Tofacitinib for the Treatment of Tumor Necrosis Factor-α Inhibitor Refractory Esophageal Crohn's Disease

A Case Report

Sunina Nathoo; William A. Hood; Sara Keihanian; Amy L. Collinsworth; Sarah C. Glover


J Med Case Reports. 2016;10(264) 

In This Article


There are several presentations of esophageal CD that the reader should be made aware of. These include dysphagia or odynophagia as seen in our patient due to deep ulcers, strictures with or without fistula in an older patient, or asymptomatic in patients with normal endoscopy results but abnormal histology.[1–3] The latter is seen in pediatric patients, who have a high prevalence of esophageal CD when surveyed with upper endoscopy.[1] Patients may also present with chest pain, heartburn, nausea, and vomiting.[8] Almost all cases are seen with CD affecting other segments of the gastrointestinal tract, although isolated esophageal involvement has also been reported.[3,9] Diagnosis is aided by endoscopy but requires an integration of clinical, endoscopic, histological, and radiographic data.[2,3] Findings on endoscopy include aphthous ulcers, superficial erosions, friability, and nodular thickening.[3] The importance of biopsies cannot be underscored enough given the broad differential diagnosis, although histological findings may not be specific for CD, making the diagnosis difficult.[2] The transmural nature of CD is also a factor, which cannot be assessed with superficial biopsies taken during endoscopy. Histological findings include chronic, non-specific inflammation with or without granulomas, although these are rarely observed.[5,8,10] Granulomas are seen in only 20–30 % of grossly abnormal biopsies but are considered pathognomonic for CD diagnosis.[4]

While our patient had histological evidence of esophageal CD, the differential diagnosis would also include reflux esophagitis, pill esophagitis, viral esophagitis (cytomegalovirus and herpes simplex virus), monilial esophagitis, granulomatous diseases such as sarcoidosis, tuberculosis, necrotizing vasculitis, Behçet's syndrome, disseminated fungal infection, epidermolysis bullosa acquisita, and carcinoma.[1,3,8–10] Achalasia should also be ruled out with motility testing if symptoms are classic; however, abnormal motility has been described even in patients with inactive CD for unclear reasons and esophageal CD can present like pseudoachalasia.[10] Tuberculosis can be ruled out when biopsies are stained for acid-fast organisms.

CD is known to affect any portion of the gastrointestinal tract; however, the distal third of the esophagus alone is the most common esophageal manifestation (80 %).[3] Radiographic studies can show ulcers or strictures, but can be normal in up to 50 % of patients with esophageal CD.[3] Other findings include stricture and fistula. The management of these complications entails endoscopic dilation and esophagectomy. For fistula, closure has been described with polymer sealants and infliximab, although many require surgical repair.[4] Given that esophageal CD is a high risk feature indicative of aggressive disease activity, endoscopy should be considered in all patients with CD with upper gastrointestinal symptoms to avoid complications.[2,4]

Medical management is first line when a diagnosis of esophageal CD is made. Currently, the European Crohn's and Colitis Organisation (ECCO) consensus guidelines suggest esophageal CD should be treated with a proton pump inhibitor, in addition to steroids and thiopurines or methotrexate.[11] Treatment options have historically included 5-aminosalicylic acid preparations, although it is unclear how effective they are because their metabolites are not active in the proximal gastrointestinal tract.[8,9] Corticosteroids, systemic as well as topical, such as swallowed aerosolized budesonide, have also been described.[3,5,9] Immunomodulators including azathioprine and 6-mercaptopurine have also been described; they are steroid-sparing and treat more distal disease if present.[5,9] There is one case report on the successful use of thalidomide.[7] There are been several case reports commenting on the use of biologics for esophageal CD in recent years as these drugs have become a cornerstone of inflammatory bowel disease treatment. ECCO guidelines recommend a lower threshold for starting TNF-α inhibitors for esophageal involvement than for disease elsewhere owing to the poor prognosis associated with this site.[11] Use of infliximab, adalimumab, and ustekinumab has been associated with rapid improvement on repeat endoscopy.[2,6,12,13] These findings imply that repeat endoscopy should be performed in patients with persistent symptoms to rule out other causes or to confirm persistent disease activity. Optimization of medical therapy is important to minimize complications such as stricture and fistula formation. Patients with persistent dysphagia due to strictures may require dilatation, stent placement, or ultimately surgery for management.[3] Patients are usually also started on a proton pump inhibitor, which can help symptoms but whose role in mucosal healing is unclear.

Tofacitinib, a selective oral inhibitor of JAK 1 through 3, is currently approved for use in patients with rheumatoid arthritis. Inhibition of JAK1 and JAK3 blocks signaling for many cytokines, including IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, and IFN-γ, which are involved in immune activation and signaling.[14,15] Phase 3 trials for the treatment of moderate to severe active ulcerative colitis are currently underway after a positive result from a phase 2 trial that showed significant improvement in primary and secondary endpoints with 15 mg twice daily dosing.[14–16] A separate report from this study demonstrated statistically significant patient reported outcomes when compared to placebo, which correlated with other objective assessments of drug efficacy.[15] A phase 2 trial of tofacitinib for moderate to severe CD published in 2014 was unable to demonstrate an improvement in clinical response or clinical remission when compared to placebo, although they reported it was unclear whether this was a true negative result or related to a high placebo response rate.[14,17] Decreases in objective markers of inflammation including C-reactive protein and fecal calprotectin suggest that tofacitinib did have biologic activity in this study in patients with CD.[14]

One recent retrospective case series, the largest in esophageal CD, reported that categorization of treatment should be based on disease behavior—inflammatory, stricturing, and fistulizing.[2] It is unclear from the literature if disease activity in the esophagus mirrors more distal disease activity or phenotype, although a similarity has been noted on endoscopy.[4] Interestingly, eight patients were on TNF-α inhibitors at the time of diagnosis, and had a clinical response with dose adjustment, adding another agent, or switching TNF-α inhibitors.[2] Our patient had already had unsuccessful trials of other medications for distal disease, thus precluding their use when her esophageal CD was diagnosed. Switching to another biologic has been described and should be of consideration if there is no improvement with intensification of the current therapy.