Inflammatory Bowel Disease: A Snapshot of Current Knowledge

 

Rohitas Deshmukh*, Sujata Kumari, Ranjit K. Harwansh

Institute of Pharmaceutical Research, GLA University, Mathura-281406, India

*Corresponding Author E-mail: rohitas.deshmukh@gla.ac.in

 

ABSTRACT:

Inflammatory bowel disease (IBD) is an idiopathic inflammatory, relapsing and life threatening disorder affecting the gastrointestinal tract (GIT). The most common forms of IBD are Crohn's disease (CD) ulcerative colitis (UC) and colorectal cancer. The incidence or prevalence of IBD are increasing worldwide but is highest in the industrialized and western populations. The pathogenesis of IBD includes the various factors like environmental, immunological and genetic factors. These factors are mainly affected the gastrointestinal tract of the person based on our daily life. It causes the mild, moderate and severe inflammation in the intestine lead to IBD. In current, the diagnosis is most important technique to detect the type of IBD and helps to identify UC and CD. The diagnostic technique involves the endoscopy (capsule endoscopy, computed tomographic enterography, ileocolonoscopy etc), device assisted enteroscopy (a novel technique) and laboratory analysis (erythrocytes sedimentation rate and C-reactive protein). The therapeutic drugs such as aminosalicylates, corticosteroids, antibiotics and immunomodulators are still used to manage IBD in some extent. Thus, IBD remain challenges and need better therapeutic approach for its management.

 

KEYWORDS: IBD, Crohn’s disease, Ulcerative colitis, Inflammatory bowel disease, Colorectal cancer.

 

 


1. INTRODUCTION:

IBD is a chronic inflammatory disease of the gastrointestinal tract, particularly small and large intestine. It is a collection of idiopathic, remission, incurable and lifelong disease that affects GIT. This disease affects the millions of people worldwide, but most commonly affected the western and industrialized population. Although, more risk of colorectal cancer is increased in IBD patients and presently, colorectal cancer is fourth common deadly diseases in the world having 8,80,792 patients reported annually1. Inflammation of the GIT reduces its capability to work accurately in IBD2. Both Crohn’s disease and ulcerative colitis are the most common form of inflammatory bowel disease and affected the inflammation and remission of patients. These diseases are mostly affecting the quality of life of people3. The difference between UC and CD has been shown in table 1.

 

 

1.1. Ulcerative colitis:

UC is firstly introduced by Wilks in 18594. It is regular colonic mucosal inflammation in the rectum and mostly affected 95% patients. Inflammation in the rectum is generally restricted to the mucosa and regular involvement with pus, swelling, and spill of blood in the colon5,6 (figure 1). There are various symptoms includes distal colitis, dysentery with blood and mucus, constipation, loss of weight, cramping, stomach pain, low fever and deficiency of blood7. The extra intestinal manifestations may be acute arthropathy, erythema nodosum, anterior uveitis and aphthous ulcers etc8. There are four sub-classes of ulcerative colitis such as proctosigmoiditis, pan-ulcerative colitis, ulcerative proctitis, and left-sided colitis8,9. These sub types of UC are discussed below:

 

1.1.1. Proctosigmoiditis:

It affects the rectum and the lower part of the colon, is place right side above the rectum. Sign of illness involves the cramping, diarrhea with blood and irregular emotion of the need to pass stool, it is also called as tenesmus. Modest pain occurs in the left part of the stomach.


Table 1: Difference between the ulcerative colitis and Crohn’s disease

S. No.

Characteristics

Ulcerative colitis

Crohn’s disease

1.

Location

Mostly affect the rectum

Affect several part of the GIT but mostly affect the ileum and ileocecal part of the colon.

2.

Symptoms

Diarrhea with blood, loss of weight, cramping pain, low fever and blood deficiency

Abdominal pain, diarrhea, anorexia weight loss and rectal bleeding

3.

Types of inflammation

Continuous inflammation

Asymmetric, transmural and patchy granulomatus inflammation

4.

Complication – local

Extra intestinal manifestations

Massive hemorrhage, fulminant colitis, toxic megacolon

Eye involvement, skin disorder, joint disease

Intestinal obstruction, severe hemorrhage, fistulae and abscesses

Eye disease

 


1.1.2. Pan-ulcerative colitis:

It is affected whole colon. Symptoms include diarrhea, severe abdominal pain, cramps and extensive weight loss.

 

1.1.3. Ulcerative proctitis:

It is mild form of UC and the infection of the colon is restricted to the rectum region only and spread not more than 20 cm into the colon. This is characterized by fine ulceration in the mucosal lining of large intestine.  

 

1.1.4. Left-sided colitis:

In this type of UC the inflammation begins at the rectum and extends up to at the splenic flexure, which is the point where the colon bends, the left colon (sigmoid colon and descending colon). Sign of illness is loss of weight, stomach ache on the left part and hemorrhage.

 

Ulcerative colitis are classified as having mild, moderate or severe disease on the basis of patients. Mild disease patients shows irregular alimentary bleeding, mild crampy pain and mild diarrhea. Moderate disease patients have symptoms of loose and bloody stools (up to 10 per day), mild hemorrhage and low grade fever. In severe disease patients continuously stool loose (> 10 per day), serious cramp, a condition of high fever and require of blood transfusion and continuously loss of weight are the common symptoms9.

 

1.2. Crohn’s disease:

It was introduced by Crohn, Ginzberg and Oppenheimer in 193210. It is a chronic IBD, belonging to asymmetric, transmural and sometimes patchy granulomatous inflammation in any side of the GIT (figure 1). It commonly influences on the ileum and the ileocecal area of the colon2. The symptoms of Crohn’s disease are diarrhea, weight loss, abdominal pain, anorexia, rectal bleeding and fatigue. The extra-intestinal manifestations may be present and also affected the eyes, joints, skin and liver11. There are various signs and symptom of ulcerative colitis and Crohn’s disease which are shown in table 2.

 

Table 2: Difference between signs of ulcerative colitis and Crohn’s disease

Sign/ symptoms

Ulcerative colitis

Crohn’s disease

Affected area of GIT

Some portion of deepest covering of colon, inflammation in rectum.

Lower ileum can be eruption anywhere in the colon and patches are affected the complete intestine wall between normal tissues.

Diarrhea

Usually four events everyday

Usually four events everyday

Abdominal ache cramping

Mild softness, decreasing abdominal ache

Moderate to serious abdominal softness in right part

Bloody stool

In current, seriousness is depends on the disorder

In current, seriousness is depends on the disorder

Fatigue

Result of unnecessary blood, destruction and deficiency of blood

Result of unnecessary blood, destruction and deficiency of blood and inclusion of poor diet

Fever

Less condition in severe cases

Less condition in severe cases

Physical assessment

Rectal test can show peri-anal inflammation, cleavage and ulcers

Peritoneal inflammation,

Loss of weight /anorexia

In severe case loss of weight

Loss of weight and anorexia generally due to poor absorption and intestinal consumption

Appetite

Frequently decrease during the course of disorder exacerbation

Frequently decrease during the course of disorder exacerbation

Risk of colon cancer

Enlarged

Enlarged

 

Sub-classifications of the CD are granulomatous colitis, gastroduodenal, jejunoileitis, ileitis and ileocolitis2. These are described underneath:

 

1.2.1. Ileocolitis:

It influences the edge of the small intestine (the ileum) and the large intestine (the colon). Symptom involves cramping or pain in the right lower part of the stomach. It is frequently with serious weight loss in IBD suffering patients.

 

1.2.2. Ileitis:

This only affects the ileum. Symptoms are the same as ileocolitis. In severe cases, problems can involve fistulas or inflammatory abscess in the right lower portion of the abdomen.

 

1.2.3. Gastroduodenal Crohn’s disease:

It affects the stomach and the starting of the small intestine (the duodenum). Symptoms consist of loss of appetite, weight loss, nausea, and vomiting.

 

1.2.4. Jejunoileitis:

There is belonging to patchy regions of inflammation in the upper half of the small intestine (the jejunum). Symptoms are mild to intense abdominal pain and cramps following meals, as well as diarrhea. In severe cases or after a long time, fistulas may form.

 

1.2.5. Crohn’s (Granulomatous) colitis:

This mostly affects the colon. A symptom involves rectal bleeding, diarrhea and disease around the anus (abscess, fistulas and ulcers). Skin lesions and joint pains are more common in this form of Crohn's than in other types of Crohn’s disease.

 

2. EPIDEMIOLOGY OF IBD:

The prevalence and mortality of IBD are growing dramatically worldwide, but is great in westernized (United State and Europe) and industrialized countries12. Inflammatory bowel disease may start at any age, but it is common in 15 -30 year old people13. The IBD is multifactorial and probable cause of this disease is due to longer application of drugs like antibiotics, lifestyle and diet changes and fast food containing a certain amount of preservatives, surfactants and emulsifiers which have the ability to change natural environment (microbiome) of gut14. Over fifty percent CD patient have problem thought their life through different ways. Stenosis (narrowing of gut vessels) is a major life time issue (eight percent) in UC patients. IBD has been associated with various environmental factors and remain challenges till date15.

 

3. ETIOLOGY OF IBD:

IBD is a multi-factorial disorder associated with various factors such as environmental, genetic and immunological factors. The detail of IBD factors has been described underneath.

 

3.1. Environmental factors:

Many environmental factors, including smoking, stress and drug have been identified as risk factors in the pathogenesis for IBD16. Cigarette smoking is a one kind of environmental factor, recognized as an important risk factor for the incidence of IBD and smoking has a striking adverse effect on human population’s health as UC and CD17. Smoking increase the risk of CD by two fold as compare to healthy volunteers. Smoking enhances the occurrence of CD regression and require surgery. In contrast, smoking decrease the risk of UC. It has been observed that UC patients are generally non-smokers or exsmokers and there is an enhanced risk of developing UC in case of stopping the smoking18.

 

Stress is a reaction of the human organization to environmental stimuli and a position of disharmony homeostasis. Stress is defined as a disease of the century in 1992 by the United Nations Organization. Stress are the types of environmental condition and these are depended in family problem and related to job, emotional condition such as depression, anxiety or persistent physical stress and these factors are increasing the risk of CD and UC19,20. There have been many studies over the years which suggested that stress can be a factor for the relapse in IBD.

 

High dose of drugs like NSAIDs affects the intestinal mucosa of the stomach, small intestine and colon. NSAIDs can also increment intestinal permeability by cyclooxygenase, which decreases production of prostaglandin21. The oral contraceptives when used for a long time reported to increase the risk of UC but the effect of contraceptive drugs was less in CD22.

 

3.2. Genetic factors:

The genome wide association studies have been identified more than 200 such IBD specific genetic loci. IBD associated the 163 gene loci, 110 loci are common to both CD and UC respectively23. The NOD2 (Nucleotide binding oligomerization domain containing 2) the first sensitive gene was discovered in 2001 for CD. The NOD2 gene codes for a protein called as inflammatory bowel disease protein 1 (IBD1). They act as an intracellular receptor for gram positive and gram negative bacteria in monocytes and transduces signals leading to activate the kappa B nuclear factor24,25. Autophagy involved two genes such as ATG16L1 and IRGM. The genome wide involvement studies introduced CD with variants in ATG16L1 and IRGM26.

 

3.3. Immunological factors:

The immunological response is used in the pathogenesis of IBD. The innate immunity and adaptive immunity are part are human immune system which have role in IBD27.

3.3.1. Innate immunity:

These systems are helpful to provide the non specific protection to the host is based on the arrangement recognition of pathogenesis, although the adaptive immune system mediates the more selective and an everlasting immunity response. Intestine epithelia, macrophages, monocytes, neutrophils, dendritic cells and natural killer cells are made of innate immune system28.

 

3.3.2. Adaptive immunity:

This immunity plays an important role in the pathogenesis of the inflammatory bowel disease. The immune response is regulated with the help of T- cells in IBD. These are stimulated and separated in the presence of antigens and these are different in the peripheral blood. The main subclasses of T-helper cells are Th1, Th2, Treg and Th17. Each class produces the immune functions such as the pathogenic agents are removed with the help of the Th1 in the cells. Th2 are helpful to regulate the allergic reaction and save the body from parasites. Th17 are eliminated the extracellular bacteria and fungi. The Treg cells are helpful to increase the tissue repairing.  These are IL-1, IL-2, IL-6, IL-8, IL-12, TNF-α and IFN-γ are the different types pro- inflammatory cytokines and these are produced by the Th1 cells. The anti-inflammatory cytokines likes IL-4, IL-10 and IL-13 are secreted by the Th2 cells29,30.

 

4. DIAGNOSIS OF IBD:

The diagnosis of IBD is based on the combination of endoscopic, laboratory and radiological investigations.

 

4.1. Endoscopic tests:

Endoscopy is a most important test to diagnose IBD. The endoscopy test can differentiate the CD from UC, control disease activity and response to treatment and to determine for treating difficult complication31,32. This test is used to confirm the location of disease. The endoscopic technique helps to locate the aphthous ulcers, skip lesions, cobblestoning and strictures. In the recent year, imaging evaluation, especially computed tomographic enterography, ileocolonscopy and magnetic resonance enterography, endoscopic ultrasound, capsule endoscopy and device assisted enteroscopy plays a significant role in the diagnosis to treat the IBD34.

 

4.2. Ileocolonscopy:

It is the best tool used for the analysis of CD, UC and lelitis. It is the first line examination in suspected IBD patients30.

 

4.3. Computed tomography:

It is another technique to detect the IBD and used to diagnose and to determine the complication in the IBD. By this test various symptoms such as vomiting, abdominal pain, fever etc. are also analyzed35.

 

4.4. Endoscopic ultrasound:

It is widely used technique and has a stable role in gastrointestinal imaging (transmural and extraluminal) in diagnosis of IBD in comparison with conventional ultrasound. It is a costly system and not suitable for UC36.

 

4.5. Capsule endoscopy:

It is a good technique for diagnosis of small bowel lesions in case of CD and is used when other modalities does not provide appropriate diagnosis12. It has an ability to take photographs while moving naturally with intestinal movements, thus facilitating direct, non-invasive visualization of the intestinal mucosa. It is widely used in adults and young children between 10-18 years age for diagnosis of CD. Capsule endoscopy is also applicable for detection of ulcers, erosions and fistulas37,38. The advanced capsule endoscopy techniques are highly promising for IBD which includes wireless capsule endoscopy and balloon enteroscopy39-40.

 

4.6. Laboratory test:

In a blood test, if there is a high WBC count with increased platelet number, indicates IBD. An inflammatory blood biomarker like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) is used for identifying IBD. Stool biomarkers like calprotectin and lactoferrin is used for the identification of IBD41-43.

 

5. TREATMENT OF IBD:

The main focus of treatment of the IBD is to improve the quality of life and reduce the prevalence of IBD44. There are different classes of medicines such as anti-inflammatory drugs, corticosteroids, antibiotics, immunomodulators and anti-TNF agents used for management of IBD45 which have been represented in table 3.


 

 

Table 3: Various treatment approaches of IBD

Class

Drug

Dose

Route

Symptom

Marketed products

Amino

salicylates

Mesalazine

1.5-2.4 g/d

Oral

Headache, Watery diarrhea, Nausea, Vomiting, rash, Hemolytic anemia

Apriso, Delzicol, Lialda, Pentasa, Asacol HD

Sulfasalazine

2-4 g/d

Oral

Azulfidine, Sulfazine, Sulfazine EC

Balsalazine

6.75 g/d

Oral

Colazal

Olsalazine

2-3 g/d

Oral

Dipentum

Cortico

steroids

Prednisolone

20-60 mg/d

Oral

Edema, Growth failure, Fatigue, Osteoporosis, Altered body shape, Cataracts, Psychosis

Prelone, Orapred, Millipred, Fio-pred

Budesonide

6-9 mg/d

Oral

Eutocort, Budeson

Methylprednisolone

60 mg   3 times/d

Oral

Medrol, Medrol Dosepak

Immuno

modulators

Azathiopurine

1.5-2.5 mg/kg/d

Oral

Allergic reaction, Hepatitis, Bone marrow suppression, Nausea, Vomiting, Liver dysfunction, Stomatitis

Imuran, Azasan

6- Mercaptopurine

1.0-1.5 mg/kg/d

Oral

Purixan, Purinathol

Methotrexate

25 mg weekly

Oral

Trexall, Rasuvo, Otrexup,

Antibiotics

Ciprofloxacin

500 mg 2 times/d

Oral I.V

Nausea, Diarrhea, Rash, Fatigue, Dizziness

Cipro, Cipro XR, Cipro I.V

 

400mg 2 times/d

Oral I.V

Metronidazole

10-20 mg/kg/d

 

Flgyl, Flagyl IV, Flagyl ER

Biological

Agents

Infliximab

5 mg/kg

I.V

Infsion related reaction, Rash, Fever, Headache, Activation of tuberculosis

Remicade, Remsima

Adalimumab

40 mg

Inj.Oral

Humira

Golimumab

50 mg

Inj.

Simponi

 


5.1. Anti-inflammatory drugs:

An anti-inflammatory drug like 5-amino salicylates (5-ASA) is the first line therapy used for UC and CD. It is safe and well tolerated in most of the cases46.  Rectal formulations are available in suppositories (1g/day) or enemas (4g/day) form. Sulfasalazine is the first choice drug for the treatment of IBD47. Mesalazine/mesalamine is another choice of drug used in the treatment of mild to moderate conditions of IBD. The oral dose of mesalamine is 1.05 to 2.04 g every day and the mesalamine dose has similar efficacy to sulfasalazine dose is 2.0 to 3.0 g every day in patients for UC48.

 

5.2. Corticosteroids:

When aminosalicilates does not give desired results corticosteroids are recommended. It is also used as a first line drug for the treatment of CD and UC49. Oral dose of corticosteroid like prednisone is 20 mg/day to 60 mg/day. It is also available in the topical and enema formulation. Another drug, budesonide is used for the treatment of CD at single oral dose (9 mg/day) for eight week50.

 

5.3. Immunomodulators:

Immunomodulators are used when the patient failed with mesalamine treatment or in corticosteroids dependent patients for corticosteroids-sparing effect. The most commonly immunomodulators used for the treatment of IBD are 6-mercaptopurine (6-MP) and azathiopurine (AZA) belongs to the family of drugs known as the thiopurines51, 52. For more than 30 years, azathiopurine and its metabolite 6-mercaptoprine is used in the treatment of IBD. AZA and 6-MP after metabolism convert into 6-thioguanine nucleotide (6-TGN) which is responsible for inhibition of DNA and RNA synthesis leading to apoptosis of T-cells. The recommended dose of azathiopurine for IBD is 1.5-2.5mg/kg/day and the dose of 6- mercaptopurine is 1.0-1.5mg/kg/day. In addition, other immunomodulators like methotrexate, cyclosporines and tacrolimus are used as second line drugs in the treatment to maintain remission53, 54.

 

5.4. Antibiotics:

IBD is characterized by microbial dysbiosis which make a theoretical sense to use antibiotics in the management of the disease. It has been reported that antibiotics, mainly metronidazole, ornidazole, rifaximin and ciprofloxacin are beneficial for the patient of IBD, and these are used as a first line treatment for fistulating perianal Crohn’s disease patients. A meta-analysis of 10 trials with 1160 patients for the IBD treatment with antibiotics showed benefit to patients as compared to placebo. These drugs are generally suggested to stimulate remission in mild to moderate CD. These drugs are also helpful for managing fistulas, bacterial overgrowth. Metronidazole and ciprofloxacin either alone or in combination were found to decrease perianal fistula drainage compared to placebo55.

 

5.5. Anti-TNF agents:

TNF-α (Tumor necrosis factor alpha) are the cytokines which are increased in the setting of inflammatory conditions like IBD and rheumatoid arthritis. Therefore, blocking the TNF-α is also an approach for the treatment of IBD. Monoclonal antibodies are the agents which bind to cytokines and inhibit inflammation. Till date the anti TNF agents approved for the treatment of IBD are infliximab, adalimumab, golimumab and certolizumab56. Infliximab is a chimeric monoclonal antibodies used for both UC and CD for long term use.  Adalimumab is also used for both CD and UC but certolizumab are used for CD only57.

6. CONCLUSION:

IBD is a multifactorial, complex and immune mediated inflammatory disorder occurred in GIT including the small and large intestine. IBD has involvement of complex factors for the disease, although, it is difficult to find out a curative therapy for the IBD. Still IBD therapy for is challenging and require better treatment strategies. Various medicines such as the aminosalicylates, immunomodulators, antibiotics and anti -TNF agents are used by the physician for the management and remission of the IBD. Therefore, the goal of the therapy should be focused on clinical remission with healing of the mucosal layer, avoiding surgery and improving the patient’s quality of the life. Research are going on for the search of novel therapy for the better treatment of IBD. The future therapy would be inhibitors of RNA, faecal microbiota transplant and use of probiotics.

 

7. CONFLICT OF INTEREST:

Authors have no conflict of interest.

 

8. ACKNOWLEDGEMENT:

Authors are grateful to the IPR, GLA University, Mathura, for providing necessary facility to carryout work.

 

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Received on 05.07.2019            Modified on 21.08.2019

Accepted on 17.09.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(2):956-962.

DOI: 10.5958/0974-360X.2020.00180.8