Letter to the Editor
Clonal T lymphocytosis resolution after adalimumab discontinuation
Resolución de una linfocitosis T clonal tras la suspensión de adalimumab
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In healthy adults, γδ-T cells represent less than 5% of circulating lymphocytes. Nevertheless, notable changes in γδ-T cells have been observed in the IBD population following anti-TNFα treatment (ATA).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> This observation suggests that a patient subgroup with increased γδ-T cells may have a lower threshold for clonal expansion when treated with anti-TNF-α agents. Supporting this notion, we presented the first case report of a patient experiencing clonal γδ-T lymphocytosis during adalimumab treatment, showing the absence of T-cell receptor (TCR) clonality post-treatment discontinuation.</p><p id="par0015" class="elsevierStylePara elsevierViewall">A 48-year-old man with ileocolic Crohn's disease (Montreal classification A2 L3 B1) and associated spondylarthritis was referred to the Hematology Department for lymphocytosis evaluation. He had a previous history of steroid-dependent disease, necessitating adalimumab treatment as a steroid-sparing agent from February 2017. The maintenance dosage was administered until October 2022, when a new onset of intestinal symptoms required a dose intensification. This led to the emergence of a lymphocytosis, with a total count of 5.88<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span> lymphocytes/μl in peripheral blood (PB). Flow cytometry analysis revealed 11% of circulating reactive γδ-T cells (CD5+, CD38++, CD56w, CD2, CD7w, CD28−, CD45RA+, CD57+, granzyme B+, and perforin+) and PCR-based detection of rearranged TCR confirmed the presence of monoclonal TCR. Despite the presence of clonality, the phenotypic profile found did not match with HSCTL immunophenotype mainly due to CD5, CD57 positivity, and the presence of cytotoxic markers (granzyme B and perforin).</p><p id="par0020" class="elsevierStylePara elsevierViewall">A CT scan was performed to rule out lymphadenopathies or other organomegalies, revealing no significant radiological findings. However, based on the evidence that clonal lymphocytosis may precede HSCTL development, it was suggested to discontinue adalimumab. Ustekinumab was initiated in November 2022 with excellent tolerance. Three months after discontinuation, total lymphocyte counts normalized, circulating reactive γδ-T cells decreased to 6.5% of total lymphocytes, and molecular studies corroborated a polyclonal TCR rearrangement.</p><p id="par0025" class="elsevierStylePara elsevierViewall">First described in 2002, the association between lymphoma and ATA monotherapy has raised concerns.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> The etiopathogenic mechanisms behind the development of HSCTL in these patients remain poorly understood. This is due to the absence of well-designed studies, long-term follow-up, and the use of concurrent treatments, all of which may bias conclusions. While some studies have not shown an increased rate of HSTCL in patients with IBD receiving anti-TNF, others suggest an elevated risk, particularly in young male patients.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> The latest update from the FDA Adverse Events Reporting System (FAERS) included a total of 62 cases of HSTCL among patients with IBD exposed to biological therapy, with all cases reporting previous exposure to anti-TNF-α agents.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Recently, Kelsen et al.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> hypothesized that a multistep process resulting in clonal γδ-T cell expansion may precede neoplastic transformation to HSCTL. Their study investigated γδ-T cell behavior in 46 patients with Crohn's disease (CD): 20 were treated with infliximab and 26 with adalimumab. A group of 16 healthy individuals was used as a control. The analysis revealed that, in the CD group, 25% of patients had increased baseline γδ-T levels (range 5–15%), whereas no similar cases were identified in the control group. Furthermore, in this subgroup with an increased proportion of γδ-T cells, the initiation of anti-TNF-α treatment led to a significant in vivo expansion of these lymphocytes. Additional in vitro analysis of anti-TNF-α agents ruled out the presence of indirect effects mediated by inflammatory factors or the redistribution of the intestinal lymphocyte pool.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Here, we describe the first case report that shows polyclonal TCR after discontinuing adalimumab. The clone's disappearance, along with the normalization of total lymphocyte counts and the reduction in circulating γδ-T cells after changing the CD treatment, bolsters the hypothesis that the drug might play an etiological role in T cell clone expansion.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Although the benefits of long-term biological therapy are clear, identifying high-risk patients for lymphoma development is crucial for minimizing risks. Monitoring T cell clone expansion, especially in young male patients, before and after using anti-TNF-α agents could assist in selecting the most suitable therapy.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical considerations</span><p id="par0045" class="elsevierStylePara elsevierViewall">The patient had provided informed consent for publication of the case.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors have no support or funding to report.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare that they have no competing interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 3 => array:2 [ "identificador" => "xack741337" "titulo" => "Acknowledgments" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.M. Foss" 1 => "S.M. Horwitz" 2 => "M. Civallero" 3 => "M. Bellei" 4 => "L. Marcheselli" 5 => "W.S. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ajh.25674" "Revista" => array:6 [ "tituloSerie" => "Am J Hematol" "fecha" => "2020" "volumen" => "95" "paginaInicial" => "151" "paginaFinal" => "155" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31709579" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Kelsen" 1 => "A. Dige" 2 => "H. Schwindt" 3 => "F. D’Amore" 4 => "F.S. Pedersen" 5 => "J. Agnholt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0017890" "Revista" => array:3 [ "tituloSerie" => "PLoS One" "fecha" => "2011" "volumen" => "6" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0040" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.L. Brown" 1 => "M.H. Greene" 2 => "S.K. Gershon" 3 => "E.T. Edwards" 4 => "M.M. Braun" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10679" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "3151" "paginaFinal" => "3158" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12483718" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.B. Hanauer" 1 => "B.G. Feagan" 2 => "G.R. Lichtenstein" 3 => "L.F. Mayer" 4 => "S. Schreiber" 5 => "J.F. Colombel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(02)08512-4" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2002" "volumen" => "359" "paginaInicial" => "1541" "paginaFinal" => "1549" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12047962" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systematic review: hepatosplenic T-cell lymphoma on biologic therapy for inflammatory bowel disease, including data from the Food and Drug Administration Adverse Event Reporting System" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E.D. Shah" 1 => "E.S. Coburn" 2 => "A. Nayyar" 3 => "K.J. Lee" 4 => "J.L. Koliani-Pace" 5 => "C.A. Siegel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/apt.15637" "Revista" => array:6 [ "tituloSerie" => "Aliment Pharmacol Ther" "fecha" => "2020" "volumen" => "51" "paginaInicial" => "527" "paginaFinal" => "533" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31990422" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack741337" "titulo" => "Acknowledgments" "texto" => "<p id="par0060" class="elsevierStylePara elsevierViewall">The authors gratefully acknowledge the contribution of the Gastroenterology Department and the Flow Cytometry Laboratory of Hospital de Getafe. We also thank the subject for his participation and for his informed written consent.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/00257753/0000016200000008/v2_202404281220/S0025775323006772/v2_202404281220/en/main.assets" "Apartado" => array:4 [ "identificador" => "66430" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Cartas al Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/00257753/0000016200000008/v2_202404281220/S0025775323006772/v2_202404281220/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323006772?idApp=UINPBA00004N" ]
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