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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