New tools and approaches for improved management of inflammatory bowel diseases

Abstract

Background and aims : Inflammatory bowel diseases are part of a wider conglomeration of immune-mediated inflammatory diseases. New management approaches need to be developed as we understand more of the epidemiology and aetiology of inflammatory bowel diseases and medical care becomes more complex.

Methods : Selected new tools and approaches for improved management of inflammatory bowel diseases are presented, based on published evidence and clinical experience.

Results : Setting quality of care standards that are consistent across different inflammatory bowel disease care settings will be paramount and require collaboration between specialist and non-specialist centres. Alongside this, the value of care will need to be evaluated in terms of maximising outcomes over the entire care cycle for a patient. In moving towards a value-based approach to management, it is important to determine the progression rate of the disease by measuring cumulative bowel damage. As well as understanding the course of disease in individual patients, it is also becoming more feasible to individualise therapy and exploit drug pharmacology to achieve better and more long-term responses. Finally, it is timely to consider formal collaborations between specialists in immune-mediated inflammatory diseases to ensure more cohesive patient care.

Conclusions : The potential for improved management of patients with inflammatory bowel diseases continues to increase as we look to understand when and how to intervene in the disease process and how to adopt a collaborative management approach that promotes networking and reduces heterogeneity of care across different care settings.

Crohn's disease, Ulcerative colitis, Disease monitoring, Healthcare delivery, Individualised medicine, Value

1 Introduction

Inflammatory bowel diseases (IBD) represent a chronic and complex spectrum of diseases that are part of a wider conglomeration of immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, psoriatic arthritis, psoriasis, spondyloarthropathies and systemic lupus erythe-matosus. As we understand more of the epidemiology and aetiology of IBD and medical care becomes more complex, new management approaches need to be developed. This will involve setting quality standards that are consistent across different IBD care settings, careful evaluation of the value of IBD care, developing more sophisticated methods to monitor disease progression, tailoring drug therapy to individual patients and synergistic collaborations with other IMID specialists.

2 Reducing discrepancies across different IBD care settings

In an ideal scenario, patients would be able to access the same standard of care irrespective of where they lived or went for treatment. In reality, notable variations in an individual IBD patient's care exist. This is influenced by a number of variables including the patient's type of care facility, their geographical location (within and between countries), standards of treatment, philosophies of treatment, adherence to clinical guidelines, patient and physician preferences, access to support staff and payer perspectives.

Several retrospective or cross-sectional studies have illustrated country-specific and care setting-specific variations in IBD care, although it is not yet clear as to whether such differences are detrimental to clinical outcomes. ¹ , ² A recent comparison of prescription rates among elderly patients with IBD in the USA, UK, Denmark and Canada found a high degree of variability between the four countries. ³ In Crohn's disease (CD), the USA had the highest rate of thiopurine usage and Canada had the highest rate of methotrexate prescriptions. Both North American countries prescribed higher rates of oral 5-aminosalicylates (5-ASA) and infliximab than the UK or Denmark. In patients with ulcerative colitis (UC), oral steroid prescriptions were highest in the USA and lowest in the UK, and oral 5-ASA use was highest in the USA and Canada. Infliximab and adalimumab prescriptions were significantly higher in the USA than other countries. However, while this analysis shows notable differences in prescription patterns across regions, it gives us little insight into the actual impact (if any) of these differences in care on clinical outcomes. Most recently, the POLARIS study has provided interesting insight into variance in treatment patterns and quality of care from the perspective of patients with CD and their healthcare providers (HCPs), with preliminary results showing greater use of immunomodulators and biologics in IBD centres compared with non-IBD centres. ⁴ Of course, it is likely that patients attending IBD centres have more severe disease and, therefore, are more likely to be prescribed aggressive therapy than those attending non-specialist centres. Further analysis of this study should evaluate whether care setting (both in terms of country and in terms of specialist vs. non-specialist centre) has an independent effect on clinical outcome in CD patients.

Efforts to set standards in quality of care are underway in various geographical and specialist society jurisdictions. Clinical quality indicators to guide, monitor and improve the quality of IBD care have been developed by several groups over the past few years and provide an important step towards delivery of consistent, evidence-based care that meets a specific minimum standard. ⁵ – ⁷ In addition to this, we require well-designed prospective studies to understand this variation in care in terms of outcome. The cluster-randomised REACT study (NCT01030809), which is evaluating a treatment algorithm compared with usual care for the management of CD, should provide valuable insight into the impact of tailoring therapy to meet precise treatment goals on the likelihood of remaining in remission at 24 months’ follow-up. This is the first cluster-randomised study to be performed across different IBD care settings.

Given the wide variation in IBD care, it is proposed that a network model is used within an IBD centre to reduce heterogeneity in care, with an example shown in Fig. 1 . This type of model would allow non-IBD centres to reach out to IBD centres that, in turn, could access important specialist services, allowing care to be harmonised across different settings.

Figure 1

A proposed model of networking within an IBD centre, allowing harmonisation of IBD care. IBD care takes place in a variety of different settings, including specialist-IBD centres, non-specialist centres, community-based gastroenterology practices, surgical centres (including those that specialise in colorectal surgery) and general practitioner clinics. In a large IBD centre, essential components include a triage centre, an ambulatory outpatient centre, a hospital or inpatient service and surgical service including an operating room. Facilities for clinical research, animal research, human biomaterial research and tissue banking should be available. Support services such as radiology, endoscopy and a clinical trials centre are also included in the model. In the network, other affiliated centres (such as non-specialist or community centres, surgical centres and primary care centres) may access all services through the specialist IBD centre.

3 Moving towards value-based healthcare for IBD

IBD is an expensive chronic disease, with substantial direct and indirect costs. ⁸ – ¹¹ These are further increased in patients with fistulising disease, ¹² patients with more severe disease ¹³ or patients who are non-adherent to therapy. ¹⁴ While improving quality of care in IBD is a laudable goal, this may also result in increases in cost that need to be balanced against longer term improvements in patient outcomes.

In order to contain costs, we need to change our focus from charging a fee for services to receiving payment for quality care. In other words, we need to improve the actual health outcomes for each dollar spent, rather than simply providing less costly services. ¹⁵ , ¹⁶ Value-based healthcare involves maximising outcomes over the entire care cycle for a patient, as opposed to minimising the cost of each specific intervention. ¹⁵ , ¹⁶ This is particularly relevant in a chronic disease such as IBD. Value can be expressed as a value quotient, with outcomes as the numerator and total costs as the denominator. Of course, for the value quotient to be calculated, outcomes must firstly be measured, reported and compared. These should include health benefit, quality of life and productivity.

Prioritising and measuring value improvement in IBD has the potential to empower and deliver good outcomes for our patients with this disease, with the further ability to allow cost efficacy to be re-examined in the context of a full cycle of care. In an anecdotal example of value-based healthcare, the University of California at Los Angeles Center for Inflammatory Bowel Diseases has developed a novel approach to measuring and improving value for patients with IBD ( http://gastro.ucla.edu/body.cfm?id=138 ). In this model, patients participate in their own care through enrolling in online programmes focusing on disease education, work ability, mental health and disease research. Clinicians adhere to a tight disease control infrastructure, which includes proactive clinical management of IBD based on the most up-to-date IBD practice guidelines. Patients use personal communications devices to submit information on their current disease activity, quality of life, work productivity and laboratory data to the centre, and care is fine-tuned around these inputs. This allows the value of care to be assessed and improved by channelling patients and healthcare providers towards the most achievable and cost-effective value quotients for individual patients.

At present, we only have anecdotal evidence to support the benefits of a value-based approach to IBD care. The impact of such a programme on actual clinical outcomes including disease recurrence, requirement for surgery, disease progression and disability needs to be evaluated in a robust fashion, together with complementary quality of life and cost–benefit analyses, to determine its wider utility.

4 Capturing bowel damage in Crohn's disease — the Lémann score

It is becoming increasingly evident that CD has a natural history that leads to irreversible bowel damage, with intestinal resection required in the large majority of patients. ¹⁷ In moving towards a value-based approach to CD management, it is important to be able to measure cumulative damage to the bowel over time in order to determine the progression rate of the disease.

Current scoring systems to estimate disease activity, ¹⁸ – ²¹ mucosal inflammation ²² – ²⁴ or histological activity ²⁵ assess the severity of disease at a specific time point without reference to the history of the disease. Conversely, the International Program to develop New Indexes in Crohn's disease (IPNIC) has developed the Crohn's Disease Digestive Damage Score (Lémann score), which is a new instrument that measures cumulative structural bowel progression at a specific point in an individual's disease history (based on medical history, endoscopy and other imaging methods) and can be used to assess the impact of treatment strategies on the progression of digestive damage. ²⁶ , ²⁷ This is the first such score to be developed in IBD. The tool assessment methods are damage driven — taking damage location, severity, extent and progression of disease into account. To calculate the score, the digestive tract is divided into four organs (upper digestive tract, small bowel, colon and rectum, and anus), then each organ is divided into segments (3, 20, 6 and 1 segment[s], respectively) ( Fig. 2 ). For each segment, information about previous surgery and presence of stricturing and/or penetrating lesions ranked per grade of severity is recorded ( Table 1 ). A segmental score ranging from 0 (no lesion) to 10 (complete resection of the segment) is given, taking into account the presence and severity of lesions. An organ score is automatically calculated as the sum of the segmental scores provided by the investigators plus the scores attributed to resected segments in case of previous resection weighted by the relative weight of each segment within the organ. Finally, a global score is calculated, taking into account the four organ damage scores. This tool should provide a highly useful measurement of the severity of bowel damage and may be used to measure cumulative bowel damage over time. Future studies will examine the effect of early therapeutic intervention on damage protection in patients with CD.

Table 1

Example of the scoring system used when calculating the Lémann score: severity scale for small bowel lesions according to the lesions or history of surgery or any other interventional procedures. Each segment within the small bowel is scored according to this ordinal scale.

Table adapted and reproduced from Pariente et al. ²⁶ with permission from Lippincott Williams & Wilkins, Inc. © 2011.

Grade	Stricturing lesions	Penetrating lesions	History of surgery or any other interventional procedure
0	Normal	Normal	No procedure
1	Wall thickening <3 mm and/or segmental enhancement without prestenotic dilatation		Endoscopic dilatation
2	Wall thickening ≥ 3 mm and/or mural stratification without prestenotic dilatation	Transmural fissure with increased density in perienteric fat	By-pass diversion or stricturoplasty
3	Stricture with restenotic dilatation	Abscess or fistula	Resection

Figure 2

Assessment of digestive damage using the Lémann Score: segmentation of the digestive tract. To calculate the score, the digestive tract is divided into four organs (upper digestive tract, small bowel, colon and rectum, and anus), then each organ is divided into segments, which are individually scored for damage on an ordinal scale ranging from 0 (normal) to 3 (maximal). ²⁶

It is currently unclear as to whether chronic UC also has a tendency to progress to irreversible bowel damage, although there is some evidence that ongoing inflammation may have a detrimental effect on the physiology of the colon, driving proximal extension of disease and structural and functional damage below the level of the gastrointestinal mucosa. ²⁸ The evolution of UC needs to be further characterised to determine the respective roles of conventional therapy, early and aggressive therapy, and surgery in preventing complications associated with disease progression. Tools to capture cumulative bowel damage in UC may be useful in this process.

5 Individualising therapy with monoclonal antibodies to optimise treatment

As well as understanding the course of disease in individual patients, it is also becoming more feasible to predict and modulate the effects of therapy in individual patients. Individualised medicine, whereby treatment is optimised according to the needs of the individual patient rather than using standardised regimens deduced from clinical trials, is a more realistic goal than ever before.

Humanised monoclonal antibodies (mAbs) directed against tumour necrosis factor (TNF)- α have had a tremendous influence on the treatment of CD and UC. ²⁹ However, while these mAbs are highly effective for induction and maintenance of clinical remission, not all patients respond and many patients lose response over time. ²⁹ Understanding the principles governing the pharmacology of mAbs and how to manipulate these may provide a means to improving long-term response rates. ³⁰ , ³¹

Response to a drug is dependent on achieving and maintaining adequate drug levels. Drug concentrations need to be maintained above a target concentration in order to see a response. The pharmacology of mAbs is complex and depends on the structure of the antibody, the properties of the target antigen and on patient characteristics ( Table 2 ).

Table 2

Factors influencing the pharmacokinetics of anti-tumour necrosis factor (TNF) monoclonal antibodies (mAbs).

Table adapted and reproduced from Ordás et al. ³¹ with permission from Nature Publishing Group. © 2012.

Factor		Impact on pharmacokinetics of anti-TNF mAbs
Immunogenicity	Presence of anti-drug antibodies	Increased mAb clearance resulting in decreased serum mAb levels
	Concomitant use of Immunosuppressants	Reduces anti-drug antibody formation Decreases mAb clearance resulting in increased serum mAb levels
Disease severity	High baseline serum TNF-α levels	May decrease free serum mAb levels through binding, thereby increasing clearance
	Low baseline albumin levels	Associated with increased mAb clearance
	High baseline C-reactive protein levels	Associated with increased mAb clearance
Personal characteristics	High body weight	Increases mAb clearance
	High body mass index	May increase mAb clearance
		Higher production of TNF via adipose tissue
		Reduces bioavailability of subcutaneously administered mAbs
	Gender	Males have higher mAb clearance, usually due to higher body weight

Anti-TNF mAbs used in CD and UC demonstrate linear pharmacokinetic relationships between dose and serum concentrations ³² ; however, the trough level for any given dose (that is, the serum concentration immediately before the next dose of drug is administered) varies between patients. This has clinical implications, as high trough concentrations are associated with substantial clinical improvement, ³³ while low trough concentrations are associated with poor clinical response ³³ or greater likelihood of treatment discontinua-tion. ³⁴ However, this is further complicated by the observation that mAbs typically have a very long delay between exposure and measurable response because the drug has a preliminary effect that is then propagated to achieve a clinical effect at a later point in time. Plotting drug trough concentrations with clinical activity is relatively meaningless because of the time lag between drug administration and observation of a clinical response.

Low serum mAb trough concentrations are often associated with the formation of anti-drug antibodies (ADAs). ³⁴ , ³⁵ These can limit drug bioavailability and shorten half-life ³⁶ through the formation of immune complexes that accelerate drug clearance and/or impair binding. The development of ADAs depends on actual levels of drug exposure ³⁷ and may also be exacerbated by drug holidays, episodic dosing and protracted low drug concentrations. Measurable trough concentrations need to be maintained throughout the dosing interval to minimise the chance of developing ADAs.

Manipulating the dosing regimen of anti-TNF therapies in IBD may be useful for maintaining measurable trough concentrations and decreasing the likelihood of developing ADAs. Shortening the dosing interval may be more beneficial than increasing the drug dose because it takes approximately four to five half-lives to clear drug from the body and the half-life does not change with dose for many mAbs. Patient factors should also be taken into account when considering dosing modifications. Patients with greater disease severity, as reflected in lower albumin or higher C-reactive protein levels, may have greater drug clearance. ³⁶ , ³⁸ , ³⁹ Patients with a high TNF-receptor burden (particularly when the disease is first diagnosed) may require a higher dose initially, and monitoring of drug concentrations in patients with low bodyweight is important. Furthermore, when patients are chronically noncompliant, there is a slow fall-off in trough levels that will not come back up unless loading (or induction) is re-initiated. While the relationship between low trough concentrations of mAbs and poor clinical effect has been demonstrated, ³³ the correlation between higher serum mAb levels and clinical improvement is more controversial. It may also be that patients in remission are able to reduce their mAb dose to maintain therapeutic trough levels, with important drug exposure and cost benefits. The Trough level Adapted infliXImab Treatments (TAXIT) study evaluated treat-to-target dosing based on infliximab trough levels in patients with IBD. ⁴⁰ , ⁴¹ In this study, 263 patients underwent an induction phase where their infliximab dose was optimised to achieve a target trough level of 3–7 μg/mL. During this phase of the study, dose intensification of infliximab in CD patients (but not UC patients) with trough levels <3 μg/ml resulted in significantly better disease control (p = 0.02), whereas dose reduction in CD and UC patients with trough levels >7 μg/ml resulted in lower drug exposure while maintaining disease control. Following infliximab dose optimisation, patients were randomised to dose adjustment based on clinical symptoms and C-reactive protein levels (n = 123) or based on infliximab trough levels (n = 128). No significant between-group differences were reported in the primary endpoint of both clinical and biological remission one year after randomisation, although more efficient use of drug and a lower incidence of ADA formation were seen in the group that underwent dose adjustment based on infliximab trough level.

While there may be benefits to modifying treatment regimens to achieve target serum trough levels of anti-TNF therapy, further concentration-controlled clinical trials need to be undertaken in order to further understand the applications of this approach. A randomised double-blind study (Netherlands Trial Register NTR3943) is currently being performed to evaluate the cost effectiveness of trough level-based dose reduction during maintenance treatment for CD, which will provide further interesting insight as to the benefits of therapeutic drug monitoring on outcomes.

6 Collaborating with other IMID specialists

It is increasingly apparent that inflammatory diseases are not discrete entities confined to a particular organ; rather, we are finding that multiple different manifestationsof inflammatory disease have a generic inflammatory pathophysiology. In an analysis of the Swiss IBD cohort, it was shown that 38% of IBD patients had extraintestinal manifestations, including arthritis, aphthous stomatitis, uveitis and ankylosing spondylitis. ⁴² Overlapping syndromes and comorbidities are clinically underestimated, which can have a significant impact on patient well-being and, ultimately, mortality. Furthermore, different genetic aetiologies can induce uniform phenotypes of IMID and, conversely, IMIDs can present with different phenotypes in patients with similar genetic backgrounds. ⁴³ , ⁴⁴

It is timely to consider formal collaboration between IMID specialists to ensure more cohesive patient care. A model of this form of collaboration has been developed by the Comprehensive Center for Inflammatory Medicine based at University Hospital Schleswig-Holstein in Kiel, Germany. This academic patient-care facility allows collaboration between gastroenterology, dermatology, ophthalmology, pulmonology, rheumatology, hepatology, nephrology and immunology. Clinical care is integrated with basic research, which involves in-depth phenotyping and studies of genetics, epigenetics and epidemiology. The patient is appraised by a multidisciplinary team and discussed in case conferences. Therapeutic decision making is highly standardised, with specific rules of engagement. These include compulsory discussion of cases before therapy with biologics; formalised case presentation with protocols reflecting discussion results; binding joint decisions for the future care of the patient and standardised follow-up of all patients. This model should allow better outcomes for all patients with IMIDs, as well as allowing concentrated evaluation of the underlying molecular basis to disease.

7 Summary and conclusions

The potential for improved management of patients with IBD continues to increase as we look to understand when and how to intervene in the disease process. This will be influenced by more sophisticated tools for monitoring disease progression, such as the newly-developed Lémann score, and greater understanding of how to manipulate treatment at an individual level. Improving the management of IBD is likely to require a collaborative approach to promote networking and reduce heterogeneity of care across different IBD care settings. Such an approach will also require collaboration between different IMID specialities.

Contributorship

This manuscript summarises presentations made by Subrata Ghosh, Daniel Hommes, Benjamin Pariente, Diane Mould and Stefan Schreiber at the Leading Change in IBD meeting, held in Madrid on 18–19 January 2013, which was sponsored by AbbVie. AbbVie provided funding to the Lucid Group, Burleighfield House, Buckinghamshire, UK, to manage the Leading Change in IBD meeting, for which AbbVie provided topic ideas and participated in development of the meeting content. AbbVie paid consultancy fees to Subrata Ghosh, Daniel Hommes, Benjamin Pariente, Diane Mould and Stefan Schreiber for their participation in the meeting, and travel to and from the meeting was reimbursed. This manuscript reflects the opinions of the authors and each author reviewed the manuscript at all stages of development to ensure that it accurately reflects the content of their presentation. Joel Petersson, an employee of AbbVie, is an author of this manuscript and was involved in the development and review of the manuscript with the authors and the medical writer. The authors determined final content, and all authors read and approved the final manuscript. The authors maintained complete control over the content of the paper. No payments were made to the authors for the writing of this manuscript.

Juliette Allport of Leading Edge (part of the Lucid Group), Burleighfield House, Buckinghamshire, UK, provided medical writing and editorial support to the authors in the development of this manuscript. From slides provided by the authors and the audio recording of the meeting, Leading Edge prepared a draft outline manuscript for author comment and approval. Leading Edge subsequently supported incorporation of comments into final drafts for author approval, and editorial styling required by the journal. Financial support to Leading Edge for medical writing and editorial assistance was provided by AbbVie.

Conflict of interest

Financial arrangements of the authors with companies whose products may be related to the present report are listed below, as declared by the authors.

Professor Ghosh has received honoraria for speaking at educational events organised by AbbVie, Ferring, Millennium, MSD and Shire Pharmaceuticals; received research funding from AbbVie and MSD; and participated in ad-hoc advisory boards organised by AbbVie, Bristol-Myers Squibb, Centocor, MSD, Pfizer and Shire Pharmaceuticals.

Dr Pariente has received honoraria for speaking at educational events organised by AbbVie, Ferring and MSD.

Dr Mould is the president of Projections Research Inc., a consulting company that works with pharmaceutical companies to develop new drugs.

Professor Schreiber has received speaker and consultancy fees from AbbVie, MSD, Millennium, and Pfizer; and has been an advisor for Applied Biosystems.

Dr Petersson is an employee of and shareholder in AbbVie.

Professor Hommes has received consulting fees, lecture fees and/or research support from AbbVie, AstraZeneca, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, ELAN, Falk, Ferring, Genentech, Giuliani Pharma, IBM, Janssen, Johnson & Johnson, Leo Pharma, MSD, Otsuka, Novimmune, PDL BioPharma, Philips, Procter & Gamble, Roche, Schering Plough, Serono, Tramedico and UCB Pharma.

*

This manuscript summarises presentations made during the ‘Leading Change in IBD’ meeting held in Madrid on 18-19 January 2013 and sponsored by AbbVie.

Abbreviations:

Abbreviations:
• 5-ASA

  5-aminosalicylates

• IMID

  immune-mediated inflammatory diseases

• IPNIC

  International Program to develop New Indexes in Crohn's disease

• mAb

  monoclonal antibody