The treatment of ulcerative colitis (UC) and Crohn’s Disease (CD) remains challenging, despite several decades since sulphasalazine became first available. In the last 15 years, with better understanding of the pathophysiology of IBD, newer and exciting modalities of treatment have emerged. UC and CD represent chronic recurrent conditions of the intestinal tract with involvement of pro-inflammatory cytokines and chemokines. Biologic agents have emerged that include monoclonal antibodies, recombinant peptides or proteins. These agents aim to restore balance between pro-anti inflammatory responses. Biologic agents induce rapid healing of the mucosa of the intestine, whereas immunomodulators like azothioprine and 6 mercaptopurine take as long as six months. Conventional agent like sulphasalazine (SASP) and 5-acetyl salicylic acid (5-ASA) and corticosteroids do not cause mucosal healing. To understand their mode of action and understanding of the events leading to mucosal activation is required.

T-cells release both pro-inflammatory and anti-inflammatory responses when activated by macrophages and antigen presenting cells. CD and UC have different patterns of cytokine release. CD is characterized by Th1 response with increased levels of interleukin-12 (IL), tumour necrosis factor TNF and interferon (IFN). UC is characterized by Th2 response with elevated IL-5 and IL-13 levels. TNF levels are moderately elevated in UC. These cytokine differences may explain the variable efficacy of biologic agents in different forms of IBD.

Biologic therapies can be classified according to their general mechanism of action.

I. Agents that inhibit pro-inflammatory pathway

A. Tumour necrosis factor blockers constitute the majority of drugs currently available. Anti-TNF a AbcA2 - infliximab was first used in CD in 1993. It is a chimeric, i.e. part human, part mouse antibody with a 25% murine component. It is indicated in patients with moderate to severe CD for inducing and maintaining clinical remission when conventional therapy fails. It is also used to treat fistulizing CD and for extra-intestinal manifestations like uveitis, ankylosing spondylitis, and pyoderma gangrenosum. Recently UC patients with moderate to severe disease who had failed therapy with 5-ASA, corticosteroids, 6 mercaptopurine (6MP), azathioprine (AZTP), prior to colectomy were given infusions of infliximab. The sustained response rate was about 25% after 30 weeks of treatment. Infliximab is given as a 5 mg/kg IV infusion at 0, 2, and 6 weeks for induction and subsequently every 8 weeks. Dose escalation to 10 mg/kg could be done in patients whose initial response was good and subsequent response was inadequate. Infliximab works much better in CD than UC with remission rates of 65-80% out of which 40-45% are in sustained remission at week 30.

Factors favorably affecting response to infliximab are young age, non-smokers, Crohn’s Colitis rather than ileitis, and non-fistulizing disease. Patients with elevated C-reactive protein respond better. CD patients with perinuclear antineutrophil cytoplasmic antibody (pANCA) respond poorly.

Mechanism of action - Infliximab binds to soluble TNF a and also to membrane bound TNF a neutralizing its pro-inflammatory activity. The most important mechanism of action is T-cell and mononuclear cell apoptosis or programmed cell death, which occurs as quickly as 24 hours after a single infusion and lasts beyond the half-life of the drug.

Complications of infliximab therapy
Infusion reactions characterized by headache, dizziness, nausea, injection site irritation, and chest pain can occur in about 20% of patients. Infusion reaction occurs in patients with antibodies to infliximab (ATI) due to its murine component.

ATI causes decreased response to treatment. There is a higher incidence of ATI in patients treated episodically (30-60%) than those on maintenance treatment (7-10%). ATI were also less in patients who were concurrently on immunomodulators like 6-MP/AZTP.

Serious bacterial upper respiratory tract infections occur in 3-4% of patients. Intracellular infection with tuberculosis (TB) can occur and the recommendation is to do chest X-ray and tuberculin test prior to therapy and treat TB, if necessary.

Infliximab can rarely cause drug induced lupus, optic neuritis, and demyelinating diseases.

Current data does not indicate an increased risk of lymphoma or malignancy during the treatment.

Etanercept is a genetically engineered fusion protein consisting of two identical chains of TNF receptor. Though highly effective in rheumatoid (RA) and psoriatic (PA) arthritis, it has no efficacy in CD. It binds to soluble and membrane TNF a but does not induce apoptosis. This implies that TNF a inhibition alone is effective in the treatment of RA and PA but in CD apoptosis is required.

Adalimumab is a fully human anti TNF monoclonal antibody capable of inducing apoptosis in mononuclear cells. It can be given subcutaneously. It is less immunogenic and can be used in patients with ATI. Recent trials demonstrate promise in IBD.

Thalidomide inhibits TNF and cytokines like IL-12. It has been tried in fistulizing CD. It has significant side effects like sedation, peripheral neuropathy, and fatigue.

Certolizumab (CDP-870) is a humanized anti TNF linked to a polyethylene glycol molecule to increase its half-life to 14 days. It is still in clinical trials and appears to be promising

B. Interferon (Blockade - fontolizumab - A humanized interferon (antibody has been used in clinical trials in CD patients with good success.

II. Biologic therapy also consists of agents that stimulate anti-inflammatory pathway (IL-10 and IL-11), they disturb T-cell activation or proliferation (CD-3 ligation, IL-2R blockade) inhibit leucocyte recruitment, promote epithelial repair. These agents are still experimental.

*Diplomat of the American Board of Gastroenterology, Attending Physicians at Kimball Medical Center Lakewood, New Jersey.