The main drugs used in the treatment of inflammatory bowel disease (IBD for short) include: aminosalicylates, glucocorticoids, antibiotics, immunosuppressive agents and biologics. Each class of drugs has a certain status in the treatment of the disease, and it is possible to avoid drug side effects by being familiar with the adverse effects of drugs.
Aminosalicylates (5-ASA)
Numerous clinical trials have confirmed that salazosulfapyridine (SASP) is significantly more effective than placebo in the treatment of active inflammatory bowel disease. However, SASP treatment is accompanied by a high incidence of adverse reactions, with an incidence of about 10-45%. Adverse reactions are mainly due to the presence of sulfonamide groups in the drug, and the most common adverse reactions include: headache, nausea, dyspepsia, and muscle and joint pain. Some patients are hypersensitive to the mesalazine component and may develop rash, megaloblastic anemia, and fever, but the incidence is very low. In male patients SASP can cause reversible sperm abnormalities. Yang Rongping, Department of Gastroenterology, Shenzhen Sixth People’s Hospital (Nanshan Hospital)
For patients who cannot tolerate SASP, the switch to a simple 5-aminosalicylic acid (5-ASA) preparation is tolerated by most patients. 5-ASA has a low incidence of adverse effects, mainly diarrhea, headache, nausea, dyspepsia, and rash, but they are usually not very serious. The incidence of nephrotoxicity and pancreatitis is extremely low, but noteworthy.
Glucocorticoids
The side effects of glucocorticosteroids are well known. During treatment of active CD, the incidence of side effects has been reported to be 55% with 40 mg of prednisone per day. The occurrence and severity of side effects are related to the dose of the drug as well as the duration of treatment. Adverse effects of hormones are found almost throughout the body. The most common ones include fluid retention, full moon face, acne, fatty lines, weight gain, hypertension, hyperglycemia, glaucoma, cataracts, and affective disorders. Complications of musculoskeletal joints include osteoporosis and bone loss. Bone loss is a very common and more serious complication that can occur within weeks to months of treatment. In addition, hormones increase the risk of infection.
It is due to the high incidence of adverse reactions to conventional glucocorticoids that new glucocorticoid preparations, such as budesonide, have been introduced into the treatment of IBD, which acts mainly locally on the intestinal mucosa and has minimal systemic effects. Several controlled studies have demonstrated comparable efficacy and significantly fewer adverse effects of budesonide compared to traditional systemic-acting glucocorticosteroids for the control of active CD.
Antibiotics
Many clinical experiences and clinical data support the role of intestinal flora in the pathogenesis of IBD and, therefore, antibiotics are also used in the treatment of these diseases. Metronidazole is one of the most widely used antibiotics in the treatment of IBD, especially in the treatment of perianal lesions of CD. However, the adverse effects of metronidazole remain noteworthy. Short-term adverse reactions, such as gastrointestinal intolerance and metallic taste in the mouth, occur in approximately 50% of patients and are usually reversible and resolve upon discontinuation, although multiple neuropathies occur in a minority of patients and persist even after discontinuation. Neuropathy is one of the reasons for limiting the long-term use of metronidazole.
Other antibiotics commonly used for IBD are ciprofloxacin, a quinolone antibiotic that selectively inhibits the action of intestinal flora. The drug is well tolerated in the short term, and the most common adverse effects are gastrointestinal symptoms, skin lesions, and elevated transaminases. However, Achilles tendonitis and Achilles tendon rupture can occur in a small number of patients, especially when glucocorticoids are taken concomitantly.
The most recent antibiotic used for the treatment of IBD is rifaximin, a derivative of rifamycin, a broad-spectrum antibiotic with the greatest characteristic of oral non-absorption (less than 1% absorption) and a highly effective and low-toxicity enteric antibiotic.
Immunosuppressants
Azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP) are the most commonly used immunosuppressive agents in the treatment of IBD, usually for the treatment of hormone-dependent or hormone-resistant IBD. Meta-analysis showed that 9% of patients discontinued treatment due to adverse reactions. These adverse reactions can be classified as non-dose dependent (allergic reactions) or dose dependent. Allergic reactions can occur in approximately 5-10% of patients, usually within the first month of treatment. The main manifestations are: acute pancreatitis, nausea, arthralgia, fever, abdominal pain, and skin erythema. 6-MP can be tried in patients sensitive to AZA, but should be avoided in patients who develop pancreatitis. The most common dose-dependent adverse reaction is myelosuppression, mainly manifested as leukopenia. Its incidence has been reported in the literature to be 2.2-15%. Leukopenia can occur at any time during treatment but can be restored by dose reduction or discontinuation of the drug. Another dose-dependent adverse effect is hepatotoxicity. The association of this class of drugs with lymphoma is not well understood. One study reported a 4-fold increased risk of lymphoma in patients with IBD treated with AZA or 6-MP.
Methotrexate (MTX) is another immunosuppressant commonly used in the treatment of IBD. Common adverse effects include nausea, vomiting, aphthous ulcers and leukopenia. Serious complications include: hepatic fibrosis and hypersensitivity pneumonitis. MTX is contraindicated in pregnancy due to its adverse effects on the fetus.
Cyclosporine (CsA) is mainly used in severe UC where hormonal therapy has failed. the most common adverse effects are nephrotoxicity, opportunistic infections, hypertension, tremor, gingival hyperplasia and seizures.
Biological agents
TNF-a, an inflammatory factor in the immunomodulatory process, plays an important role in the cascade response of IBD. Direct antagonism of TNF by biologic agents has ushered in a new era of IBD treatment. Commonly used biologic agents include infliximab (abbreviated as IFX) and adalimum, whose safety has been clinically proven.
Infection is the most significant safety concern for this treatment. Upper respiratory tract infections and urinary tract infections are the most frequently occurring infectious events and are usually easily managed. However, some more serious infections such as pneumonia, infections, sepsis, opportunistic fungal infections, and viral infections can also be observed. Biologics should not be used in patients with active infections and all patients should be screened for potential TB infection before applying biologic therapy. From large foreign database data, it appears that the increased risk of inflammatory infection with IFX therapy may be related to the severity of CD disease in these patients and may also be related to the concomitant use of glucocorticoids and immunosuppressive drugs in these patients.
There is no evidence to confirm that the drug increases the incidence of lymphoma and malignancy. Studies in Italy have found that the risk of tumor development in CD patients treated with IFX is comparable to that in patients not treated with IFX. However, recently, a very rare, more malignant form of non-Hodgkin’s lymphoma, hepatosplenic T-cell lymphoma, has been reported to occur in young IBD patients treated with IFX in combination with azathioprine.
Antibody production to IFX may lead to acute or delayed infusion reactions and may result in decreased efficacy. Regular maintenance IFX therapy, concomitant use of immunosuppressive agents, and the use of glucocorticoids prior to treatment can reduce antibody production. Other adverse reactions to IFX include abnormal liver function, skin lesions, worsening of congestive heart failure, rare blood abnormalities, and neurological demyelination.