Guidelines in Diagnosis and Management of Inflammatory Bowel Disease (IBD)


Authors: Dr. Hasdi Malagapi; Dr. Adhi Setyawan; Dr. Samida Karupunda; Dr. Mimbar Sejarah; Dr. Oska Mesanti; Dr. Syaifun Niam

Introduction

Southeast Asia (SEA) refers to a vast region within Asia that encompasses countries between the Indian Ocean and the Pacific Ocean with diverse ethnic populations and sociocultural backgrounds. Countries that fall within this region are Vietnam, Laos, Cambodia, Thailand, Myanmar, Malaysia, Indonesia, Singapore, Philippines, Brunei and Timor Leste. As can be seen from this list, SEA nations are of varying national affluence and industrialization status; these are factors that significantly impact access to healthcare in general. This translates to variations in the availability of routine vs specialized modalities in working-up a patient suspected to have IBD. Additionally, once diagnosed, managing these patients may also represent a challenge in view of limited access to newer therapeutic options.

Epidemiology of IBD

Asia's developing nations are facing increasing rates of inflammatory bowel disease (IBD), similar to those witnessed in the West over the last century. Using IBD as an example of a multifactorial disease with genetic and environmental elements involved in disease pathogenesis, it is clear that environmental factors are predominately responsible for the increasing incidence of these diseases (1). The incidence and prevalence of IBD within SEA varies widely from one country to another. In developed countries, the use of clinical registries as an integral part of the health system ensures that patient information is captured and relevant statistical is data obtained. Unfortunately, this is not the case for many SEA nations. There are also issues of adequately defining catchment areas as well as having standardized criteria for the diagnosis of IBD. IBD cases which are reported would most likely come from hospital-based data in larger cities, which may not accurately reflect actual incidence and prevalence rates for the whole country. Patients too may opt for alternative medical practices; gender and cultural norms would also affect healthcare-seeking behaviour. These issues combined further illustrate the challenges faced in obtaining and reporting SEA IBD epidemiological information (2).

Nevertheless, despite these limitations, it has been shown that the incidence and prevalence of IBD in the SEA region are on the rise; mirroring what is seen in the Asian continent generally. In comparison with the number of new IBD cases in Western countries which is thought to have plateaued, the incidence of new IBD patients within SEA member countries have been shown to be rapidly increasing in line with the pace of modernization. To a certain degree, the rise in incidence may be attributed to increased awareness regarding IBD, leading to a higher rate of new diagnoses being made. However, this would fully not explain the rapid rise in the number of new cases of IBD being diagnosed year after year.

The incidence of IBD across Asia was 1.37 per 100,000, with China having the highest incidence at 3.4 per 100,000 individuals. Across Asia, the incidence of IBD varies from 0.5 to 3.4 per 100,000 people, and seems to be greater in highly urbanized countries (3).

The ACCESS paper in 2013 provided some valuable insight into the epidemiology of IBD within the Asia Pacific region. Several SEA nations participated in this study; namely Thailand, Malaysia, Singapore and Indonesia. It was shown that the age-standardized incidence of IBD for Thailand (Bangkok) was 0.58, Thailand (Chiangmai) was 0.54, Malaysia 1.01, Singapore 0.97 and Indonesia 0.83 (per 100,000 persons respectively). The ACCESS study also included Australian data, which showed an age-standardized incidence of 24.54/100,000 persons; much higher than the rates seen within the SEA countries that took part in the study (4).

Within the SEA region, there are more cases of ulcerative colitis (UC) as compared to those with Crohn’s disease (CD). This contrasts with Western countries, where the gap between the numbers of UC and CD patients is smaller. Rates of IBD also varies from one ethnic group to another.

For example, in the multi-ethnic countries of Malaysia andSingapore, the incidence of UC is higher amongst ethnic Indians than the Chinese or Malays. Conversely, Malays from these countries have less CD as compared to other ethnic groups (5).

Diagnosis

As mentioned earlier, increased awareness regarding the features of IBD has helped to contribute to better pickup rates. Nevertheless, before a diagnosis of IBD could be made, it is essential that possible differential causes be ruled out first (6). Common alternative diagnoses that may mimic the colonic lesions of IBD include infectious causes such asClostridium difficile, enterotoxigenic Escherichia coli, Mycobacterium tuberculosis or Entamoeba histolytica. Examples of non-infectious causes that may also be mistaken as IBD include ischaemic colitis, non-steroidal anti-inflammatory drug use and Behçet’s disease (7).

Whilst most infectious causes are self-limiting and tend to be identified after a short duration, the issue of differentiating gastrointestinal tuberculosis (TB) from IBD (especially CD) remains a significant problem within SEA. TB is endemic in many SEA countries and must be considered as a differential cause for those that present with signs and symptoms suggestive of IBD. The diagnosis of IBD is made on clinical, endoscopic, histological and radiological features using standard criteria. As a start, a careful history must be taken to exclude other potential causes with a focus on determining prior contact with TB patients. History-wise, post-infectious irritable bowel syndrome may be mistaken as symptoms of IBD. Nevertheless, in endemic areas, the patient may not even be aware of TB exposure, and thus a high index of suspicion for TB must be maintained. This is followed by a physical examination for signs suggestive of IBD but at the same time being on the lookout for other alternative diagnoses (8).

Subsequently, the patient will need to undergo further investigations to confirm a diagnosis of IBD (9).

Laboratory investigations

Apart from markers of inflammation (e.g., leucocyte count, erythrocyte sedimentation rate, C-reactive protein), serological markers may also be used to assist in the diagnosis of IBD. Whilst anti- Saccharomyces cervisiae antibody (ASCA) and atypical perinuclear anti-neutrophil antibody (pANCA) testing are typically used to assist in diagnosing IBD, several other serological tests, e.g., anti-chitobioside antibody (ACCA), anti-laminaribioside antibody (ALCA) and anti-mannobioside antibody (AMCA), have also been suggested as additional tests to confirm a diagnosis of IBD (10). The utility of such tests within SEA, however, may be limited. A comparison of these tests between Hong Kong Asian vs Australian Caucasian IBD patients showed differing serologic responses. Extrapolation of these results to a broader SEA community would indicate that such testing would probably be of limited value. These tests would also not be readily available at many local SEA centers; for many, it would be an expensive test to order as samples are couriered and processed internationally (11-13).

In TB endemic areas, interferon-gamma release assay (IGRA) testing is recommended to exclude latent TB. IGRA testing is especially important prior to commencing immunotherapy (14).

Radiological modalities

In many SEA nations, access to radiological modalities, e.g., computed tomography (CT) or magnetic resonance imaging (MRI), may be limited. Such modalities may only be accessible within larger cities – leaving those from rural areas without much choice with regards to radiological investigations to assist in making a diagnosis of IBD (15). Specialized radiological procedures such as CT or MRI colonoscopy, or even CT enterography/enteroclysis may not be available, thus leaving clinicians with limited options to assist in diagnosing (and managing) patients with IBD. Even when available, the cost of having such investigations may be prohibitive, thus limiting the use of such modalities. In such cases, the use of barium meal follow-through or barium enema studies may help in diagnosing IBD. Having said this, abdominal CT is a valuable tool to assist in differentiating intestinal TB from CD (16).

Nevertheless, as gut TB may also mimic the signs and symptoms of IBD, at the very least a chest radiograph is helpful before starting treatment. Immunosuppressive treatment may lead to worsening of pre-existing TB, which could be catastrophic for the patient (17).

Endoscopic evaluation

Gastrointestinal endoscopy remains the cornerstone of diagnosing IBD as it allows for visualization of mucosal lesions, as well as allowing for histopathological tissue samples to be obtained. Again, there may be a limited number of centers that offer this service, and even then, prolonged waiting times could lead to delays in diagnosing and managing IBD (18). 

The mucosal lesions seen during ileo-colonoscopy in patients with IBD (especially Crohn’s disease) may be indistinguishable from that of intestinal TB. However, it has been suggested that several endoscopic features may assist in differentiating the ileo-caecal lesions of CD as compared to those of intestinal TB; an involvement of less than four segments of the colon, a patulous ileo-caecal valve, transverse ulcers, and a greater amount of scarring all point to a preferred diagnosis of intestinal TB (19).

Management of IBD Consensus statements on the management of CD and UC have been released for the Asia-Pacific region (20,21). Generally, clinicians in SEA countries follow these statements to assist them in the optimal management of patients with IBD (20-22). These guidelines summarize the available evidence and provide recommendations as to the use of topical therapies, intravenous and oral corticosteroids, immunomodulators (thiopurines and calcineurin inhibitors especially) as well as the appropriate use of biologics and the role of surgical intervention. Apart from the Asia-Pacific consensus statements, clinicians in Malaysia also have access to a treatment algorithm which incorporates widely accepted IBD management strategies that have been customized according to locally-available treatment modalities (23). 

Due to financial constraints, it is expected that conventional medications would remain the mainstay of treatment for patients with IBD. However, biologic therapy is recommended in patients that have indicators of poor disease outcomes (e.g., younger age, fistulizing disease, multiple relapses) or in those that have moderate to severe IBD (Table 1). It is a recognized fact that IBD treatment is costly; this is even more so when biologics are needed. Unfortunately, not many SEA countries offer public medical insurance to offset the high costs of biologic use. Singapore, for example, has a high public health insurance coverage rate; this is low in Malaysia (24). 

As highlighted previously, the use of immunosuppressive, immunomodulator and/or biologic therapy carries a significant risk of concomitant infection, of which tuberculosis is a significant concern. A negative screening prior to initiation of biologic therapy does not eliminate the possibility of the patient having TB later. Thus, it has been suggested that gut-specific therapies (anti-integrins) or even biologics that target the IL12/23 pathway should be preferred over initiation with anti-tumour necrosis alpha biologics as these therapies have been associated with low risk of TB infection (24). 

At the same time, it must be kept in mind that there is a high prevalence of Hepatitis B virus (HBV) infection within SEA nations. Thus, it is important to screen patients with IBD for the presence of HBV prior to commencing immunosuppressive, immunomodulator and/or biologic therapies; those with a positive screening result will need to have prophylactic antiviral therapy to prevent HBV flares during this period (25).

Name Indication(s) Antibody type Mode of action Administration Dosing intervals
1. Infliximab Crohn’s disease and Ulcerative colitis Chimeric monoclonal antibody Anti-tumour necrosis factor Intravenous infusion Induction: Week 0,
2 and 6
Maintenance: every
8 weeks
2. Adalimumab Crohn’s disease and Ulcerative colitis Fully humanised monoclonal antibody Anti-tumour necrosis factor Subcutaneous injection Induction: Week 0 and 2
Maintenance: every
2 weeks
3. Golimumab Ulcerative colitis Fully humanised monoclonal antibody Anti-tumour necrosis factor Subcutaneous injection Induction: Week 0 and 2
Maintenance: every
4 weeks
4. Vedolizumab Crohn’s disease and Ulcerative colitis Fully humanised monoclonal antibody Anti-α4α7 integrin Intravenous infusion Induction: Week 0,
2 and 6
Maintenance: every
8 weeks


Treatment for Ulcerative Colitis

Acute severe/fulminant ulcerative colitis (Truelove and Witt’s criteria) (26):
  • ≥6 bloody stools/day WITH
  • Fever (temp >37.8°) or
  • Tachycardia (pulse >90bpm) or
  • Anaemia (Hb <10.5g/dl)or
  • ESR (>30mm/h) or raised CRP
Adequate response: <3 stools/day or 3-8 stools/day with CRP<45mg/L
Inadequate response: >8 stools/day or 3-8 stools/day and CRP>45mg/L 

Endoscopic assessment:
Mucosal healing
Adequate: Endoscopic Mayo score 0,1
Inadequate: Endoscopic Mayo score 2,3 

Consider stepping up therapy regardless of symptoms in patients with inadequate mucosal healing. Faecal calprotectin <150mg/kg may be used as a surrogate marker for mucosal healing (27). 

Relapse investigation protocol
In patients with flares not responding to therapy, send stools for microscopy and culture and Clostridium difficile toxin as well as biopsies to look for coexisting CMV colitis (28). 

THERAPY:

5-aminosalicylates
  • Sulphasalazine (SSZ) can be considered as an alternative to mesalazine but higher risk of side effects (Steven Johnson syndrome, oligospermia) and higher doses less well tolerated (29).
  • SSZ may provide better symptom relief than mesalazine in patients with IBD related arthopathy (30).
Thiopurines / Immunomodulators
  • Azathioprine usually used, 6MP 1-1.5mg/kg/day , can be used if patient develops nausea (31).
  • Start azathioprine at low dose, typically in increments of 50mg every 6-8 weeks to a dose of 1.5-2.5 mg/kg/day if no biochemical/haematological abnormalities or side effects.
  • FBC & LFT’s weekly for 4 weeks then 2 weekly for 4 weeks, at initiation or following dose increase. Once the dose is stable, reduce to 3 monthly.
  • TPMT levels and metabolite monitoring 6-TGN and 6-MMP(R) recommended in all patients if possible but should particularly be considered in patients who are intolerant/have significant side effects to the drug or in patients who have frequent relapses despite standard weight based regime (32,33).
  • At present, data for use of methotrexate still limited but can be considered in thiopurine intolerant individuals.
  • Methotrexate can be given as a loading dose 25mg/week subcutaneously or intramuscularly for 12-16 weeks with oral folic acid 5mg stat on Day 3 after administration. This is followed by maintenance of 15mg/week either orally or sc/ im. Blood monitoring similar as for thiopurines (34).
Anti-TNF therapy
  • Although generally used as long-term maintenance therapy, can consider stopping biologic in 6 months to one year with thiopurine maintenance if complete mucosal healing achieved (35).
  • Drug and antibody monitoring not available at present.
Screening pre biologic therapy:
  • Latent TB: CXR or CT chest AND Tuberculin skin test (TST) or Interferon-gamma release assays (IGRA) such as Quantiferon Gold and T-SPOT. TB test (36).
  • For current or previous chronic hepatitis B: Hep B sAg, IgG HBc Ab.
Vaccinations
  • Consider all vaccinations especially in the elderly population.
  • Main vaccines should include varicella, HPV, influenza, pneumococcal, Hepatitis B.
  • Live vaccines should not be given within three weeks before commencing anti- TNF and within three months after last dose (37).
Steroids
  • Taper prednisolone therapy as soon as clinical remission achieved, ideally patient should be steroid free within 3 months.
  • Always prescribe with calcium/vitamin D supplements as per algorithm (38).
Rescue therapy in acute severe ulcerative colitis
  • Infliximab preferred in thiopurine refractory patients (35).
  • Cyclosporin best reserved in thiopurine naïve patients as long term side effects of cyclosporin limits its use as maintenance therapy (39).
  • Sequential use of infliximab followed by cyclosporin or vice versa not recommended unless in specialized centres.
  • Other rescue medications such as tacrolimus, leucocyte apheresis used depending on availability.

Treatment for Crohn’s Disease

Fistula
Simple - superficial/low, without signs of abscess formation or anorectal stricture. 

Complex - high/multiple openings with abscesses; rectovaginal fistula; anorectal stricture with rectal Inflammation. 

Adequate response - Closure of fistula based on clinical symptoms and external examination (40). 

Endoscopic Assessment
Mucosal healing - Although no clear definition exists, generally defined as absence or almost complete absence of ulcers and erosions. 

Stepping up therapy to achieve mucosal healing should be considered in all patients with Crohn’s disease regardless of symptoms in patients to avoid long term complications and surgery. 

Faecal calprotectin <150mg/kg may be used as a surrogate marker for mucosal healing (41). 

Enteral nutrition
Polymeric formula (eg Ensure) or dipeptide based formula (eg Peptamen) 30kcal/ kg/day can be used as exclusive enteral nutrition for 4-6 weeks or as a supplement to normal diet (42). 

5 Aminosalicylates
Limited evidence for mesalazine except for in mild colonic disease (43). 

Thiopurines/Immunomodulators
  • Azathioprine usually used, 6MP can be used if patient develops nausea.
  • Start azathioprine at a low dose, typically in increments of 50 mg every 6-8 weeks to a dose of 1.5-2.5 mg/kg/day if no biochemical/haematological abnormalities or side effects (44).
  • FBC & LFT’s weekly for 4 weeks then 2 weekly for 4 weeks, initially or during dose increase. Once the dose is stable, reduce to 3 monthly.
  • TPMT levels and metabolite monitoring 6-TGN, 6-MMP(R) recommended in all patients if possible but should particularly be considered in patients who are intolerant/have significant side effects to the drug or in patients who have frequent relapses despite standard weight based regime.
  • At present, data for use of methotrexate still limited but can be considered in thiopurine intolerant individuals.
  • Methotrexate can be given as a loading dose 25mg/week subcutaneously or intramuscularly for 12-16 weeks with oral folic acid 5mg stat on Day 3 after administration. This is followed by maintenance of 15mg/week either orally or sc/ im. Blood monitoring similar as for thiopurines (44). 
 Anti-TNF therapy
  • Although generally used as long-term maintenance therapy, can consider stopping biologic in 6 months to one year with thiopurine maintenance if complete mucosal healing achieved (35).
  • Drug and antibody monitoring not available at present. 
 Screening pre biologic therapy:
  • For current or previous chronic hepatitis B: Hep B sAg, IgG HBc Ab (36). 
 Vaccinations
  • Consider all vaccinations especially in the elderly population.
  • Main vaccines should include varicella, HPV, influenza, pneumococcal, hepatitis B.
  • Live vaccines should not be given three weeks before commencing anti-TNF and three months after last dose (37). 
Steroids
  • Taper prednisolone therapy as soon as clinical remission achieved, ideally patient should be steroid free within 3 months (45).
  • Always prescribe with calcium/vitamin D supplements as per algorithm.
  • Budesonide if available.

Follow up and cancer surveillance

IBD patients tend to be followed up every three to six months in all the major public hospitals although there are a significant number of patients who are lost to follow up. IBD clinics with specialist nurses are not available in many countries due to the small number of cases in each hospital. There are no specific guidelines for in terms of CRC surveillance in IBD patients so established guidelines from British Society of Gastroenterology(BSG, European Crohnʼs and Colitis Organisation (ECCO) and American Gastroenterology Association (AGA) are generally used. However, there is still limited data on the prevalence of dysplasia and IBD associated CRC in SEA. A recent study at Malaysia Medical Centre based on 518 colonoscopies and 163 IBD patients (111 UC, 52 Crohnʼs colitis), the overall prevalence rate of confirmed dysplasia was 3.7% with a cumulative risk of 4.7% at 10 years and 6% at 20 years from diagnosis. There were two interval cancers despite regular surveillance according to guidelines and both were Dukeʼs C carcinomas. This is indeed very sobering as it appears that despite surveillance, interval cancers in advanced stages are still being picked up as opposed to low or high grade dysplasia before the development of cancers. Most endoscopists are not familiar with the regular use of chromoendoscopy and other forms of image enhanced endoscopy(eg NBI and are therefore likely to miss subtle dysplastic lesions. This knowledge and experience is essential in order to perform targeted biopsies during surveillance, which have largely replaced the practice of performing random colonic biopsies. There is also often confusion between dysplastic lesions and pseudopolyps. Endoscopic submucosal dissetion(ESD)of endoscopically resectable dysplastic lesions is also rarely carried out due to lack of expertise (46).

Conclusion

Southeast Asia is a large region that encompasses many countries with diverse cultural, ethnic and socioeconomic backgrounds. Although the incidence and prevalence of IBD in this region is low as compared to Western countries, rates are increasing, which may be linked to lifestyle, dietary and environmental changes. It is important that a diagnosis of IBD be made early as to prevent further disease-related complications; however, care must be taken to exclude the presence of tuberculosis which may mimic IBD. Prior to initiating therapy, one must make sure that patients are screened for HBV apart from other communicable diseases; and during therapy, patients will need to be constantly monitored for tuberculosis too as these infections are endemic within the SEA region.

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