American Journal of Therapeutics 23, e963–e968 (2016)
Diffuse Autoimmune Enteropathy and Colopathy in an Adult Patient Successfully Treated With Adalimumab and a Review of the Literature Syed Shafae Hasan, DO,1* Nauman Saleem Siddiqui, MD,1 Sri Krishna Chaitanya Arudra, MD,2 Luis de Las Casas, MD,2 Basil Akpunonu, MD,1 and Ali Nawras, MD3
Autoimmune enteropathy (AIE) is a rare disease that causes intractable diarrhea not responsive to a gluten free diet and must be distinguished from refractory sprue. It is associated with circulating autoantibodies against goblet cells and enterocytes. AIE mainly involves the small intestines, with very few cases reported in adults. Because of the paucity of cases, the epidemiology of the disease remains unclear, and treatment is based on the cases found in the literature. Of the 35 adult cases reported, only 4 involved the colon. Because of the low number of cases, there have been no clear recommendations on treatment modalities with most reports heavily emphasizing steroids as the mainstay of treatment. We present the case of adult female patient who developed postpartum AIE and colopathy with profuse diarrhea successfully treated with adalimumab and a review of the literature. To the best of our knowledge, this case is only the fourth case of a tumor necrosis factor alpha antagonist being used in the treatment of AIE and the first case of adalimumab being used. Keywords: adult onset, autoimmune enteropathy, colopathy, adalimumab
INTRODUCTION Autoimmune enteropathy (AIE) is a rare disease that was first described in 1982 by Unsworth and WalkerSmith in a child, with the first published adult cases in 1997 by Corazza.1,2 It is manifested by intractable diarrhea not responsive to a gluten-free diet and is associated with circulating autoantibodies against goblet cells and enterocytes. AIE mainly involves the small intestine and is most commonly found in children. Because of the paucity of cases, the epidemiology of the disease Departments of 1Medicine and 2Pathology, University of Toledo Medical Center, Toledo, OH; and 3Department of Medicine, Division of Gastroenterology, University of Toledo Medical Center, Toledo, OH. The authors have no conflicts of interest to declare. *Address for correspondence: University of Toledo Medical Center, 3000 Arlington Avenue, MS# 1150, Toledo, OH 43614. E-mail: [email protected]
remains unclear.1 We present the case of adult female patient who developed postpartum AIE with profuse diarrhea successfully treated with adalimumab.
CASE REPORT The patient is a 28-year-old woman who presented 3 days after delivery due to diarrhea and cramping abdominal pain. She was having 20–40 episodes of voluminous green liquid stool per day, with no blood or tenesmus. Stool cultures for Giardia, Cryptosporidium, Campylobacter, Salmonella, Yersinia, adenovirus, Enterovirus, HIV, ova, and parasites were all negative. Shiga toxin was negative as was polymerase chain reaction for Clostridium difficile. Colonoscopy showed mildly edematous mucosa in the terminal ileum. Preliminary pathologic interpretation revealed chronic active colitis. The patient underwent workup for secretory diarrhea, neuroendocrine neoplasm, and testing for celiac disease all of which
1075–2765 Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e964
were negative. While waiting for results of these tests, the patient was started on octreotide therapy without relief. While she had no history of autoimmune diseases, an autoimmune panel was ordered, including anti–extractable nuclear antigens (anti-ENA), antiDNA, antinuclear antibodies, rheumatoid factor, endomysial antibodies, CCP, Gliadin antibodies, and Sjogren antibodies, all of which were negative. Because of persistent symptoms, she underwent repeat colonoscopy and esophagogastroduodenoscopy, which were unremarkable except for mildly edematous mucosa in the duodenum and ileum. Biopsy specimens taken from the small bowels revealed severe chronic active enteritis, far more than would be expected from an infection, and were suggestive of AIE. Biopsies from the colon showed severe chronic active colitis, patchy architectural distortions, cryptitis, crypt abscesses, increased number of intraepithelial lymphocytes, and abundant apoptosis, and chronic inflammatory cells in the lamina propria. No granulomas, viral changes, microorganisms, or dysplasia was present. The changes were compatible with AIE (Figures 1–4). Anti–enterocyte antibody testing by immunofluorescence revealed positive staining of IgG along the surface of the enterocytes, supportive of AIE (Figure 5). The patient was started on methylprednisolone 60 mg IV daily. She went from having 20–40 liquid bowel movements per day to 7–10 bowel movements per day with pasty consistency and was progressively improving. She returned 12 days later in a follow-up visit to the clinic while on a slow taper of prednisone 50 mg, with only partial resolution of her symptoms. After reviewing the literature on various treatment options,
FIGURE 1. Duodenum: expansion of the lamina propria by a lymphoplasmacytic infiltrate (hematoxylin and eosin stain; 340 original magnification). American Journal of Therapeutics (2016) 23(3)
Hasan et al
FIGURE 2. Jejunum: cryptitis (shown by arrow) and expansion of the lamina propria (hematoxylin and eosin stain; 3200 original magnification).
the decision was made to start her on a tumor necrosis factor (TNF)-alpha antagonist. The patient was started on adalimumab 40 mg while continuing her steroid taper and achieved good response and control of her diarrhea within 1 month.
DISCUSSION AIE is a rare disease that is most frequently seen in children. It is associated with chronic diarrhea and malabsorption. There are very few cases reported in adults, leading to a lack of epidemiological data,
FIGURE 3. Ileum: intense lymphoplasmacytic and neutrophilic infiltrate (hematoxylin and eosin stain; 340 original magnification). www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Diffuse Autoimmune Enteropathy and Colopathy
FIGURE 4. Colon: cryptitis and crypt abscess (shown by arrow) (hematoxylin and eosin stain; 3400 original magnification).
disease course, and guidelines for treatment options. The lack of data regarding this disease and subsequently awareness of this disease by clinicians and pathologist causes a scarcity of histologic expertise makes the diagnosis difficult to make. Because of the rarity of the disease, it is important that the pathology is viewed by a gastrointestinal pathologist with experience dealing with AIE. Clinically, the diagnosis of AIE can be very difficult and has many convoluting factors such as the possibility of infection, toxins, or other autoimmune processes such as celiac disease or inflammatory bowel disease. To add to the diagnostic dilemma was the fact that our patient developed adult-onset AIE involvement of
FIGURE 5. Antienterocyte IgG demonstrating linear deposition on the surface of enterocytes (immunofluorescence 3400 original magnification). www.americantherapeutics.com
e965
the colon. AIE most often is restricted to the small bowel, but there have been a small number of case reports showing extra-small intestinal manifestations, and these are mostly seen in children. To the best of our knowledge, there have been only 4 cases reported of adult-onset AIE with associated colitis.3,4 The diagnosis of AIE should be suspected in patients who meet the following 4 criteria: (1) chronic diarrhea of greater than 6 weeks duration that is refractory to treatment with diet modification or motility agents, (2) malabsorption, (3) histology, including villous atrophy, apoptotic bodies, and crypt lymphocytic proliferation, and (4) exclusion of other disorders with similar presentation (such as celiac disease).5 The presence of anti–enterocyte and anti–goblet cell antibodies is not needed for the diagnosis though is strongly supportive. As a result, it is important suspect to AIE to make the diagnosis. As with other autoimmune disorders, AIE is seen to be associated with autoimmune diseases, specifically those involving the thyroid, systemic lupus erythematosus, Sjogren, and myasthenia gravis.4 Diarrhea associated with AIE can be extremely voluminous and frequent. Our patient experienced as much as 15 gallons of stool loss and up to 50 episodes of diarrhea in a single day. The prognosis of these patients is often related to the volume of diarrhea and supportive care they receive, therefore, limiting the length of the flare is vital and making the correct diagnosis is critical. Histology is among the mandatory criteria for diagnosis. Key histologic features in AIE include partial to complete villous blunting on small bowel biopsy specimens, crypt abscesses, cryptitis, apoptotic bodies, and lymphocytosis in gland crypt epithelium with decreased lymphocytes in the surface epithelium.5 In patients who meet the 4 criteria for diagnosis, the diagnosis can be further supported by sending for antibodies against enterocytes and goblet cells. Very few laboratories are able to test for anti-enterocyte (AEA) and anti–goblet cell antibodies (AGCA). These anti–epithelial cell antibodies are not specific for AIE, and diagnosis should not solely be based on their presence, rather they may be used to support the diagnosis. AEA may be found in diseases such as ulcerative colitis, Crohn disease, and HIV enteropathy. AGCA are also found in other bowel diseases such as celiac sprue. According to Bishu et al,6 anti–epithelial cell antibodies (AEA and AGCA) may be seen in up to 85% of patients with AIE. Two separate studies (involving both adults and children) evaluated the prevalence of autoimmune antibodies in AIE, showing 22/26 (85%) and 13/15 (87%) of patients with AIE.1,7 Our review showed that of the 35 adult cases reported in the literature (Table 1), at least 28/35 (80%) were American Journal of Therapeutics (2016) 23(3)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Pt No
Age at Dx/ (reference) 1
Gender
Gut epithelial antibodies
Other autoantibodies
37 751 461 421 381 761 551 401 541 671 451 591
M M F F F F M M M M F M
AE IgG+ AE and AG IgG+ AG IgG+ AG IgG+ AG IgG+ AE IgG+ Negative AE IgM+ AG IgG+ AE IgA+ AE and AG IgG+ AE IgG
ANA AchR, anti-GAD65, striated muscle Ab
13 14 15 16 17
751 611 591 619 5310
M F F F F
Not checked AE IgG+ AE IgG+ AE IgG+ AE IgM+
ASCA pANCA, ANA ANA
18
286
F
19
6311
F
Only AE IgA checked (neg) Not checked
20 21 22 23 24 25 26 27 28 29
6512 3513 198 8214 381 471 591 521 481 581
M F M F F F M M F F
AE IgG+ AE IgG+ AE IgG+ AE IgG+ AE IgG/IgA+ AE IgG/IgA+ Not checked AE IgG+ AE IgG/IgA2 AE IgG/IgA2
Parietal cell Ab ANA ANA
Anti-SSA, antiphospholipid ANA
Antigliadin, antiendomysial, anti-hTTG, anti-AIE-75 pANCA Antiendomysial, antigliadin, HLADQZ, HLADR3, HLADR4 Not checked AGA IgG+ Antimitochondrial
Antimicrosomal, antiparietal cell Anti-IF
ANA, antimicrosomal, antithyroglobulin, antigliadin IgG
Duration of symptoms (mo) 13 8 15 204 180 5 4 32 120 36 10 18
Tx and response
13 12 360 24 360
+w/infliximab +w/high-dose pred, AZA +w/high-dose pred +w/pred +w/pred, budes, AZA Unresponsive +w/pred Partial w/pred, AZA Partial w/pred, 6-MP +w/pred +w/high-dose pred, budes +w/high-dose pred, AZA, and IFX No immune suppression Partial w/budes Unresponsive +w/MSC infusion Unresponsive
36
+w/high-dose pred
7 mo 1.5 27 5 4 23 25 3 4 24 Not reported
High-dose methylpresnisolone +w/pred and budes +w/pred and MTX +w/inflix and tacro + w/pred, 6-MP +w/high-dose pred +w/high-dose pred +w/high dose pred +w/high-dose steroid Unresponsive to IVIG and TPN Unresponsive to pred and cyclophosph (Continued on next page)
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Hasan et al
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1 2 3 4 5 6 7 8 9 10 11 12
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American Journal of Therapeutics (2016) 23(3)
Table 1. Cases of adult onset autoimmune enteropathy identified in the literature review
www.americantherapeutics.com
anti-ENA, anti-DNA, ANA RF, antiendomysial, anti-CCP, antigliadin
Dx, diagnosis; Pt, patient; Tx, treatment; MSC, mesenchymal stromal cells; pred, prednisone; budes, budesonide; AZA, azathioprine; IFX, infliximab; MTX, methotrexate; Tacro, tacrolimus.
+w/pred +w/pred, MTX, abatacept +w/adalimumab and pred 48 Not reported 1 Not checked AE+ AE IgG+ M F F 211 4915 28 34 35 36 (our case)
F F M 31 32 33
501 391 581
AE IgG+ AE IgG+ AE IgG+
Antigliadin Antimicrosomal, antithyroglobulin Antiparietal cell, antithyroglobulin, antithyroid peroxidase ANA, RF
120 15
+to high-dose pred cyclospor, tacrolimus +w/pred and budes +w/high-dose pred and IVIG +w/cyclosporine 3 mo ANA, pANCA M 30
541
AE IgG+
Duration of symptoms (mo) Other autoantibodies Gut epithelial antibodies Gender Age at Dx/ (reference) Pt No
Table 1. (Continued) Cases of adult onset autoimmune enteropathy identified in the literature review
Tx and response
Diffuse Autoimmune Enteropathy and Colopathy
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positive for some type of anti–epithelial cell antibody whether it was AEA or AGCA. Of these 28 patients, 22 were AEA positive, 4 were AGCA positive, and 2 were positive for both AEA and AGCA. It is important to note that 3 of the patients in the literature were not screened for either of these antibodies. There were 4 patients who had negative anti–epithelial cell antibodies reported in the literature, although 2 of these patients were only screened for AEA, and AGCA was not mentioned as having been checked. As a result, the presence of AEA and AGCA is not diagnostic, nor can they be used as markers of the severity of disease. Additionally, other autoantibodies may also be found in patients who have AIE, including ANA, pANCA, and antimicrosomal antibodies. As with other autoantibodies, when used in conjunction with the diagnostic criteria above, AEA and AGCA can be useful in supporting the diagnosis of AIE. Because of the paucity of cases, there have been no formal guidelines developed to treat AIE. Steroid therapy has been the mainstay of management. Of the 35 cases of adult onset AIE found in our review of the literature (Table 1), 23 had partial to good response to a therapy regimen that involved steroids, most often prednisone and/or budesonide. Steroids can be used as monotherapy or in conjunction with nonbiologic disease modifying antirheumatic drugs such as azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate; or biologic disease modifying antirheumatic drugs such as anti–TNF-alpha agents. At least 3 case reports in adults have shown a role for anti–TNF-alpha agents in the management of the disease. All 3 reports used infliximab, 1 in conjunction with tacrolimus,8 1 with steroids and azathioprine,1 and 1 as monotherapy.1 These cases reported improvement in patient symptoms. In our case, the patient was offered infliximab and adalimumab, which she preferred due to ease of administration. To the best of our knowledge, this is the first case involving the use adalimumab and only the fourth case of a TNF-alpha inhibitor being used to achieve remission in a patient with incomplete control of AIE with steroids.1 Although further study in this field would be required, there is now anecdotal evidence to suggest a strong role for TNF-alpha inhibitors in patients with AIE, especially refractory AIE and those who require steroid sparing treatment programs.
REFERENCES 1. Akram S, Murray JA, Pardi DS, et al. Adult autoimmune enteropathy: Mayo Clinic Rochester experience. Clin Gastroenterol Hepatol. 2007;5:1282–1290; quiz 1245. American Journal of Therapeutics (2016) 23(3)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e968 2. Corazza GR, Biagi F, Volta U, et al. Autoimmune enteropathy and villous atrophy in adults. Lancet. 1997;350: 106–109. 3. Carroccio A, Volta U, Di Prima L, et al. Autoimmune enteropathy and colitis in an adult patient. Dig Dis Sci. 2003;48:1600–1606. 4. Mitomi H, Tanabe S, Igarashi M, et al. Autoimmune enteropathy with severe atrophic gastritis and colitis in an adult: proposal of a generalized autoimmune disorder of the alimentary tract. Scand J Gastroenterol. 1998;33:716–720. 5. Murray JA, Rubio-Tapia A Diarrhoea due to small bowel diseases. Best Pract Res Clin Gastroenterol. 2012;26:581–600. 6. Bishu S, Arsenescu V, Lee EY, et al. Autoimmune enteropathy with a CD8+ CD7- T-cell small bowel intraepithelial lymphocytosis: case report and literature review. BMC Gastroenterol. 2011;11:131. 7. Gentile NM, Murray JA, Pardi DS. Autoimmune enteropathy: a review and update of clinical management. Curr Gastroenterol Rep. 2012;14:380–385. 8. von Hahn T, Stopik D, Koch M, et al. Management of severe refractory adult autoimmune enteropathy with infliximab and tacrolimus. Digestion. 2005;71:141–144. 9. Ciccocioppo R, Russo ML, Bernardo ME, et al. Mesenchymal stromal cell infusions as rescue therapy for
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corticosteroid-refractory adult autoimmune enteropathy. Mayo Clin Proc. 2012;87:909–914. Malamut G, Verkarre V, Callens C, et al. Enteropathyassociated T-cell lymphoma complicating an autoimmune enteropathy. Gastroenterology. 2012;142:726–729. e723; quiz e713–e724. Pinero Perez C, Velasco Guardado A, Fernandez Pordomingo A, et al. Autoimmune enteropathy in an adult patient [in Spanish]. Gastroenterol Hepatol. 2010;33: 704–708. Gonzalez G, Castro FP, Berho M, et al. Autoimmune enteropathy associated with cessation of interferonalpha therapy in chronic hepatitis C. Dig Dis Sci. 2010; 55:1490–1493. Volta U, De Angelis GL, Granito A, et al. Autoimmune enteropathy and rheumatoid arthritis: a new association in the field of autoimmunity. Dig Liver Dis. 2006;38: 926–929. Elwing JE, Clouse RE. Adult-onset autoimmune enteropathy in the setting of thymoma successfully treated with infliximab. Dig Dis Sci. 2005;50:928–932. Gupta NK, Yilmaz O, Fisher M, et al. Abatacept: a new treatment option for refractory adult autoimmune enteropathy. J Clin Gastroenterol. 2014;48:55–58.
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Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Diffuse Autoimmune Enteropathy and Colopathy in an Adult Patient Successfully Treated With Adalimumab and a Review of the Literature Syed Shafae Hasan, DO,1* Nauman Saleem Siddiqui, MD,1 Sri Krishna Chaitanya Arudra, MD,2 Luis de Las Casas, MD,2 Basil Akpunonu, MD,1 and Ali Nawras, MD3
Autoimmune enteropathy (AIE) is a rare disease that causes intractable diarrhea not responsive to a gluten free diet and must be distinguished from refractory sprue. It is associated with circulating autoantibodies against goblet cells and enterocytes. AIE mainly involves the small intestines, with very few cases reported in adults. Because of the paucity of cases, the epidemiology of the disease remains unclear, and treatment is based on the cases found in the literature. Of the 35 adult cases reported, only 4 involved the colon. Because of the low number of cases, there have been no clear recommendations on treatment modalities with most reports heavily emphasizing steroids as the mainstay of treatment. We present the case of adult female patient who developed postpartum AIE and colopathy with profuse diarrhea successfully treated with adalimumab and a review of the literature. To the best of our knowledge, this case is only the fourth case of a tumor necrosis factor alpha antagonist being used in the treatment of AIE and the first case of adalimumab being used. Keywords: adult onset, autoimmune enteropathy, colopathy, adalimumab
INTRODUCTION Autoimmune enteropathy (AIE) is a rare disease that was first described in 1982 by Unsworth and WalkerSmith in a child, with the first published adult cases in 1997 by Corazza.1,2 It is manifested by intractable diarrhea not responsive to a gluten-free diet and is associated with circulating autoantibodies against goblet cells and enterocytes. AIE mainly involves the small intestine and is most commonly found in children. Because of the paucity of cases, the epidemiology of the disease Departments of 1Medicine and 2Pathology, University of Toledo Medical Center, Toledo, OH; and 3Department of Medicine, Division of Gastroenterology, University of Toledo Medical Center, Toledo, OH. The authors have no conflicts of interest to declare. *Address for correspondence: University of Toledo Medical Center, 3000 Arlington Avenue, MS# 1150, Toledo, OH 43614. E-mail: [email protected]
remains unclear.1 We present the case of adult female patient who developed postpartum AIE with profuse diarrhea successfully treated with adalimumab.
CASE REPORT The patient is a 28-year-old woman who presented 3 days after delivery due to diarrhea and cramping abdominal pain. She was having 20–40 episodes of voluminous green liquid stool per day, with no blood or tenesmus. Stool cultures for Giardia, Cryptosporidium, Campylobacter, Salmonella, Yersinia, adenovirus, Enterovirus, HIV, ova, and parasites were all negative. Shiga toxin was negative as was polymerase chain reaction for Clostridium difficile. Colonoscopy showed mildly edematous mucosa in the terminal ileum. Preliminary pathologic interpretation revealed chronic active colitis. The patient underwent workup for secretory diarrhea, neuroendocrine neoplasm, and testing for celiac disease all of which
1075–2765 Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e964
were negative. While waiting for results of these tests, the patient was started on octreotide therapy without relief. While she had no history of autoimmune diseases, an autoimmune panel was ordered, including anti–extractable nuclear antigens (anti-ENA), antiDNA, antinuclear antibodies, rheumatoid factor, endomysial antibodies, CCP, Gliadin antibodies, and Sjogren antibodies, all of which were negative. Because of persistent symptoms, she underwent repeat colonoscopy and esophagogastroduodenoscopy, which were unremarkable except for mildly edematous mucosa in the duodenum and ileum. Biopsy specimens taken from the small bowels revealed severe chronic active enteritis, far more than would be expected from an infection, and were suggestive of AIE. Biopsies from the colon showed severe chronic active colitis, patchy architectural distortions, cryptitis, crypt abscesses, increased number of intraepithelial lymphocytes, and abundant apoptosis, and chronic inflammatory cells in the lamina propria. No granulomas, viral changes, microorganisms, or dysplasia was present. The changes were compatible with AIE (Figures 1–4). Anti–enterocyte antibody testing by immunofluorescence revealed positive staining of IgG along the surface of the enterocytes, supportive of AIE (Figure 5). The patient was started on methylprednisolone 60 mg IV daily. She went from having 20–40 liquid bowel movements per day to 7–10 bowel movements per day with pasty consistency and was progressively improving. She returned 12 days later in a follow-up visit to the clinic while on a slow taper of prednisone 50 mg, with only partial resolution of her symptoms. After reviewing the literature on various treatment options,
FIGURE 1. Duodenum: expansion of the lamina propria by a lymphoplasmacytic infiltrate (hematoxylin and eosin stain; 340 original magnification). American Journal of Therapeutics (2016) 23(3)
Hasan et al
FIGURE 2. Jejunum: cryptitis (shown by arrow) and expansion of the lamina propria (hematoxylin and eosin stain; 3200 original magnification).
the decision was made to start her on a tumor necrosis factor (TNF)-alpha antagonist. The patient was started on adalimumab 40 mg while continuing her steroid taper and achieved good response and control of her diarrhea within 1 month.
DISCUSSION AIE is a rare disease that is most frequently seen in children. It is associated with chronic diarrhea and malabsorption. There are very few cases reported in adults, leading to a lack of epidemiological data,
FIGURE 3. Ileum: intense lymphoplasmacytic and neutrophilic infiltrate (hematoxylin and eosin stain; 340 original magnification). www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Diffuse Autoimmune Enteropathy and Colopathy
FIGURE 4. Colon: cryptitis and crypt abscess (shown by arrow) (hematoxylin and eosin stain; 3400 original magnification).
disease course, and guidelines for treatment options. The lack of data regarding this disease and subsequently awareness of this disease by clinicians and pathologist causes a scarcity of histologic expertise makes the diagnosis difficult to make. Because of the rarity of the disease, it is important that the pathology is viewed by a gastrointestinal pathologist with experience dealing with AIE. Clinically, the diagnosis of AIE can be very difficult and has many convoluting factors such as the possibility of infection, toxins, or other autoimmune processes such as celiac disease or inflammatory bowel disease. To add to the diagnostic dilemma was the fact that our patient developed adult-onset AIE involvement of
FIGURE 5. Antienterocyte IgG demonstrating linear deposition on the surface of enterocytes (immunofluorescence 3400 original magnification). www.americantherapeutics.com
e965
the colon. AIE most often is restricted to the small bowel, but there have been a small number of case reports showing extra-small intestinal manifestations, and these are mostly seen in children. To the best of our knowledge, there have been only 4 cases reported of adult-onset AIE with associated colitis.3,4 The diagnosis of AIE should be suspected in patients who meet the following 4 criteria: (1) chronic diarrhea of greater than 6 weeks duration that is refractory to treatment with diet modification or motility agents, (2) malabsorption, (3) histology, including villous atrophy, apoptotic bodies, and crypt lymphocytic proliferation, and (4) exclusion of other disorders with similar presentation (such as celiac disease).5 The presence of anti–enterocyte and anti–goblet cell antibodies is not needed for the diagnosis though is strongly supportive. As a result, it is important suspect to AIE to make the diagnosis. As with other autoimmune disorders, AIE is seen to be associated with autoimmune diseases, specifically those involving the thyroid, systemic lupus erythematosus, Sjogren, and myasthenia gravis.4 Diarrhea associated with AIE can be extremely voluminous and frequent. Our patient experienced as much as 15 gallons of stool loss and up to 50 episodes of diarrhea in a single day. The prognosis of these patients is often related to the volume of diarrhea and supportive care they receive, therefore, limiting the length of the flare is vital and making the correct diagnosis is critical. Histology is among the mandatory criteria for diagnosis. Key histologic features in AIE include partial to complete villous blunting on small bowel biopsy specimens, crypt abscesses, cryptitis, apoptotic bodies, and lymphocytosis in gland crypt epithelium with decreased lymphocytes in the surface epithelium.5 In patients who meet the 4 criteria for diagnosis, the diagnosis can be further supported by sending for antibodies against enterocytes and goblet cells. Very few laboratories are able to test for anti-enterocyte (AEA) and anti–goblet cell antibodies (AGCA). These anti–epithelial cell antibodies are not specific for AIE, and diagnosis should not solely be based on their presence, rather they may be used to support the diagnosis. AEA may be found in diseases such as ulcerative colitis, Crohn disease, and HIV enteropathy. AGCA are also found in other bowel diseases such as celiac sprue. According to Bishu et al,6 anti–epithelial cell antibodies (AEA and AGCA) may be seen in up to 85% of patients with AIE. Two separate studies (involving both adults and children) evaluated the prevalence of autoimmune antibodies in AIE, showing 22/26 (85%) and 13/15 (87%) of patients with AIE.1,7 Our review showed that of the 35 adult cases reported in the literature (Table 1), at least 28/35 (80%) were American Journal of Therapeutics (2016) 23(3)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Pt No
Age at Dx/ (reference) 1
Gender
Gut epithelial antibodies
Other autoantibodies
37 751 461 421 381 761 551 401 541 671 451 591
M M F F F F M M M M F M
AE IgG+ AE and AG IgG+ AG IgG+ AG IgG+ AG IgG+ AE IgG+ Negative AE IgM+ AG IgG+ AE IgA+ AE and AG IgG+ AE IgG
ANA AchR, anti-GAD65, striated muscle Ab
13 14 15 16 17
751 611 591 619 5310
M F F F F
Not checked AE IgG+ AE IgG+ AE IgG+ AE IgM+
ASCA pANCA, ANA ANA
18
286
F
19
6311
F
Only AE IgA checked (neg) Not checked
20 21 22 23 24 25 26 27 28 29
6512 3513 198 8214 381 471 591 521 481 581
M F M F F F M M F F
AE IgG+ AE IgG+ AE IgG+ AE IgG+ AE IgG/IgA+ AE IgG/IgA+ Not checked AE IgG+ AE IgG/IgA2 AE IgG/IgA2
Parietal cell Ab ANA ANA
Anti-SSA, antiphospholipid ANA
Antigliadin, antiendomysial, anti-hTTG, anti-AIE-75 pANCA Antiendomysial, antigliadin, HLADQZ, HLADR3, HLADR4 Not checked AGA IgG+ Antimitochondrial
Antimicrosomal, antiparietal cell Anti-IF
ANA, antimicrosomal, antithyroglobulin, antigliadin IgG
Duration of symptoms (mo) 13 8 15 204 180 5 4 32 120 36 10 18
Tx and response
13 12 360 24 360
+w/infliximab +w/high-dose pred, AZA +w/high-dose pred +w/pred +w/pred, budes, AZA Unresponsive +w/pred Partial w/pred, AZA Partial w/pred, 6-MP +w/pred +w/high-dose pred, budes +w/high-dose pred, AZA, and IFX No immune suppression Partial w/budes Unresponsive +w/MSC infusion Unresponsive
36
+w/high-dose pred
7 mo 1.5 27 5 4 23 25 3 4 24 Not reported
High-dose methylpresnisolone +w/pred and budes +w/pred and MTX +w/inflix and tacro + w/pred, 6-MP +w/high-dose pred +w/high-dose pred +w/high dose pred +w/high-dose steroid Unresponsive to IVIG and TPN Unresponsive to pred and cyclophosph (Continued on next page)
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1 2 3 4 5 6 7 8 9 10 11 12
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American Journal of Therapeutics (2016) 23(3)
Table 1. Cases of adult onset autoimmune enteropathy identified in the literature review
www.americantherapeutics.com
anti-ENA, anti-DNA, ANA RF, antiendomysial, anti-CCP, antigliadin
Dx, diagnosis; Pt, patient; Tx, treatment; MSC, mesenchymal stromal cells; pred, prednisone; budes, budesonide; AZA, azathioprine; IFX, infliximab; MTX, methotrexate; Tacro, tacrolimus.
+w/pred +w/pred, MTX, abatacept +w/adalimumab and pred 48 Not reported 1 Not checked AE+ AE IgG+ M F F 211 4915 28 34 35 36 (our case)
F F M 31 32 33
501 391 581
AE IgG+ AE IgG+ AE IgG+
Antigliadin Antimicrosomal, antithyroglobulin Antiparietal cell, antithyroglobulin, antithyroid peroxidase ANA, RF
120 15
+to high-dose pred cyclospor, tacrolimus +w/pred and budes +w/high-dose pred and IVIG +w/cyclosporine 3 mo ANA, pANCA M 30
541
AE IgG+
Duration of symptoms (mo) Other autoantibodies Gut epithelial antibodies Gender Age at Dx/ (reference) Pt No
Table 1. (Continued) Cases of adult onset autoimmune enteropathy identified in the literature review
Tx and response
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positive for some type of anti–epithelial cell antibody whether it was AEA or AGCA. Of these 28 patients, 22 were AEA positive, 4 were AGCA positive, and 2 were positive for both AEA and AGCA. It is important to note that 3 of the patients in the literature were not screened for either of these antibodies. There were 4 patients who had negative anti–epithelial cell antibodies reported in the literature, although 2 of these patients were only screened for AEA, and AGCA was not mentioned as having been checked. As a result, the presence of AEA and AGCA is not diagnostic, nor can they be used as markers of the severity of disease. Additionally, other autoantibodies may also be found in patients who have AIE, including ANA, pANCA, and antimicrosomal antibodies. As with other autoantibodies, when used in conjunction with the diagnostic criteria above, AEA and AGCA can be useful in supporting the diagnosis of AIE. Because of the paucity of cases, there have been no formal guidelines developed to treat AIE. Steroid therapy has been the mainstay of management. Of the 35 cases of adult onset AIE found in our review of the literature (Table 1), 23 had partial to good response to a therapy regimen that involved steroids, most often prednisone and/or budesonide. Steroids can be used as monotherapy or in conjunction with nonbiologic disease modifying antirheumatic drugs such as azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate; or biologic disease modifying antirheumatic drugs such as anti–TNF-alpha agents. At least 3 case reports in adults have shown a role for anti–TNF-alpha agents in the management of the disease. All 3 reports used infliximab, 1 in conjunction with tacrolimus,8 1 with steroids and azathioprine,1 and 1 as monotherapy.1 These cases reported improvement in patient symptoms. In our case, the patient was offered infliximab and adalimumab, which she preferred due to ease of administration. To the best of our knowledge, this is the first case involving the use adalimumab and only the fourth case of a TNF-alpha inhibitor being used to achieve remission in a patient with incomplete control of AIE with steroids.1 Although further study in this field would be required, there is now anecdotal evidence to suggest a strong role for TNF-alpha inhibitors in patients with AIE, especially refractory AIE and those who require steroid sparing treatment programs.
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