Inflammatory Bowel Disease (IBD)

Introduction and Facts

Inflammatory bowel disease (IBD) describes an inflammatory condition of the digestive system that is chronic and idiopathic. It is generally divided into ulcerative colitis (KU), Crohn's disease (PC), and unclassified IBD (IBDU, formerly known as indeterminate colitis). There is no epidemiological study on IBD in Indonesia; the data is still based on hospital reports only (hospital-based). Simadibrata from Jakarta in 2002 reported 5.2% of PC and KU cases of the total colonoscopy cases performed at Cipto Mangunkusumo Hospital.

From data from endoscopy units at several hospitals in Jakarta (RSCM, Tebet Hospital, Siloam Gleneagles Hospital, Jakarta Hospital), there is an impression that IBD cases ranged from 12.2% of cases sent with chronic diarrhea, 3.9% of hematoschezia cases, 25.9% of cases. Chronic diarrhea, bloody and abdominal pain, while in the case of abdominal pain, they found it around 2.8%. This data also states that, in general, the incidence of KU is more than PC cases. Globally, the incidence of IBD is 10 cases per 100,000 population, KU 2.2–14.3 cases per 100,000 population, and PC 3.1–14.6 cases per 100,000 population.

Pathophysiology

To date, the exact etiology of IBD is not fully understood. Many theories have been proposed, but there is no single known cause of IBD. One approach is believed to be the role of immunological mediation in genetically susceptible individuals. IBD is believed to result from an aberrant immune response and reduced tolerance in the normal gut flora, which results in chronic inflammation of the gut.

This condition is supported by finding antibodies against microbial antigens and identifying the CARD15 gene as a susceptibility gene for IBD. Genetically, it is stated that the presence of mutations in the NOD2 gene (IBD1 gene) or CARD15 (NOD2 gene) on chromosome 16 can be associated with the occurrence of IBD (especially for PC). However, these genes are not said to be causal to IBD. In general, it is estimated that the pathogenesis of IBD begins with an infection, toxins, bacterial products, or colonic intraluminal diet in susceptible individuals and is influenced by genetic factors, immune defects, and the environment, resulting in a cascade of inflammatory processes in the intestinal wall.

Many inflammatory mediators have been identified in the pathogenesis of IBD. In response to various antigenic stimuli, cytokines released by macrophages bind to various receptors and produce autocrine, paracrine, and endocrine effects. Cytokines convert lymphocytes into T cells where T helper-1 (Th-1) cells play a role in PC pathogenesis and T-helper 2 (Th-2) cells in KU. This immune response will eventually damage the gastrointestinal mucosa and trigger a cascade of chronic inflammatory processes.

Risk Factors

Some risk factors for IBD are:

• Age. More people with IBD are diagnosed before the age of 30. However, some people don't develop IBD until they are 50 or 60 years old. 
• Tribe or ethnicity. Although IBD is more common in white people, this disease can occur in any race or ethnicity. Cases are also increasing in other tribes and ethnicities.
• Family history of illness.
• Smoke. Smoking is the most important risk factor that can be controlled to prevent the onset of Crohn's disease. Smoking can help prevent ulcerative colitis. However, the harm to overall health outweighs the benefits, and quitting smoking can improve the general health of your digestive tract, as well as provide many other health benefits.
• Use of non-steroidal anti-pain drugs (NSAIDs). Some NSAIDs such as ibuprofen, naproxen sodium, diclofenac sodium, can increase the risk of IBD or worsen IBD itself.

Clinical Symptoms and Complications

In general, IBD complaints are chronic diarrhea with or without blood and abdominal pain. In addition, manifestations outside the gastrointestinal tract (extraintestinal) are often found, such as arthritis, uveitis, pyoderma gangrenosum, erythema nodosum, and cholangitis. While systemically, it can be found to impact existing pathological conditions such as anemia, fever, nutritional disorders. One thing that is important to remember is that the clinical course of IBD is chronic exacerbation remission or is generally characterized by an active phase and a remission phase.

Diagnosis

There are no laboratory-specific parameters for IBD. Generally used are general inflammatory marker parameters such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). In PC, serum CRP levels were positively correlated with disease activity and with other inflammatory markers according to the PC activity index. Elevated CRP levels > 45 mg/L in IBD patients can help clinicians decide the need for colectomy.

The examination of stool cultures could help determine whether the inflammation was caused by infection or non-infection. Endoscopic examination plays a crucial role in establishing the diagnosis and therapy for IBD, with a diagnostic accuracy of around 89%. Generally, endoscopic examination is followed by histopathological examination of biopsy preparations. Other tests, such as dual-contrast imaging, can be performed as an endoscopic confirmation tool.

Medication and Treatment

In general, the principles of IBD therapy are:

1. Treat the active inflammation of IBD rapidly until remission is achieved.
2. Prevent recurrent inflammation by maintaining remission as long as possible.
3. Treat and prevent complications.

Giving antibiotics such as metronidazole in divided doses of 1500 – 3000 mg per day is said to be quite helpful in reducing the degree of disease activity, especially PC. As for KU, antibiotics are rarely given. Antibiotics were given against the background that one of the proinflammatory agents was caused by intraluminal bacteria.

Most intraluminal bacteria are commensal and do not induce inflammatory reactions. However, they can still influence the immune response and persuade intestinal epithelial cells to suppress chemotaxis, decrease proinflammatory cytokine expression and increase interleukin 10 production. This interaction between host bacteria is known as dysbiosis. Administration of probiotics such as lactobacilli plays a role in achieving 85% clinical and endoscopic remission in post-colectomy patients.

Glucocorticoid drugs are still the drugs of choice for moderate and severe IBD in the active inflammatory phase. The selection of conventional steroid drugs, such as prednisone, methylprednisolone, or steroid enema, is still the prima donna because of the low price and wide availability. The usual dose is the equivalent of 40-60 mg of prednisone. However, do not forget the systemic effects of these drugs. Ideally, high levels of steroids in the gut wall are achieved but with low systemic effects. Generally, the preparations used today are budesonide. Remission is usually achieved within 8-12 weeks, followed by a tapering down of about 10 mg per week until a dose of 40 mg or 5 mg per week is reached up to 20 mg. Then the dose is tapered off 2.5 mg per week.

Aminosalicylic Acid Preparations 5-aminosalicylic acid (5-ASA) or mesalazine are preferred over sulfasalazine preparations because of the fewer side effects, although their effectiveness is relatively the same. In Indonesia, sulfasalazine is marketed in 250 mg and 500 mg tablets, 4 g/60 mL enemas, and 500 mg suppositories. The average dose to achieve remission is 2-4 grams per day, although literature mentions the use of 5-ASA at least 3 grams per day. Remission is generally performed in 16-24 weeks, followed by a maintenance dose. The maintenance dose is 1.5 – 3 grams per day. For the left or distal intestine cases, mesalazine suppositories or enemas can be given, while for severe cases, it is usually not sufficient to use 5-ASA preparations.

To prevent recurrent inflammation, efforts are made to maintain remission as long as possible through individual maintenance doses of 5-ASA or replacing steroid drugs in the acute inflammation phase with immunosuppressive medications, anti-tumor necrosis antibodies, and probiotics. Immunomodulators Azathioprine and 6-mercaptopurine, cyclosporine, and methotrexate are some of the immunomodulatory groups of drugs. The initial dose of azathioprine 50 mg is given until a substitution effect is achieved and gradually increased to 2.5 mg per kg body weight. Generally, a new therapeutic effect is achieved in 2 – 3 months.

Side effects often reported are nausea, dyspepsia, leukopenia, lymphoma, hepatitis, and pancreatitis. Intravenous cyclosporine is helpful for acute cases of refractory KU with a 50-80% success rate. Commonly reported side effects to include renal impairment and opportunistic infections. At the same time, methotrexate is known as adequate preparation for steroid-dependent PC cases as well as to maintain remission in KU. An induction dose of 25 mg intramuscularly or subcutaneously per week until completion of tapering off steroids.

References:

1. Firmansyah MA. Recent developments in the diagnosis and management of inflammatory bowel disease. CDK. 2013;203:40(4): 274-52.
2. Mayo Clinic. Inflammatory bowel disease (IBD) [Internet]. 2022. Available from: https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/symptoms-causes/syc-20353315