Induction of Remission in a Child With Autoimmune Enteropathy Using Mycophenolate Mofetil

INTRODUCTION Intractable diarrhea of infancy is a term used to define different disease processes that share similar symptoms and histologic findings of mucosal injury. Autoimmune enteropathy is an extremely rare cause of intractable diarrhea. In most cases, it is associated with high mortality and morbidity (1–7). In this disorder, the inflammatory process usually is severe, involves the small intestinal and colonic mucosa, and is associated with circulating anti-enterocyte antibodies, malabsorption, and diarrhea (1–4,8). Autoimmune enteropathy is usually treated with elemental formula and/or parenteral nutritional support along with immunosuppressive therapy. Its response to immunosuppressive therapy such as steroids, cyclosporine, azathioprine, cyclophosphamide, methotrexate, and tacrolimus has been variable (1–14). We report a case of autoimmune enteropathy diagnosed at 4 months of age in a patient who presented with intractable diarrhea and required parenteral nutritional support. Remission of the autoimmune process was achieved with the addition of Mycophenolate Mofetil (MMF) to her immunosuppressive therapy. This therapy allowed discontinuing parenteral nutrition and tapering of corticosteroid to a low level. CASE REPORT The patient presented for the first time as a 4-month-old female who was well until four weeks before admission when she developed persistent yellow-green, watery stools without blood or mucous. She did not have fever, vomiting, or upper respiratory tract symptoms. Her family history was negative for allergies, autoimmune disorders, or celiac disease. She was born at full term without perinatal complications. Her birth weight was 3.2 kg. She was on a cow milk protein-based formula before her diarrhea started. When diarrhea began, she was changed to a soy protein-based formula without improvement of stool frequency or diarrhea (Fig. 1). Attempts at use of multiple elemental formulas failed. Her weight was 4.5 kg (Zweight = −1.88) and height was 55.9 cms (Zheight = –2.00) on admission (Fig. 2). She was started on total parenteral nutrition (PN) support at that time.FIG. 1.: Bowel movement pattern and percentage of parenteral nutritional support during the clinical course. Bowel movements (BM), Parenteral Nutrition (PN), Steroids (S), Cyclosporine (CyA) and Mycophenolate Mofetil (MMF). At 7 months, prednisone (S) was started at 2 mg/kg/d. At 9 months, CyA was started keeping levels between 150 and 250 mg/ml and S dose was 1.5 mg/kg/d. At 15 months, while her CyA levels and S dose were kept the same, MMF was started at 30 mg/kg/d. At 24 months, S dose was 0.2 mg/kg/d, while her CyA levels and MMF dose were kept the same. By 36 months, her S dose was 0.1 mg/kg/d, her CyA levels were between 150 and 175 mg/ml, and her MMF dose was 25 mg/kg/d. Her stools became formed at 17 months. She was toilet trained by 29 months of age. At 36 months, 50% of her enteral intake is through gastrostomy tube feedings.FIG. 2.: Trend of her weight and height during the clinical course. Steroids (S), Cyclosporine (CyA), Mycophenolate Mofetil (MMF), Zscore weight (Zwt), and Zscore height (Zht). Prednisone (S) was started at 7 months, CyA was added at 9 months, and MMF was added at 15 months of age.Her initial laboratory evaluation showed metabolic acidosis (HCO3 17 meq/L normal: 22–34) and hypoalbuminemia (3.0 g/dl normal: 3.7–4.8). The rest of her chemistry panel and liver function tests were within normal limits. Her stools were positive for blood, had 4 to 5 WBC/Hpf, and contained no bacterial pathogens or Charcot-Leyden crystals. Stool viral cultures and examination for ova and parasites were negative. Stools electrolytes confirmed secretory diarrhea. Stools reducing substances were positive (1%) and pH was 4. Stools α1-antitrypsin was 9.3 mg/g (normal: <3). Complete blood count was within normal limits without atypical lymphocytes, lymphocytosis, or eosinophilia. Urinalysis was within normal values and urine culture was negative. At 5 months of age, since her stool output remained elevated (>120 ml/kg/day) without feeding and attempts at enteral feeding had failed, she underwent upper and lower endoscopies to obtain tissue for diagnostic evaluation. Her small bowel biopsies showed severe villous atrophy and crypt hyperplasia in the small bowel and nonspecific marked inflammatory changes in the lamina propria throughout the small intestine (duodenum, proximal jejunum, and distal ileum) and colon. Serum analysis was performed to detect the presence of circulating anti-enterocyte antibodies. This test was done through an indirect immunofluorescence technique as previously described (1,3). In short, successive dilutions of our patient's serum were applied to frozen acetone-fixed sections of normal human small bowel. After this, a thorough washing was completed in phosphate-buffered saline and FITC-conjugated rabbit anti-human IgG, IgA, and IgM were applied (Dako Corp., Ontario, Canada) at predetermined dilutions. She tested positive for circulating anti-enterocyte antibodies, mainly IgG type (titer 1:200). Other autoimmune markers such as anti-nuclear, anti-DS DNA, anticardiolipin, lupus anticoagulant, anti-mitochondrial, anti-smooth muscle, and anti-pancreatic islet cells antibodies were negative. Her evaluation for human immunodeficiency virus was negative. Her serum immunoglobulins (IgG, IgA, IgM) and lymphocyte subsets (CD3, CD4, CD8, CD16, CD19, and CD56) were within normal limits. At 7 months of age, she was started on prednisone at 2 mg/kg/d. Two months later, after several unsuccessful attempts to wean her from prednisone, cyclosporine (CyA) was added. CyA levels were kept between 150 and 250 mg/ml. At this point, due to several deep vein thrombotic episodes, she underwent an extensive evaluation for hypercoagulable state that disclosed a heterozygous mutation of the Factor V gene (Factor V Leiden defect). Appropriate anticoagulation therapy was started. Over the next 6 months, she had a relapsing pattern of diarrheal episodes every time the prednisone dose was decreased below 1.5 mg/kg/d. Her stools were always loose and she averaged 8 bowel movements (BM) a day (Fig. 1). At 15 months of age, she was still receiving 80% of her calories through PN. At this time, Mycophenolate Mofetil (MMF) was added at 30 mg/kg/d. Over the next 2 months, her prednisone dose was decreased by 50%, her PN was reduced to 40% of her caloric requirement, and her stools became formed for the first time (Fig. 1). At 24 months of age, her PN was stopped, and her prednisone dose was 0.2 mg/kg/d while keeping her CyA levels between 150 and 250 mg/ml and MMF at the same initial dose of 30 mg/kg/d. At 36 months of age, she remains off PN and has been slowly introduced to a regular diet while using an elemental formula to fulfill her caloric needs. Her albumin was 4.2 g/dl (normal: 3.7–4.8) and her complete blood count was within normal limits. When last tested, her stools were negative for blood, had 0 WBC/Hpf, reducing substances were negative, and pH was 6. The α1-antitrypsin in her stool was normal (normal: <3 mg/g). Her Zheight and Zweight were −3.5 and −2.0 respectively (Fig. 2). Even though she has improved, we believe that her growth pattern has been affected by the long-term steroid therapy. She has had no relapses since MMF was started. DISCUSSION In autoimmune enteropathy, patients typically have serum autoantibodies against the components of the epithelial cells of the gut (1,2,8,13). Moreover, the presence of other specific and nonspecific autoantibodies causing manifestations outside the gastrointestinal tract has been demonstrated in some patients with autoimmune enteropathy (1,4,6,12,14–17). The condition has also been associated with immunodeficiency disorders and lymphoid tissue tumors (18–21). Autoimmune enteropathy may be part of a more complex disorder such as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (22). In addition, autoimmune enteropathy has been described in association with nephropathy (7,12,17). A 75-KD autoantigen that is expressed by differentiated epithelial cells of the intestine and kidney that could potentially explain the pathogenesis of this process has been identified (17). These observations suggest that there is significant heterogeneity within the broad diagnostic classification of autoimmune enteropathy and provides some explanation for the variability of its natural history and response to medical and immunosuppressive therapy. Our patient had Factor V Leiden defect. This association has been described before in a patient with late-onset autoimmune enteropathy at 16 years of life and recurrent deep venous thrombosis (23). In our patient, the deep venous thrombosis episodes were associated with central venous catheter (CVC) use. Catheter-related thrombosis has been linked to hypercoagulable states including factor V Leiden mutation (24). The presence of factor V Leiden mutation may be incidental. However, the association of hypercoagulable states and autoimmune processes has been well established. Anticardiolipin antibodies and lupus anticoagulant are found in patients with thrombosis and systemic lupus erythematosus or other rheumatic disorders (25,26). The correlation between autoimmune enteropathy and a hypercoagulable state should be considered while caring for children with autoimmune enteropathy since they often require CVC for parenteral nutritional support. Different therapeutic modalities have been tried in autoimmune enteropathy, most of them including immunosuppressive therapy. Although there have been reports of some patients responding to dietary management alone (1,4,6), immunosuppressors are generally used in association with elemental diets and parental nutrition (1–14). Corticosteroids alone do not seem to have a major impact in this process (6,8,10,12). The addition of cyclosporine has induced good clinical remission in around half of most reported patients (3,10,11,14) while resistance to cyclosporine has also been described (12,13). Azathioprine, cyclophosphamide, and methotrexate have also been tried with different degrees of success (1–5,7,12,13). Tacrolimus has been reported to induce good clinical response in patients resistant to other immunosuppressive therapy (9), yet incomplete clinical resolution has also been observed with tacrolimus (3). Bone marrow transplantation has been performed in patients with autoimmune enteropathy and underlying immunodeficiency disorder (9,22). Recently, allogeneic bone marrow transplant was tried in a patient with IPEX with complete remission yet the patient died of hemophagocytic syndrome (22). Unfortunately, there has not been a universal response to a given immunosuppressive regimen. This is most likely due to the fact that autoimmune enteropathy is a variety of disorders clustered together along with the variable response to immunosuppressive therapy that may be seen in the same autoimmune process. Mycophenolate mofetil (MMF) is an ester pro-drug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase and potently suppresses lymphocyte proliferation (27). MMF has been used to prevent rejection after solid organ transplantation and in various autoimmune and chronic inflammatory disorders (28–32). MMF has been successfully used as a therapeutical alternative in patients with Crohn disease who failed more conventional therapies (31,32). To the best of our knowledge, this is the first case of autoimmune enteropathy successfully treated with MMF. In our patient, MMF induced remission of her autoimmune process allowing improvement of her intestinal absorption and linear growth. MMF may be an additional therapeutic option for autoimmune enteropathy as it is in other autoimmune disorders.

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