Advances in Nonresponsive and Refractory Celiac Disease.

Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might benefit patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten-independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open-capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T-cell lymphoma; more efficient therapy is needed.

Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease.

The nature of gut intraepithelial lymphocytes (IELs) lacking antigen receptors remains controversial. Herein we showed that, in humans and in mice, innate intestinal IELs expressing intracellular CD3 (iCD3(+)) differentiate along an Id2 transcription factor (TF)-independent pathway in response to TF NOTCH1, interleukin-15 (IL-15), and Granzyme B signals. In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity. As a result, NOTCH1 target genes indispensable for T cell differentiation were silenced and precursors were reprogrammed into innate cells with T cell marks including intracellular CD3 and T cell rearrangements. In the intraepithelial lymphoma complicating celiac disease, iCD3(+) innate IELs acquired gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3, which enhanced their response to IL-15. Overall we characterized gut T cell-like innate IELs, deciphered their pathway of differentiation and showed their malignant transformation in celiac disease.

Adalimumab in Biologic-naïve Patients With Crohn's Disease After Resolution of an Intra-abdominal Abscess: A Prospective Study From the GETAID.

BACKGROUND & AIMS: The management of intra-abdominal abscesses complicating Crohn's disease (CD) is challenging, and surgery with delayed intestinal resection is often recommended. The aims of this study were to estimate the success rate of adalimumab (ADA) in patients with CD with an intra-abdominal abscess resolved without surgery, and to identify predictive factors for success. METHODS: A multicenter, prospective study was conducted in biologic-naïve patients with CD with resolved intra-abdominal abscess treated with ADA with a 2-year follow-up. The primary endpoint was ADA failure at week (W) 24 defined as a need for steroids after W12, intestinal resection, abscess recurrence, and clinical relapse. Secondary post-hoc endpoint was the long-term success defined as the survival without abscess relapse or intestinal resection at W104. The factors associated with ADA failure at W24 and W104 were identified using a logistic and a Cox regression, respectively. RESULTS: From April 2013 to December 2017, 190 patients from 27 GETAID centers were screened, and 117 were included in the analysis. Fifty-eight patients (50%) were male, and the median age at baseline was 28 years. At W24, 87 patients (74%; 95% confidence interval [CI], 65.5%-82.0%; n = 117) achieved ADA success. Among the 30 patients with ADA failure, 15 underwent surgery. At W104, the survival rate without abscess recurrence or surgery was 72.9% (95% CI, 62.1%-79.8%; n = 109). Abscess drainage was significantly associated with ADA failure at W24 (odds ratio, 4.18; 95% CI, 1.06-16.5; P =0 .043). Disease duration (hazard ratio [HR], 1.32; 95% CI, 1.09-1.59; P = .008), abscess drainage (HR, 5.59; 95% CI, 2.21-14.15; P = .001), and inflammatory changes in mesenteric fat (HR, 0.4; 95% CI, 0.17-0.94; P = .046) were significantly associated with ADA failure at W104. CONCLUSION: Provided that the abscess was carefully managed before initiating medical treatment, this study showed the high efficacy of ADA in the short and long term in biologic-naïve patients with CD complicated by an intra-abdominal abscess. CLINICALTRIALS: gov, Number: NCT02856763.

Immunopathogenesis and environmental triggers in coeliac disease.

Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.

Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus.

OBJECTIVE: Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. DESIGN: An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. RESULTS: Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. CONCLUSION: This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

Oncogenetic landscape of lymphomagenesis in coeliac disease.

OBJECTIVE: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. DESIGN: Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines. RESULTS: 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines. CONCLUSION: Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.

Feline low-grade intestinal T cell lymphoma: a unique natural model of human indolent T cell lymphoproliferative disorder of the gastrointestinal tract.

Indolent T cell lymphoproliferative disorder (LPD) of the gastrointestinal tract (GI-TLPD) is a rare human primary gastrointestinal T cell lymphoma that was recently included in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Low-grade intestinal T cell lymphoma (LGITL), an emerging disease in the domestic cat, shares a number of features with human GI-TLPD. In this prospective study, we determined whether feline LGITL might serve as a model of human GI-TLPD. We analyzed clinical, laboratory, and radiological data and performed histopathological and molecular studies on small intestinal biopsies from 22 domestic cats diagnosed with LGITL. This cancer mostly affects aging cats, is associated with nonspecific gastrointestinal tract signs, and is usually characterized by an indolent course. A histopathological analysis indicated that LGITL was mainly located in the jejunum. The small intestinal lamina propria was infiltrated by large numbers of small CD3+ T cell lymphocytes with various CD4 and CD8 expression profiles (CD4+ CD8- (4 out of 11, 36%), CD4- CD8+ (3 out of 11, 27%), and CD4- CD8- (4 out of 11, 36%)). Intraepithelial lymphocyte (IEL) counts were elevated in all cases. Ki67 was expressed in lamina propria lymphocytes and IELs at a low level (<30%). Most LGITLs were labelled by antibodies against phosphorylated STAT5, but were negative for CD56 and phosphorylated STAT3. T cell receptor gamma chain gene monoclonality was found in 86% of cases. These findings confirmed that feline LGITL shares clinical and histopathological features with human GI-TLPD. Feline LGITL may therefore constitute a relevant model of the human disease.

Celiac disease: an immunological jigsaw.

Celiac disease (CD) is a chronic enteropathy induced by dietary gluten in genetically predisposed people. The keystone of CD pathogenesis is an adaptive immune response orchestrated by the interplay between gluten and MHC class II HLA-DQ2 and DQ8 molecules. Yet, other factors that impair immunoregulatory mechanisms and/or activate the large population of intestinal intraepithelial lymphocytes (IEL) are indispensable for driving tissue damage. Herein, we summarize our current understanding of the mechanisms and consequences of the undesirable immune response initiated by gluten peptides. We show that CD is a model disease to decipher the role of MHC class II molecules in human immunopathology, to analyze the mechanisms that link tolerance to food proteins and autoimmunity, and to investigate how chronic activation of IEL can lead to T cell lymphomagenesis.

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.

OBJECTIVES: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs). DESIGN: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies. RESULTS: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo. CONCLUSION: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.

Outcomes 7 Years After Infliximab Withdrawal for Patients With Crohn's Disease in Sustained Remission.

BACKGROUND & AIMS: Little is known about long-term outcomes of patients with Crohn's disease (CD) after infliximab withdrawal. We aimed to describe the long-term outcomes of patients with CD in clinical remission after infliximab treatment was withdrawn. METHODS: We performed a retrospective analysis of data from the 115 patients included in the infliximab discontinuation in patients with CD in stable remission on combined therapy with antimetabolites (STORI) study, performed at 20 centers in France and Belgium from March 2006 through December 2009. The STORI cohort was a prospective analysis of risk and factors associated with relapse following withdrawal of maintenance therapy with infliximab, maintained on antimetabolites, while in clinical remission. We collected data from the end of the study until the last available follow-up examination on patient surgeries, new complex perianal lesions (indicating major complications), and need for and outcomes of restarting therapy with infliximab or another biologic agent. The de-escalation strategy was considered to have failed when a major complication or infliximab restart failure occurred. RESULTS: Of the 115 patients initially included, data from 102 patients (from 19 of the 20 study centers) were included in the final analysis. The median follow-up time was 7 years. Twenty-one percent of the patients did not restart treatment with infliximab or another biologic agent and did not have a major complication 7 years after infliximab withdrawal (95% CI, 13.1-30.3). Among patients who restarted infliximab, treatment failed for 30.1% 6 years after restarting (95% CI, 18.5-42.5). Overall, at 7 years after stopping infliximab therapy, major complications occurred in 18.5% of patients (95% CI, 10.2-26.8) whereas 70.2% of patients had no failure of the de-escalation strategy (95% CI, 60.2-80.1). Factors independently associated with major complications were upper-gastrointestinal location of disease, white blood cell count ≥ 5.0 × 109/L, and hemoglobin level ≤12.5 g/dL at the time of infliximab withdrawal. Patients with at least 2 of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal. CONCLUSIONS: In a long-term follow-up of the STORI cohort (7 years) one fifth of the patients did not restart infliximab or another biologic agent and did not develop major complications. Seventy percent of patients had no failure of the de-escalation strategy (no major complication and no failure of infliximab restart).

Feline low-grade alimentary lymphoma: an emerging entity and a potential animal model for human disease.

BACKGROUND: Low-grade alimentary lymphoma (LGAL) is characterised by the infiltration of neoplastic T-lymphocytes, typically in the small intestine. The incidence of LGAL has increased over the last ten years and it is now the most frequent digestive neoplasia in cats and comprises 60 to 75% of gastrointestinal lymphoma cases. Given that LGAL shares common clinical, paraclinical and ultrasonographic features with inflammatory bowel diseases, establishing a diagnosis is challenging. A review was designed to summarise current knowledge of the pathogenesis, diagnosis, prognosis and treatment of feline LGAL. Electronic searches of PubMed and Science Direct were carried out without date or language restrictions. RESULTS: A total of 176 peer-reviewed documents were identified and most of which were published in the last twenty years. 130 studies were found from the veterinary literature and 46 from the human medicine literature. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. The pathophysiology of feline LGAL still needs to be elucidated, not least the putative roles of infectious agents, environmental factors as well as genetic events. The most common therapeutic strategy is combination treatment with prednisolone and chlorambucil, and prolonged remission can often be achieved. Developments in immunohistochemical analysis and clonality testing have improved the confidence of clinicians in obtaining a correct diagnosis between LGAL and IBD. The condition shares similarities with some diseases in humans, especially human indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. CONCLUSIONS: The pathophysiology of feline LGAL still needs to be elucidated and prospective studies as well as standardisation of therapeutic strategies are needed. A combination of conventional histopathology and immunohistochemistry remains the current gold-standard test, but clinicians should be cautious about reclassifying cats previously diagnosed with IBD to lymphoma on the basis of clonality testing. Importantly, feline LGAL could be considered to be a potential animal model for indolent digestive T-cell lymphoproliferative disorder, a rare condition in human medicine.

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

A novel data-driven workflow combining literature and electronic health records to estimate comorbidities burden for a specific disease: a case study on autoimmune comorbidities in patients with celiac disease.

BACKGROUND: Data collected in EHRs have been widely used to identifying specific conditions; however there is still a need for methods to define comorbidities and sources to identify comorbidities burden. We propose an approach to assess comorbidities burden for a specific disease using the literature and EHR data sources in the case of autoimmune diseases in celiac disease (CD). METHODS: We generated a restricted set of comorbidities using the literature (via the MeSH® co-occurrence file). We extracted the 15 most co-occurring autoimmune diseases of the CD. We used mappings of the comorbidities to EHR terminologies: ICD-10 (billing codes), ATC (drugs) and UMLS (clinical reports). Finally, we extracted the concepts from the different data sources. We evaluated our approach using the correlation between prevalence estimates in our cohort and co-occurrence ranking in the literature. RESULTS: We retrieved the comorbidities for 741 patients with CD. 18.1% of patients had at least one of the 15 studied autoimmune disorders. Overall, 79.3% of the mapped concepts were detected only in text, 5.3% only in ICD codes and/or drugs prescriptions, and 15.4% could be found in both sources. Prevalence in our cohort were correlated with literature (Spearman's coefficient 0.789, p = 0.0005). The three most prevalent comorbidities were thyroiditis 12.6% (95% CI 10.1-14.9), type 1 diabetes 2.3% (95% CI 1.2-3.4) and dermatitis herpetiformis 2.0% (95% CI 1.0-3.0). CONCLUSION: We introduced a process that leveraged the MeSH terminology to identify relevant autoimmune comorbidities of the CD and several data sources from EHRs to phenotype a large population of CD patients. We achieved prevalence estimates comparable to the literature.

Refractory celiac disease: epidemiology and clinical manifestations.

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.

Interleukin-15, a master piece in the immunological jigsaw of celiac disease.

BACKGROUND: The immune response causing celiac disease (CD) depends on the activation of intestinal CD4+ T cells by gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 molecules, the main genetic risk factor. However, additional factors are necessary to impair immune tolerance to dietary gluten, to stimulate intraepithelial lymphocytes (IEL) and to induce intestinal damage. KEY MESSAGES: Current data point to a central role of interleukin-15 (IL-15). In situ and ex vivo studies indicate that IL-15 stimulates the accumulation and cytotoxic activation of CD8+ T IEL in active CD, and that of the malignant innate-like IEL in type II refractory CD (RCDII). Other studies show that IL-15 impairs the immunoregulatory control of effector T cells, notably CD8+. Recently, animal models have been designed to investigate the respective role of CD4+ T cells and IL-15 in CD. We discuss more particularly our results in such a model, which shows that IL-15 produced in excess in the intestine can cooperate with CD4+ T cells specific for a dietary antigen to trigger a celiac-like enteropathy. In this mouse model, CD4+ T cells activated by dietary ovalbumin secreted IL-2 which, along with IL-15, stimulated the expansion of noncognate intestinal cytotoxic CD8+ T cells containing large amounts of granzyme B. In the presence of IL-15, the latter cells did not respond to regulatory T cells, and accumulated in the intestine close to epithelial damage. CONCLUSION: On the basis of these data, we propose that, in CD, gluten-specific CD4+ T cells synthesize cytokines that synergize with IL-15 to license the expansion and activation of cytotoxic IEL, which drive tissue damage. We suggest that IL-15 is a meaningful therapeutic target, notably in patients with RCDII in which malignant IEL can respond to IL-15 independently of signals provided by CD4+ T cells.

Therapy in RCDII: Rationale for Combination Strategies?

Refractory coeliac disease type II (RCDII) is characterized by a continuous gluten-independent duodenal immune activation with an extremely high risk of malignant transformation. It is therefore considered as an indolent lymphoma. RCDII is characterized by the presence of villous atrophy (Marsh III A-C) in combination with an aberrant intra- epithelial lymphocyte (IEL) population consisting of >20% sCD3-CD7+iCD3+ IELs. The sCD3-CD7+iCD3+ IELs are a heterogeneous lineage-negative cell population, consisting of cells that do or do not express CD127/IL7Rα. Experiments using IEL from non-RCDII patients have indicated that while the CD127- cells are IL-15 responsive, the CD127+ cells are not. Together with the observation that some patients express an aberrant (monoclonal) TCRγδ phenotype, this confirms the heterogeneity of the aberrant IEL population in RCDII and suggests that the aberrant cells are heterogeneous with respect to their response to common γ-chain cytokines. Although cladribine with or without autologous stem cell transplantation is effective in the treatment of signs and symptoms of RCDII and improves survival as compared to symptomatic topical steroid therapy, cladribine failures still bear a high risk of malignant transformation, and the rate of enteropathy-associated T-cell lymphoma (EATL) development in this subgroup is extremely high. It might be hypothesized that the heterogenous nature of aberrant IEL and the high risk of malignant transformation require a treatment strategy which is effective despite this heterogeneity. RCDII should be seen more in the light of a low-grade/no mass lymphoma or pre-EATL. We would suggest an upfront combination therapy approach integrating inhibition of downstream Jak-STAT signalling pathways with conventional therapy (2-CDA) to hopefully effectively treat signs and symptoms of RCDII and accomplish a more effective EATL prevention.

[CELIAC DISEASE]. / Maladie cœliaque.

Celiac disease is an inflammatory enteropathy, autoimmune-like, due to gluten intake in genetically predisposed persons with HLA-DQ2/DQ8 genotyping. Prevalence rates are approaching 1% of population in Europe and USA. Clinical expression of celiac disease is extremely various. Screening is based on detection of serum celiac antibodies and diagnosis is confirmed with duodenal biopsy. Treatment relies on gluten free diet (GFD) with eviction of wheat, barley and rye. GFD allows prevention of osteopenia, autoimmune diseases and malignant complications. The main cause of resistance to GFD because is its bad observance.

Small intestinal CD4+ T-cell lymphoma is a heterogenous entity with common pathology features.

BACKGROUND & AIMS: Little is known about intestinal CD4+ T-cell lymphoma; this rare malignancy is misdiagnosed frequently. We evaluated diagnostic criteria and factors that might affect its development and outcome. METHODS: In a retrospective analysis, we analyzed medical records and intestinal specimens from 10 patients diagnosed with intestinal CD4+ T-cell lymphoma among 115 consecutive patients examined for severe enteropathy with villous atrophy. Samples were analyzed by histology, flow cytometry, and comparative genomic hybridization. RESULTS: Small-intestine epithelial and lamina propria tissues from patients who presented with chronic diarrhea and malnutrition had variable levels of infiltration of CD3+ CD4+ T cells. Flow cytometry showed a high frequency of CD4+ intraepithelial cells, which frequently expressed a specific Vß chain. T-cell receptor ß clonality was confirmed by DNA sequencing. Two patients had HLA and serology results compatible with celiac disease and autoimmune enteropathy, respectively. Two patients were found to have antibodies against human T-cell leukemia virus and 2 patients had signs of a recent infection with the herpes viruses. Comparative genomic hybridization analyses showed heterogeneous chromosomal abnormalities. Symptoms were reduced in patients treated with steroids (n = 5), but not in patients given purine analogues or chemotherapy. Antibodies against CD52 produced clinical and histologic responses in 2 of 2 patients, whereas severe adverse effects developed in 1 patient. At the latest follow-up evaluation, all patients were alive. CONCLUSIONS: There is much heterogeneity in the onset and genetic features of intestinal CD4+ T-cell lymphomas, despite their common presentation as indolent lymphoproliferations of the intestinal mucosa. Patients should be treated with steroids, and possibly antibodies against CD52 (for the most aggressive forms of this disorder).