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Intest Res > Volume 16(4); 2018 > Article
Danese, Banerjee, Cummings, Dotan, Kotze, Leong, Paridaens, Peyrin-Biroulet, Scott, Assche, Wehkamp, and Yamamoto-Furusho: Consensus recommendations for patient-centered therapy in mild-to-moderate ulcerative colitis: the i Support Therapy-Access to Rapid Treatment (iSTART) approach

Abstract

Symptomatic ulcerative colitis (UC) can be a chronic, disabling condition. Flares in disease activity are associated with many of the negative impacts of mild-to-moderate UC. Rapid resolution of flares can provide benefits to patients and healthcare systems. i Support Therapy-Access to Rapid Treatment (iSTART) introduces patient-centered care for mild-to-moderate UC. iSTART provides patients with the ability to self-assess symptomology and self-start a short course of second-line treatment when necessary. An international panel of experts produced consensus statements and recommendations. These were informed by evidence from systematic reviews on the epidemiology, mesalazine (5-ASA) treatment, and patient use criteria for second-line therapy in UC. Optimized 5-ASA is the first-line treatment in all clinical guidelines, but may not be sufficient to induce remission in all patients. Corticosteroids should be prescribed as second-line therapy when needed, with budesonide MMX® being a preferred steroid option. Active involvement of suitable patients in management of UC flares has the potential to improve therapy, with patients able to show good accuracy for flare self-assessment using validated tools. There is a place in the UC treatment pathway for an approach such as iSTART, which has the potential to provide patient, clinical and economic benefits.

INTRODUCTION

Continued improvements in the management of UC are needed to enable the most efficacious and efficient treatment possible for this disease. This is particularly important for UC of a mild-to-moderate severity, as the prevalence and incidence of UC is increasing worldwide [1-3], and a mild-to-moderate severity is most common at diagnosis [4-9]. The treatment of this chronic disease is primarily aimed to induce and then maintain remission in the long-term [10-12], with remission normally defined as a normal bowel frequency (≤ 3 per day), absence of rectal bleeding and normal mucosal appearance on endoscopy [10,13]. Even when remission is achieved, the majority of the patients experience a relapse at some point [14,15]. Rapid treatment and resolution of relapses is a key treatment requirement as active disease has many negative impacts for patients, healthcare systems and society. Active UC is associated with reduced quality of life (QoL) for patients [16-19], higher utilization of healthcare resources [20-22], and personal costs to patients, such as time off work and reduced productivity [23,24]. Therefore, improvements to the treatment of disease flares in mild-to-moderate UC patients is beneficial.

iSTART

i Support Therapy-Access to Rapid Treatment (iSTART) is an initiative to improve patient-centered management to UC. The iSTART initiative gives mild-to-moderate UC patients (selected by their physician) the ability to self-assess UC symptomology, increase dosing of first-line therapy to an optimized level and self-start second-line treatment. iSTART is designed to fit within the framework supplied by published treatment guidelines. Clinicians should select only the most appropriate patients, including, for example: those at a high risk of relapse, those with limited access to healthcare services, those who take an active interest in their disease and its treatment, and those at a low risk of Clostridium difficile infection. Under iSTART, patients on optimized first-line therapy will be provided with training on how to identify a symptomatic flare, and provided with a prescription for second-line treatment for use when optimized first-line treatment is insufficient to maintain remission. If the patient experiences a flare they will self-start a short course of second-line therapy whilst contacting their clinic who will manage any ongoing treatment. The short course prescribed ensures that patients cannot self-medicate unsupervised and iSTART emphasizes that clinicians must be informed if the prescription is used to allow long-term changes in disease management.
The iSTART approach will allow for the fast treatment of flares, producing benefits for patients and healthcare systems. For patients, iSTART aims to improve day-to-day QoL and to create a sense of empowerment over their disease. Empowering patients to reliability self-assess a UC flare would allow faster commencement of second-line therapy, reducing the duration of active disease and associated damage and reduced patient QoL. Furthermore, this would reduce the number of patients seeking emergency healthcare, decreasing the clinical and healthcare burden of mild-to-moderate UC treatment. iSTART will also provide additional support to patients with limited access to their physician, such as those whose location or distance from their physician leave them unable to access timely treatment, and allow them access to rapid care that is currently unavailable to them.
iSTART will need to be adapted into an appropriate form to fit around different healthcare systems and local populations. This consensus paper provides a general outline of the principles of iSTART and the scientific evidence behind them from the physicians’ perspective. For future implementation, consideration of local factors in areas where iSTART is to be implemented will be necessary. In addition, patient involvement to guide the implementation of iSTART to match patients’ requirements and treatment goals is necessary; but these considerations are better addressed at a local level to match the cultural situation and healthcare systems in a particular area.

CONSENSUS METHODS

An expert panel of gastroenterologists, including clinicians from Europe, Asia, Australia, and Latin America were assembled in Amsterdam to generate consensus on patient-centered second-line therapy in the form of the iSTART initiative. Supporting evidence was brought together from 3 literature reviews reflecting the global epidemiology of UC; mesalazine (5-ASA) treatment and its failure; second-line therapy and validated tools suitable for self-led patient assessment. Searches were performed using the PubMed, Embase, Cochrane Library and clinicaltrials.gov platforms. Advisors voted on draft consensus statements based on the evidence-based reviews and in line with current guidelines for mild-to-moderate UC. Advisors voted whether they “strongly agree,” “agree” or “disagree/uncertain” for each statement. A statement was passed if ≥ 75% of the panel agreed/strongly agreed with a statement; if consensus was not reached, statements were revised via group discussion. The agreed consensus was then used as the basis to produce a series of recommendations, which were voted on using the same methodology. A full list of consensus statements and the literature supporting them was compiled (Supplementary Material 1).

CURRENT TREATMENT REGIMEN

The current treatment protocol for mild-to-moderate UC is well established and is outlined in all major guidelines on UC [10-12]. 5-ASA is the recommended first-line therapy for the induction and maintenance of remission in mild-to-moderate UC [10-12]. Although exact regimens vary depending on disease extent, the recommendations for the induction of remission are combination therapy consisting of rectal (1 g/day) and high dose oral 5-ASA (2-4 g/day) [10-12]. This optimized 5-ASA therapy is designed to induce remission quickly and effectively; such regimens are able to induce remission in 50% to 70% of patients [25].
For patients that do not respond sufficiently to optimized 5-ASA, oral or rectal corticosteroids are the recommended second-line treatment in all major guidelines [10-12]. A key consideration in corticosteroid treatment is the adverse event profile often associated with these treatments, especially when a systemic mode of delivery is used, as corticosteroids are associated with a number of well-known side effects, such as adrenal suppression [26,27]. To overcome the drawbacks of corticosteroid therapy, “second-generation” steroids have been developed, such as budesonide and more advanced formulations [26,27]. Oral budesonide has a high first-pass metabolism which significantly reduces systemic exposure and it has been formulated for UC using MMX® Multimatrix technology to provide a targeted colonic delivery [26,27]. Budesonide MMX® has shown high levels of efficacy in clinical trials [28,29], and equally as importantly no difference in adverse events to placebo (RR, 0.85; 95% CI, 0.53-1.38) [28]. These characteristics make budesonide MMX® a corticosteroid that has a profile suited to an initiative such as iSTART.

PATIENT-CENTERED TREATMENT IN UC

For an initiative such as iSTART to be successful requires reliable methods for patients to self-assess their condition. A number of simple indices for disease evaluation in UC have been developed that could be used by patients to monitor their disease. However, to have confidence in the use of such an index in clinical practice requires its validation. Three such validated indices that have been identified: the PRO2, the patient-reported UC activity index (PRUCSI) and the mobile health index for UC (mHI-UC) [30-32]. The PRO2 uses 2 indicators, stool frequency and rectal bleeding, and has an area under the receiver operating characteristic curve (AUC) of 0.90 in a validation cohort using an endoscopy score of ≤ 1 to define remission (AUC was 0.80 when using a score of 0 to define remission) [30]. The PRUCSI uses the 6-point Mayo score with the addition of patient-defined “general well-being.” [31] The PRUCSI has a validated AUC of 0.91, with a sensitivity of 78% and specificity of 84% [31]. The mHI-UC incorporates patient-reported measurements derived from UC disease activity indices [32]. The mHI-UC uses 4 questions covering stool frequency, rectal bleeding, abdominal pain and overall well-being within a complex scoring system to define flares [32]. The mHI-UC has reported an AUC of over 0.91, with a sensitivity of 72% and a specificity of 90% [32]. AUC values of 0.8 or higher are accepted to show a good predictive value, and values of 0.9 or greater show an excellent predictive value. These results show that these 3 indices all have a strong power for identifying flares and the potential to be used within iSTART.
Evidence of the benefits of patient-centered care in UC comes from a number of studies. In Denmark, a self-care web portal increased adherence in a validation group of 333 UC patients, and reduced the duration of relapses (18 days vs. 77 days for control cohort) [33-35]. The UC home telemanagement system (UC HAT), from the United States, used self-reporting of symptoms through 14 computerized questions to produce treatment recommendations [36,37]. A clinical trial of UC HAT found that it improved patient QoL compared to standard care [37]. A UK study used individualized patient-directed management plans to trigger additional treatment when a relapse occurred [38]. Compared to controls, this intervention caused a non-significant reduction in the average number of relapses (1.53 vs. 1.93), a significant reduction in time to treatment of a relapse (14.8 hours vs. 49.6 hours, P<0.0001), a non-significant decrease in the length of flares and a significant decrease in average number of general practitioner and hospital visits (P<0.0001) [38]. These studies show the potential of patient-centered management within UC, and the advantages for rapid treatment of flares for patients, clinicians and health systems.

CONCLUSIONS

Active disease in mild-to-moderate UC causes a significant health burden that can have a great impact on the daily life and QoL of those affected. The burden of disease in this group is particularly important with the increasing global incidence of UC and mild-to-moderate disease being the most common at diagnosis. There is therefore the potential for iSTART to have an impact on improving treatment in this large and important group of patients.
Although optimized 5-ASA treatment is an effective first-line treatment, it is not sufficient to control active UC in all patients. Steroids are the accepted second-line treatment and oral budesonide MMX® should be considered as a preferred corticosteroid option for mild-to-moderate disease, due to its high efficacy and low incidence of steroid-related adverse events. Timely and appropriate access to second-line therapy is necessary to minimize the impact of active UC on both healthcare systems and patients.
The potential for patient-centered care in UC has been demonstrated in a number of studies. However, these have also shown that clear guidance and definitions are required for accurate self-reporting. A small number of validated patient-reported outcome measures for disease activity in UC have been developed. The use of these indices within iSTART should allow an accurate and rapid initiation of treatment for a flare. Whilst there are potential benefits to all patients from iSTART, clinicians should select only the most appropriate patients. iSTART also makes clear to patients that upon experiencing a flare, they must contact their clinicians to allow their ongoing disease management to be reassessed. The recommendations of the expert panel are shown below, and these outline the basic principles of iSTART as have been summarized above.

RECOMMENDATIONS

Recommendation 1: In line with current treatment guidelines, it is recommended that the primary focus of treatment in UC is the rapid induction of remission followed by maintenance of this remission in the long-term.
(strongly agreed 90.0%; agreed 10.0%; disagreed 0.0%: CONSENSUS REACHED)
Recommendation 2: It is recommended that in the event of a flare, patients with mild-to-moderate UC should be treated as soon as possible to get them back into remission:
  • • Optimization of 5-ASA therapy to a high dose oral and/or rectal therapy should occur before any other therapy is considered

  • • Rapid access to second-line therapies is important due to flares causing a clinical and economic impact that can be reduced by fast treatment

    (strongly agreed 50.0%; agreed 40.0%; disagreed 10.0%: CONSENSUS REACHED)
Recommendation 3: It is recommended that treatment for mild-to-moderate UC should begin with optimized 5-ASA therapy: high dose oral and/or at least 1 g/day topical, in line with current treatment guidelines.
(strongly agreed 81.8%; agreed 9.1%; disagreed 9.1%: CONSENSUS REACHED)
Recommendation 4: It is recommended that oral budesonide MMX® is a preferred corticosteroid in patients with a mild-to-moderate flare:
  • • In line with previous recommendations, this therapy should be initiated as soon as possible by patients who experience a flare that does not respond to optimized 5-ASA

    (strongly agreed 81.8%; agreed 18.2%; disagreed 0.0%: CONSENSUS REACHED)
Recommendation 5: It is recommended that patients with mild-to-moderate UC should have active involvement in their disease management and therapy to enable rapid treatment:
  • • Patient-reported outcome monitoring can rapidly identify a flare and give opportunities to swiftly initiate therapy prior to seeing a clinician

  • • This is particularly important for high-risk individuals (e.g., those with frequent flares, or those with new diagnoses and additional risk factors, or any patient deemed high risk by treating physician) or those in locations or health care systems with difficulties in quickly accessing healthcare

  • • Good communication between physician and patient is vital for this to work

    (strongly agreed 60.0%; agreed 30.0%; disagreed 10.0%: CONSENSUS REACHED)
Recommendation 6: It is recommended that patient-reported outcome measures:
  • • Have the potential to be used for flare identification

  • • Can be used by patients to monitor disease activity

  • • Have the potential to be used by patients to initiate treatment of flares

  • • Should be initiated as a management tool for suitable patients

    (strongly agreed 72.7%; agreed 27.3%; disagreed 0.0%: CONSENSUS REACHED)
Recommendation 7: It is recommended that PRO2 and PRUCSI are appropriate patient-reported indices for self-assessment, as they are simple, validated and have a strong discriminatory power for flares:
  • • The PRO2 or PRUCSI can be used by patients to assess disease by monitoring changes in stool frequency and rectal bleeding

  • • An increase in PRUCSI or PRO2 score of >1 over a 3-5 days could be used to identify a flare

    (strongly agreed 63.6%; agreed 27.4%; disagreed 9.0%: CONSENSUS REACHED)
Recommendation 8: The group recommends that a program such as iSTART could provide improved treatment of flares in UC patients.
(strongly agreed 72.7%; agreed 27.3%; disagreed 0.0%: CONSENSUS REACHED)

NOTES

FINANCIAL SUPPORT

Sponsorship and article processing charges for this study were funded by Ferring. Ferring provided funding to Strategen Limited to undertake the systematic reviews and to provide editorial assistance in the preparation of this manuscript.

CONFLICT OF INTEREST

Silvio Danese has served as speaker, consultant and advisory board member for AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, TiGenix, UCB Pharma, Vifor Pharma, Biogen, Celgene, Allergan, Celltrion, Sandoz and Boehringer Ingelheim.

Rupa Banerjee has served as member of advisory boards, speaker and KOL for Janssen, Takeda, Ferring, Cipla, Cadila, Abbott and Menarini, India.

Fraser Cummings has received consulting fees from MSD, AbbVie, Janssen, Ferring, Vifor, Pharmacosmos, Hospira, Celltrion, Takeda, Sandoz, Biogen, Shield Therapeutics, Dr Falk and NAPP and lecture fees from Merck, AbbVie, Takeda, Janssen, Takeda, Mundipharma, Pfizer, Pharmacosmos, Shield Therapeutics, and Vifor.

Iris Dotan has served on advisory boards for Janssen, AbbVie, Takeda, Genentech, Pfizer, Ferring, Rafa Laboratories, Given Imaging, Protalix, Medison, Celgene; has received Speakers Bureaus from Janssen, AbbVie, Takeda, Genetech, Pfizer, Ferring, Falk Pharma, MSD, Given Imaging; and has received research funding from the Leona M and Harry B Helmsley Charitable Trust, Janssen, AbbVie.

Paulo G Kotze has received honoraria from AbbVie, Ferring, Janssen, Pfizer and Takeda as a speaker and member of advisory boards.

Rupert W Leong has served on advisory boards for Aspen, AbbVie, Ferring, Hospira, Janssen, MSD, Pfizer, Takeda and has received research funding from Shire, Janssen, Endochoice and the Gastroenterological Society of Australia.

Kristine Paridaens is an employee of Ferring Pharmaceuticals.

Laurent Peyrin-Biroulet has received consulting fees from AbbVie, MSD, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Shire, Tillots, Vifor, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Celltrion, Takeda, Boehringer-Ingelheim, Lilly, Pfizer, HAC-Pharma, Amgen, Sandoz, Celgene, Biogen, Samsung Bioepis and lecture fees from Merck, AbbVie, Takeda, Janssen, Ferring, Norgine, Tillots, Vifor, Therakos, Mitsubishi, HAC-pharma.

Glyn Scott has served on advisory boards for AbbVie and Ferring and as a speaker for Ferring.

Gert Van Assche has been a consultant for MSD, Takeda, Genentech/Roche, AbbVie, Pfizer, Janssen and Ferring. He has received payment for lecturing at continuing medical education events from AbbVie, Takeda, MSD, Janssen and Ferring. He receives research funding from AbbVie, Pfizer, The Broad Foundation and The Fonds voor Wetenschappelijk Onderzoek Vlaanderen.

Jan Wehkamp has served as a consultant for MSD, Takeda, Novartis, Shire, AbbVie, Ardeypharm, Pfizer, Biogen, Johnson and Ferring, and received payment for lecturing at continuing medical education events from the Falk Foundation, AbbVie, Takeda, MSD, Johnson, Roche, Ferring, Novartis and Shire. He has received research funding from the Deutsche Forschungsgemeinschaft and the European Union (ERC), and received third-party research funding for carrying out clinical trials on behalf of Amgen, Novartis, Falk Pharma, and AbbVie. He is a member of the board of Defensin Therapeutics. He serves as president of the Alfred Nissle society and is also the chair of the German society of mucosal immunology and microbiome (DGIM).

Jesús K Yamamoto-Furusho has received honoraria from AbbVie, Ferring, Takeda, Janssen, UCB, Almirall, Pfizer, Novartis, Farmasa and Danone as speaker, key opinion leader and member of advisory boards at national and international levels. He is President of the Pan American Crohn´s and Colitis Organization (PANCCO).

AUTHOR CONTRIBUTION

Conceptualization: all authors. Methodology: all authors. Formal analysis: Not applicable. Funding acquisition: S.D. Project administration: S.D. Visualization: all authors. Writing - original draft: S.D. Writing - review and editing: all authors. Approval of final manuscript: all authors.

ACKNOWLEDGEMENTS

Strategen Limited undertook the systematic reviews and provided editorial assistance in the preparation of this manuscript. Ferring had the opportunity to review and comment on the completed manuscript but final editorial control rested fully with the authors. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

SUPPLEMENTARY MATERIAL

Supplementary Material 1.

CONSENSUS STATEMENTS
ir-2018-00073-suppl.pdf

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