Enteropathy associated T cell lymphoma in celiac disease: A large retrospective study

Malamut, Georgia; Chandesris, Marie-Olivia; Verkarre, Virginie; Meresse, Bertrand; Callens, Céline; Macintyre, Elizabeth; Bouhnik, Yoram; Gornet, Jean–Marc; Allez, Matthieu; Jian, Raymond; Berger, Anne; Châtellier, Gilles; Brousse, Nicole; Hermine, Olivier; Cerf‐Bensussan, Nadine; Cellier, Christophe

doi:10.1016/j.dld.2012.12.001

Cited by 121 publications

(147 citation statements)

References 31 publications

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“…EATL may develop into intestinal but also extraintestinal lesions of RCDII, with expression of the same IEL-specific integrin CD103. In most cases of EATL, histology reveals an infiltration of lymphoma cells of pleiomorphic appearance or large or anaplastic-like cells, with a high expression of the CD30 and KI67 mitotic index in contrast to RCDII cells, which are negative for both of these markers [21]. The clonal filiation between RCDII IEL and EATL is demonstrated by evidence of the same TCR γ-chain rearrangement [13,21].…”

Section: Complications and Outcomementioning

confidence: 99%

“…In most cases of EATL, histology reveals an infiltration of lymphoma cells of pleiomorphic appearance or large or anaplastic-like cells, with a high expression of the CD30 and KI67 mitotic index in contrast to RCDII cells, which are negative for both of these markers [21]. The clonal filiation between RCDII IEL and EATL is demonstrated by evidence of the same TCR γ-chain rearrangement [13,21]. Regular follow-up is required for these high-risk patients; it includes control enteroscopy, computed tomography scan or MRI small bowel follow-through and positron emission tomography (PET) necessary to screen EATL as early as possible.…”

Section: Complications and Outcomementioning

confidence: 99%

“…Treatment of RCDII will probably combine conventional chemotherapy agents and targeted therapy by anti-IL-15 monoclonal antibody or JAK3 inhibitors in the near future. Finding an efficient treatment is necessary to prevent the onset of EATL whose prognosis is even poorer than that of RCDII [21]. …”

Section: Treatmentmentioning

confidence: 99%

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Refractory Celiac Disease: Epidemiology and Clinical Manifestations

Malamut¹,

Cellier²

2015

Dig Dis

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A small subset of celiac disease (CD) patients becomes refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. This is a rare (probably less than 2% of adult CD patients), but serious disorder, with a high risk of progression to an overt T-cell lymphoma. Diagnosis of this condition defined as refractory CD (RCD) is made after exclusion of other small bowel diseases with villous atrophy. RCD has been subdivided into two subgroups according to the normal (RCDI) or abnormal phenotype of intraepithelial lymphocytes (RCDII). Whereas RCDI is hardly distinguishable from active noncompliant CD, RCDII has a severe clinical presentation and a very poor prognosis. We precisely describe below the different types of RCD and propose diagnostic and therapeutic guidelines for its clinical management.

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Section: Complications and Outcomementioning

confidence: 99%

Section: Complications and Outcomementioning

confidence: 99%

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Refractory Celiac Disease: Epidemiology and Clinical Manifestations

Malamut¹,

Cellier²

2015

Dig Dis

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“…The most severe process connected with untreated CD is enteropathy-associated T-cell lymphoma (EATL). 8 There are also well-known associations between CD and endocrine conditions, such as insulin-dependent diabetes, thyroid dysfunction, and adrenal insufficiency. As with other immune conditions, there appear to be higher rates of CD in the female population, although this may partially be due to a higher incidence of osteoporosis and anemia in this population, which leads to increased diagnosis of CD.…”

Section: Clinical Presentation and Disease Burdenmentioning

confidence: 99%

Is 'Gluten-Free' Gluten-Free? Celiac Disease in Canada 2015

Forbes¹,

Kassam²,

Morgan³

2014

CJGIM

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SummaryOur understanding of celiac disease (CD) has improved dramatically in recent years. Once considered a rare childhood malabsorption syndrome, we now recognize CD as a complex enteropathy mediated by immune, genetic, and environmental factors. CD affects a large proportion of the Canadian population, and its disease burden is substantial in terms of proven reduction in quality of life. Symptom recognition and referral to a gastroenterologist for diagnosis are crucial. As CD is caused by intolerance to gluten, the only effective treatment is strict gluten avoidance. Canadian food product guidelines have only recently become sufficiently rigid, incorporating newer evidence that suggests lower limits of gluten tolerability in this patient population than previously thought. RésuméDans les dernières années, nous en avons appris énormément sur la maladie coeliaque. Il fut un temps où nous pensions qu'il s'agissait d'un syndrome de malabsorption infantile rare, mais nous savons désormais que la maladie coeliaque est une entéropathie complexe où entrent en jeu des facteurs immunitaires, génétiques et environnementaux. La maladie touche une grande proportion de la population canadienne et a des répercussions considérables sur la qualité de vie. La détection des symptômes et l'aiguillage du patient en gastroentérologie en vue de l'établissement du diagnostic sont des éléments cruciaux de la prise en charge. Étant donné que la maladie provient d'une intolérance au gluten, le régime alimentaire strict sans gluten constitue le seul traitement efficace. Ce n'est que récemment que les lignes directrices canadiennes sur les produits alimentaires ont été resserrées à la lumière de nouvelles données probantes indiquant que la tolérabilité au gluten dans ce groupe de patients est moindre que ce que l'on pensait auparavant.

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“…Approximately 33-52% of patients with RCDII develop a type I EATL within 5 y after diagnosis (11). This EATL is routinely treated with chemotherapy and corticosteroids (e.g., CHOP: cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone), but this treatment lacks efficacy, with an estimated 5-y survival rate of only 8-25% (12,13). Thus, a more effective treatment for RCDII is urgently needed.…”

mentioning

confidence: 99%

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

Kooy–Winkelaar

Bouwer

Janssen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin − IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin − IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin − IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4 + T cells. We now show that gluten-specific CD4 + T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin − IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4 + T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-x L . Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4 + T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin − IELs and CD3 − CD56 + IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4 + T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.celiac disease | refractory celiac disease | enteropathy-associated T-cell lymphoma | small-molecule inhibitor | intraepithelial lymphocyte

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Enteropathy associated T cell lymphoma in celiac disease: A large retrospective study

Abstract: Our study underlines the prognostic value of celiac disease type in patients with T-cell lymphoma, and suggests that a combination of nutritional, chemotherapy and reductive surgery may improve survival.

Cited by 121 publications

References 31 publications

Refractory Celiac Disease: Epidemiology and Clinical Manifestations

Refractory Celiac Disease: Epidemiology and Clinical Manifestations

Is 'Gluten-Free' Gluten-Free? Celiac Disease in Canada 2015

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

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