Best Practice & Research Clinical Gastroenterology 29 (2015) 451e458
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Best Practice & Research Clinical Gastroenterology
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Complications of coeliac disease Georgia Malamut, MD, PhD a, b, c, Christophe Cellier, MD, PhD a, b, c, * Universit e Paris Descartes, Paris, France ^pital Europ Gastroenterology Department, Ho een Georges Pompidou APHP, Paris, France c Inserm UMR1163 Institut Imagine, Paris, France a
b
a b s t r a c t Keywords: Autoimmune disease Unresponsive coeliac disease Refractory coeliac disease Enteropathy-associated T cell lymphoma
Within the past 20 years the spectrum of complications of coeliac disease (CD) has been considerably extended. Besides the classic complications, autoimmune diseases and osteopenia, numerous forms of CD non-responsive to a gluten-free diet have been recently identified. Among the non-responsive CD, the majority of patients presents as long term responders. However a small subset of CD patients becomes refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. Whereas refractory coeliac disease type I (RCDI) is hardly distinguishable from active CD, the type II (RCDII) has a severe clinical presentation and a very poor prognosis. Enteropathy Associated T cell Lymphoma (EATL) is even more aggressive with a five year survival of 20%. Classic adriamycin-based chemotherapy is poorly efficient in the lymphomatous complications of CD and current therapeutic strategies focus on more intensive regimen with autologous or allogenic stem cell transplantation. Notable pathogenic advances let us to test targeted therapy both in low (RCDII) and high grade lymphomatous (EATL) complications associated with CD. © 2015 Elsevier Ltd. All rights reserved.
^ pital Europe en Georges Pompidou, 20 rue Leblanc, 75015 Paris, * Corresponding author. Gastroenterology Department Ho France. Tel.: þ33 1 56 09 35 52; fax: þ33 1 56 09 35 29. E-mail address: [email protected] (C. Cellier). http://dx.doi.org/10.1016/j.bpg.2015.05.005 1521-6918/© 2015 Elsevier Ltd. All rights reserved.
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Introduction Coeliac disease (CD) is an inflammatory enteropathy induced by gluten in genetically predisposed individuals. Its prevalence is of 1% in Europe and USA. Treatment relies on a life-long gluten free diet which prevents bone, autoimmune and malignant complications. Different types of resistance to a gluten free diet (GFD) have been described within the past 20 years. The majority of those patients are long term responders whereas a small group of them develop an authentic refractory celiac disease. We describe below the panel of CD complications with a particular detailed description of malignant complications. Bone complications Fifty to seventy percent of CD patients suffer from a loss of bone mass at diagnosis. Conversely, increased prevalence of CD in osteoporotic patients was reported [1]. Consequently, bone densitometry is recommended for all CD patients at diagnosis. Mechanisms involve both calcium malabsorption and inflammatory factors related to intestinal mucosal inflammation [2,3]. Osteopenia is major in the forearm which is the most common fracture site [4]. Gluten free diet may partially correct osteopenia but normalization is rarely observed [5]. The risk of fracture is significantly increased before diagnosis of CD but not under gluten free-diet [6]. Besides gluten-free diet, clinical management of osteopenia includes a daily calcium intake of 1500 mg, and vitamin D supplementation, if inadequate serum levels. Autoimmune complications The link between CD and autoimmunity is now firmly established. Five to 10% of patients with type I diabetes develop CD, while conversely, 15e20% of CD patients have or will develop autoimmune disorders [7]. Besides dermatitis herpetiformis which appears more as an extra-intestinal manifestation of CD, type I diabetes and autoimmune thyroiditis appear as the most frequent autoimmune diseases €gren's syndrome, systemic associated with CD, before Rheumatoid arthritis, autoimmune hepatitis, Sjo lupus, addison's disease, antiphospholipid syndrome or myasthenia gravis [7e9]. Indeed, type I diabetes and CD share frequently susceptibility HLA-type II genotypes DQ2/DQ8. Individuals who are heterozygous for DQ2.5 (DQA1*05:01/DQB1*02:01) and DQ8 (DQA1*03:01/DQB1*03:02) are also susceptible to type I diabetes with an almost five-fold higher risk than those who are homozygous for either of the DQ variants [10,11]. Besides HLA genes, some CD-associated variants within coding sequences have also been found in association with other autoimmune diseases. One such interesting variant is an SNP in SH2B3 that is associated with other autoimmune, type I diabetes and rheumatoid arthritis [12]. Autoimmune diseases such as type I diabetes and thyroiditis are not clearly improved by gluten free diet, not surprisingly as pancreatic and thyroid lesions are irreversible, but GFD might reduce the risk to develop autoimmune diseases after diagnosis of CD, pointing to the link between exposure to gluten and onset of autoimmunity outside the gut [7,12,13]. Asymptomatic patients with persisting villous atrophy on a gluten free diet Persisting villous atrophy despite a strict GFD is not a rare situation outside refractory coeliac disease. In our experience in Paris, villous atrophy was still present in 70 (44%) patients assessed after one year on GFD. Strict observance of the diet was comparable both in patients with or without full histological recovery (approximately 70% of the cases). Patients however differed significantly by the frequency of iron deficiency anaemia which was more often observed in patients with (20/70; 29%) than without (11/88; 12.5%) villous atrophy (p ¼ 0.015; OR: 2.78). Similarly, low ferritinemia was more frequent in patients with (23; 33%) than without (21; 24%) villous atrophy (p ¼ 0.065) [14]. Persistent villous atrophy does not seem to be associated with an increased mortality, but a higher risk for lymphoproliferative malignancies was reported among patients with persistent villous atrophy [15]. Further studies are necessary to better assess the long term follow-up of these coeliac
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patients presenting commonly minor clinical symptoms but residual mucosal damage after one year of GFD. Refractory coeliac disease RCD is defined by persisting malabsorption and villous atrophy after one year of strict GFD ascertained by a dietician. Indeed, bad adherence to a GFD needs to be first eliminated accordingly with the fact that less than 50% of patients are compliant [16]. Diagnosis of RCD also needs to exclude other causes of intestinal villous atrophy such as autoimmune enteropathy [17], tropical sprue [18] or common variable immunodeficiency (CVID) [19]. When the diagnosis of refractory CD is ascertained, the next step is to define the type of RCD by analysing the phenotype and clonality of small intestinal intraepithelial lymphocytes (IEL). RCDI is defined by increased number of intraepithelial lymphocytes (IEL) bearing a normal phenotype with surface CD3 and 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 [20,21]. Mean age at diagnosis of RCD is around 50 years. Patients with RCDI and RCDII are primary refractory to a GFD in roughly one third and half cases, respectively [22]. Whatever its type, RCD occurs two to three times more in women than in men [22,23]. Frequency of RCDI and RCDII remains unknown. The Derby cohort reports around 0.7% of RCDII patients in series of 713 celiac patients [24] but diagnosis of RCDII patients was only based on ulcerative jejunitis [24] causing possible errors leading to underestimate RCDII and overestimate RCDI. A single North American referral centre study suggests a cumulative incidence of 1.5% for both RCDI and RCDII among CD patients initially diagnosed in this centre [25]. A higher frequency of cases of RCDI than of RCDII was also observed in two other studies from the US [26] and from Germany [27]. In contrast, we and the Amsterdam group reported a higher frequency of RCDII over RCDI [22,23]. 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 severity of CD was correlated with the number of HLA-DQ2 copies: homozygosity for HLA-DQ2 was observed in 25.5% of RCD I, 44.1% of RCDII, and 53.3% of EATL patients vs 20.7% of uncomplicated CD patients and 2.1% of controls [28]. Studies are in progress and ongoing genome wide association studies suggest differences in susceptibility variants between CD and RCDII [29]. RCDII commonly has a severe clinical presentation associated with frequent ulcerative jejunitis responsible of severe protein loss enteropathy. In contrast, symptoms are notably less severe in RCDI which is hardly to differentiate from active CD except the strict adherence to a GFD [22]. Diagnosis relies on endoscopic assessment of upper gastrointestinal tract with intestinal biopsy. Small bowel videocapsule and device assisted enteroscopy are required in suspicion of RCDII for a better assessment of ulcers particularly for evidence of ulcerative jejunitis found in roughly 70% of patients [22,30]. 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 IEL with normal phenotype. No other diagnostic criteria have been yet defined for RCDI. In contrast, the hallmark abnormal population, detected by three combined techniques, makes the diagnosis of RCDII more specific: over 25% of the CD103þ or CD45þ IEL lacking surface CD3-T cell receptor expression as determined by flow cytometry or more than 50% IEL expressing intracellular CD3ε but no CD8 in formol fixed sections and/or the presence of a detectable clonal rearrangement of the gamma chain of the T cell receptor (TCR) in duodenal biopsies [22]. Similar features allow detecting lymphocytic gastritis and colitis containing the same abnormal population in around 50% and 30% of RCDII patients, respectively [22]. Analysis of the delta chain rearrangement may be useful for diagnosis of RCDII in patients presenting oligoclonal rearrangement of the gamma chain [22]. Others have suggested interest of detecting of the beta chain of the TCR [31]. Finally, specificity of the PCR product needs to be attested by formation of homoduplexes [22]. Diagnosis of RCDII has become highly specialized. Flow cytometry allows distinguishing RCDII from other malignant complication of CD such as large granular lymphocytic leukaemia [32] or intestinal CD4 lymphoproliferations [33]. Such distinction is crucial for choosing the adequate treatment such as cyclosporine for
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CD complicated by large granular lymphocytic leukaemia and in contrast chemotherapy and autologous haematopoietic stem cells transplantation for RCDII (see below). 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 later condition, MRI small bowel follow-through and computed tomography scan (CT-scan) also frequently detect enlarged mesenteric lymph nodes frequently involved by abnormal cells. Besides the diagnosis of persisting villous atrophy, capsule endoscopy allows the visualization of ulcers all along the intestinal tract possibly found in RCDII patients [34,35]. The more severe malnutrition combined with the higher risk of developing overt lymphoma explains the higher mortality in RCDII when compared to RCDI [22]. Indeed, RCDII patients have a 5-year survival rate of 44%e58% [22,23,26]. 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 [26,27]. There is as yet no curative treatment for RCD, immunosuppressive treatment being poorly efficient and possible triggers the development of overt lymphoma [36]. It has not yet been possible to find real efficient treatment for RCD I or II. Steroids transiently improved clinical symptoms in most patients with either type of RCD with a histological response only in 30e40% of cases [22]. Steroid dependence resorted to test immunosuppressors such as azathioprine, cyclosporine or anti-TNF-a with some clinical responses but rare mucosal improvement [22]. In RCDII immunosuppressive drugs have no impact on the abnormal clonal IEL population and could even enhance the risk of overt lymphoma as reported with azathioprine or anti-CD52 [22,36]. The poor prognosis of RCDII led to more aggressive treatments such as chemotherapy but this was found poorly efficient with respect to eradicating the non-proliferative RCDII cells [22]. Purine analogues such pentostatine or cladribine (2 CDA) have been largely used in the past with slight therapeutic effect [37,38]. Cladribine may induce clinical and even histological response but appears also to enhance the risk of transformation into EATL [22,38]. Autologous haematopoietic stem cells transplantation constitutes another possible alternative strategy. It was shown to induce clinical and histological response but no sustained reduction of abnormal IEL in the thirteen treated patients [39,40]. The use of chemotherapy before autologous haematopoietic stem cells transplantation may probably increase haematological response and we are currently evaluating this strategy in a prospective phase II trial. Setting up targeted strategy appears necessary to complete the therapeutic armoury to treat RCDII. Identification of the IL-15 induced anti-apoptotic signalling pathway mechanisms underlying the onset of RCDII may help finding potential therapeutic targets [41]. Blocking IL-15 may thus help to reduce the numbers of clonal IEL and to prevent epithelial damage. The recent development of a humanized antiIL-15 antibody which has already been used without any major side effects in a phase I-II trial in rheumatoid arthritis, suggests the feasibility of this therapeutic approach [42]. Indeed, treatment in vivo, treatment, by a human anti-IL-15 antibody of mice overexpressing human IL-15 in small bowel wiped out the IEL hyperplasia observed in these mice [41]. Another possibility is to block the downstream molecules activated by IL-15 such JAK3 molecule [43]. Based on these data, JAK3 inhibitor, currently used in treating rheumatoid arthritis [44], 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 next future. Finding an efficient treatment is necessary to prevent onset of EATL whose prognosis is even poor than RCDII one [45] (see Fig. 1). Enteropathy associated T cell lymphoma (Eatl) Incidence of Non Hodgkin Lymphoma associated with CD has been evaluated to 0.45, 3.75 and 2.7 for 1000 patients-year [46e48]. Based on a nation-wide collection of data between 2000 and 2006, Verbeek et al. have reported a crude incidence of 0.10/100,000 cases of EATL in the total Dutch population with an incidence of 2.08/100,000 in the over 50-year-olds [49]. In contrast, in a very recent study based on the Surveillance, Epidemiology, and End Results (SEER) database of the US National Cancer Institute between 1973 and 2008 (a database that covers approximately 28% of the US population). R Z. Sharaiha et al. observed a much lower overall incidence of EATL of 0.016 per 100,000 (and of
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Fig. 1. Proposal for therapeutic strategies in RCDII and EATL: INCa French regimen for treating patients with RCDII combines chemotherapy (6 cycles of Fludarabin-Endoxan given intravenously) with autologous stem cell transplantation (ASCT). Treatment of EATL depends of expression of CD30: in main cases (z80%), EATL express CD30 and can be treated according to the French regimen CHP-SGN35 combining CHP, anti-CD30 antibody and autologous stem cell transplantation. EATL which does not express CD30 can be treated by the Scottish regimen IVE-MTX high dosage-autologous stem cell transplantation.
0.05 per 100,000 in the population aged >60 years) [50]. These authors noted however an increased incidence from 0.006 per 100,000 to 0.024 per 100,000 during the study period, which coincides with the recent increase in CD incidence in the US [51,52]. In the same study, it was also noted that EATL were common in men, an unexpected finding given the higher incidence of CD and RCDII in women. In addition, the highest incidence rate was in individuals of Hispanic origin with an age-adjusted incidence rate, of 0.033 per 100,000, further suggesting differences between populations of different geographical origins. Overt B cell lymphoma is at least six times less common that EATL. In comparison with Non Hodgkin Lymphoma, intestinal adenocarcinoma is very rare [53]. Indeed, 33%e52% of RCDII patients develop Enteropathy Associated-T cell Lymphoma (EATL) within the five years after diagnosis [22,23]. Onset of EATL in RCDI is much lower than in RCDII, with a five-year rate of 14% in the more pessimistic studies [22]. The increased risk of transformation in RCDII probably relies on its malignant nature as it is itself a low grade lymphoma [21]. Indeed, at this stage, clonal IEL are already engaged in malignant transformation as attested by their clonality, the presence of their chromosomal abnormalities, the recurrent partial trisomy 1q22-q44 and their tendency to disseminate in and outside of the intestine [22,54]. Abnormal IEL may be found in mesenteric lymph nodes, blood, bone marrow, and in different epitheliums such as lung and skin [22]. Diagnosis of extraintestinal RCDII lesions may be performed by evidence of the same clonal TCRg/d chain rearrangement that present in duodenum but also by immunohistochemistry showing CD103þCD3iþCD8- T cells. EATL may develop into intestinal but also extraintestinal lesions of RCDII, with expression of the same IEL-specific integrin CD103. The clonal connection between RCDII IEL and EATL is demonstrated by evidence of the same TCRg chain rearrangement [21,45]. Regular follow-up is required for these high risk patients; it includes control enteroscopy, CT-scan or MRI small bowel follow-through and positron emission tomography (Pet-scan) necessary to screen EATL as early as possible. No established interval has been yet defined. Specialized investigations can be reasonably performed every year and six months in RCDI and RCDII patients, respectively [22]. Pet-san is of particular interest because high intensity is correlated with location of proliferating overt lymphoma cells contrasting with the low intensity of non-proliferating RCDII cells [55]. It can further guide realization of radiological guided biopsy or explorative coelioscopy. Treatment of EATL relies on chemotherapy. The Scottish regimen associating ifosfamide-etopesideepirubicin-methotrexate high dosage and autologous stem cell transplantation appears more efficient than classic regimen including anthracyclin [56]. Evidence of expression of C30 on more than 80%
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of EATL [45] may imagine targeting therapy using anti-CD30 antibodies. To that aim, we propose a French therapeutic regimen including cyclophosphamide, doxorubicin, prednisone (CHP) and Brentuximab-vedotin (combining anti-C30 antibody with vedotin): Phase 2 Study of Brentuximab Vedotin and CHP Followed by Autologous Stem-Cell Transplantation as Frontline Treatment of Enteropathy-Associated T-Cell Lymphoma (coordinators: Pr Olivier Hermine, Dr David Sibon) (see Fig. 1). Conclusion Besides the commonly known complications such as osteoporosis and autoimmune diseases, nonresponsive CD to a GFD has become a concerning concept since the last 10 years. Patients with long term response to a gluten free diet should be differentiated from patients with RCD even if both remains exposed to increased risk of intestinal lymphoma and need to be regularly investigated. Diagnosis of lymphomatous complications requires small bowel investigations (enteroscopy, videocapsule endoscopy) and very specialized techniques of IEL analyses (immunohistochemistry, molecular biology, flow cytometry). Prognosis of malignant complications of CD remain poor but recent advances in comprehension of pathogenesis of lymphomatous complications associated with CD offer some hope for hope for targeted therapy.
Practice points Malignant complications of CD are rare (z1%) but have very poor prognosis. Diagnosis of the type of malignancy (RCD2, EATL, Large granular lymphocytic leukaemia) requires specialized small bowel investigations (enteroscopy, small bowel imaging) and diagnostic tools (immunohistochemistry, molecular analysis, flow cytometry of isolated IEL). Therapeutic arsenal is poor but recent advances in pathogenesis, particularly in RCDII, offer new basis for targeted therapy such as anti-IL-15 antibodies.
Research agenda Detailed studies are necessary to define the natural long-term history of CD patients with persistent villous atrophy after one year of gluten free diet. The pathogenesis of RCDI needs to be investigated. Mechanisms of transformation of CD, RCDI and RCDII into EATL remain to be elucidated in order to define prognostic factors.
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[40] Tack GJ, Wondergem MJ, Al-Toma A, Verbeek WH, Schmittel A, Machado MV, et al. Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy. Bone Marrow Transplant 2011;46(6):840e6. *[41] Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 2010;120(6):2131e43. [42] Waldmann TA. Targeting the interleukin-15 system in rheumatoid arthritis. Arthritis Rheumatism 2005;52(9): 2585e8. [43] Yokoyama S, Perera PY, Waldmann TA, Hiroi T, Perera LP. Tofacitinib, a janus kinase inhibitor demonstrates efficacy in an IL-15 transgenic mouse model that recapitulates pathologic manifestations of celiac disease. J Clin Immunol 2013;33(3): 586e94. [44] Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012;64(3): 617e29. [45] Malamut G, Chandesris O, Verkarre V, Meresse B, Callens C, Macintyre E, et al. Enteropathy associated T cell lymphoma in celiac disease: a large retrospective study. Dig Liver Dis 2013;45(5):377e84. [46] Cottone M, Termini A, Oliva L, Magliocco A, Marrone C, Orlando A, et al. Mortality and causes of death in celiac disease in a Mediterranean area. Dig Dis Sci 1999;44(12):2538e41. [47] Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358(9279):356e61. [48] Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology 2002;123(5):1428e35. [49] Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ, Coupe VM. Incidence of enteropathyeassociated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands. Scand J Gastroenterol 2008;43(11): 1322e8. [50] Sharaiha RZ, Lebwohl B, Reimers L, Bhagat G, Green PH, Neugut AI. Increasing incidence of enteropathy-associated T-cell lymphoma in the United States, 1973e2008. Cancer 2012;118(15):3786e92. [51] Telega G, Bennet TR, Werlin S. Emerging new clinical patterns in the presentation of celiac disease. Arch Pediatr Adolesc Med 2008;162(2):164e8. [52] Green PH. Mortality in celiac disease, intestinal inflammation, and gluten sensitivity. JAMA 2009;302(11):1225e6. [53] Landgren AM, Landgren O, Gridley G, Dores GM, Linet MS, Morton LM. Autoimmune disease and subsequent risk of developing alimentary tract cancers among 4.5 million US male veterans. Cancer 2011;117(6):1163e71. [54] Verkarre V, Romana SP, Cellier C, Asnafi V, Mention JJ, Barbe U, et al. Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue. Gastroenterology 2003;125(1):40e6. [55] Hoffmann M, Vogelsang H, Kletter K, Zettinig G, Chott A, Raderer M. 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) for assessment of enteropathy-type T cell lymphoma. Gut 2003;52(3):347e51. [56] Sieniawski M, Angamuthu N, Boyd K, Chasty R, Davies J, Forsyth P, et al. Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. Blood 2011;115(18):3664e70.
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Best Practice & Research Clinical Gastroenterology
7
Complications of coeliac disease Georgia Malamut, MD, PhD a, b, c, Christophe Cellier, MD, PhD a, b, c, * Universit e Paris Descartes, Paris, France ^pital Europ Gastroenterology Department, Ho een Georges Pompidou APHP, Paris, France c Inserm UMR1163 Institut Imagine, Paris, France a
b
a b s t r a c t Keywords: Autoimmune disease Unresponsive coeliac disease Refractory coeliac disease Enteropathy-associated T cell lymphoma
Within the past 20 years the spectrum of complications of coeliac disease (CD) has been considerably extended. Besides the classic complications, autoimmune diseases and osteopenia, numerous forms of CD non-responsive to a gluten-free diet have been recently identified. Among the non-responsive CD, the majority of patients presents as long term responders. However a small subset of CD patients becomes refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. Whereas refractory coeliac disease type I (RCDI) is hardly distinguishable from active CD, the type II (RCDII) has a severe clinical presentation and a very poor prognosis. Enteropathy Associated T cell Lymphoma (EATL) is even more aggressive with a five year survival of 20%. Classic adriamycin-based chemotherapy is poorly efficient in the lymphomatous complications of CD and current therapeutic strategies focus on more intensive regimen with autologous or allogenic stem cell transplantation. Notable pathogenic advances let us to test targeted therapy both in low (RCDII) and high grade lymphomatous (EATL) complications associated with CD. © 2015 Elsevier Ltd. All rights reserved.
^ pital Europe en Georges Pompidou, 20 rue Leblanc, 75015 Paris, * Corresponding author. Gastroenterology Department Ho France. Tel.: þ33 1 56 09 35 52; fax: þ33 1 56 09 35 29. E-mail address: [email protected] (C. Cellier). http://dx.doi.org/10.1016/j.bpg.2015.05.005 1521-6918/© 2015 Elsevier Ltd. All rights reserved.
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Introduction Coeliac disease (CD) is an inflammatory enteropathy induced by gluten in genetically predisposed individuals. Its prevalence is of 1% in Europe and USA. Treatment relies on a life-long gluten free diet which prevents bone, autoimmune and malignant complications. Different types of resistance to a gluten free diet (GFD) have been described within the past 20 years. The majority of those patients are long term responders whereas a small group of them develop an authentic refractory celiac disease. We describe below the panel of CD complications with a particular detailed description of malignant complications. Bone complications Fifty to seventy percent of CD patients suffer from a loss of bone mass at diagnosis. Conversely, increased prevalence of CD in osteoporotic patients was reported [1]. Consequently, bone densitometry is recommended for all CD patients at diagnosis. Mechanisms involve both calcium malabsorption and inflammatory factors related to intestinal mucosal inflammation [2,3]. Osteopenia is major in the forearm which is the most common fracture site [4]. Gluten free diet may partially correct osteopenia but normalization is rarely observed [5]. The risk of fracture is significantly increased before diagnosis of CD but not under gluten free-diet [6]. Besides gluten-free diet, clinical management of osteopenia includes a daily calcium intake of 1500 mg, and vitamin D supplementation, if inadequate serum levels. Autoimmune complications The link between CD and autoimmunity is now firmly established. Five to 10% of patients with type I diabetes develop CD, while conversely, 15e20% of CD patients have or will develop autoimmune disorders [7]. Besides dermatitis herpetiformis which appears more as an extra-intestinal manifestation of CD, type I diabetes and autoimmune thyroiditis appear as the most frequent autoimmune diseases €gren's syndrome, systemic associated with CD, before Rheumatoid arthritis, autoimmune hepatitis, Sjo lupus, addison's disease, antiphospholipid syndrome or myasthenia gravis [7e9]. Indeed, type I diabetes and CD share frequently susceptibility HLA-type II genotypes DQ2/DQ8. Individuals who are heterozygous for DQ2.5 (DQA1*05:01/DQB1*02:01) and DQ8 (DQA1*03:01/DQB1*03:02) are also susceptible to type I diabetes with an almost five-fold higher risk than those who are homozygous for either of the DQ variants [10,11]. Besides HLA genes, some CD-associated variants within coding sequences have also been found in association with other autoimmune diseases. One such interesting variant is an SNP in SH2B3 that is associated with other autoimmune, type I diabetes and rheumatoid arthritis [12]. Autoimmune diseases such as type I diabetes and thyroiditis are not clearly improved by gluten free diet, not surprisingly as pancreatic and thyroid lesions are irreversible, but GFD might reduce the risk to develop autoimmune diseases after diagnosis of CD, pointing to the link between exposure to gluten and onset of autoimmunity outside the gut [7,12,13]. Asymptomatic patients with persisting villous atrophy on a gluten free diet Persisting villous atrophy despite a strict GFD is not a rare situation outside refractory coeliac disease. In our experience in Paris, villous atrophy was still present in 70 (44%) patients assessed after one year on GFD. Strict observance of the diet was comparable both in patients with or without full histological recovery (approximately 70% of the cases). Patients however differed significantly by the frequency of iron deficiency anaemia which was more often observed in patients with (20/70; 29%) than without (11/88; 12.5%) villous atrophy (p ¼ 0.015; OR: 2.78). Similarly, low ferritinemia was more frequent in patients with (23; 33%) than without (21; 24%) villous atrophy (p ¼ 0.065) [14]. Persistent villous atrophy does not seem to be associated with an increased mortality, but a higher risk for lymphoproliferative malignancies was reported among patients with persistent villous atrophy [15]. Further studies are necessary to better assess the long term follow-up of these coeliac
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patients presenting commonly minor clinical symptoms but residual mucosal damage after one year of GFD. Refractory coeliac disease RCD is defined by persisting malabsorption and villous atrophy after one year of strict GFD ascertained by a dietician. Indeed, bad adherence to a GFD needs to be first eliminated accordingly with the fact that less than 50% of patients are compliant [16]. Diagnosis of RCD also needs to exclude other causes of intestinal villous atrophy such as autoimmune enteropathy [17], tropical sprue [18] or common variable immunodeficiency (CVID) [19]. When the diagnosis of refractory CD is ascertained, the next step is to define the type of RCD by analysing the phenotype and clonality of small intestinal intraepithelial lymphocytes (IEL). RCDI is defined by increased number of intraepithelial lymphocytes (IEL) bearing a normal phenotype with surface CD3 and 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 [20,21]. Mean age at diagnosis of RCD is around 50 years. Patients with RCDI and RCDII are primary refractory to a GFD in roughly one third and half cases, respectively [22]. Whatever its type, RCD occurs two to three times more in women than in men [22,23]. Frequency of RCDI and RCDII remains unknown. The Derby cohort reports around 0.7% of RCDII patients in series of 713 celiac patients [24] but diagnosis of RCDII patients was only based on ulcerative jejunitis [24] causing possible errors leading to underestimate RCDII and overestimate RCDI. A single North American referral centre study suggests a cumulative incidence of 1.5% for both RCDI and RCDII among CD patients initially diagnosed in this centre [25]. A higher frequency of cases of RCDI than of RCDII was also observed in two other studies from the US [26] and from Germany [27]. In contrast, we and the Amsterdam group reported a higher frequency of RCDII over RCDI [22,23]. 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 severity of CD was correlated with the number of HLA-DQ2 copies: homozygosity for HLA-DQ2 was observed in 25.5% of RCD I, 44.1% of RCDII, and 53.3% of EATL patients vs 20.7% of uncomplicated CD patients and 2.1% of controls [28]. Studies are in progress and ongoing genome wide association studies suggest differences in susceptibility variants between CD and RCDII [29]. RCDII commonly has a severe clinical presentation associated with frequent ulcerative jejunitis responsible of severe protein loss enteropathy. In contrast, symptoms are notably less severe in RCDI which is hardly to differentiate from active CD except the strict adherence to a GFD [22]. Diagnosis relies on endoscopic assessment of upper gastrointestinal tract with intestinal biopsy. Small bowel videocapsule and device assisted enteroscopy are required in suspicion of RCDII for a better assessment of ulcers particularly for evidence of ulcerative jejunitis found in roughly 70% of patients [22,30]. 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 IEL with normal phenotype. No other diagnostic criteria have been yet defined for RCDI. In contrast, the hallmark abnormal population, detected by three combined techniques, makes the diagnosis of RCDII more specific: over 25% of the CD103þ or CD45þ IEL lacking surface CD3-T cell receptor expression as determined by flow cytometry or more than 50% IEL expressing intracellular CD3ε but no CD8 in formol fixed sections and/or the presence of a detectable clonal rearrangement of the gamma chain of the T cell receptor (TCR) in duodenal biopsies [22]. Similar features allow detecting lymphocytic gastritis and colitis containing the same abnormal population in around 50% and 30% of RCDII patients, respectively [22]. Analysis of the delta chain rearrangement may be useful for diagnosis of RCDII in patients presenting oligoclonal rearrangement of the gamma chain [22]. Others have suggested interest of detecting of the beta chain of the TCR [31]. Finally, specificity of the PCR product needs to be attested by formation of homoduplexes [22]. Diagnosis of RCDII has become highly specialized. Flow cytometry allows distinguishing RCDII from other malignant complication of CD such as large granular lymphocytic leukaemia [32] or intestinal CD4 lymphoproliferations [33]. Such distinction is crucial for choosing the adequate treatment such as cyclosporine for
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CD complicated by large granular lymphocytic leukaemia and in contrast chemotherapy and autologous haematopoietic stem cells transplantation for RCDII (see below). 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 later condition, MRI small bowel follow-through and computed tomography scan (CT-scan) also frequently detect enlarged mesenteric lymph nodes frequently involved by abnormal cells. Besides the diagnosis of persisting villous atrophy, capsule endoscopy allows the visualization of ulcers all along the intestinal tract possibly found in RCDII patients [34,35]. The more severe malnutrition combined with the higher risk of developing overt lymphoma explains the higher mortality in RCDII when compared to RCDI [22]. Indeed, RCDII patients have a 5-year survival rate of 44%e58% [22,23,26]. 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 [26,27]. There is as yet no curative treatment for RCD, immunosuppressive treatment being poorly efficient and possible triggers the development of overt lymphoma [36]. It has not yet been possible to find real efficient treatment for RCD I or II. Steroids transiently improved clinical symptoms in most patients with either type of RCD with a histological response only in 30e40% of cases [22]. Steroid dependence resorted to test immunosuppressors such as azathioprine, cyclosporine or anti-TNF-a with some clinical responses but rare mucosal improvement [22]. In RCDII immunosuppressive drugs have no impact on the abnormal clonal IEL population and could even enhance the risk of overt lymphoma as reported with azathioprine or anti-CD52 [22,36]. The poor prognosis of RCDII led to more aggressive treatments such as chemotherapy but this was found poorly efficient with respect to eradicating the non-proliferative RCDII cells [22]. Purine analogues such pentostatine or cladribine (2 CDA) have been largely used in the past with slight therapeutic effect [37,38]. Cladribine may induce clinical and even histological response but appears also to enhance the risk of transformation into EATL [22,38]. Autologous haematopoietic stem cells transplantation constitutes another possible alternative strategy. It was shown to induce clinical and histological response but no sustained reduction of abnormal IEL in the thirteen treated patients [39,40]. The use of chemotherapy before autologous haematopoietic stem cells transplantation may probably increase haematological response and we are currently evaluating this strategy in a prospective phase II trial. Setting up targeted strategy appears necessary to complete the therapeutic armoury to treat RCDII. Identification of the IL-15 induced anti-apoptotic signalling pathway mechanisms underlying the onset of RCDII may help finding potential therapeutic targets [41]. Blocking IL-15 may thus help to reduce the numbers of clonal IEL and to prevent epithelial damage. The recent development of a humanized antiIL-15 antibody which has already been used without any major side effects in a phase I-II trial in rheumatoid arthritis, suggests the feasibility of this therapeutic approach [42]. Indeed, treatment in vivo, treatment, by a human anti-IL-15 antibody of mice overexpressing human IL-15 in small bowel wiped out the IEL hyperplasia observed in these mice [41]. Another possibility is to block the downstream molecules activated by IL-15 such JAK3 molecule [43]. Based on these data, JAK3 inhibitor, currently used in treating rheumatoid arthritis [44], 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 next future. Finding an efficient treatment is necessary to prevent onset of EATL whose prognosis is even poor than RCDII one [45] (see Fig. 1). Enteropathy associated T cell lymphoma (Eatl) Incidence of Non Hodgkin Lymphoma associated with CD has been evaluated to 0.45, 3.75 and 2.7 for 1000 patients-year [46e48]. Based on a nation-wide collection of data between 2000 and 2006, Verbeek et al. have reported a crude incidence of 0.10/100,000 cases of EATL in the total Dutch population with an incidence of 2.08/100,000 in the over 50-year-olds [49]. In contrast, in a very recent study based on the Surveillance, Epidemiology, and End Results (SEER) database of the US National Cancer Institute between 1973 and 2008 (a database that covers approximately 28% of the US population). R Z. Sharaiha et al. observed a much lower overall incidence of EATL of 0.016 per 100,000 (and of
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Fig. 1. Proposal for therapeutic strategies in RCDII and EATL: INCa French regimen for treating patients with RCDII combines chemotherapy (6 cycles of Fludarabin-Endoxan given intravenously) with autologous stem cell transplantation (ASCT). Treatment of EATL depends of expression of CD30: in main cases (z80%), EATL express CD30 and can be treated according to the French regimen CHP-SGN35 combining CHP, anti-CD30 antibody and autologous stem cell transplantation. EATL which does not express CD30 can be treated by the Scottish regimen IVE-MTX high dosage-autologous stem cell transplantation.
0.05 per 100,000 in the population aged >60 years) [50]. These authors noted however an increased incidence from 0.006 per 100,000 to 0.024 per 100,000 during the study period, which coincides with the recent increase in CD incidence in the US [51,52]. In the same study, it was also noted that EATL were common in men, an unexpected finding given the higher incidence of CD and RCDII in women. In addition, the highest incidence rate was in individuals of Hispanic origin with an age-adjusted incidence rate, of 0.033 per 100,000, further suggesting differences between populations of different geographical origins. Overt B cell lymphoma is at least six times less common that EATL. In comparison with Non Hodgkin Lymphoma, intestinal adenocarcinoma is very rare [53]. Indeed, 33%e52% of RCDII patients develop Enteropathy Associated-T cell Lymphoma (EATL) within the five years after diagnosis [22,23]. Onset of EATL in RCDI is much lower than in RCDII, with a five-year rate of 14% in the more pessimistic studies [22]. The increased risk of transformation in RCDII probably relies on its malignant nature as it is itself a low grade lymphoma [21]. Indeed, at this stage, clonal IEL are already engaged in malignant transformation as attested by their clonality, the presence of their chromosomal abnormalities, the recurrent partial trisomy 1q22-q44 and their tendency to disseminate in and outside of the intestine [22,54]. Abnormal IEL may be found in mesenteric lymph nodes, blood, bone marrow, and in different epitheliums such as lung and skin [22]. Diagnosis of extraintestinal RCDII lesions may be performed by evidence of the same clonal TCRg/d chain rearrangement that present in duodenum but also by immunohistochemistry showing CD103þCD3iþCD8- T cells. EATL may develop into intestinal but also extraintestinal lesions of RCDII, with expression of the same IEL-specific integrin CD103. The clonal connection between RCDII IEL and EATL is demonstrated by evidence of the same TCRg chain rearrangement [21,45]. Regular follow-up is required for these high risk patients; it includes control enteroscopy, CT-scan or MRI small bowel follow-through and positron emission tomography (Pet-scan) necessary to screen EATL as early as possible. No established interval has been yet defined. Specialized investigations can be reasonably performed every year and six months in RCDI and RCDII patients, respectively [22]. Pet-san is of particular interest because high intensity is correlated with location of proliferating overt lymphoma cells contrasting with the low intensity of non-proliferating RCDII cells [55]. It can further guide realization of radiological guided biopsy or explorative coelioscopy. Treatment of EATL relies on chemotherapy. The Scottish regimen associating ifosfamide-etopesideepirubicin-methotrexate high dosage and autologous stem cell transplantation appears more efficient than classic regimen including anthracyclin [56]. Evidence of expression of C30 on more than 80%
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of EATL [45] may imagine targeting therapy using anti-CD30 antibodies. To that aim, we propose a French therapeutic regimen including cyclophosphamide, doxorubicin, prednisone (CHP) and Brentuximab-vedotin (combining anti-C30 antibody with vedotin): Phase 2 Study of Brentuximab Vedotin and CHP Followed by Autologous Stem-Cell Transplantation as Frontline Treatment of Enteropathy-Associated T-Cell Lymphoma (coordinators: Pr Olivier Hermine, Dr David Sibon) (see Fig. 1). Conclusion Besides the commonly known complications such as osteoporosis and autoimmune diseases, nonresponsive CD to a GFD has become a concerning concept since the last 10 years. Patients with long term response to a gluten free diet should be differentiated from patients with RCD even if both remains exposed to increased risk of intestinal lymphoma and need to be regularly investigated. Diagnosis of lymphomatous complications requires small bowel investigations (enteroscopy, videocapsule endoscopy) and very specialized techniques of IEL analyses (immunohistochemistry, molecular biology, flow cytometry). Prognosis of malignant complications of CD remain poor but recent advances in comprehension of pathogenesis of lymphomatous complications associated with CD offer some hope for hope for targeted therapy.
Practice points Malignant complications of CD are rare (z1%) but have very poor prognosis. Diagnosis of the type of malignancy (RCD2, EATL, Large granular lymphocytic leukaemia) requires specialized small bowel investigations (enteroscopy, small bowel imaging) and diagnostic tools (immunohistochemistry, molecular analysis, flow cytometry of isolated IEL). Therapeutic arsenal is poor but recent advances in pathogenesis, particularly in RCDII, offer new basis for targeted therapy such as anti-IL-15 antibodies.
Research agenda Detailed studies are necessary to define the natural long-term history of CD patients with persistent villous atrophy after one year of gluten free diet. The pathogenesis of RCDI needs to be investigated. Mechanisms of transformation of CD, RCDI and RCDII into EATL remain to be elucidated in order to define prognostic factors.
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