Refractory Celiac Disease Dig Dis 2015;33:221–226 DOI: 10.1159/000369519
Refractory Celiac Disease: Epidemiology and Clinical Manifestations Georgia Malamut a–c Christophe Cellier a–c a
Université Paris Descartes-Sorbonne Paris Centre, b Gastroenterology Department, Hôpital Européen Georges Pompidou APHP, and c Inserm UMR1163 Institut Imagine, Paris, France
Abstract 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. © 2015 S. Karger AG, Basel
Introduction
Celiac disease (CD) is an inflammatory enteropathy induced by gluten in genetically predisposed individuals. Its prevalence is 1% in Europe and USA. Treatment relies © 2015 S. Karger AG, Basel 0257–2753/15/0332–0221$39.50/0 E-Mail [email protected] www.karger.com/ddi
on a lifelong gluten-free diet (GFD) which prevents bone disease, autoimmune disorders and complications (nonmalignant and malignant). Resistance to a GFD is mainly due to bad compliance. Nevertheless, a small subgroup of CD patients may be primarily or secondary resistant to a GFD due to an authentic refractory CD (RCD). Diagnosis of RCD is made after exclusion of other causes of intestinal villous atrophy. RCD has been subdivided into two subgroups according to the normal [type I RCD (RCDI)] or abnormal phenotype of intraepithelial lymphocytes (IEL) [type II RCD (RCDII)]. RCDI is indistinguishable from active CD except its autonomy toward gluten exposure. RCDII is a severe enteropathy with frequent intractable ulcerative duodenojejunitis and is now considered as an intraepithelial T-cell lymphoma.
Epidemiology of RCD
The frequency of RCDI and RCDII remains unknown. Most patients show complete villous architecture recovery after a strict GFD. Nevertheless, a small percentage of patients do not respond clinically and may have a persisting villous atrophy despite a GFD. RCD is a rare disorder with prevalence estimated at 2–5% among patients diagnosed with adult CD. RCD could have been overestimated in the past because of confusion between nonresponsive CD and RCD. In fact, epidemiological studies remain very rare. The Derby cohort reports around 0.7% of RCDII patients in a series of 713 celiac patients, but the Christophe Cellier Hôpital Européen Georges Pompidou 20 rue Leblanc FR–75015 Paris (France) E-Mail christophe.cellier @ egp.aphp.fr
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Key Words Refractory celiac disease · Ulcerative jejunitis · Aberrant intraepithelial lymphocytes · T-cell receptor · Clonal rearrangement
Diagnosis of RCD
Definition RCD is defined as persisting malabsorption and villous atrophy after 1 year of strict GFD ascertained by a dietician. Indeed, bad compliance with a GFD needs to be first eliminated as less than 50% of patients are fully compliant [7]. Diagnosis of RCD also needs to exclude other causes of intestinal villous atrophy such as autoimmune enteropathy [8], tropical sprue [9] or common variable immunodeficiency (CVID) [10]. Demonstration of HLA haplotypes encoding HLA-DQ2 or DQ8 is useful as their absence excludes CD or RCD as a cause of villous atrophy [11]. Nevertheless, genotypes HLA-DQ2/DQ8 are not enough to ascertain the context of CD as they are found in 77% of CVID patients with enteropathy mimicking CD defined by intestinal intraepithelial lymphocytosis [10]. Other features such as intestinal plasmocytic rarefaction or nodular lymphoid hyperplasia allow to distinguish CVID enteropathy from CD or RCD [10]. When the diagnosis of RCD is ascertained, the next step is to define the type of RCD by analyzing the phenotype and clonality of small intestinal IEL. RCDI is defined by increased number of IEL bearing a normal phenotype with surface CD3 and 222
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CD8 expression, and RCDII is characterized by clonal expansion of abnormal IEL lacking surface markers CD3, CD8 and T-cell receptor (CD3s–, CD8s–, TCR–) and preserved expression of intracellular CD3 [12, 13]. Diagnosis Mean age at diagnosis of RCD is around 50 years, and the diagnosis is extremely rare in children or teenagers with CD. Patients with RCDI and RCDII are primary refractory to a GFD in roughly one third and half of cases, respectively [6]. Whatever its type, RCD occurs 2–3 times more often in women than men [5–7]. RCDII has commonly a severe clinical presentation associated with endoscopic ulcerative jejunitis responsible for severe protein loss enteropathy. Symptoms are notably less severe in RCDI, and clinical features are similar to those found in active CD [6]. Diagnosis relies on endoscopic assessment of the upper gastrointestinal tract with intestinal biopsy. Double balloon enteroscopy is required in suspicion of RCDII for a better assessment of ulcers, particularly for evidence of ulcerative jejunitis found in roughly 70% of patients [6, 14]. Enteroscopy allows realization of proximal small bowel biopsy necessary for definitive diagnosis and classification of RCD. In RCDI, histological examination is similar to that found in active CD with villous atrophy and increased normal IEL. No other diagnostic criteria have yet been defined for RCDI. In contrast, the hallmark abnormal population detected by 3 combined techniques makes the diagnosis of RCDII more specific: over 25% of the CD103+ or CD45+ IEL lacking surface CD3-T-cell receptor complexes on flow cytometry or more than 50% IEL expressing intracellular CD3ε but no CD8 in formolfixed sections and/or the presence of a detectable clonal rearrangement of the γ-chain of the TCR in duodenal biopsies [6]. Similar features allow detecting lymphocytic gastritis and colitis containing the same abnormal population in around 50 and 30% of RCDII patients, respectively. Analysis of the δ-chain rearrangement may be useful for RCDII diagnosis in patients presenting oligoclonal rearrangement of the γ-chain [6]. Others have suggested detecting the β-chain of the TCR [15]. Finally, the specificity of the PCR product needs to be attested by the formation of homoduplexes [6]. Extension of the disease is assessed by capsule endoscopy. It requires preliminary radiological imaging of the small bowel in order to rule out stricturing disease frequently observed in RCDII. In this latter condition, MRI small bowel follow-through and computed tomography scan also frequently detect enlarged mesenteric lymph Malamut /Cellier
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diagnosis of RCDII patients was only based on aspects of ulcerative jejunitis [1] causing possible errors leading to the underestimation of RCDII and overestimation of RCDI. A single North American referral center study suggests a cumulative incidence of 1.5% for both RCDI and RCDII among CD patients initially diagnosed in this center [2]. A higher frequency of cases of RCDI than of RCDII was also observed in 2 other studies from the US [3] and from Germany [4]. In contrast, we and others reported a higher frequency of RCDII than RCDI [5, 6]. These discrepancies among referral centers may be due to the systematic use of FACS analysis in France and Netherlands leading to more RCDII diagnoses. Outside RCD, persisting villous atrophy without symptoms or without aberrant IEL population is not so rare and has been observed in 5–20% among asymptomatic CD patients on GFD. The cause of this absence of ‘mucosal healing’ has not been assessed, but may be associated, in our experience, to a persisting iron deficiency that should probably be corrected. The long-term duration of asymptomatic CD without ‘mucosal healing’ is not known, but a long-term follow-up is mandatory since it may be associated with the occurrence of lymphomatous complications.
Complications and Outcome
The more severe malnutrition combined with the higher risk of developing overt lymphoma explains the higher mortality in RCDII when compared to RCDI [6]. Indeed, RCDII patients have a 5-year survival rate of 44– 58% [3, 5, 6]. Even if the prognosis of RCDI is much better as compared to RCDII, the rates of complications and mortality have been reported to be much higher than those of uncomplicated CD [3, 4]. Chronic inflammation could favor subepithelial accumulation of collagen and increase resistance to a GFD. In their series of 19 patients with collagenous sprue, Vakiani et al. [18] observed that 17 had CD. Nine were primary or secondary resistant to a GFD at time of diagnosis of collagenous sprue, 8 with RCDI and 1 with RCDII. There is as yet no curative treatment for RCD, immunosuppressive treatment being poorly efficient and a possible trigger of overt lymphoma [19]. Indeed, 33–52% of RCDII patients develop enteropathy-associated T-cell lymphoma (EATL) within the 5 years after diagnosis [5, 6]. The onset of EATL in RCDI is much lower than in RCDII, with a 5-year rate of 14% in the more pessimistic studies [6]. The increased risk of transformation in RCDII probably relies on its malignant nature as it is itself a low-grade lymphoma [13]. Indeed, at this stage, clonal IEL are already engaged in malignant transformation as attested by their clonality, their abnormal phenotype, the presence of their chromosomal abnormalities, the recurrent partial trisomy 1q22–q44 and their tendency to disseminate in and outside of the intestine [6, 20]. Abnormal IEL may be found in mesenteric lymph nodes, blood, bone marrow, and in different epitheliums such as lung and skin [6]. The diagnosis of extraintestinal RCDII lesions may be made by evidence of the same clonal TCR γ/δ-chain rearrangement that presents in the duodenum but also by immunohistochemistry showing CD103+CD3i+CD8– T cells. 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 RCD: Epidemiology and Clinical Manifestations
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. No established interval has yet been defined. Specialized investigations can be reasonably performed every year and 6 months in RCDI and RCDII patients, respectively [6]. PET is of particular interest because high intensity is correlated with the location of proliferating overt lymphoma cells in contrast with the low intensity of nonproliferating RCDII cells [22]. It can further assist in performing radiology-guided biopsy or explorative celioscopy.
Pathogenesis
A particular genetic background differentiating RCD patients from patients with uncomplicated CD is a plausible hypothesis. The small numbers of patients are the main limitations of genetic investigations. It has been reported that the severity of CD was correlated with the number of HLA-DQ2 copies: homozygosity for HLADQ2 was observed in 25.5% of RCDI, 44.1% of RCDII, and 53.3% of EATL patients versus 20.7% of uncomplicated CD patients and 2.1% of controls [23]. Studies are in progress, and ongoing genome-wide association studies suggest differences in susceptibility variants between CD and RCDII [24]. Specific mechanisms underlying the pathogenesis of RCDI need to be investigated. One plausible hypothesis is that the immunological reaction initiated by gluten has evolved toward autoimmunity. Accordingly, symptoms improve under immunosuppressive treatments [5, 6]. Therefore, the hypothesis/mechanism of intestinal autoimmunity remains to be substantiated. More progress has recently been made in the understanding of the pathogenesis of RCDII. The phenotype is now well defined with accumulation of small clonal IEL without proliferation but with apoptosis defect [25]. Ten years ago, in vitro and ex vivo experiments showed that the cytokine IL-15 could be the putative factor involved in resistance to apoptosis [25]. In active CD and RCDII, IL-15 is produced in excess by enterocytes and lamina Dig Dis 2015;33:221–226 DOI: 10.1159/000369519
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nodes frequently involved by abnormal cells. Besides the diagnosis of persisting villous atrophy, capsule endoscopy allows the visualization of ulcers that may be found all along the intestinal tract in RCDII patients [16, 17]. In conclusion, upper endoscopy, capsule endoscopy and abdominal imaging are currently three complementary exams essential for the diagnosis and assessment of RCD.
Treatment
It has not yet been possible to find real efficient treatment for RCDI or RCDII. Steroids transiently improved clinical symptoms in most patients with either type of RCD, with a histological response only in 30–40% of cases [6]. Steroid dependence resorted to test immunosuppressors such as azathioprine, cyclosporine or antiTNF-α with some clinical response but rarely mucosal improvement. Indeed, in most cases of RCDI they induce clinical response but no histological effect. Finding 224
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the mechanisms underlying the pathogenesis of RCDI will probably allow investigation of new efficient treatments [6]. In RCDII, immunosuppressive drugs have no impact on the abnormal clonal IEL population and could even increase the risk of overt lymphoma as reported with azathioprine or anti-CD52 [6, 19]. The bad prognosis of RCDII has led to more aggressive treatments such as chemotherapy, but they are poorly efficient at eradicating nonproliferative RCDII cells [6]. Purine analogues such pentostatin or cladribine have been largely used in the past with slight therapeutic effect [40, 41]. Cladribine may induce clinical and even histological response but appears also to enhance the risk of transformation into EATL [6, 41]. Autologous hematopoietic stem cell transplantation constitutes another possible alternative strategy. It was shown to induce clinical and histological response but no sustained reduction of abnormal IEL in the 13 treated patients [42, 43]. The use of chemotherapy before autologous hematopoietic stem cell transplantation may probably increase hematological response, and we are currently evaluating this strategy in a prospective phase 2 trial. Setting up targeted strategy appears necessary to complete the therapeutic armory to treat RCDII. Identification of the IL-15-induced anti-apoptotic signaling pathway mechanisms underlying the onset of RCDII may help finding potential therapeutic targets [29]. Blocking IL-15 may thus help to reduce the numbers of clonal IEL and to prevent epithelial damage. The recent development of a humanized anti-IL-15 antibody which has already been used without any major side effects in a phase 1–2 trial in rheumatoid arthritis suggests the feasibility of this therapeutic approach [44]. Indeed, treatment in vivo by a human anti-IL-15 antibody of mice overexpressing human IL-15 in the small bowel suppressed the IEL hyperplasia observed in these mice [29]. Another possibility is to block the downstream molecules activated by IL-15 such as the JAK3 molecule [45]. Based on these data, JAK3 inhibitor, currently used in treating rheumatoid arthritis [46], is another interesting drug to treat RCD. 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].
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propria mononuclear cells. On one hand, IL-15 induces the expression of cytotoxic proteins (perforin, granzymes) in RCDII IEL and stimulates their production of IFN-γ which all contribute to the prominent apoptosis observed in the flattened surface epithelium [25–27]. Moreover, IL-15 is able to activate the NKG2D-dependent cytotoxicity of IEL against enterocyte lines [28]. On the other hand, IL-15 exerts potent antiapoptotic effects that prevent the elimination of activated IEL and promote their massive accumulation despite very low in situ proliferation [25]. Indeed, IL-15 is able to activate a lymphocytic antiapoptotic signaling pathway through IL-15Rβγ by activation of Jak3, STAT5 and the anti-apoptotic factor Bcl-xL [29]. All the factors involved in the production of IL-15 represent potential triggers of RCD. Gluten exposure may increase IL-15 production. Concordantly, the risk of lymphoma was reported to be four times higher in patients noncompliant with a GFD than in compliant patients [30]. IL-15 is also induced by a variety of intracellular pathogens [31–34]. We observed B or C hepatitis at onset of refractoriness in 20 and 10% of RCDI and RCDII patients, respectively [6]. Epidemiological factors argue that viral agents such as rotavirus may increase the risk of CD in genetically predisposed individuals [35]. More than a specific virus, it is rather suspected that the components of the antiviral responses and notably type I interferons might promote the onset of chronic inflammatory disorders [reviewed in 36]. Accordingly, increased secretion of type I IFN or an IFN-stimulated gene signature is observed in a spectrum of autoimmune diseases correlating with increased disease severity [37]. Type I interferon may notably stimulate the survival and proliferation of CD8+ T cells and NK cells [37] either directly or via the induction of IL-15 [38]. A virus might also stimulate IL15 induction via stimulation of Toll-ligand receptor 3 [39].
Conclusion
The concept of RCD has recently emerged and refers to two distinct entities sustained by two different pathogenic mechanisms. Diagnosis requires small bowel investigations (enteroscopy, videocapsule endoscopy) and very specialized techniques of IEL analyses (immunohistochemistry, molecular biology, flow cytometry). Survival of RCDI patients has been described as worse than that of CD patients, and the onset of EATL has already been reported [3, 6]. The prognosis of RCDII is very poor due to severe malnutrition and high risk of EATL. Altogether, these rare but resistant and severe forms of CD require efficient treatments. Recent evidence of a scientific rationale for a targeted therapy for the more severe form of RCD offers some hope for an efficient treatment to cure RCD and prevent overt lymphoma. The take-home message can be listed as follows: • The concept of RCD has recently emerged and refers to 2 distinct entities. • RCDI is indistinguishable from active CD except in its autonomy toward gluten exposure.
• RCDII is characterized as a low-grade intestinal lymphoma characterized by clonal expansion of abnormal intestinal IEL. • Small bowel endoscopy such as double balloon enteroscopy with biopsy assists in diagnosis. • Specialized analysis of intestinal IEL including immunohistochemistry, flow cytometry of isolated intestinal lymphocytes and multiplex PCR is required for diagnosis. • Survival of patients with RCDI is slightly inferior to that of CD patients. • The 5-year survival rate of patients with RCDII is around 50%. This poor prognosis is due to severe malnutrition and increased risk of overt lymphoma. • Advances in the understanding of pathogenic mechanisms of RCD, RCDII in particular, offer a new therapeutic target by inhibiting IL-15 effects.
Disclosure Statement The authors declare no competing financial interest.
References
RCD: Epidemiology and Clinical Manifestations
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Refractory Celiac Disease: Epidemiology and Clinical Manifestations Georgia Malamut a–c Christophe Cellier a–c a
Université Paris Descartes-Sorbonne Paris Centre, b Gastroenterology Department, Hôpital Européen Georges Pompidou APHP, and c Inserm UMR1163 Institut Imagine, Paris, France
Abstract 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. © 2015 S. Karger AG, Basel
Introduction
Celiac disease (CD) is an inflammatory enteropathy induced by gluten in genetically predisposed individuals. Its prevalence is 1% in Europe and USA. Treatment relies © 2015 S. Karger AG, Basel 0257–2753/15/0332–0221$39.50/0 E-Mail [email protected] www.karger.com/ddi
on a lifelong gluten-free diet (GFD) which prevents bone disease, autoimmune disorders and complications (nonmalignant and malignant). Resistance to a GFD is mainly due to bad compliance. Nevertheless, a small subgroup of CD patients may be primarily or secondary resistant to a GFD due to an authentic refractory CD (RCD). Diagnosis of RCD is made after exclusion of other causes of intestinal villous atrophy. RCD has been subdivided into two subgroups according to the normal [type I RCD (RCDI)] or abnormal phenotype of intraepithelial lymphocytes (IEL) [type II RCD (RCDII)]. RCDI is indistinguishable from active CD except its autonomy toward gluten exposure. RCDII is a severe enteropathy with frequent intractable ulcerative duodenojejunitis and is now considered as an intraepithelial T-cell lymphoma.
Epidemiology of RCD
The frequency of RCDI and RCDII remains unknown. Most patients show complete villous architecture recovery after a strict GFD. Nevertheless, a small percentage of patients do not respond clinically and may have a persisting villous atrophy despite a GFD. RCD is a rare disorder with prevalence estimated at 2–5% among patients diagnosed with adult CD. RCD could have been overestimated in the past because of confusion between nonresponsive CD and RCD. In fact, epidemiological studies remain very rare. The Derby cohort reports around 0.7% of RCDII patients in a series of 713 celiac patients, but the Christophe Cellier Hôpital Européen Georges Pompidou 20 rue Leblanc FR–75015 Paris (France) E-Mail christophe.cellier @ egp.aphp.fr
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Key Words Refractory celiac disease · Ulcerative jejunitis · Aberrant intraepithelial lymphocytes · T-cell receptor · Clonal rearrangement
Diagnosis of RCD
Definition RCD is defined as persisting malabsorption and villous atrophy after 1 year of strict GFD ascertained by a dietician. Indeed, bad compliance with a GFD needs to be first eliminated as less than 50% of patients are fully compliant [7]. Diagnosis of RCD also needs to exclude other causes of intestinal villous atrophy such as autoimmune enteropathy [8], tropical sprue [9] or common variable immunodeficiency (CVID) [10]. Demonstration of HLA haplotypes encoding HLA-DQ2 or DQ8 is useful as their absence excludes CD or RCD as a cause of villous atrophy [11]. Nevertheless, genotypes HLA-DQ2/DQ8 are not enough to ascertain the context of CD as they are found in 77% of CVID patients with enteropathy mimicking CD defined by intestinal intraepithelial lymphocytosis [10]. Other features such as intestinal plasmocytic rarefaction or nodular lymphoid hyperplasia allow to distinguish CVID enteropathy from CD or RCD [10]. When the diagnosis of RCD is ascertained, the next step is to define the type of RCD by analyzing the phenotype and clonality of small intestinal IEL. RCDI is defined by increased number of IEL bearing a normal phenotype with surface CD3 and 222
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CD8 expression, and RCDII is characterized by clonal expansion of abnormal IEL lacking surface markers CD3, CD8 and T-cell receptor (CD3s–, CD8s–, TCR–) and preserved expression of intracellular CD3 [12, 13]. Diagnosis Mean age at diagnosis of RCD is around 50 years, and the diagnosis is extremely rare in children or teenagers with CD. Patients with RCDI and RCDII are primary refractory to a GFD in roughly one third and half of cases, respectively [6]. Whatever its type, RCD occurs 2–3 times more often in women than men [5–7]. RCDII has commonly a severe clinical presentation associated with endoscopic ulcerative jejunitis responsible for severe protein loss enteropathy. Symptoms are notably less severe in RCDI, and clinical features are similar to those found in active CD [6]. Diagnosis relies on endoscopic assessment of the upper gastrointestinal tract with intestinal biopsy. Double balloon enteroscopy is required in suspicion of RCDII for a better assessment of ulcers, particularly for evidence of ulcerative jejunitis found in roughly 70% of patients [6, 14]. Enteroscopy allows realization of proximal small bowel biopsy necessary for definitive diagnosis and classification of RCD. In RCDI, histological examination is similar to that found in active CD with villous atrophy and increased normal IEL. No other diagnostic criteria have yet been defined for RCDI. In contrast, the hallmark abnormal population detected by 3 combined techniques makes the diagnosis of RCDII more specific: over 25% of the CD103+ or CD45+ IEL lacking surface CD3-T-cell receptor complexes on flow cytometry or more than 50% IEL expressing intracellular CD3ε but no CD8 in formolfixed sections and/or the presence of a detectable clonal rearrangement of the γ-chain of the TCR in duodenal biopsies [6]. Similar features allow detecting lymphocytic gastritis and colitis containing the same abnormal population in around 50 and 30% of RCDII patients, respectively. Analysis of the δ-chain rearrangement may be useful for RCDII diagnosis in patients presenting oligoclonal rearrangement of the γ-chain [6]. Others have suggested detecting the β-chain of the TCR [15]. Finally, the specificity of the PCR product needs to be attested by the formation of homoduplexes [6]. Extension of the disease is assessed by capsule endoscopy. It requires preliminary radiological imaging of the small bowel in order to rule out stricturing disease frequently observed in RCDII. In this latter condition, MRI small bowel follow-through and computed tomography scan also frequently detect enlarged mesenteric lymph Malamut /Cellier
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diagnosis of RCDII patients was only based on aspects of ulcerative jejunitis [1] causing possible errors leading to the underestimation of RCDII and overestimation of RCDI. A single North American referral center study suggests a cumulative incidence of 1.5% for both RCDI and RCDII among CD patients initially diagnosed in this center [2]. A higher frequency of cases of RCDI than of RCDII was also observed in 2 other studies from the US [3] and from Germany [4]. In contrast, we and others reported a higher frequency of RCDII than RCDI [5, 6]. These discrepancies among referral centers may be due to the systematic use of FACS analysis in France and Netherlands leading to more RCDII diagnoses. Outside RCD, persisting villous atrophy without symptoms or without aberrant IEL population is not so rare and has been observed in 5–20% among asymptomatic CD patients on GFD. The cause of this absence of ‘mucosal healing’ has not been assessed, but may be associated, in our experience, to a persisting iron deficiency that should probably be corrected. The long-term duration of asymptomatic CD without ‘mucosal healing’ is not known, but a long-term follow-up is mandatory since it may be associated with the occurrence of lymphomatous complications.
Complications and Outcome
The more severe malnutrition combined with the higher risk of developing overt lymphoma explains the higher mortality in RCDII when compared to RCDI [6]. Indeed, RCDII patients have a 5-year survival rate of 44– 58% [3, 5, 6]. Even if the prognosis of RCDI is much better as compared to RCDII, the rates of complications and mortality have been reported to be much higher than those of uncomplicated CD [3, 4]. Chronic inflammation could favor subepithelial accumulation of collagen and increase resistance to a GFD. In their series of 19 patients with collagenous sprue, Vakiani et al. [18] observed that 17 had CD. Nine were primary or secondary resistant to a GFD at time of diagnosis of collagenous sprue, 8 with RCDI and 1 with RCDII. There is as yet no curative treatment for RCD, immunosuppressive treatment being poorly efficient and a possible trigger of overt lymphoma [19]. Indeed, 33–52% of RCDII patients develop enteropathy-associated T-cell lymphoma (EATL) within the 5 years after diagnosis [5, 6]. The onset of EATL in RCDI is much lower than in RCDII, with a 5-year rate of 14% in the more pessimistic studies [6]. The increased risk of transformation in RCDII probably relies on its malignant nature as it is itself a low-grade lymphoma [13]. Indeed, at this stage, clonal IEL are already engaged in malignant transformation as attested by their clonality, their abnormal phenotype, the presence of their chromosomal abnormalities, the recurrent partial trisomy 1q22–q44 and their tendency to disseminate in and outside of the intestine [6, 20]. Abnormal IEL may be found in mesenteric lymph nodes, blood, bone marrow, and in different epitheliums such as lung and skin [6]. The diagnosis of extraintestinal RCDII lesions may be made by evidence of the same clonal TCR γ/δ-chain rearrangement that presents in the duodenum but also by immunohistochemistry showing CD103+CD3i+CD8– T cells. 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 RCD: Epidemiology and Clinical Manifestations
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. No established interval has yet been defined. Specialized investigations can be reasonably performed every year and 6 months in RCDI and RCDII patients, respectively [6]. PET is of particular interest because high intensity is correlated with the location of proliferating overt lymphoma cells in contrast with the low intensity of nonproliferating RCDII cells [22]. It can further assist in performing radiology-guided biopsy or explorative celioscopy.
Pathogenesis
A particular genetic background differentiating RCD patients from patients with uncomplicated CD is a plausible hypothesis. The small numbers of patients are the main limitations of genetic investigations. It has been reported that the severity of CD was correlated with the number of HLA-DQ2 copies: homozygosity for HLADQ2 was observed in 25.5% of RCDI, 44.1% of RCDII, and 53.3% of EATL patients versus 20.7% of uncomplicated CD patients and 2.1% of controls [23]. Studies are in progress, and ongoing genome-wide association studies suggest differences in susceptibility variants between CD and RCDII [24]. Specific mechanisms underlying the pathogenesis of RCDI need to be investigated. One plausible hypothesis is that the immunological reaction initiated by gluten has evolved toward autoimmunity. Accordingly, symptoms improve under immunosuppressive treatments [5, 6]. Therefore, the hypothesis/mechanism of intestinal autoimmunity remains to be substantiated. More progress has recently been made in the understanding of the pathogenesis of RCDII. The phenotype is now well defined with accumulation of small clonal IEL without proliferation but with apoptosis defect [25]. Ten years ago, in vitro and ex vivo experiments showed that the cytokine IL-15 could be the putative factor involved in resistance to apoptosis [25]. In active CD and RCDII, IL-15 is produced in excess by enterocytes and lamina Dig Dis 2015;33:221–226 DOI: 10.1159/000369519
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nodes frequently involved by abnormal cells. Besides the diagnosis of persisting villous atrophy, capsule endoscopy allows the visualization of ulcers that may be found all along the intestinal tract in RCDII patients [16, 17]. In conclusion, upper endoscopy, capsule endoscopy and abdominal imaging are currently three complementary exams essential for the diagnosis and assessment of RCD.
Treatment
It has not yet been possible to find real efficient treatment for RCDI or RCDII. Steroids transiently improved clinical symptoms in most patients with either type of RCD, with a histological response only in 30–40% of cases [6]. Steroid dependence resorted to test immunosuppressors such as azathioprine, cyclosporine or antiTNF-α with some clinical response but rarely mucosal improvement. Indeed, in most cases of RCDI they induce clinical response but no histological effect. Finding 224
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the mechanisms underlying the pathogenesis of RCDI will probably allow investigation of new efficient treatments [6]. In RCDII, immunosuppressive drugs have no impact on the abnormal clonal IEL population and could even increase the risk of overt lymphoma as reported with azathioprine or anti-CD52 [6, 19]. The bad prognosis of RCDII has led to more aggressive treatments such as chemotherapy, but they are poorly efficient at eradicating nonproliferative RCDII cells [6]. Purine analogues such pentostatin or cladribine have been largely used in the past with slight therapeutic effect [40, 41]. Cladribine may induce clinical and even histological response but appears also to enhance the risk of transformation into EATL [6, 41]. Autologous hematopoietic stem cell transplantation constitutes another possible alternative strategy. It was shown to induce clinical and histological response but no sustained reduction of abnormal IEL in the 13 treated patients [42, 43]. The use of chemotherapy before autologous hematopoietic stem cell transplantation may probably increase hematological response, and we are currently evaluating this strategy in a prospective phase 2 trial. Setting up targeted strategy appears necessary to complete the therapeutic armory to treat RCDII. Identification of the IL-15-induced anti-apoptotic signaling pathway mechanisms underlying the onset of RCDII may help finding potential therapeutic targets [29]. Blocking IL-15 may thus help to reduce the numbers of clonal IEL and to prevent epithelial damage. The recent development of a humanized anti-IL-15 antibody which has already been used without any major side effects in a phase 1–2 trial in rheumatoid arthritis suggests the feasibility of this therapeutic approach [44]. Indeed, treatment in vivo by a human anti-IL-15 antibody of mice overexpressing human IL-15 in the small bowel suppressed the IEL hyperplasia observed in these mice [29]. Another possibility is to block the downstream molecules activated by IL-15 such as the JAK3 molecule [45]. Based on these data, JAK3 inhibitor, currently used in treating rheumatoid arthritis [46], is another interesting drug to treat RCD. 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].
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propria mononuclear cells. On one hand, IL-15 induces the expression of cytotoxic proteins (perforin, granzymes) in RCDII IEL and stimulates their production of IFN-γ which all contribute to the prominent apoptosis observed in the flattened surface epithelium [25–27]. Moreover, IL-15 is able to activate the NKG2D-dependent cytotoxicity of IEL against enterocyte lines [28]. On the other hand, IL-15 exerts potent antiapoptotic effects that prevent the elimination of activated IEL and promote their massive accumulation despite very low in situ proliferation [25]. Indeed, IL-15 is able to activate a lymphocytic antiapoptotic signaling pathway through IL-15Rβγ by activation of Jak3, STAT5 and the anti-apoptotic factor Bcl-xL [29]. All the factors involved in the production of IL-15 represent potential triggers of RCD. Gluten exposure may increase IL-15 production. Concordantly, the risk of lymphoma was reported to be four times higher in patients noncompliant with a GFD than in compliant patients [30]. IL-15 is also induced by a variety of intracellular pathogens [31–34]. We observed B or C hepatitis at onset of refractoriness in 20 and 10% of RCDI and RCDII patients, respectively [6]. Epidemiological factors argue that viral agents such as rotavirus may increase the risk of CD in genetically predisposed individuals [35]. More than a specific virus, it is rather suspected that the components of the antiviral responses and notably type I interferons might promote the onset of chronic inflammatory disorders [reviewed in 36]. Accordingly, increased secretion of type I IFN or an IFN-stimulated gene signature is observed in a spectrum of autoimmune diseases correlating with increased disease severity [37]. Type I interferon may notably stimulate the survival and proliferation of CD8+ T cells and NK cells [37] either directly or via the induction of IL-15 [38]. A virus might also stimulate IL15 induction via stimulation of Toll-ligand receptor 3 [39].
Conclusion
The concept of RCD has recently emerged and refers to two distinct entities sustained by two different pathogenic mechanisms. Diagnosis requires small bowel investigations (enteroscopy, videocapsule endoscopy) and very specialized techniques of IEL analyses (immunohistochemistry, molecular biology, flow cytometry). Survival of RCDI patients has been described as worse than that of CD patients, and the onset of EATL has already been reported [3, 6]. The prognosis of RCDII is very poor due to severe malnutrition and high risk of EATL. Altogether, these rare but resistant and severe forms of CD require efficient treatments. Recent evidence of a scientific rationale for a targeted therapy for the more severe form of RCD offers some hope for an efficient treatment to cure RCD and prevent overt lymphoma. The take-home message can be listed as follows: • The concept of RCD has recently emerged and refers to 2 distinct entities. • RCDI is indistinguishable from active CD except in its autonomy toward gluten exposure.
• RCDII is characterized as a low-grade intestinal lymphoma characterized by clonal expansion of abnormal intestinal IEL. • Small bowel endoscopy such as double balloon enteroscopy with biopsy assists in diagnosis. • Specialized analysis of intestinal IEL including immunohistochemistry, flow cytometry of isolated intestinal lymphocytes and multiplex PCR is required for diagnosis. • Survival of patients with RCDI is slightly inferior to that of CD patients. • The 5-year survival rate of patients with RCDII is around 50%. This poor prognosis is due to severe malnutrition and increased risk of overt lymphoma. • Advances in the understanding of pathogenic mechanisms of RCD, RCDII in particular, offer a new therapeutic target by inhibiting IL-15 effects.
Disclosure Statement The authors declare no competing financial interest.
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RCD: Epidemiology and Clinical Manifestations
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