Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract comprising Crohn’s disease (CD), ulcerative colitis (UC) and IBD-unclassified (IBD-U).[[1,2]] IBD is of unknown origin, but is characterised by chronic, relapsing and remitting gut inflammation due to an interplay between genetic susceptibility and environmental elements resulting in maladaptive immune responses.[[1,3,4]] There is no cure for IBD, with the main therapy being constant monitoring and a careful life-long medication regimen, besides surgery and other interventions. As IBD is diagnosed mainly at a young age, it places a considerable social burden on patients’ education, careers and relationships etc., alongside its impact on their health.[[5]] Moreover, as well-controlled IBD has a minimal impact on the lifespan, patients bear the disease burden for the majority of their lives.

IBD is characterised by periods of active disease, flare-ups and quiescent times with varying impact on patients’ wellbeing. During times of active disease, patients with IBD might face a range of symptoms including (bloody) diarrhoea, urgency/tenesmus, constipation/loading, abdominal discomfort/pain, weight loss etc., limiting their quality of life (QoL) and overall productivity.[[1]] Furthermore, uncontrolled IBD might lead to complications including strictures, fistulae or abscesses, amongst others. Patients with IBD may also experience extra-intestinal manifestations, which worsen patients’ QoL, such as inflammation in the eye (e.g., uveitis/episcleritis), skin (e.g., pyoderma gangrenosum and erythema nodosum) and joints (e.g., ankylosing spondylitis), alongside several others including pancreatitis and osteoporosis.[[1,6]]

Moreover, IBD poses considerable costs to the patient and society. In New Zealand, the yearly cumulative direct and indirect (loss of productivity etc.) costs of IBD amounted to approximately $245 million NZD, as at 2017,[[7]] and costs are likely to have risen since then with increased prevalence and general economic inflation.

Global burden of IBD

IBD is a global disease, with its incidence/prevalence expected to grow particularly as global life expectancy rises.[[5]] However, there is a marked difference in its geographical burden as industrialised Western countries have much greater IBD incidence/prevalence than others, although developing countries have higher growth rates of IBD.[[5,8,9]]

IBD is most prevalent in Europe and North America, with high levels of Crohn’s disease (CD) and ulcerative colitis (UC) of 319 per 100,000 in Canada and 505 per 100,000 in Norway, respectively.[[9]] Across Europe, CD and UC prevalence is as high as 213 and 294 cases per 100,000 persons, respectively.[[10]] Nonetheless, incidence rates in developing regions, such as Africa, South America and Asia, have been on the rise for the past three decades. Case in point, Brazil has an annual growth in CD and UC incidence of 11.1% and 14.9%.[[9]] Similarly, in Taiwan, CD and UC incidence rises by 4% and 4.8% yearly.[[9]]

IBD incidence in Western countries is plateauing, whilst that of developing countries is accelerating.[[1,9]] Nonetheless, the disease burden remains greatest in the “Western” world with prevalence exceeding 0.3% in most nations of Europe, North America and Oceania.[[9]] Seventy-five thousand Australians have IBD with over 1,600 new diagnoses made annually; whereas, in New Zealand, IBD prevalence stood at 20,792 people as at 2017, and by 2028, this value will have doubled due to an annual growth rate of 5.6%.[[1,7,11]]

IBD incidence has increased in tandem with the development and “Westernisation” (in dietary/societal norms etc.) of industrialising nations.[[3,5,8,10]] Diet has been associated with the development of IBD, especially consumption of high sugar, fat and processed foods, which are common in Western diets.[[5]] The higher prevalence of IBD in Europe and North America, whose countries have been industrialised for longer, as compared to Asia and Africa is in consonance with this development-incidence trend.[[9]] Thus, it can be expected that IBD rates will grow as even more countries develop in the coming decades; further heightening the global impact of the disease.[[5]]

IBD therapy: constraints in New Zealand

IBD requires complex lifelong therapy impacted by various factors and thus ideally provided by a multidisciplinary team composed of a gastroenterologist, nurse (IBD, stoma therapy specialist), dietician, pharmacist, colorectal surgeon, psychologist and others.[[1]] The overarching purpose of therapy includes: inducing and maintaining disease remission; decreasing complications (e.g., abscesses, strictures, fistulae); bettering patients’ QoL; reducing medication toxicity; re-establishing and sustaining good nutrition, as well as minimising the risk for surgery and/or hospitalisation.[[2]]

Classes of medications used in IBD therapy include: 5-aminosalicylic acid drugs - 5-ASAs (e.g., sulfasalazine, mesalamine); corticosteroids (e.g., prednisone/prednisolone, budesonide); and immunomodulators (e.g., thiopurines—azathioprine, 6-mercaptopurine (6-MP), and methotrexate besides the newer ozanimod).[[12,13]] Others are: antibiotics (e.g., ciprofloxacin, metronidazole) and, more recently, biologic agents (e.g., infliximab [IFX], adalimumab [ADA], certolizumab pegol [CZP], golimumab [GOL], [all of which are TNF inhibitors], natalizumab [NAT] [α4-integrin inhibitor], vedolizumab [VDZ] [α4b7 inhibitor] and ustekinumab [UST] [IL-12/IL-23 inhibitor]), and Janus kinase inhibitors (JAKi) (tofacitinib, upadacitinib and filgotinib).[[4,12–14]] Additionally, exclusive enteral nutrition (EEN), a dietary intervention, is also used in IBD therapy.[[1]] The combinations of medications prescribed depend on factors such as disease activity, therapy target (e.g., attain vs maintain remission), side effects and comorbidities, amongst others; thus, other medicines might also be utilised as the disease progresses. Only some of the aforementioned medicines are publicly funded in New Zealand (see Figure 1).

View Figures.

Conventional IBD therapy, particularly in New Zealand, takes a “bottom-up”/“step-up” approach entailing the incremental usage of more affordable—symptom controlling—medications, with gradual escalation to (more expensive) disease pathophysiology modifying therapeutics until the target disease outcomes are attained (see Figure 2).[[7,15,16]] However, some specialists argue that such an approach focusses on remedying already entrenched disease, often missing the “window of opportunity” where prevention or reversal of damage to the bowel might best be possible.[[17]] Therefore, other treatment paradigms including the “top-down” approach are recommended. This entails the use of top-disease pathophysiology modifying drugs (e.g., biologics alone/alongside immunomodulators) from the outset of therapy to arrest disease progression and swiftly attain remission, following which the medications are gradually withdrawn.[[15,16,18]] Central to this strategy is providing patients with timeous specialist (gastroenterology) care; but in practice, it can take months for patients to access publicly funded specialist care in some places, like New Zealand, due to specialist workforce limitations.[[11]] Hence, greater awareness at the primary care level leading to timeous specialist referrals for diagnosis is essential. Also, disease monitoring is important both to measure the effect of therapy and to assess adverse side effects concomitant with the powerful medications utilised. However, due to the prohibitive costs of advanced medications, and specialist shortages, amongst others, “bottom-up” therapy is the sole option for clinicians and patients in many (non-Western) countries, including New Zealand.

A critical review of the literature found that studies reported mixed results when assessing the “top-down” vs “bottom-up” approaches, with results varying based on factors including: medications used, therapy initiation point, outcomes assessed etc.[[18]] Nonetheless, “top-down” therapy shows marked promise; for instance, some studies found using joint biologic and immunomodulator therapy early in adult CD to be better at achieving certain patient outcomes (e.g., remission, mucosal healing) than the “step-up” approach.[[18]] Notwithstanding, more research is needed to compare clinical outcomes in patients adopting the two approaches, particularly in light of the high costs of top disease pathophysiology modifying drugs amongst other considerations.[[1,18]] This is also important as the “top-down” approach holds the risk of “overtreating” patients,[[17]] who might never have faced disease progression but cannot be identified ab initio as predicting disease progression is difficult, leading to unnecessary costs and side effects/risk exposure.

A major pivot of advanced IBD therapy is the use of biologics, which are disease pathophysiology modifying IBD therapeutics used for inducing and maintaining disease remission. Their availability is particularly limited in non-Western countries and their prescription is typically restricted.[[1]] In New Zealand, the only biologics approved for IBD therapy are IFX, ADA, VDZ and UST, but special authority from the Pharmaceutical Management Agency (PHARMAC) must be obtained to receive funding.[[19–21]] These biologics are approved for use only as IBD escalation therapy; and certain clinical criteria must be met e.g., severe active disease (with specific evidentiary indicators), failure of standard (step-up) therapy, when surgery is not clinically advisable etc., for publicly-funded prescription to be permitted.[[19,21]] Moreover, as these criteria do not involve therapeutic drug monitoring, this provides limited flexibility in further prescription of biologics in cases of low biologic drug levels in patients. Other use of these medications would require patients to pay for them, at significant out-of-pocket cost. Nonetheless, other therapeutics are publicly funded and unrestricted, including immunomodulators e.g., azathioprine, 6-mercaptopurine, methotrexate; 5-ASA medications; and (some) corticosteroids, amongst others.

The New Zealand Society of Gastroenterology (NZSG) notes that the range of medications approved for use in New Zealand is limited as compared to other countries where more novel therapeutics are available.[[11]] This in turn makes it extremely important that IBD patients adhere to the medication regimen, so disease progression is slowed, halted or reversed as there are limited advanced medications available/accessible to treat complex disease.  

In recent years, as a testament to their utility at inducing and/or maintaining remission in IBD, several novel biologic medications have been approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for use in IBD treatment.[[4]] The FDA has approved seven IBD biologics (IFX, ADA, CZP, GOL, NAT, VDZ and UST) alongside tofacitinib and others,[[14]] thus providing US-based clinicians with a range of the most cutting-edge therapeutics to handle advanced disease or, yet still, adopt the “top-down” treatment strategy. We contend that a change in the criteria for public-funding of the top-disease pathophysiology modifying medications to allow for use in early-stage therapy in New Zealand would be beneficial to many patients. Furthermore, the public-funding of even more advanced medicines with different action mechanisms, e.g., anti-integrins like NAT, and JAKi, would provide treatment flexibility as loss-of-response to others like adalimumab (anti-TNF) occurs in some patients.[[16]] The discrepancy in the availability of biologics between countries is due in no small part to their high cost. Hence, countries with more fully publicly funded health systems, such as New Zealand, typically restrict or do not fund the use of biologics. Noting the costs of newer therapeutics, however, the NZSG suggests that their availability in the country would considerably reduce the financial burden associated with IBD therapy in New Zealand—especially inpatient care and surgery.[[11]]

Medication adherence in IBD—an important necessity

Given the foregoing, it is especially important that IBD patients adhere to their medication regimens for maximally efficient disease management. MA is “the process by which patients take their medication as prescribed”.[[22]] Adequate MA is a major pivot in IBD management and substantially increases the likelihood of achieving desired clinical outcomes for patients, which might allow them to enjoy a better QoL. However, MA in IBD patients is often sub-optimal due to both medical and social factors that impact the patients. Hence, ensuring sufficient MA in IBD poses a substantial healthcare challenge requiring immediate address.

Up to a third of patients with IBD are insufficiently or non-adherent to their medication regimens, with 12.1% and 13.3% of patients with CD and UC in the Netherlands, respectively; 31.1% of IBD patients in southern New Zealand and 36.2% of IBD patients in South Korea found to have poor MA.[[23–25]] IBD patients’ perceptions of their own MA have also been found to differ substantially from the MA as assessed using standardised tools.[[25]] Failure to adhere properly to the drug regimen can lead to worse treatment outcomes e.g., flare-ups and complications in turn causing escalation of therapy, including frequent corticosteroid use and surgery, as well as increased morbidity and mortality, disability and health costs.[[14]]

For context, two-thirds of the costs of UC therapy, in the US, are composed of total pharmacy-related (pharmaceuticals, administration and monitoring) costs and over half of the costs attributable to UC are related to anti-TNF (biologic) medications pharmacy costs.[[26]] These findings spotlight the medication expenses associated with regular therapy, which, it can be surmised, would increase in cases of non-adherence as the use of more (expensive) disease pathophysiology modifying medications would become necessary. The added costs due to non-adherence by IBD patients are not just those of wasted medicines and escalated therapy e.g., using expensive biologics, but also time and effort of healthcare professionals expended in re-treatment as well as the extra burden on the health system in general.

In New Zealand, there are limited studies into MA in IBD patients, with our research team pioneering such research. Notwithstanding, amongst several issues, MA generally is hampered by challenges of access to publicly funded medicines. PHARMAC notes that medicine access inequities abound, with poverty, poor living conditions, inadequate social support, lower income, and importantly, racism, besides others being associated with worse health access.[[27]] Evidencing this, Māori, Pasifika and disabled people experience worse access to and utilisation of publicly financed medications than non-Māori.[[27,28]]  

PHARMAC categorises the barriers to medicine access into three: barriers to healthcare access such as delayed access, costs, transport etc.; structural barriers including organisation of care—for example, accessing appointments, wait times, completing referrals etc.; and provider capacity to meet an individual patient’s needs (e.g., cultural safety and competency, knowledge and skills etc.).[[27]]

We recognise that there have been various interventions to promote medication adherence in New Zealand; for example, the Medication Use Review and Adherence Support Service (MUR) available in some areas.[[29]] A pharmacist interviews patients to assess MA, identify/proffer solutions to their individual barriers to MA and educate them on MA in general. Although patients can join on their own initiative, participation is mostly via GP or nurse recommendation but the criteria for enrolment includes presence of comorbidities, polypharmacy etc.[[29]] However, the status of such services in the new Te Whatu Ora – Health New Zealand system is unclear. Furthermore, most adherence interventions in New Zealand are targeted at the senior (>60yrs) population; this is unsuited to IBD patients who are diagnosed mainly in youth.

Conclusion

In New Zealand, MA is of extreme importance to IBD patients, especially given the limited therapy options available. Only four biologic agents are publicly funded for use in IBD and, with little flexibility, only for escalation therapy. This effectively precludes the use of the several more cutting-edge and advanced medications (JAKi/biologics) that have been developed in the past few years, despite New Zealand IBD patients often having aggravated disease at the point of diagnosis due to barriers to healthcare access. It also pre-empts the trialling of emerging therapeutic strategies, such as the “top-down” approach, which could lead to better treatment outcomes for patients.

Whilst MA is important to any disease therapy, MA remains extremely important in IBD therapy in New Zealand, and countries with similar situations, where public-funding is not readily available for the use of newer advanced therapeutics, including JAKi/biologics, as first line medications. Therefore, IBD patients need to derive maximum benefits from the available therapeutics by sticking to the prescribed medication regimens to avoid the worse outcomes related to poor MA. This is particularly until the therapy options are expanded to include newer therapeutics/treatment paradigms, which we would welcome.

Consequently, we maintain that concerted efforts and investments to support multidisciplinary research into the MA landscape in New Zealand are needed to fill current gaps in the research corpus. Such research would cover adherence levels (and its relation to hospitalisations and demographic factors), costs of non-adherence, patients’ perspectives on adherence and their desired support interventions, the barriers to good adherence, and solutions needed. These should be complemented by public health interventions to help IBD patients practice good adherence. The government is best positioned to facilitate these through its ministries and agencies, and by collaborating with universities and research institutions besides the private sector; although these other entities can and should act on their own initiative. Moreover, we hope that the recently launched Te Whatu Ora – Health New Zealand will feature a robust MA promotion service alongside a strong medicines policy that balances access, equity and cost, as well as a sustainable health workforce. These are all necessary to support the recommendations made to PHARMAC, in their recent review, for them to work more closely with the wider health system to reduce inequities in medicines availability and access.[[28]] The benefits from MA improvement services would also accrue to patients with diseases other than IBD, presumably resulting in an overall healthier population and fewer health costs in general.