- Gastroenterology Education and CPD for trainees and specialists - http://www.gastrotraining.com -

Refractory Coeliac Disease (RCD)

How do you define RCD?

RCD can be defined as persisting or recurring villous atrophy with crypt hyperplasia and
increased intraepithelial lymphocytes (IEL’s) in spite of a strict GFD for more than 12 months or when severe persisting symptoms necessitate intervention independent of the duration of the GFD. RCD may not respond primarily or secondarily to GFD.

What are the Types of RCD?

2 immunologic categories


RCD Type I RCD Type II
  • There is a normal and polyclonal population of intraepithelial lymphocytes.
  • Better prognosis (96%, 5 year survival in one study) with low risk of development of lymphoma.
  • Type I does not appear to evolve into type II.
  • RCD II exhibits an abnormal IEL clonal population. IEL’s have normal cytological feature but abnormal phenotype with associated clonal TCR gene rearrangements.
  • Poorer prognosis (5 year survival of less than 50%) and high risk of development of lymphoma. Also known as cryptic intestinal T cell lymphoma.

What are the clinical features of RCD?
Most of the patients (particularly Type II) develop severe malabsorption with weight loss, abdominal pain and diarrhoea.

What is the cause of RCD?

Unknown.

How do you approach a patient of RCD?

RCD is a diagnosis of exclusion.

  • Reassess the initial diagnosis of CD
  • Assessment of GFD
  • Exclude other causes of diarrhoea
  • Exclude malignant complications of CD


Discuss D2 biopsies in RCD?

  • Multiple D2 (at least 10) are needed for histological, immunohistochemical and TCR gene rearrangement studies by flow cytometry.  The storage medium for immunohistochemical and flow cytometry should be checked with the lab.An abnormal clonal IEL population, characterized by a low ratio of CD8+/CD3+ and TCR-gamma gene rearrangement can be shown in 80% of RCD cases. This is associated with a high risk of ulcerative jejunitis and lymphomatous transformation.
  • Clinically, a simple immunohistochemical method using 2 T-cell markers, CD3 and CD8, on paraffin sections is used to differentiate CD and RCD. An abnormal phenotype in the context of a flat biopsy is indicative of RCD, whereas a normal phenotype is more suggestive of continuing gluten ingestion as a cause of the villous atrophy. Those with an abnormal phenotype require TCR gene rearrangement studies because the presence of a clonal configuration indicates a poor prognosis in most with uncontrolled malabsorption and the development of lymphoma.

How do you treat RCD?
RCD Type I- These patients benefit from an immunosuppressive treatment. Induction is with corticosteroids (hydrocortisone 100mg IV qds or 40-60 mg of oral prednisolone). The dose can be tapered to the lowest dose needed after a few weeks in responding patients.  Azathioprine and 6-mercaptopurine appear to be effective steroid-sparing agent. Dose and duration of treatment with azathioprine are not established.
Cyclosporine A, infliximab, oral budesonide and tacrolimus have been reported to be effective in case reports. These agents should only be considered in cases of clinical deterioration despite corticosteroid therapy or intolerance to azathioprine.
RCD type II- is usually resistant to medical therapies.

  • Some patients may benefit from steroids/azathioprine. However, response to corticosteroids treatment does not exclude underlying EATL. Caution is required when initiating immunosuppressive therapy, as this may induce a high risk of progression to an overt lymphoma.
  • CHOP-like regimens
  • Case reports of success with infliximab have been published.
  • Cytotoxic chemotherapy with cladribine has been used on the assumption that some patients with RCD II may have a low-grade EATL.
  • Autologous stem cell transplantation in RCD II seems to be promising.

When do you suspect Ulcerative jejunitis/intestinal lymphoma?

  • RCD unresponsive to steroids.
  • CD patients with symptoms of lassitude, anorexia, weight loss, abdominal pain, diarrhea, and fever.
  • Clinical features like hepatomegaly, splenomegaly, duodenal mass, or ascites, are very suggestive of lymphoma. Lymphoma may also present with acute perforation, gastrointestinal obstruction, or GI bleed.

What is EATL?
Enteropathy-associated T-cell lymphoma (EATL) is a rare form of high-grade, T-cell non-Hodgkin lymphoma (NHL) of the upper small intestine that is specifically associated with CD. EATL commonly develops in the jejunum but may also be found in the ileum and lymph nodes and less frequently in the stomach and the colon. It is often multifocal with ulcerative lesions.
This NHL subtype arises in patients with either previously or concomitantly diagnosed CD. In a subgroup of patients, there is progressive deterioration of a RCD. EATL derives from a clonal proliferation of IEL’s and is often disseminated at diagnosis. Extra intestinal presentations are not uncommon in the liver/spleen, thyroid, skin, nasal sinus, and brain.
What is the lag period between CD diagnosis and EATL?
EATL occur in adults, with a peak in the sixth decade of life. Many years of latency is needed between the onset of CD and the development of EATL. If CD has been diagnosed first, lymphoma mostly develops in the following 5 to 10 years, although the time lag may occasionally be very long (up to 60 years).
How do you diagnose these conditions?

  • Most patients present with malaise, anorexia, weight loss, and diarrhea often associated with abdominal pain. Physical signs include fever, lymphadenopathy, skin rash, and hepatomegaly and a palpable abdominal mass.
  • The suspicion of EATL prompts an extensive diagnostic work-up that may include upper and lower intestinal endoscopy, CT scans, MR enteroclysis, video capsule endoscopy and double balloon enteroscopy. The final diagnosis is made on either endoscopic biopsies or full-thickness, laparoscopic, small bowel biopsies. PET scan can help identify suspicious lesions. Enlarged mesenteric lymph nodes often accompany RCD, without necessarily being specific for a T cell lymphoma.
  • Ulcerative Jejuno-ileitis: This is an unusual complication in which unresponsive CD is associated with ulceration and stricturing.  Patients may become very unwell and are often unresponsive to medical therapy.  The discrimination between this and lymphoma can normally only be made at surgery, and in some instances lymphoma seems to have developed on a background of jejuno-ileitis.  Patients should be advised to continue with a gluten-free diet, but early surgery is indicated if there is no resolution of symptoms.
  • It has an unfavorable prognosis. Up to one-third of patients die from complications. The prognosis can be improved if the ulcerated or strictured segment can be resected.

What is the prognosis?
These lymphomas are usually of high-grade histology and the prognosis is poor. Five-year survival is approximately 10 percent.
Multidrug therapy may be helpful in patients with minimal GI symptoms, who can tolerate therapy. Patients should also be maintained on a gluten-free diet.

Ref

  1. Al-toma A et al. Update on the Management of Refractory Coeliac disease. J Gastrointestin Liver Dis 2007; 16(1): 57-63

Article printed from Gastroenterology Education and CPD for trainees and specialists: http://www.gastrotraining.com