Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy

Abstract

Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.

Introduction

“Intractable diarrhea of infancy” was first described in 1968 as chronic unremitting diarrhea occurring in infants less than 3 months of age. It was typically unresponsive to medical treatment with a high mortality rate even with parenteral nutrition support [1]. Rather than a discrete disease entity, the initial description defined a complex of symptoms, characterized by anorexia, malabsorption, and failure to thrive. Over time, this description has been largely replaced by the term protracted diarrhea, an entity that encompasses a number of etiologies [2]. Attempts have been made to design an etiological classification for protracted diarrhea to help aid in its diagnosis and management. Sherman et al. proposed a classification based on villus architecture. Normal villus crypt architecture etiologies include transport defects (e.g., lipid transport defects), micronutrient deficiencies (e.g., acrodermatitis enteropathica), enzyme deficiencies (e.g., congenital lactase deficiency), and short bowel syndrome. Conditions that involve villus atrophy encompass autoimmune enteropathy (AIE), microvillus inclusion disease, allergic enteropathy, and infections among other disorders [3]. Most of the conditions described above are well described in the medical literature. However, AIE was only relatively recently recognized, and knowledge about its diagnosis and management is evolving. The objective of this narrative review is to describe the medical literature around AIE, regarding definition, epidemiology, clinical presentation, pathophysiology, diagnosis, treatment, and prognosis. A literature search was conducted on PubMed using key terms related to “autoimmune enteropathy,” “intractable diarrhea,” and “protracted diarrhea” with no restrictions on the date of publication or language. We also searched the reference list of key papers and prior systematic reviews. Data were abstracted in an Excel sheet and are described in subsequent sections.

Definition

AIE is an evolving diagnosis, with attempts being made at establishing clear-cut diagnostic criteria. The historical background of AIE dates back to 1985, when Unsworth et al. primarily used the term AIE to describe an immune-mediated, severe, and persistent diarrhea in the pediatric population [4]. The diagnostic criteria initially proposed included the presence of intractable diarrhea that did not improve with dietary modifications, villous atrophy of the small intestine, and the presence of circulating autoantibodies in the absence of a known immunodeficiency [4]. Initially believed to be a strictly pediatric disease, Unsworth’s criteria were groundbreaking. However, with the documentation of adult presentations of AIE and a better understanding of distinguishing histological features, the criteria have been refined and expanded [5, 6]. These now include chronic diarrhea of more than 6 weeks with malabsorption, histological findings of partial or complete blunting of small intestinal villi, increased apoptotic bodies, and deep crypt lymphocytosis with minimal intraepithelial lymphocytosis [5]. The presence of circulating autoantibodies provides major diagnostic support, but its absence does not exclude AIE [6].

Epidemiology

Data on the epidemiology of this disease are relatively scarce, particularly given the difficulty in defining the disease. A study from Sweden surveyed all the pediatric hospitals for cases of AIE from 1985 to 2002 and reported three potential cases, with one case fulfilling the diagnostic criteria for AIE. Incidence was reported as 0.06 per 100,000 children 0–16 years of age [7]. A study from Italy reported the incidence of severe and protracted diarrhea as 0.64–0.95 per 100,000 children infants per year. The most common diagnosis in this cohort was AIE (8 of 32 patients) [8]. No data were available with regard to the incidence or prevalence of AIE in adults.

Clinical Presentation

AIE occurs predominantly in males and initially was thought to be an X-linked disorder. However, cases have also been reported in females suggesting an autosomal or polygenic inheritance or acquired disorder as well [9–12]. The average age of presentation in the pediatric age group is less than 6 months, predominantly between 2 and 4 weeks of age. Children present with chronic diarrhea and malabsorption, electrolyte abnormalities, inability to tolerate oral feeds, and failure to thrive [8, 13, 14]. In addition to malabsorption, the diarrhea in children is a severe and protracted hyper-secretory diarrhea unresponsive to conventional measures and dietary restrictions [15]. Multiple watery stools are passed daily with variable stool volumes that, at their extreme, can sometimes exceed 5000 ml per day [16]. The diarrhea is mostly non-bloody and often associated with steatorrhea, while the workup for pathogenic bacteria and parasites is negative [5]. Older children may also report abdominal pain and vomiting [17]. AIE often has extra-gastrointestinal involvement signifying that it might be part of a multi-organ disease. Patients may present with associated autoimmune diseases, including diabetes mellitus, autoimmune hepatitis, alopecia, hypothyroidism [11, 18], and interstitial nephritis [19]. Severe forms of AIE can be associated with identified syndromes, namely IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) and APECED (autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy) syndrome [15].

Adult-onset AIE is less common than that in the pediatric population. Adult cases of AIE present with chronic diarrhea which can be extremely voluminous and frequent, such that a patient can experience as much as 15 gallons of stool loss and up to 50 episodes of diarrhea in a single day [6, 20–22]. The diarrhea is persistent and non-bloody and is associated with significant weight loss [23]. Similar to the pediatric population, adults with AIE can also suffer from other autoimmune conditions such as rheumatoid arthritis [24], thymoma [25], or combined variable immunodeficiency (CVID) [6].

Pathophysiology

As research continues to explore the pathological basis of AIE, newer associations with other autoimmune disorders have been discovered. Ruemmele et al., in a review of the molecular basis of AIE, classified AIE into three separate entities: (1) AIE linked to syndromes such as IPEX and APECED syndrome; (2) an isolated GI form of AIE with presence of anti-enterocyte antibodies with no extra-intestinal manifestations; and (3) any form of AIE in girls associated with any other autoimmune phenomena [14]. This classification was based on syndromal associations of AIE, the presence of anti-enterocyte antibodies, and the pattern of inheritance.

The pathophysiological basis of AIE is widely debated and remains complex, with both humoral and cell-mediated immunity playing significant roles [10, 14]. The intestinal epithelium not only serves as a medium for absorption of nutrients into the bloodstream but is also an interface between luminal antigens and the local immune response. Enterocytes are the major component of the intestinal epithelium that regulates immune response via constitutive expression of major histocompatibility complex (MHC) class II molecules [26]. The expression of MHC class II molecules provides the basis for an autoimmune response that characterizes this rare disease. Hill et al. studied 8 children with AIE and positive circulating anti-enterocyte antibodies and reported that the expression of MHC class II molecules in AIE differs from normal physiologic expression. AIE patients showed aberrant production of HLA II products in enterocytes. However, the MHC class I expression was normal, which is in contrast to classical autoimmune disorders [27]. AIE is also associated with predominant overexpression of the HLA DR subtype [28]. The overexpression of MHC molecules results in the proliferation of CD4+ and CD8+T lymphocytes that exert their effect either through direct cytotoxicity by secreted lymphokines or through indirect antibody-dependent cytotoxicity. TNF-α, IFN-γ, IL-13, and IL-17 are particularly elevated [21, 28, 29]. B cells are also implicated in the pathogenesis, with CVID [30] and selective IgA deficiency also seen in some cases of AIE [31].

IPEX syndrome represents a distinct form of AIE. Classically described as immune dysfunction with a triad of polyendocrinopathy, enteropathy, and dermatitis, IPEX is a rare disease entity that presents in male infants within the first few months of life. IPEX results from mutations in the FOXP3 gene located at the Xp11.23-q13.3 locus [32]. FOXP3 is widely expressed in CD4/CD25+ subsets of T cells and encodes for a transcription factor critical for the development and function of regulatory T cells [33]. Regulatory T cells are potent immunosuppressive cells of the adaptive immune system, and their absence results in loss of immune homeostasis. Histologically, IPEX is characterized by lymphocytic infiltration of different organs and a global autoimmune response. Insulin-dependent diabetes mellitus, severe diarrhea, hemolytic anemia, and eczema are the hallmark features. Less common are thrombocytopenia, hypothyroidism, and glomerulonephritis [34]. AIE when associated with IPEX has a serious course as demonstrated by multiple case reports summarized in supplementary Table 1. Several different mutations have been observed, which signifies the heterogeneity of this syndrome, suggesting that the genetic basis needs to be further delineated by future research [32, 34, 35]. It is known, however, that FOXP3 mutations that result in the complete absence of FOXP3 protein result in a severe clinical course. It is imperative to identify such patients early, and screening for IPEX via FOXP3 immunohistochemical staining can be implemented as a screening tool [36].

Another rare disease associated with autoimmune enteropathy is APECED, also known as the autoimmune polyglandular syndrome (APS 1). APECED is caused by biallelic mutations in the autoimmune regulatory or AIRE gene that has been mapped to chromosome 21q22.3. The AIRE gene encodes for a transcription factor that is pivotal for autoantigen presentation in the thymus and stringent negative selection of autoreactive T cells. Absent function results in defective elimination of autoreactive T cells and subsequent systemic autoimmunity. APECED has an autosomal recessive pattern of inheritance with no association with the MHC complex [37]. Systemic manifestations include AIE, endocrine autoimmunity including development of Addison’s disease, hypoparathyroidism, and hypogonadism, and chronic, recurrent mucocutaneous candidiasis. Similar to IPEX, APECED is a severe variant of AIE and screening for AIRE gene mutations may identify patients with genetic predisposition to autoimmunity earlier in the course of disease allowing better intervention and favorable outcome [38].

Diagnosis

Establishing the diagnosis of AIE has always been challenging. We reviewed 57 pediatric and 41 adult cases reported in the literature, as shown in supplementary Tables 1 and 2. The references for all the included studies are available in the supplementary tables. In the pediatric group, there were 11 females and 46 males with ages ranging from 1 day to 16 years, whereas in the adult group there were 24 females and 17 males, with ages ranging from 21 to 82 years. Eleven subjects in the pediatric age group and 6 cases in the adult group reported had negative anti-enterocyte antibody testing. Thirty-five pediatric cases and 25 adult cases were also positive for other antibodies such as anti-endomysial, antigliadin, anti-smooth muscle, anti-thyroglobulin, anti-reticulin, anti-adrenal, anti-goblet cell (AGCA), and anti-renal cell brush border. As expected, AIE was associated with other autoimmune diseases. Fifty-one pediatric and 30 adult cases presented with other autoimmune disorders including diabetes mellitus type 1, autoimmune hemolytic anemia, selective IgA deficiency, adrenal insufficiency, nephrotic syndrome, hypothyroidism, CVID, thymoma, arthritis, and atopic eczema.

The role of anti-enterocyte antibodies in the diagnosis of autoimmune enteropathy is the subject of ongoing debate. Their presence was part of the initial diagnostic criteria, but, over time, evidence has shown that they are not pathognomonic of AIE, nor does the serum titer correlate with the severity of the enteropathy [39, 40]. These antibodies can be regarded as a secondary epiphenomena, as they mostly appear after the onset of disease and resolve before the restoration of normal mucosa. Anti-enterocyte antibodies are mainly of the IgG subtype, complement-fixing and associated with IgG and C3 deposits in the lamina propria. In some cases IgM and IgA have also been implicated [11, 41]. These antibodies are directed against the intestinal brush border, the cytoplasm of enterocytes and goblet cells [42]. Although reported in around 50% of the cases of autoimmune enteropathy, detection of anti-enterocyte antibodies lacks specificity as they are also seen in low titers in other gastrointestinal disorders, such as inflammatory bowel disease, cow’s milk allergy, and also HIV [14, 40, 43]. Anti-goblet cell antibodies (AGCA) have also been studied in AIE. A study conducted on 95 serum samples from both healthy and diseased populations showed a prevalence of 30% of AGCA, highlighting that these antibodies are very common and nonspecific [44].

Kobayashi et al. identified a novel antibody directed against a 75 kilodalton (kDa) antigen, and this antigen has been named autoimmune enteropathy associated 75 kDa antigen (AIE 75) [45]. AIE 75 is involved in interactions between membrane associated proteins and the cytoskeletal elements, maintaining the permeability of enterocytes and preserving tight junctions. The antibody directed against tight junctions appears to alter the intestinal permeability and contributes to the pathogenesis of the enteropathy. The genomic sequence of AIE 75 is located on the chromosome 11p14.3 and the antigen is expressed in duodenal, jejunal, and renal tissue, suggesting that multiple organs can be affected [45]. AIE 75 seemed to be highly specific as it only reacted with sera of patients with AIE or AIE with tubulin nephropathy and not with sera from 58 controls [45]. Another 55 kDa antibody has been observed in a case of AIE complicated by immune-mediated glomerulonephritis. The epitope was expressed on both intestinal and renal epithelia [46]. In summary, serum antibodies may be helpful in the diagnosis of AIE; however, no single set of antibodies is pathognomonic for the diagnosis of AIE.

The histological presentation of autoimmune enteropathy is variable and shows an array of presentations [47]. Most cases involve the duodenum, with the most common finding of moderate-to-severe villous atrophy and dense lymphoplasmacytic infiltration and neutrophil cryptitis with or without crypt abscess [48, 49]. In a review of 25 cases with AIE, Masia et al. reported gastrointestinal mucosal abnormalities outside the small intestine in 24 biopsies, with the stomach being affected in 86% of cases, followed by the colon (64%), and the esophagus (28%). Findings in non-small intestinal sites were variable and included mixed active and chronic inflammation, chronic inflammation alone, intraepithelial lymphocytosis, and increased apoptosis that resembled acute graft-versus-host disease (GVHD) [49]. The abnormalities identified elsewhere highlight that AIE may be regarded as a pan-gastrointestinal disorder. Thus, biopsies from non-small intestinal sites may support its diagnosis. In adults, normal architecture with reduced number of enteroendocrine cells, goblet cells, and paneth cells has been reported [23]. In a few cases, the morphological features are similar to celiac disease with the duodenum exhibiting changes indistinguishable from celiac disease, with villous blunting and intraepithelial lymphocytosis [49], but, unlike celiac, there is relative scarcity of intraepithelial lymphocytes expressing the T cell receptor αβ [21]. In our review of all the published case reports, the most common biopsy findings in both adult and pediatric groups were total villous atrophy, lymphoplasmocytic infiltration, and crypt hyperplasia. Intra epithelial lymphocytes were noted in those with concurrent celiac disease, and findings of gastric ulcers and generalized colitis were also noted.

The variable histological features are nonspecific and do not allow distinguishing autoimmune enteropathy from other inflammatory disorders. The biopsy finding combined with presence of anti-enterocyte and AGCA increases the specificity of the diagnosis; however, the diagnosis remains to be a mainly clinical one by combining clinical findings with supportive evidence from blood tests and biopsies, and a positive response to immunosuppressive therapies. Confirming or excluding monogenic disorders resulting in autoimmune syndromes may also be helpful.

Differential Diagnosis

The differential diagnoses for AIE are multiple and differ between the adult and pediatric populations.

In the pediatric age group, the differential diagnosis includes intestinal infections, particularly viral infections such as rotavirus, adenovirus, and norovirus and parasites such as giardiasis. Other considerations would be celiac disease, food allergies, very early onset inflammatory bowel disease, monogenic congenital diarrheal disorders, such as glucose–galactose malabsorption, sucrase–isomaltase deficiency, congenital lactase deficiency, congenital chloride diarrhea, congenital sodium diarrhea, microvillous inclusion disease, trichohepatoenteric syndrome, IL-10/IL10-receptor deficiency, as well as common variable immune deficiency.

The differential diagnosis for the adult age group includes celiac disease, inflammatory bowel disease, food allergies, infections, pancreatic insufficiency, and drug reactions. Among the drugs mimicking an AIE-like pattern, olmsartan has been identified to cause intestinal pathology similar to AIE [50]. Furthermore, immunomodulators like ipilimumab, nivolumab, and pembrolizumab also cause immune checkpoint inhibitor colitis which can share features similar to AIE [51].

Though most of the above chronic conditions are rare, celiac disease is common. There are multiple clues in the history, physical examination, laboratory findings, histology, and response to treatment that can help differentiate celiac disease from AIE. First is the age of presentation; celiac disease almost never presents in early infancy due to lack of antigen exposure, while AIE most commonly presents during infancy. The clinical presentation of AIE is marked by voluminous diarrhea that leads to nutritional failure quickly, while in celiac disease, the disease onset might be slower. Extra-intestinal manifestations are common in both diseases. Blood studies in AIE might show anti-enterocyte antibodies, AGCA, increased IgE, and eosinophilia on peripheral blood examination, while celiac disease is typically associated with anti-TTG and anti-endomysium antibodies. Histological examination in celiac disease might show villous blunting and intraepithelial lymphocytes. In AIE, there might be apoptotic bodies, lymphocytic infiltration, and abscesses in the crypt epithelium, as well as loss of goblet cells and paneth cells. Celiac disease will respond to a gluten-free diet, while AIE will not respond to a gluten-free diet but often responds to immunosuppression. AIE due to IPEX or APECED would be supported by the presence of corresponding extra-intestinal manifestations [5, 15, 27].

Treatment

AIE is a potentially fatal disease and needs to be managed aggressively. In pediatric patients, the management aims at sufficient nutritional support and hydration to allow optimum growth, while suppressing the inappropriate immune response. With the recent advances in understanding of the pathological basis of AIE, developments have been made in its treatment modalities. Immunosuppression with steroids and other immunomodulators has been used with apparent benefits. The treatment modalities for the 57 pediatric and 41 adult cases reported to date are shown in supplementary Tables 1 and 2. There were 5 reported mortalities among adult cases and 23 in pediatric cases. Of the total 98 cases (both adult and pediatric), 44 of them needed total parenteral nutrition (TPN), highlighting the fact that total parenteral nutrition often represents an essential step in management, providing adequate nutrition, and preventing dehydration and electrolyte imbalance. Long-term dependence on TPN is associated with fatal complications such as central line sepsis as reported in two cases, serving to emphasize that efforts should be made to promote enteral feedings [52].

Steroids were the most commonly reported first line of treatment, and 25 (13 pediatrics) out of 98 cases responded to steroids with no further need for second- or third-line agents. Supplementary Tables 1 and 2 show the response to various immunological agents in pediatric and adult populations. Apart from steroids, other agents were also found to be successful in inducing remission, including Cyclosporine (7 cases), Tacrolimus (4 cases), and Cyclophosphamide (3 cases). In a few cases, Azathioprine [11] and Mycophenolate Mofetil [12] were also successful. Rapamycin has proven to be a beneficial agent in IPEX patients [53] and should be considered as a treatment agent for this disorder. Apart from inducing remission, immunomodulators also served as adjuncts to steroids, and, when used as maintenance therapy, helped in preventing long-term complications of steroid use. With the advent of biological agents, improvement has been seen in severe cases of AIE refractory to conventional immunosuppression. Infliximab, a chimeric monoclonal antibody effective in various inflammatory disorders has been successful in inducing remission in both adult and pediatric patient refractory to steroids. However, its use has been associated with significant hypersensitivity reactions [54, 55]. The response to infliximab is due to its antagonist effect to TNF-α, the lymphocyte factor implicated in the pathogenesis of AIE. In a few cases, infliximab was used successfully used as a third-line agent [54]. Newer biologics, like adalimumab (anti-TNF-α) and abatacept (CTLA-4 mimetic), were also used in two cases [22, 56].

The role of hematopoietic stem cell transplantation (HSCT) in patients with AIE is evolving and has been used as a curative therapy for patients with IPEX. Resolution of IPEX manifestations by HSCT is accomplished by engraftment of donor CD4+ CD25+ FOXP3+ regulatory T cells that can provide adequate suppression of autoreactive T and B cells. HSCT of IPEX patients is complicated by extreme comorbidities including malnutrition, organ damage, and repetitive infections secondary to immunosuppressive therapy. Because of their poor health pre-HSCT, many IPEX patients are conditioned with low doses of chemotherapy (i.e., reduced intensity) to prevent transplant-related morbidity and mortality while being sufficiently immunosuppressive to dampen the inflammatory state prior to bone marrow infusion. Use of low doses of chemotherapy is often associated with lower percentages of donor cells engrafting in the recipient. However, because establishment of donor regulatory T cells is able to suppress both recipient and donor adaptive immune cells, IPEX can be cured with mixed chimerism (presence of both donor and recipient cells) as long as there are enough donor cells to produce regulatory T cells [57]. The % donor cells necessary to establish an adequate number of regulatory T cells are not firmly established, but it is likely that only a minority of cells are required, particularly if donor cells are driven to produce regulatory T cells preferentially which has been proposed in the report of one anecdotal patient cured with mixed chimerism [58].

An overview of case reports and small case series reported for HSCT in IPEX patients is provided in Tables 1 and 2. A total of 28 reports were available from our literature review. All transplants occurred in pediatric patients with an age range at HSCT of 4 months–16 years. All patients had refractory disease that did not respond to conventional therapy. In terms of donors, 7 patients had related donors and 21 had unrelated donors. The source of hematopoietic cells was bone marrow for 20 patients and peripheral blood for 8.

Table 1.

Characteristics of patients undergoing stem cell transplant for IPEX

Study	Cases	Age at transplant/gender	Race	Clinical features	FOXP3 mutation	Donor type and source	Conditioning regimen
Rao [67]	1	7 years/M	White	FTT, AIHA, colitis, eczema, FA	A > G splice junction mutation intron 9	URD BM	Alt/Flu/Mel
	2	1.4 years/M	African/American	FTT, AIHA, colitis, eczema, FA	303_304 del TT	URD BM	Alt/Flu/Mel
	3	4 years/M	White	Colitis, FA, eczema, MGN	1271 G > A, C424Y	RD BM	Alt/Flu/Mel
	4	0.5 years/M	White	Colitis, AIHA	1226 A > G, D409G	URD BM	Alt/Flu/Mel
Mazzaloni [68]	1	1 year/M		Colitis, dermatitis	Low FOXP3 mrna	RD BM	Flu/Bu/Cy/ATG
Baud [69]	1	4 months/M		Colitis, AIHA, IDDM,	Guanine → thiamine (exon 10)	RD BM	ATG/Bu/Cy
Wildin [34]	1	13 years/M	White	UC, IDDM	Missense mutation at winged helix of scrufin protein	RD BM	Cys/ATG
	2	9 years/M	White	IDDM, Enteritis, AR, ITP	Deletion of amino acid in scrufin, silent mutation serine 181	URD BM	Cys/TBI/ATG
Zhan [70]	1	5 months/M	White	Colitis, FA	T3801 mutation in exon 10	URD PBSC	Alt/Cys/Flu/anti-CD45 monoclonal antibody
Seidel [71]	1	11 months/M	White	IDDM	NA	URD PBSC	Flu/Alt/Mel
Nadeemi [72]	1	6 months/F		Chronic diarrhea, FTT, eczema, AIHA	c.1157G > A p. R386H	RD BM	Bu/Cys
	2	10 months/F		Chronic diarrhea, FTT, AIHA	c.*876A > G	URD PBSC	Bu/Cys
	3	10 months/M		Chronic diarrhea, FTT, eczema, AIHA, ITP	c.758T > C p. L253P	URD BM	Bu/Cys
	4	10 months/M		Chronic diarrhea	c.816 + 5G > A	URD PBSC	Treo/Cys
	5	6 months/M		Chronic diarrhea, FTT, eczema, AIHA	c.1037T > C p. I346T	URD PBSC	Treo/Flu
Lucas [73]	1	6 years/M	White	IDA, pneumonia, dermatitis, FTT	NA	URD PBSC	Flu/Bu/ATG
Kucuk [74]	1	14.2 years/M	White	IDDM.	NA	RD BM	Cys/ATG/TBI
	2	9.2 years/M	White	IDDM, AIE, ITP	NA	URD BM	Cys/ATG/TBI
	3	6 months/M	White	IDDM, AIE, AIHA	NA	URD BM	Alt/Flu/Mel
	4	29 months/M	White	Eczema, FA, AIE	NA	URD PBSC	Alt/Flu/Mel
	5	16 months/M	African/American	Eczema, FA, EGID	NA	URD BM	Bu/Cys/ATG
	6	5.41 years/M	White	Eczema, EGID, celiac, AIHA	NA	URD BM	RIC unspecified
	7	9.7 years 1st HSCT/10, 9 years 2nd HSCT/M	White	Eczema, FA, AIE, AR, AIH	NA	URD BM	RIC unspecified
Burroughs [75]	1	9 months/M		AIHA, infections, diarrhea. IDDM, FTT	c.210_210 + 1GG > AC	URD PBSC	Flu/TBI
	2	16 years/M		AIHA, infections, diarrhea, IDDM, FTT	c.816 + 7G > C	URD BM	Flu/TBI
Dorsey [76]	1	7 months/M		FTT, diarrhea	point mutation AAT AAA– → AATAAG	URD BM	Alt/Flu/Mel
Kasow [77]	1	6 months/M	White	FTT, diarrhea, eczema	Missense mutation (A384T)	URD BM	Alt/Flu/Mel/Thiotepa
Horino [58]	1	6 years/M	Asian	FTT, diarrhea	Missense mutation (T1117G)	RD BM	Flu/Cys

Alt Alemtuzumab, ATG anti-thymocyte globulins, AIHA autoimmune hemolytic anemia, AR arthritis, BM bone marrow, Bu Busulfan, Cys cyclophosphamide, EGID eosinophilic gastrointestinal disease, F female, FA food allergies, Flu fludarabine, FTT failure to thrive, IDDM insulindependent diabetes mellitus, IDA iron deficiency anemia, ITP idiopathic thrombocytopenia, INF infections, M male, Mel melphalan, MSC mesenchymal cell, NA not available, PBSC peripheral blood stem cells, RIC reduced intensity conditioning, RD related donor, TBI total body irradiation, Treo treosulfan, UC ulcerative colitis, URD unrelated donor, c.*876A > G = the variation is located at the 876 nucleotide 3′ of the translation stop codon (*876)

Table 2.

Follow-up of patients who underwent stem cell transplant for IPEX

Study	Cases	Follow-up time	Donor chimerism % (unfractionated leukocytes unless specified)	Developed GVHD: yes/no	Off IST at last follow-up yes/no	Vital status: survived/died	Notes: complications: posttransplant
Rao [67]	1	25	100	Yes	No	Survived	Complications: Clostridium difficile, Enterococcus faecalis, s Histoplasma capsulatum, Enterococcus faecium, and Staphylococcus hominis
	2	19	100	No	Yes	Survived
	3	11	89	No	Yes	Survived
	4	6	85	No	No	Survived
Mazollari [68]	1	16	T 70, B 30, PMN 50	Yes	Yes	Survived	No complications
Baud [69]	1	23	Mixed chimerism	No	Yes	Died	Developed hemophagocytic syndrome
Wildin [34]	1	5	100 decreasing to 50	No	Yes	Died	Pneumonia
	2	3	100 decreasing to 70	No	Yes	Died	EBV and CMV infection, sclerosing pancreatitis,
Zhan [70]	1	30	100	Yes	Yes	Survived	No complications
Seidel [71]	1	6 years	Range: 53–91	Yes	Yes	Survived	No complication
Nadeemi [72]	1	10 years	T 68, B 57, CD15 57	No	Yes	Survived	Autoimmune cytopenias
	2	9 years	100	No	Yes	Survived
	3	8 years	100	No	Yes	Survived
	4	5 years	T 32, B 36, CD15 31	Yes	Yes	Survived
	5	3.5 years	T 41, B 35, CD15 34	No	Yes	Survived
Lucas [73]	1	14 months	81 at 1 month, 98 at 8 months	Yes	Yes	Survived	EBV
Kucuk [74]	1	197 days	Mixed	No	Yes	Died	Autoimmune cytopenias
	2	93 days	Mixed	No	Yes	Died
	3	8 years	Mixed	No	Yes	Survived
	4	7 years	Mixed	No	No	Survived
	5	5 years	–	Yes	No	Survived
	6	4 years	Mixed	No	No	Survived
	7	77 days	Mixed	No	No	Survived
Burroughs [75]	1	4 years	100	Yes	Yes	Survived	No improvement in diabetes and hypothyroidism. Grade 4 pulmonary toxicity and bacteremia
	2	4 years	Mixed	Yes	Yes	Survived
Dorsey [76]	1	NA	100	No	Yes	Survived	Staphylococcus epidermides bacteremia and HTN
Kasow [77]	1	3 years	Mixed	No	Yes	Survived	Resolution of all clinical disease
Horino [58]	1	2 years	Mixed	Yes	No	Survived	GVHD of skin (grade 1) and development of ALL at 2 years

ALL acute lymphoblastic leukemia, CMV cytomegalovirus, HSCT hematopoietic stem cell transplant, HTN hypertension, EBV Epstein–Barr virus, NA not applicable

The transplant was successful in 23 patients and unsuccessful in 5, with one failed patient re-transplanted (Table 2). Out of 28 who underwent HSCT for IPEX-related diagnosis, 5 (21%) died. Complications developed in all 28 patients and included infections (viral/bacterial), autoimmune cytopenias, pancreatitis, and in 10 patients (39%), GVHD. Most patients developed mixed chimerism (range of 30–100% donor cells) with resolution of IPEX symptoms occurring despite the presence of residual recipient cells.

A recent report evaluated the long-term follow-up of IPEX patients receiving HSCT or prolonged immune suppression [53]. Although survival was similar between both cohorts, mortality in those transplanted was primarily within the first 2.5 years post-HSCT, while the non-transplanted patients continued to accumulate additional mortality. As expected, disease manifestations were far greater in the non-transplanted cohort leading to lower disease-free survival. HSCT outcomes were also impacted by the disease burden pre-transplant, with improved outcomes in patients coming to transplant without significant organ damage. This highlights the importance of an early diagnosis of IPEX and prompt progression to HSCT in identified patients. Given the long-term consequences of poorly controlled autoimmunity, HSCT for severe IPEX is considered standard of care once a diagnosis is confirmed. However, the role of HSCT in patients with autoimmune enteropathy without FOXP3 mutations is less defined and further investigations are still needed for this population.

Mesenchymal stem cell (MSC) infusion is a newly emerging therapeutic strategy which may offer a potential treatment for AIE. MSCs are multipotent stromal cells that can modulate T and B cell activity in vitro and therefore is an attractive potential treatment for autoimmune disorders. Experimental suppressive activity of MSCs includes expansion of T regulatory cells, down-regulation of CD8 and natural killer cells [59], and inhibition of activation, proliferation, and immunoglobulin secretion of B cells [60]. In mice lacking regulatory T cells resulting in multi-organ autoimmunity, MSC infusion resulted in improved histopathology of the ileum and improved markers of immune suppression including increased levels of the suppressive cytokine IL-10 [61]. MSC infusion has been anecdotally successful in human patients with immune disorders including Crohn’s disease [62], but only one report of its use in AIE has been reported to date. Ex vivo expanded autologous MSCs were infused in a 61-year-old patient with AIE resulting in increased mucosal regulatory T cell numbers, but only short-term remission of gastrointestinal symptoms was achieved [63]. Unlike HSCT, the mesenchymal stem cell treatment does not include the risks of conditioning therapy or GVHD. Therefore, further evaluation of the use of this safer modality continues to be pursued.

Prognosis

Autoimmune enteropathy is a complex ailment and is potentially life-threatening with a mortality rate as high as 30% in pediatric patients who were on TPN [64]. The prognosis of AIE patients depends on the age of onset, severity of signs and symptoms, the severity and extent of histological lesions along the gastrointestinal tract, and the presence of extra-intestinal involvement [14, 27, 64]. Pediatric patients seemed to have more complications and required second-and third-line therapies compared to adults (supplementary Table 1 and 2). However, outcome data were only available from case reports and case series and might overrepresent successful outcomes. The disease is often associated with poor prognosis as patients often have long-term dependence on parenteral nutrition for survival [64]. Parenteral nutrition may be associated with fatal complications including infections, cholelithiasis, and superior vena cava thrombosis [55, 64]. The use of immunosuppression further increases the risk of infections, neurotoxicity, and lymphoproliferative diseases [65]. In association with related syndromes, the management becomes more complicated. In addition to parenteral nutrition and immunosuppressive regimes, symptomatic treatments for various other ongoing abnormalities have to be implemented. With IPEX, hematic transfusions and exogenous insulin for diabetes may become essential, while APECED often involves hormone replacement therapies and systemic therapy against Candida infections. Patients also require close monitoring for the development of new disease components of the respective syndromes [66].

Future Research

Our knowledge of AIE has increased over the last decade, with increased understanding of its pathophysiology and diagnostic approaches. New treatment options are also available; however, outcome data are only available in the form of retrospective charts reviews and case reports. This type of data has the risk of selective reporting as successful cases are more likely to be selected for reporting and publication in a journal. In order to improve knowledge of both successful and unsuccessful cases, establishing a central registry where multiple institutions participate might help to understand this disease and its treatment. A central registry might also help to collaboratively assess the efficacy of certain treatment modalities as a single center might not have enough patients with this rare disorder.

Conclusion

Based on a review of the reported data, we propose a diagnostic and treatment plan for AIE, as outlined in Fig. 1.

Fig. 1.

Proposed outline for workup and management of AIE. The diagram shows proposed workup strategy for a patient with intractable diarrhea who might have AIE. This is based on evidence from case reports and case series and might be reconsidered when more evidence is available. AIE autoimmune enteropathy, APECED autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy, 5 ASA the aminosalicylate, AZA azathioprine, CD cluster designation, Ig immunoglobulin (A, G, M, E), IL Interleukin, IFN interferon, IPEX immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, 6 MP 6 mercaptopurine, MHC major histocompatibility complex, MVID microvillous inclusion disease, MSC mesenchymal stem cell, TNF tumor necrosis factor, TPN total parenteral nutrition

The diagnosis of AIE remains a difficult one and requires a high index of clinical suspicion in the appropriate clinical setting. Cumulative clinical experience with management of AIE has allowed improved outcomes. Along with nutrition support, immunosuppressive treatments and immunomodulators can help control the disease, with a potential cure obtainable in IPEX patients with HSCT. With recent advances in molecular biology, the pathological basis of this unique disorder is becoming clearer. This should help in improving diagnostic tools and refining standard treatment options for AIE in the future. HSCT can be curative but remains an aggressive treatment and currently reserved for severely affected patients such as those with damaging FOXP3 mutations. MSC infusions appear to be a promising avenue but needs further exploration.

Abbreviations

AIE

Autoimmune enteropathy

APECED

Autoimmune polyendocrinopathy–candidiasis—ectodermal dystrophy

IL

Interleukin

IFN

Interferon

IPEX

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

MHC

Major histocompatibility complex

MSC

Mesenchymal stem cell

TNF

Tumor necrosi sfactor

TPN

Total parenteral nutrition