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Case Reports

Oropharyngeal and Proximal Esophageal Involvement During Adalimumab Treatment of Crohn Disease

Nguyen, Kim-Doan Katrina*; Alexis, Richard; Schwarz, Steven M*

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Journal of Pediatric Gastroenterology and Nutrition: February 2010 - Volume 50 - Issue 2 - p 225-226
doi: 10.1097/MPG.0b013e3181a712db
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Esophageal involvement is an uncommon but increasingly recognized complication of Crohn disease (CD). The reported prevalence of esophageal CD is variable in both the pediatric and adult populations. In adults, underestimation of its diagnosis may be partly related to reliance on visual endoscopic evidence as the sole criterion for identification of esophageal disease (1). Variability of reported pediatric prevalence data may be a consequence, at least in part, of differences in clinician-determined criteria for performing upper gastrointestinal tract endoscopic examinations in children without upper tract symptoms. In the case presented herein, we report an adolescent patient with known ileocolonic CD in clinical remission, who developed oropharyngeal and proximal esophageal disease during maintenance treatment with adalimumab. To our knowledge, this represents the first case report of esophageal CD occurring both during adalimumab treatment, as well as in the absence of lower gastrointestinal tract symptoms.

CASE REPORT

A 19-year-old African American female with ileocolonic CD presented with increasing complaints of difficulty in swallowing. At the time of diagnosis 3 years earlier, initial evaluation included a positive antisaccharomyces cerevisiae antibody serology, along with a negative perinuclear anti-neutrophil cytoplasmic antibody study. Ileocolonic involvement consistent with CD was confirmed both by colon biopsy evidence and by small intestinal radiographic findings. An esophagogastroduodenoscopy at the time of diagnosis did not demonstrate upper gastrointestinal tract mucosal disease. During the course of illness, she had been treated with corticosteroids, metronidazole, sulfasalazine, 6-mercaptopurine, and subsequently infliximab for refractory disease. As a consequence of loss of responsiveness to infliximab after 15 months of treatment, prednisone (40 mg daily) and adalimumab (titrated to 40 mg q2wk) were started. Clinical remission was achieved within 2 weeks of commencing therapy. At 3 months after instituting this course of treatment, the prednisone dosage had been tapered to 15 mg daily. She remained asymptomatic and a follow-up colonoscopy, performed 1 month before the current presentation, demonstrated evidence of patchy, mild-to-moderate chronic inflammation. Shortly thereafter fevers, odynophagia, and dysphagia developed, without associated diarrhea, abdominal pain, or bleeding. Physical examination demonstrated visible, ulcerated lesions in the posterior oropharynx. A trial of intravenous gancyclovir/valgancyclovir did not improve signs or symptoms; and serologies for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and HIV were subsequently negative. An upper gastrointestinal endoscopy showed circular, raised white shallow lesions with surrounding normal mucosa involving only the proximal one third of the esophagus, with associated mucosal friability and erythema (Fig. 1). No strictures were noted. Endoscopic biopsies demonstrated deep esophageal ulcerations with florid granulation tissue, but specimens did not show evidence of infection with fungi, herpes simplex virus, or cytomegalovirus (Fig. 2). In the absence of both any confirmed evidence for an infectious etiology as well as any clinical response to antiviral medications, a presumptive diagnosis of esophageal CD was made and treatment commenced with oral prednisone 40 mg daily. This course resulted in immediate improvement of symptoms and complete disappearance of the oral ulcerations within 48 hours. Repeat upper gastrointestinal endoscopy, 1 week after starting corticosteroids, showed complete resolution of visible esophageal lesions, and biopsies demonstrated no significant histopathology (Fig. 3). Because esophageal disease developed despite concomitant adalimumab therapy, this medication was discontinued and ongoing treatment included oral prednisone and subcutaneous methotrexate 25 mg once per week. The patient is currently improved clinically on a regimen comprising methotrexate 25 mg subcutaneous weekly and prednisone 10 mg per OS daily, without further evidence of upper gastrointestinal tract involvement.

FIGURE 1
FIGURE 1:
EGD showing ulcerations only in the proximal one third of the esophagus.
FIGURE 2
FIGURE 2:
Histological sections from esophageal biopsy showing ulceration with florid granulation tissue.
FIGURE 3
FIGURE 3:
Histological sections from esophageal biopsy showing complete healing of previous ulcers after corticosteroids.

DISCUSSION

CD involving the esophagus is uncommonly reported but increasingly recognized. The prevalence of esophageal CD in adults ranges from 0.2% to 11.2% and in children from 6.5% to 43% (1). This variability is partly a consequence of using macroscopic, endoscopic evidence as the sole criteria for diagnosis of esophageal CD in adults, whereas differences in pediatric patients may be related to differences in the decision among pediatric gastroenterologists to perform an upper endoscopy (1). The patient presented herein represents, to our knowledge, the first reported case of esophageal CD occurring both during adalimumab therapy and in the absence of symptomatically active lower gastrointestinal tract disease.

The absence of granulomata on histological sections from mucosal biopsies certainly does not rule out a diagnosis of esophageal CD in our patient. In a recently published pediatric CD cohort comprising 210 patients, of whom 144 underwent upper gastrointestinal tract endoscopy (1), only 27 children (12.8%) were found to have histopathological evidence of esophageal mucosal involvement. Interestingly, clinical symptoms suggesting upper gastrointestinal tract inflammation were present in only 9 of these 27 children. In this series, esophageal mucosal granulomata were identified in only 7 (26%) of these subjects. Similarly, a previous literature review (2) indicated that only 5 of 13 patients (38%) with presumed esophageal CD demonstrated histological granuloma formation.

Similar to previous reports, our patient's extraesophageal CD preceded the diagnosis of esophageal involvement (1,3). In fact, Ramaswamy et al (1) did not find any children with isolated esophageal CD. Previous reports suggest that morphologic changes of esophageal CD are mostly limited to the middle to lower part of the esophagus (3–6). In contrast, our patient had evidence of CD involving the oropharynx and proximal one third of the esophagus. Huchzermeyer et al (5) concluded that no specific differentiation from other forms of esophagitis is possible. However, in some cases, shallow ulcerations within intervening normal mucosa may be a distinctive feature of esophageal CD. Although the pathognomonic finding of esophageal granulomata was not present in our patient, the florid esophageal inflammation along with rapid resolution of both upper gastrointestinal symptoms and endoscopic lesions, following systemic corticosteroids in a patient with previously confirmed CD, is strongly suggestive of esophageal CD.

The management of esophageal CD is variable. No standardized therapies exist, but acid-suppressive therapy, corticosteroids, immunomodulators, and biologic agents directed against tumor necrosis factor have been shown to be effective. Treem and Ragsdale (2) reported a 12-year-old male with dysphagia and diarrhea, who was diagnosed with esophageal, gastric, and colonic CD on the basis of histopathological evidence of granulomata. Symptoms rapidly improved upon corticosteroid treatment without acid suppression. Ramaswamy et al (1) used acid-suppressive treatment of esophageal CD in children with upper gastrointestinal symptoms and/or endoscopic lesions. Adult patients with esophageal CD have responded to immunomodulators alone or in combination with corticosteroids (1). Adult and pediatric patients may present with esophageal strictures and/or fistulas that require esophageal dilation or resection (4,6). Kwan et al (3) reported successful treatment of esophageal CD using adalimumab in an adult patient who had an attenuated response to infliximab. This patient had also been treated with cyclosporine and 6-mercaptopurine but did not maintain an adequate clinical response.

In our patient, the delay in diagnosis of esophageal CD was a consequence, in part, of its “atypical” location (ie, oropharynx and proximal esophagus), the absence of lower tract symptoms, and of its development during treatment with an agent (adalimumab) previously reported to be effective in ameliorating esophageal CD ulceration. The lack of an infectious etiology, as indicated by negative serologies, cultures and biopsy findings, and the rapid clinical and histopathologic responses to corticosteroids are supportive of the diagnosis of esophageal CD.

REFERENCES

1. Ramaswamy K, Jacobson K, Jevon G, et al. Esophageal Crohn disease in children: a clinical spectrum. J Pediatr Gastroenterol Nutr 2003; 36:454–458.
2. Treem WR, Ragsdale BD. Crohn's disease of the esophagus: a case report and review of the literature. J Pediatr Gastroenterol Nutr 1988; 7:451–455.
3. Kwan LY, Conklin JL, Papadakis KA. Esophageal Crohn's disease treated successfully with adalimumab. Inflamm Bowel Dis 2007; 13:639–640.
4. Rahhal RM, Banerjee S, Jensen CS, et al. Pediatric Crohn disease presenting as an esophageal stricture. J Pediatr Gastroenterol Nutr 2007; 45:125–129.
5. Huchzermeyer H, Paul F, Seifert E, et al. Endoscopic results in five patients with Crohn's disease of the esophagus. Endoscopy 1977; 8:75–81.
6. Remes-Troche JM, Argote-Greene M, Rubio-Tapia A, et al. Progressive dysphagia caused by isolated esophageal involvement of Crohn's disease. Inflamm Bowel Dis 2005; 11:515–517.
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