Introduction

Due to the rarity of Cronkhite-Canada syndrome (CCS) it is not a well understood disorder partly due to difficulties in gathering a large number of patients in order to perform robust studies. Therefore there is no strong evidence for specific treatments, no clear understanding of the aetiology (the cause), and the pathogenesis is relatively unknown (the biochemical steps that underlies the disorder). There is some evidence that CCS is an autoimmune disorder, meaning that something causes the bodies own immune system to start targeting itself^1–3. Treatment for CCS is largely anecdotal, generally composed of nutritional support, steroids, or immune suppression⁴.

Steroids

Currently most patients are treated with glucocorticoids (part of the steroid “family”; commonly known as corticosteroids) which include medications such as prednisone, prednisolone, and cortisone. It is also used in many other disorders such as rheumatoid arthritis, sarcoidosis, and inflammatory bowel disease. The rationale behind this, is that the corticosteroids suppress the immune system by suppressing T cell activation, inducing lymphocyte death, and altering lymphocyte recirculation. By decreasing the immune response, there should be a decrease in inflammation resulting in a decrease in cellular damage and symptoms⁵. However this is generally for symptomatic relief meaning it can help ablate the CCS symptoms of diarrhoea and malabsorption whilst it doesn’t deal with the underlying cause of this disorder.

Anti-TNFα

Tumor necrosis factor alpha (TNFα) is a cytokine known to be a key part of the inflammatory process. It is also associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease as it essentially increases the inflammation. Although the exact cause and mechanism of CCS is still unknown, a 2010 case report highlighted a patient with elevated levels of TNFα, providing some evidence that it plays an important role in the development of this disease⁶.

Infliximab (trade name: remicade) is an anti-TNFα drug. It targets the aforementioned TNFα and prevents it from activating. The drug is known as a monoclonal antibody – it is an antibody made in the lab, so it is like a homing missile targeted and specific just for TNF molecule. Due to this, it is also relatively expensive. It is believed that if TNFα is blocked by infliximab or other “anti-TNF” drugs, then this stops a key step of the CCS pathway (inflammation) allowing time to heal and thus halting progression.

Following this 2010 report, there have been 3 reports in the literature of anti-TNFα being used. They are summarised below.

1. Tran et al. (2010)⁷: first case report of infliximab being used for refractory CCS. The patient was a 37 year old male with 45 lb weight loss and low albumin. He was treated with oral prednisone, subcutaneous octreotide, antibiotics, ranitidine, and cromolyn, however over a 12 month period his symptoms continued to wax and wane, eventually leading to a relapse. As this was not responding to treatment it is known as refractory. Infliximab and total parenteral nutrition (TPN) was started and at 12 weeks the patient displayed weight gain and albumin increase. After 12 months of infliximab therapy the patient was asymptomatic.

2. Watanabe et al. (2014)⁸: a 57 yo male with severe CCS was treated with corticosteroids, however symptoms persisted. Infliximab was used “His general condition improved, and colonoscopy performed 20 months after induction of anti-TNF therapy showed complete remission with the disappearance of polyposis. He now receives 200 mg of infliximab every 8 weeks, and has been symptom free for 3 years since the initial administration”.

3. Boland et al. (2016)⁴: a 40 yo female presented with CCS. TPN and intravenous steroids were administered without improvement. Azathioprine and infliximab regiments were then started which resulted in rapid clinical improvement.

To conclude, there are now three reported cases of infliximab being used to very good effect. However a sample size of 3 is not large and depending on the country infliximab can be very expensive. Further research must be performed investigating the use of infliximab as a first line therapy for CCS.

References

1. Zong, Y. et al. Case report—malignant transformation in cronkhite–canada syndrome polyp: Medicine 96, e6051 (2017).

2. Ota, S. et al. Cronkhite–canada syndrome showing elevated levels of antinuclear and anticentromere antibody. Clinical Journal of Gastroenterology 8, 29–34 (2015).

3. Kopáčová, M. et al. Cronkhite-canada syndrome: Review of the literature. Gastroenterology Research and Practice 2013, 1–9 (2013).

4. Boland, B. S. et al. Cronkhite canada syndrome: Significant response to infliximab and a possible clue to pathogenesis. The American Journal of Gastroenterology 111, 746–748 (2016).

5. Head, B. M. Experimental and clinical pharmacology: Corticosteroids in autoimmune disease. Australian Prescriber 22, 9–11 (1999).

6. Martinek, J. et al. A fulminant course of cronkhite-canada syndrome. Endoscopy 42, E350–E351 (2010).

7. Tran, V. T., Reicher, S., Chung, D. S., Eysselein, V. E. & Pham, B. V. M1252 infliximab therapy in refractory cronkhite canada syndrome. Gastroenterology 138, S–364 (2010).

8. Watanabe, D. et al. Successful treatment of cronkhite–canada syndrome using anti-tumor necrosis factor antibody therapy. Endoscopy 46, E476–E477 (2014).

Author

Please contact Aaron Khoo akhoo1@uq.edu.au if there are any queries or concerns.