Introduction

Pouchitis

Pouchitis is an inflammatory condition that can develop following surgery to remove the colon and create an internal pouch (termed an ileal pouch-anal anastomosis or IPAA) in a person with ulcerative colitis; this surgery is generally performed on patients requiring further surgical intervention because of treatment failure or for an abnormal cell growth condition termed dysplasia.¹

Pathophysiology

Pouchitis has an immune-mediated origin, with bacterial and structural components. Neutrophils and macrophages infiltrate the pouch tissue through adhesion molecules, which act as gateways to migration. Further stimulation of the immune response involves bacterial components, such as lipopolysaccharides (LPS) and colon metaplasia (an abnormal change in tissue), which leads to the secretion of pro-inflammatory cytokines (IL-8, IL-1, TNF), increasing inflammation and causing tissue damage. Autoantibodies, in some patients, such as pANCA, activate granulocytes and can make the condition worsen. Additionally, short-chain fatty acids have a key role in the barrier function of the intestines, such that a deficiency in short-chain fatty acids makes the pouch even more susceptible to damage. It is a confluence of chronic inflammation, which leads to most symptoms, including diarrhoea, abdominal pain, and urgency.²

Risk factors

Pouchitis can develop due to genetic factors, poor blood flow, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs). A high number of harmful bacteria, faecal buildup, and changes in the pouch lining can trigger inflammation. Weak mucus protection and problems with nutrient absorption further damage the pouch, leading to the progression of pouchitis.³

Importance of immunosuppressants and biologic therapy

Biologics and immunosuppressants serve a valuable role in the management of chronic pouchitis, particularly in scenarios where the ailment poses resistance to standard antibiotic interventions. The American Gastroenterological Association (AGA) recommends that patients suffering from chronic antibiotic-independent pouchitis or antibiotic-resistant pouchitis, who are not satisfied with standard antibiotic treatment, be considered for advanced immunosuppressive treatment options. These treatment modalities encompass biologics and/or oral small-molecule drugs that have gained approval for use in inflammatory bowel disease (IBD).⁴

Immunosuppressants in chronic pouchitis

Calcineurin inhibitors

Calcineurin inhibitors, such as tacrolimus and cyclosporine, are prescribed in extremely difficult cases of pouchitis to modulate the immune response and decrease inflammation. Both tacrolimus and cyclosporine inhibit calcineurin, which is an enzyme that activates T-cells in the immune system. Inside the immunised protoplasm, they bind to two different proteins: cyclosporine adheres to cyclophilin, whereas tacrolimus binds to FK-binding protein (FKBP); this creates a complex that prevents the activation of nuclear factors of activated T-cells (NFAT), leading to decreased production of inflammatory cytokines, such as interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) in the body. The suppression of the immune response impacts the chronic inflammation that is seen in pouchitis.⁵ 

The use of calcineurin inhibitors for the treatment of pouchitis remains a matter of debate due mainly to adverse events, such as nephrotoxicity, hypertension, and neurotoxicity. Perianal itching and burning sensations have been attributed specifically to tacrolimus. Due to the potential risks, calcineurin inhibitors are generally reserved for the management of severe, refractory pouchitis cases in which conventional therapies have failed.⁶

Immunomodulators

Immunomodulators such as azathioprine, mercaptopurine, and methotrexate have historically been used as secondary agents in chronic antibiotic-refractory pouchitis. As the pro-drug active molecule, azathioprine is a good oral drug in this class. Its unique incorporation into rapidly dividing cells, including activated T and B lymphocytes, ultimately inhibits nucleic acid synthesis and, thereby, inhibits lymphocyte proliferation and, subsequently, reduces pro-inflammatory cytokine production. 

Methotrexate inhibits the enzyme dihydrofolate reductase, causing a decrease in the levels of tetrahydrofolate necessary for purine and pyrimidine synthesis. The inhibition of dihydrofolate reductase decreases DNA and RNA synthesis, which damages rapidly dividing cells, such as lymphocytes. Additionally, methotrexate enhances the release of anti-inflammatory cytokines, such as interleukin-10 (IL-10), thereby furthering its immunosuppressive effects.⁷ However, data regarding their applicability in this condition are limited. 

The role of these agents in the treatment scenario is greatly influenced by the availability and accessibility of biologics, which are now the preferred option for the management of refractory cases. While immunomodulators are beneficial in attenuating the immune response or inflammation, they are typically used when biologics are unavailable or as a component of combination therapy to enhance overall response.⁸

Biologics in pouchitis

Anti-integrin therapy (vedolizumab)

Vedolizumab is a monoclonal antibody used in the treatment regimen for ulcerative colitis (UC) and Crohn's disease (CD). As pouchitis resembles the above two conditions, vedolizumab has been tried in some patients with chronic antibiotic-dependent or refractory pouchitis. Vedolizumab works in approximately 20 to 25 per cent of UC and CD patients who had not benefited from TNF inhibitors. Vedolizumab acts by inhibiting the entrance of certain immune cells into the gut, thus reducing inflammation. Additionally, improved quality of life was found in the long-term safety assessments on vedolizumab. As a gut-selective agent, vedolizumab is thought to carry a lower risk of systemic immunosuppression than other biologics. Nevertheless, monitoring for infections, liver function abnormalities, and neurological symptoms remains warranted during treatment.⁹

Anti-TNF agents

Tumour necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine for the immune system regulation. Excessive activity of the TNF-α causes permanent inflammation and injury to the mucosa in the pouch in chronic refractory pouchitis. TNF-α blocking agents, including infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept, all act by inhibiting the binding of TNF-α to its receptors and downstream inflammatory pathways. A study of 33 patients receiving infliximab for chronic pouchitis showed that 33% were in remission at 26 weeks, while 27% were in remission at 52 weeks. Adalimumab benefited eight patients who had failed infliximab, with 13% attaining remission, and 62% demonstrating improvement.¹⁰

FAQs

What is pouchitis?

Pouchitis is an inflammatory condition that can develop following surgery to remove the colon and create an internal pouch (termed an ileal pouch-anal anastomosis or IPAA) with ulcerative colitis.

What are immunosuppressants, and how do they help with pouchitis?

Calcineurin inhibitors (such as tacrolimus and cyclosporine) and immunomodulating agents (such as azathioprine and methotrexate) are immunosuppressive drugs that reduce inflammation by suppressing immune activity. They are often used when antibiotics fail; however, they could lead to certain side effects, such as renal toxicity or increased susceptibility to infections.

What are biologics, and why are they important in pouchitis?

Biologics like anti-TNF agents (e.g., Infliximab and Adalimumab) and anti-integrin therapy (e.g. Vedolizumab) have emerged as advanced therapeutic options in pouchitis that is resistant to other treatments. These agents act on specific molecules that are involved in the inflammation, thereby controlling symptoms and promoting remission.

Summary

Pouchitis is an inflammation that can occur after surgery to construct an internal pouch for people with ulcerative colitis. It develops from an exaggerated immune response, which damages and inflames the pouch. Triggers include various factors such as genes, poor blood supply, and nonsteroidal anti-inflammatory drugs (NSAIDs). Chronic pouchitis causes symptoms such as diarrhoea, pain, and urgency regarding defecation. 

Immuno-suppressive agents and biologics are the main drugs used to treat chronic pouchitis, especially when antibiotics fail. Drugs like calcineurin inhibitors (e.g. tacrolimus) help suppress inflammation by inhibiting the activation of immune cells; however, their major adverse effect is damage to the kidney. Additionally, immunomodulators (e.g., azathioprine, methotrexate) are available; however, they are less effective than biologics. Biologics such as anti-TNF agents (Infliximab and Adalimumab) are highly effective for chronic pouchitis, blocking the action of TNF-α, which is a molecule that causes inflammation. Studies have suggested that these biologics can achieve dramatic improvement and remission in many patients with chronic, antibiotic-refractory pouchitis.