Cladribine Therapy in Refractory Celiac Disease With Aberrant T Cells

doi:10.1016/j.cgh.2006.07.007

Clinical Gastroenterology and Hepatology

Volume 4, Issue 11, November 2006, Pages 1322-1327

https://doi.org/10.1016/j.cgh.2006.07.007 Get rights and content

Background & Aims: Refractory celiac disease (RCD) may be subdivided into RCD types I and II with phenotypically normal and aberrant intraepithelial T-cell populations, respectively. In RCD II, transition into enteropathy-associated T-cell lymphoma (EATL) is seen frequently. We have evaluated the effect of cladribine (2-CDA), a purine analogue inducing T-cell depletion, on clinical, histopathologic, and immunologic parameters, as well as the toxicity and side effects in a group of RCD II patients. Methods: Between 2000 and 2005, 17 patients were included (8 men, 9 women). All patients had a clonal rearrangement of the T-cell receptor γ gene and immunophenotyping showed an aberrant T-cell population lacking surface expression of CD3, CD8, and T-cell receptor αβ, in the presence of expression of surface CD103 and intracytoplasmic CD3. Treatment consisted of 2-CDA (0.1 mg/kg/day) intravenously for 5 days, given in 1–3 courses every 6 months depending on the response. Results: All patients tolerated 2-CDA without serious side effects. Six patients (35.8%) showed a clinical improvement (weight gain, improvement of diarrhea, and hypoalbuminemia). In 10 patients (58.8%) a significant histologic improvement and in 6 patients (35.2%) a significant decrease in aberrant T cells was seen. Seven patients (41.1%) developed EATL and died subsequently. One patient died of progressive refractory state with emaciation. Conclusions: Treatment with 2-CDA in RCD II is feasible, well tolerated, and can induce clinical and histologic improvement as well as a significant decrease of aberrant T cells in a subgroup of patients, albeit it does not prevent EATL development. However, the earlier reported potential risk of precipitating an overt lymphoma should be taken into consideration.

Section snippets

Patients and Methods

This study was performed as an open-label, prospective, phase II pilot study. Between January 2000 and April 2005, 17 patients with RCD II were included (8 men, 9 women; mean age, 63.9 y; range, 54–76 y). They were referred for treatment to 2 tertiary referral centers for CD in the Netherlands: the Rijnstate Hospital in Arnhem and the VU University Medical Center in Amsterdam.

Results

Table 1 shows the clinical and laboratory characteristics of the treated patients at baseline and 12 weeks after completing the first treatment course. Ten of 17 (58.8%) patients were homozygous for HLA-DQ2 haplotype, the remaining 7 (41.2%) were DQ2 heterozygous.³¹

Discussion

Closer investigation of refractory celiac patients suggests 2 subgroups involving patients with and without aberrant T-cell lines in the small-bowel mucosa. Patients with aberrant T cells (RCD II) particularly seem to be at high risk of developing EATL and subsequent death.1, 2, 7, 14 Because the outcome of disease in patients with EATL is usually very poor despite chemotherapy, it seems obvious that the clinical focus should be on earlier diagnosis and intervention before progression to overt

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AGA Clinical Practice Update on Management of Refractory Celiac Disease: Expert Review
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The purpose of this expert review is to summarize the diagnosis and management of refractory celiac disease. It will review evaluation of patients with celiac disease who have persistent or recurrent symptoms, differential diagnosis, nutritional support, potential therapeutic options, and surveillance for complications of this condition.
This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations.
Best Practice Advice Statements
In patients believed to have celiac disease who have persistent or recurrent symptoms or signs, the initial diagnosis of celiac disease should be confirmed by review of prior diagnostic testing, including serologies, endoscopies, and histologic findings.
In patients with confirmed celiac disease with persistent or recurrent symptoms or signs (nonresponsive celiac disease), ongoing gluten ingestion should be excluded as a cause of these symptoms with serologic testing, dietitian review, and detection of immunogenic peptides in stool or urine. Esophagogastroduodenoscopy with small bowel biopsies should be performed to look for villous atrophy. If villous atrophy persists or the initial diagnosis of celiac disease was not confirmed, consider other causes of villous atrophy, including common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy.
For patients with nonresponsive celiac disease, after exclusion of gluten ingestion, perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, lactose or fructose intolerance, and small intestinal bacterial overgrowth.
Use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies to distinguish between subtypes of refractory celiac disease and to exclude enteropathy-associated T-cell lymphoma. Type 1 refractory celiac disease is characterized by a normal intraepithelial lymphocyte population and type 2 is defined by the presence of an aberrant, clonal intraepithelial lymphocyte population. Consultation with an expert hematopathologist is necessary to interpret these studies.
Perform small bowel imaging with capsule endoscopy and computed tomography or magnetic resonance enterography to exclude enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis at initial diagnosis of type 2 refractory celiac disease.
Complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies in patients diagnosed with refractory celiac disease. Check albumin as an independent prognostic factor.
Correct deficiencies in macro- and micronutrients using oral supplements and/or enteral support. Consider parenteral nutrition for patients with severe malnutrition due to malabsorption.
Corticosteroids, most commonly open-capsule budesonide or, if unavailable, prednisone, are the medication of choice and should be used as first-line therapy in either type 1 or type 2 refractory celiac disease.
Patients with refractory celiac disease require regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy. Identify local experts with expertise in celiac disease to assist with management.
Patients with refractory celiac disease without response to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials.
Immune-mediated enteropathies: From bench to bedside
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Immune-mediated enteropathies are caused by excessive reactions of the intestinal immune system towards non-pathogenic molecules. Enteropathy leads to malabsorption-related symptoms and include (severe) chronic diarrhea, weight loss and vitamin deficiencies. Parenteral feeding and immunosuppressive therapy are needed in severe cases. Celiac disease has long been recognized as the most common immune-mediated enteropathy in adults, but the spectrum of immune-mediated enteropathies has been expanding. Histological and clinical features are sometimes shared among these enteropathies, and therefore it may be challenging to differentiate between them. Here, we provide an overview of immune-mediated enteropathies focused on clinical presentation, establishing diagnosis, immunopathogenesis, and treatment options.
Nonresponsive and complicated coeliac disease
2021, Coeliac Disease and Gluten-Related Disorders
Whilst most individuals will display improvement in symptoms and signs of coeliac disease following institution of the GFD, up to 30% will continue to experience symptoms and/ or have persisting intestinal inflammation. These individuals can be classified as having nonresponsive coeliac disease (NRCD), which can be the result of dietary indiscretion, gluten supersensitivity, slow healing, or an alternative condition initially masquerading as persistent coeliac disease. Individuals with coeliac disease are also at risk of developing serious complications, including refractory coeliac disease, ulcerative jejunitis and small bowel malignancies, which are typically classified together as complicated coeliac disease (CCD). The aim of this chapter is to provide an overview of the causes of NRCD and CCD and highlight a clinical approach to the patient with NRCD/ CCD.
Refractory celiac disease
2021, Gluten-Related Disorders: Diagnostic Approaches, Treatment Pathways, and Future Perspectives
In celiac disease (CeD), lack of mucosal healing is associated with a risk of complications; such as a high fracture risk and also the development of lymphomas. Most cases of delayed response to gluten-free diet (GFD) and persistence of villus atrophy are due to bad dietary adherence. Nevertheless, a subgroup of CeD patients are refractory to a strict GFD with persistent symptoms of malabsorption and intestinal villus atrophy. The diagnosis of refractory CeD (RCD) is made after exclusion of other intestinal diseases with villus atrophy and lymphoma. In active CeD and type-II RCD, interleukin (IL)-15 produced in excess exerts potent antiapoptotic effect that prevents the elimination of activated intraepithelial lymphocytes and promotes their massive accumulation by activating a survival signal. The risk of lymphomatous transformation is reported to be four times higher in those nonadherents to a GFD than adherent patients. This high risk may rely on more intense production of IL-15 under gluten exposure.
Cellular and molecular bases of refractory celiac disease
2021, International Review of Cell and Molecular Biology
Refractory celiac disease (RCD) encompasses biologically heterogeneous disorders that develop in a small proportion (0.3%) of individuals with celiac disease that are associated with high morbidity. Two broad categories are currently recognized, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the intraepithelial lymphocytes (IELs). RCD I is characterized by a polyclonal expansion of IELs displaying a normal immunophenotype, while RCD II represents a clonal proliferation of immunophenotypically “aberrant” IELs, and is considered a low-grade lymphoproliferative disorder. The pathogenesis of RCD I has not been clarified, but limited studies suggest multifactorial etiology. On the other hand, recent immunologic, molecular and immunophenotypic analyses have proposed lineage-negative innate IELs to be the cell of origin of a proportion of RCD II cases. Furthermore, sequencing studies have identified frequent, recurrent, activating mutations in members of the JAK-STAT pathway in RCD II. This finding, in conjunction with prior in vitro experimental observations, suggests roles of deregulated cytokine signaling in disease pathogenesis. In this review, we describe current understanding of environmental, immune and genetic factors associated with the development of RCD and briefly discuss diagnostic and therapeutic considerations.
Refractory Celiac Disease
2019, Gastroenterology Clinics of North America

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: A.A. and M.S.G. contributed equally to this article.

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Original articleCladribine Therapy in Refractory Celiac Disease With Aberrant T Cells

Section snippets

Patients and Methods

Results

Discussion

Best Pract Res Clin Gastroenterol

Lancet

Gastroenterology

Best Pract Res Clin Haematol

Lancet

Semin Hematol

Dig Liver Dis

J Chron Dis

Hum Immunol

Gastroenterology

Blood

Blood

Clin Gastroenterol Hepatol

Am J Gastroenterol

Am J Gastroenterol

Am J Gastroenterol

Gastroenterology

Azathioprine and prednisone combination therapy in refractory coeliac disease

Aliment Pharmacol Ther

Coeliac disease: changing views on gluten-sensitive enteropathy

Scand J Gastroenterol Suppl

Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center

J Clin Oncol

Original article
Cladribine Therapy in Refractory Celiac Disease With Aberrant T Cells