While the incidence of the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) continues to increase or plateau in Western countries,1 their impact is also starting to be felt in the Asia–Pacific region.2,3 The increasing incidence of IBD in Asia was recently reviewed by Thia et al.4 and, with half of the world's population residing in this region, the challenge posed by the number of patients affected could be enormous. However, gastroenterologists managing IBD in the Asia–Pacific will also face a number of issues that are unique to this region.
One such example, relates to making the diagnosis of IBD. Examination of the feces for pathogens is mandatory throughout the world, but in our region, where the prevalence of infectious diarrhea is high, failure to do so vastly increases the risk of misdiagnosis. Furthermore, the high prevalence of tuberculosis (TB) in many Asia–Pacific countries may contribute to diagnostic uncertainty as both TB and CD commonly cause granulomatous ileitis. Finally, limited access to colonoscopy and specialist care in some countries further increases the risks of misdiagnosis or diagnostic delay.
Nevertheless, proposed management guidelines are broadly similar for IBD in Asia and in the West.5 This seems appropriate because, despite differences with regard to the frequency of certain genetic risk factors (such as mutations in NOD2), a male preponderance, lower rates of surgery and high rates of ileocolonic disease location in CD, the disease phenotype is otherwise similar.3 A key, and highly appropriate difference between Asia–Pacific and Western management guidelines is the importance placed on the role of infections as potential complications of immunosuppression. Just as infections can make the diagnosis of IBDdifficult, they may complicate the treatment of IBD with corticosteroids, immunomodulators and biologic drugs.6 Clearly, this is of particular importance in populations where the background prevalence of infections is high.
A major problem in quantifying the risk of infectious complications in IBD patients receiving immunosuppression in the Asia–Pacific is the lack of local data. In Western countries, several epidemiological and registry studies have been helpful in quantifying this risk. For example, Hutfless et al. published mortality data from a health insurance database of 9032 IBD patients from Northern California.7 CD was associated with increased mortality from infectious and parasitic diseases (odds ratio [OR] = 4.1; 95% confidence interval [CI], 1.7–8.5) and septicemia (OR = 6.8; 95% CI, 2.2–15.8), although data concerning the use of biologic drugs in this cohort were not presented.
Of the two currently available biologic drugs, infliximab has more safety data available than adalimumab as it was the first anti-tumor necrosis factor (TNF) drug to come onto the market. However, most would agree that the safety profile of both drugs is similar when used according to the manufacturers' instructions. Data from the TREAT registry showed no increased risk of infections in those treated with infliximab, while prednisone (OR = 2.21; 95% CI, 1.46–3.34) and narcotic analgesic use (OR = 2.38; 95% CI, 1.56–3.63) were both associated with serious infections.8 Single centre data from Leuven, Belgium, of 734 infliximab- and 666 non-infliximab-treated IBD patients revealed no differences between the two groups with regard to mortality, malignancies and infection rate. While two patients (both with negative skin tests prior to infliximab) went on to develop TB, none was seen in 16 patients with positive skin tests who had TB prophylaxis. Again, the only independent risk factor for infections was concomitant steroid use (OR = 2.69; 95% CI 1.18–6.12).9
Can one extrapolate data such as these to the Asia–Pacific region? Data from the World Health Organization ‘Global tuberculosis control—surveillance, planning, financing’ report makes sobering reading.10 In 2006, there were an estimated 14.4 million prevalent TB cases worldwide, in addition to an estimated 9.2 million incident cases. The three countries with the highest incidence of TB were all in the Asia–Pacific (India, China and Indonesia). Of particular concern is that approximately 500 000 of these incident cases are likely to be due to multidrug resistant organisms. Given the critical role that TNF plays in the formation and maintenance of granulomas, aggressive blockade of this and other inflammatory molecules in patients with TB is likely to be fraught with danger. It is clear, therefore, that when treating IBD patients with immunosuppressing drugs the world is not a level playing field, at least in relation to infectious risk. In October 2007, the worldwide Periodic Safety Update Reports from Centocor reported 1051 cases of TB from 1 008 413 patients receivinginfliximab for all indications.11 Given that such registries rely on physicians reporting cases to the company, this is likely to be an underestimate of the true figure. Unfortunately region-specific data are not available.
Hence, the importance of Trinder and Lawrance's report of their initial experience of adalimumab use in Fremantle Hospital in this issue of the Journal. While this is a small series (41 patients) with relatively short follow up, they present the first published safety data from the Asia–Pacific using this drug. One case of Herpes simplex was diagnosed in a patient also receiving azathioprine and there were also cases of skin rash and nausea. However, background rates of infectious diseases, including TB, are low in Western Australia and it is important that further series are published from other parts of the Asia–Pacific with higher endemic TB rates.
In keeping with a previous publication from this group,12 they have shown that careful selection of patients based on objective evidence of inflammation can result in very high response and remission rates from biologics in IBD. While the potential risk of using biologic drugs may be significant, there is no doubting that they are amongst the most efficacious agents available for treating moderate to severe CD and, to a lesser extent, UC.
In patients who have failed or are intolerant of immunomodulators, biologic drugs are significantly more effective than placebo at inducing and maintaining remission.13–16 However, this benefit comes with a significant financial cost of up to $US18 000/patient per year for induction and maintenance therapy. Can such a cost be justified, especially in poorer countries which face many other significant health challenges? To answer this question, one must also begin to understand the costs of CD, not only to the patient but also to the wider community. The direct and indirect costs of IBD were recently assessed in the Australian population by Access Economics at approximately $US350 million and approximately $US1.5 billion, respectively.17 Their current estimate of 61 000 people in Australia with IBD is set to increase by 20–25% by 2020. It is worth noting that, while IBD accounts for only 0.1% of health expenditure, it is more common in Australia than epilepsy, multiple sclerosis and rheumatoid arthritis, and that the burden of disability is more than living with type 1 diabetes or epilepsy.
While neither panacea nor magic bullet for IBD, biologic drugs have been shown to reduce hospitalizations, surgeries and outpatient visits.18 They also lead to improved quality of life and, almost certainly, reduced indirect costs. Federal regulatory bodies in Australia now fund biologics for CD in defined clinical situations. However, this is not the case in most other Asia–Pacific countries where, with the exception of New Zealand, Japan and South Korea, biologics are available to a very small proportion of the population, or are unavailable.19 Furthermore, in some countries such as New Zealand access to biologics is geographically defined; some public hospitals prohibit their use, while others take a more realistic approach.
The burden of IBD is set to surge in the Asia–Pacific region over the coming years. If the incidence and prevalence rates of IBD mirror those in the West then this may become an epidemic. Biologic drugs will be needed as part of the therapeutic strategy to treat IBD in the Asia–Pacific but, at present, access is limited. This issue must be addressed by both health funding agencies and pharmaceutical companies. However, just as important will be the description of biologic drug use in these populations and the development of strategies that minimize the risk of serious infectious complications.