C 2005) Digestive Diseases and Sciences, Vol. 50, No. 5 (May 2005), pp. 928–932 (
DOI: 10.1007/s10620-005-2666-x

CASE REPORT

Adult-Onset Autoimmune Enteropathy in the Setting of Thymoma Successfully Treated with Infliximab JILL E. ELWING, MD, and RAY E. CLOUSE, MD KEY WORDS: autoimmune enteropathy; autoimmune disease; diarrhea; intestinal mucosa; immunosuppressive agents.

Autoimmune enteropathy (AIE) is characterized by chronic intractable diarrhea, weight loss from malabsorption, and immune-mediated damage to the intestinal mucosa. The syndrome initially was described in 1982 in a male child (1, 2). Walker-Smith formulated a set of diagnostic criteria for the disorder that remain in use: (a) small intestinal villous atrophy, (b) unresponsiveness to dietary restriction, and (c) circulating enterocyte antibodies and/or associated autoimmune conditions (3). AIE also occurs in the setting of immunoglobulin deficiencies, a known risk factor for the development of autoimmune disorders (4, 5). The first published cases of adult-onset AIE appeared in 1997 when Corazza et al. described two subjects aged 38 and 47 years with severe diarrhea and malabsorption, small bowel villous atrophy, no response to gluten-free diet, and circulating antienterocyte antibodies (6, 7). Only occasional case reports of adults with this disorder have appeared since, and similarly to pediatric cases, adultonset AIE has been associated with autoimmunity and immunoglobulin deficiency. AIE likely is but one manifestation of a more diffuse autoimmune disorder of the gastrointestinal system with heterogeneous manifestations including gastritis, colitis, hepatitis, and pancreatitis, as well as a variety of autoantibodies, such as anti–parietal cell antibodies and anti–goblet cell antibodies (4, 8, 9). Le´on et al. recently coined the term generalized autoimmune gut disorder (GAGD) for those whose autoimmune gastrointestinal damage extends beyond the small intestine, Manuscript received August 30, 2004; accepted September 27, 2004. From the Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA. Address for reprint requests: Ray E. Clouse, MD, Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8124, St. Louis, Missouri 63110, USA; [email protected].

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requiring both AIE and autoimmune colitis as minimal criteria for the diagnosis (4). The recent case described by Le´on et al. also confirmed and clarified the immunopathogenesis of AIE (or GAGD) (4, 8). Antibodies to enterocytes are pathonomonic for AIE, but it was unclear if they were responsible for tissue damage or represented a secondary phenomenon (10). The recent findings indicate that T cell activation is the probable primary pathological event, evidenced by the presence of diffuse lymphoplasmacytic infiltrates accompanying villous atrophy, colonic mucosal goblet cell depletion, and apoptotic bodies (4). Intestinal intraepithelial lymphocytes in AIE are distinguished by atypical, highly active CD4+ CD3+ CD103− T lymphocytes that produce high levels of TNFα. These T cells express the T cell receptor (TCR) αβ, unlike the T cells in celiac disease, which express TCRγ δ (4, 8). T cell survival is in part regulated by the thymus. An association between thymoma and AIE is feasible considering the known association of thymomas with development of autoimmunity and antibody deficiency. Recently, Mais et al. reported two cases of possible AIE in association with thymoma. Only one of the cases displayed antienterocyte antibodies, but both had other features consistent with AIE (11). Several cases of unclassified chronic diarrhea in association with thymoma (the majority having hypogammaglobulinemia) also have been described; most had villous atrophy as well as colonic lesions resembling graft-versus-host disease (GVHD) (12–16). Unclassified cases thymoma-associated diarrhea may actually be AIE, making the prevalence of AIE in the setting of thymoma significantly higher than originally thought. Interestingly, the CD4+ CD3+ CD103− T lymphocytes found in AIE also are incriminated in intestinal GVHD (4). Thus, it is understandable that lesions in AIE (with or without thymoma) resemble GVHD. Digestive Diseases and Sciences, Vol. 50, No. 5 (May 2005)

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AUTOIMMUNE ENTEROPATHY TREATED WITH INFLIXIMAB

AIE, a chronic autoimmune condition now thought to result from inappropriate T cell activation and increased TNFα production, typically responds to corticosteroids but invariably requires sustained immunosuppression using regimens that are acceptable for long-term use. Successful approaches in adults with AIE have included azathioprine, cyclosporin, and tacrolimus (17, 18). Infliximab would be a logical choice for the treatment for AIE given its TNFα antagonistic effects, but the response to infliximab has not been reported in adults (19). This case report describes an adult patient with a history of thymoma who was diagnosed with AIE and successfully managed with infliximab. CASE REPORT An 82 year-old Caucasian female presented complaining of 4 months of severe diarrhea and a 20-1b weight loss. She had a history of malignant thymoma diagnosed 10 years earlier that had recurred following chemotherapy and radiation treatment. Her diarrhea was watery, foul smelling, and voluminous, exceeding 2 liters in a 24-hr period. The small intestine appeared normal during upper endoscopy, but duodenal mucosal biopsies revealed villous blunting with associated inflammation consisting of plasma cells and intraepithelial lymphocytes. Circulating antibodies against endomysium and tissue transglutaminase were not detectable, and the diarrhea did not improve with a gluten-free diet. Total parenteral nutrition (TPN) was required to prevent further weight loss and dehydration. Additional evaluation revealed a mild anemia (hemoglobin, 10 g/dL) with normal renal, liver, and thyroid function. Stool examination did not reveal any bacterial, viral, or parasitic pathogens. Serum levels of vasoactive intestinal polypeptide and serotonin were within normal limits; serum gastrin was elevated, at 1100 pg/ml, but the gastrin response following secretin injection suggested a hypochlorhydric state rather than gastrinoma. Serum immunoglobulin levels (IgA, IgM, and IgG) were nor-

mal, and antinuclear antibodies were not detected. CT scan of the chest revealed enlarging right pleural-based nodules consistent with the patient’s known metastatic thymoma. An abdominal CT and small bowel barium study were normal. Colonoscopy with visualization of the terminal ileum was normal, as were biopsies from colonic and ileal mucosa. Antienterocyte antibodies (IgG) were present at a titer of 1:34, and the diagnosis of AIE was made on clinical, histological, and serological grounds. The patient was treated with prednisone, 40 mg daily, with partial improvement in symptoms. 6-Mercaptopurine was added as a steroid-sparing agent for long-term maintenance but promptly discontinued because of an allergic reaction. Infliximab, 5 mg/kg, was then initiated and the patient’s diarrhea decreased dramatically. The patient was weaned from prednisone without symptomatic rebound. Infusions were repeated at 8-week intervals, diarrhea ceasing after the second, with sustained remission for 10 months at the time of this case report. Repeat endoscopic duodenal biopsies at that time showed improvement in both the severity of villous blunting and the extent of intraepithelial lymphocytosis (Figure 1).

DISCUSSION We describe an adult patient with a history of thymoma who was diagnosed with AIE, the third reported adult patient with AIE who also had this tumor (11). The comorbidity of these conditions is consistent with the proposed disease pathogenesis. It is hypothesized that AIE represents a disorder of immune regulation that results in a constellation autoimmune processes including but not limited to insulin-dependent diabetes mellitus, autoimmune hepatitis, thyroiditis, gastritis, colitis, and nephritis as well as immunodeficiency (4, 9, 11). Immunophenotyping of the intestinal mucosa shows that the predominant inflammatory cell is the CD4+ CD3+ CD103− T lymphocyte (4, 8). Because the thymus is important in

Fig 1. Duodenal biopsies from this patient with AIE. (a) At presentation, marked villous blunting was associated with a dense lymphoplamacytic infiltrate, few goblet cells, and many intraepithelial lymphocytes (arrows). (b) Biopsies were repeated after two cycles of infliximab. Although the specimens were poorly oriented, considerable restoration of villous architecture, an increase in goblet cell population, and a decrease in inflammation were evident. (H&E; original magnification, ×10.) Digestive Diseases and Sciences, Vol. 50, No. 5 (May 2005)

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ELWING AND CLOUSE TABLE 1. REPORTED ADULT PATIENTS WITH AIE HAVING ANTIENTEROCYTE ANTIBODIES Subject No.

Sex

Age

Associated condition(s)

Therapy

Outcome*

Ref. No.

1 2

F F

38 47

NS Corticosteroids

Dead Alive

7 7

3

M

58

Cyclosporin

Alive

18

4 5 6 7 8 9 10

F M F M M F F

50 54 39 52 67 39 82

None Thyroiditis, anti–parietal cell antibodies, antiactin antibodies Anti–parietal cell antibodies, antithyroglobulin antibodies, thyroid peroxidase antibodies, adrenal cortex antibodies Colitis None Colitis, hypogammaglobulinemia Thymoma, myasthenia gravis Colitis Colitis, ileitis, lymphoma Thymoma

Corticosteroids Tacrolimus IVIG Thymectomy Steroids Nesalamide Infliximab

Alive Alive Dead Dead Alive Alive Alive

9 17 6 11 8 8 Present case

Note. NS, not stated; IVIG, intravenous immunoglobulin. *At time of report.

immune surveillance, it is likely that development of a thymoma predisposes a subject to loss of self-tolerance resulting in development of populations of T cells directed at self-antigens. Adding credibility to this hypothesis is the fact that other autoimmune conditions such as myasthenia gravis are common in patients with thymomas (11). To date (including the present case) only 16 adults with AIE have been described in the literature (10 confirmed by antienterocyte antibodies) (Tables 1 and 2), and 3 of the 16 also had thymomas. Because of this increasingly recognized association, it would appear that AIE should enter the differential diagnosis in patients with thymoma who develop chronic diarrhea. In the present case, celiac disease was considered based on the intestinal histology and clinical presentation. However, after the poor response to elimination diet and failure

to detect sprue-related antibodies, alternative explanations were sought. Corazza et al. described a similar diagnostic dilemma in two patients with diarrhea and small bowel villous blunting who initially were given the diagnosis of refractory sprue. These subjects subsequently were reclassified as AIE after celiac disease serologies were negative and antienterocyte antibodies were detected (25). The differential diagnosis of diet-resistant villous atrophy in adult subjects should include complicated and refractory celiac disease as well as AIE. It is reasonable to suspect celiac disease before considering AIE, as the former is much more common (6). Of the 16 cases of adult-onset AIE described to date, only 10 can be given the diagnosis of AIE with a high degree of confidence on the basis of antienterocyte antibodies (Table 1). In the future, immunophenotyping of the intraepithelial lymphocyte populations

TABLE 2. REPORTED ADULT PATIENTS WITH PRESUMED AIE IN WHOM ANTIENTEROCYTE ANTIBODIES WERE ABSENT OR NOT INVESTIGATED Subject No.

Sex

Age

11

F

58

12 13 14

F F M

48 33 19

15

—

—

16

M

21

Associated condition(s) Thyroiditis, gastritis, neuritis, sicca syndrome, anti–parietal cell antibodies, antithyroglobulin antibodies, thyroid peroxidase antibodies Thymoma, myasthenia gravis Antinuclear antibodies Intestinal goblet cell antibodies, hyperthyroidism Gastritis, colitis, anti–intrinsic factor antibodies Antiplatelet antibodies, positive Coomb’s test

Therapy

Outcome*

Ref. No.

NS

Dead

20

NS Corticosteroids Total parenteral nutrition NS

Dead Alive NS

11 21 22

NS

23

NS

24

NS

Note. NS, not stated. Subject no. 15 was described as an adult; sex and age not provided. *At time of report.

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may be employed to discriminate AIE from sprue, as T cells express TCR αβ in AIE but TCRγ δ in celiac disease (4, 18). Our patient was treated with prednisone, but attempts to introduce chronic immunomodulation with 6mercaptopurine (azathioprine being the prodrug) were unsuccessful. Fortunately, infliximab infusions rapidly and completely controlled her symptoms. Infliximab use previously had been reported in an infant with AIE and produced a partial response (19). The present case is the first report of infliximab use in adult-onset AIE and the first report of a complete symptomatic response in any age group. Infliximab, a potent immunosuppressant, has been employed for managing Crohn’s disease as well as other immune-related gastroenterological conditions, such as refractory sprue (26, 27). Infliximab acts as a soluble antiTNFα antibody disrupting the cytokine cascade. Recently infliximab was shown to rapidly increase the number of apoptotic T cells in inflamed mucosa of Crohn’s disease, without affecting peripheral blood mononuclear cells (28). In AIE, infliximab likely targets both the increased mucosal T lymphocytes and the TNFα production (4). Cyclosporine and tracrolimus, calcineurin antagonists which result in inhibition of T cell differentiation and proliferation, also have been used for chronic management of AIE. Similarly to infliximab, these drugs have increased risk for infection, neurotoxicity, and lymphoproliferative disease, but with infliximab the risk for hepatotoxicity, renal toxicity, and hypertension is much less. Azathioprine and 6-mercaptopurine, antimetabolites with potent antiproliferative properties, have been used less frequently in AIE. These immunomodulators have additional risks of bone marrow suppression, hepatotoxicity, and pancreatitis (29, 30). The present case offers new evidence that infliximab may provide safe, effective, and reliable immunosuppression for the long-term treatment of AIE, especially when side effects of other immunosuppressants may limit their use.

6. 7.

8. 9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

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