery prior to the onset of ustekinumab was present in 45.9% of the patients. In this group of patients, surgery was performed at least 1 year before its inclusion in the study.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Ustekinumab was used as the third line of biological treatment in 70.3% of patients, 27% in the second and 10.3% in the fourth. The dosing regimen at the time of sample extraction was 90<span class="elsevierStyleHsp" style=""></span>mg every 8 weeks (68.3%), every 7 weeks (4.9%), every 6 weeks (9.8%) and every 4 weeks (17.1%). The median treatment time was 23 months (IQR: 10–29). Eight patients (10.3%) were reinduced with an IV dose with a median time between ustekinumab reinduction and sample extraction of 34.6 weeks (IQR: 22.8–38.6). 5.4% of patients were on concomitant immunomodulatory treatment (methotrexate). Albumin serum median level was 4.47<span class="elsevierStyleHsp" style=""></span>g/dL (IQR: 4.23–4.85).</p><p id="par0030" class="elsevierStylePara elsevierViewall">Trough serum concentration was determined in all patients in the maintenance phase (median of 23 months [IQR: 10-29]). No antibodies (ADA) against ustekinumab were detected in any patient. In general, there was an increasing trend in the percentage of patients in clinical remission as the serum drug level increased (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). In samples from patients with clinical remission, median minimum serum ustekinumab concentrations were 2.78 (IQR: 1.84–4.13)<span class="elsevierStyleHsp" style=""></span>μg/mL; in the remaining samples without clinical remission the level was 2.08 (IQR: 1.05–3.5)<span class="elsevierStyleHsp" style=""></span>μg/mL (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.337) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). The CAL level was available in 68.3% of patients. In patients with biological remission, median CAL and CRP values were 116.7<span class="elsevierStyleHsp" style=""></span>μg/g (IQR: 71.8–213.9) and 1.9<span class="elsevierStyleHsp" style=""></span>mg/L (IQR: 1.3–3.1) respectively. In patients without remission the values were 206.4<span class="elsevierStyleHsp" style=""></span>μg/g (IQR: 64.5–378.1) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.595) and 3.9<span class="elsevierStyleHsp" style=""></span>mg/L (IQR: 1.85–12.3) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05) respectively. Ustekinumab serum level of patients seems to be higher in those with both clinical and biological remission which is consistent with published results on literature, however these differences were statistically non-significant probably due to the low sample size (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B and C). On the other hand, range of ustekinumab levels as quartiles has to be interpreted with caution (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A), since the possible optimal interval to achieve clinical remission is expected to be very small when ustekinumab is administered subcutaneously and with a long period between doses.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">It must be taken into account that in clinical practice conditions, the population is very heterogeneous, with different affected sites, previous lines of treatment, with or without previous surgery. Therefore, the results obtained were also analyzed by dividing them into two groups of patients, with or without intestinal resection surgery prior to ustekinumab. In patients without intestinal resection in clinical remission showed a significant higher in median trough serum drug concentrations compared to patients without clinical remission (2.77 [IQR: 2.01–4.45] vs. 1.67 [IQR: 0.58–2.06]<span class="elsevierStyleHsp" style=""></span>μg/mL; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.005) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>D).</p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, our study suggests that in CD patients without intestinal resection surgery ustekinumab serum levels may be related to clinical remission, being higher in those with clinical remission. Regarding all CD patients, ustekinumab serum levels seems to be higher in those with clinical and biological remission, but these differences did not have a statistical significance.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0045" class="elsevierStylePara elsevierViewall">This research has not received specific support from public sector agencies, commercial sector or non-profit entities.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1983 "Ancho" => 3174 "Tamanyo" => 209025 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A. Quartile distribution of ustekinumab levels according clinical remission. B. Ustekinumab levels according clinical remission. C. Ustekinumab levels according biological remission. D. Ustekinumab levels according clinical remission in patients without intestinal resection surgery. NS: not significant.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:4 [ 0 => array:3 [ "identificador" => "bib0025" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A comprehensive literature review and expert consensus statement on therapeutic drug monitoring of biologics in inflammatory bowel disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.S. Cheifetz" 1 => "M.T. Abreu" 2 => "W. Afif" 3 => "R.K. Cross" 4 => "M.C. Dubinsky" 5 => "E.V. Loftus" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.14309/ajg.0000000000001396" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2021" "volumen" => "116" "paginaInicial" => "2014" "paginaFinal" => "2025" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34388143" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0030" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Update on TDM (therapeutic drug monitoring) with ustekinumab, vedolizumab and tofacitinib in inflammatory bowel disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Restellini" 1 => "W. Afif" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/jcm10061242" "Revista" => array:5 [ "tituloSerie" => "J Clin Med" "fecha" => "2021" "volumen" => "10" "paginaInicial" => "1242" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33802816" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0035" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics and exposure response relationships of ustekinumab in patients with Crohn's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "O.J. Adedokun" 1 => "Z. Xu" 2 => "C. Gasink" 3 => "D. Jacobstein" 4 => "P. Szapary" 5 => "J. Johanns" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2018.01.043" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2018" "volumen" => "154" "paginaInicial" => "1660" "paginaFinal" => "1671" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29409871" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0040" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Monitoring vedolizumab and ustekinumab drug levels in patients with inflammatory bowel disease: hype or hope?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D. Alsoud" 1 => "S. Vermeire" 2 => "B. Verstockt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.coph.2020.09.002" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Pharmacol" "fecha" => "2020" "volumen" => "55" "paginaInicial" => "17" "paginaFinal" => "30" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33039940" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/24443824/0000004600000008/v2_202311101346/S2444382423001487/v2_202311101346/en/main.assets" "Apartado" => array:4 [ "identificador" => "77930" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letter" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/24443824/0000004600000008/v2_202311101346/S2444382423001487/v2_202311101346/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2444382423001487?idApp=UINPBA00004N" ]
