Why “the new normal” can be better than the past for patients with inflammatory bowel disease

With the acceleration of remote patient management, the cost of biosimilars coming down and the arrival of a working prognostic test for Crohn’s and ulcerative colitis, there hasn’t been a better opportunity to improve the way we treat IBD patients

Inflammatory bowel disease (IBD) sucks. It can, without warning, wreak havoc on people’s lives and wellbeing. Sufferers, often diagnosed between the ages of 18 and 30, experience painful, inconvenient and embarrassing symptoms. Those unfortunate enough to experience the most aggressive disease usually endure surgery, often repeatedly, and commonly require a stoma bag, which may need to be permanent. This can cause considerable disability and in the worst cases can even cause death due to disease complications.

Whilst there are reasons to be concerned about the future at the moment, new developments mean we can be optimistic about the opportunities we have to make real improvements to outcomes for IBD patients.

Annus horribilis

The 2020 global pandemic has posed real problems for IBD patients, many of whom are on immunosuppressive therapies. Early in the corona crisis, those on such treatments were told to shield as they might be at greater risk from infections. Months on, evidence suggests that the immunosuppressants may not themselves increase risk, but patients with poorly controlled disease are more likely to suffer poor outcomes if they contract COVID-19¹.

That’s good news then? Yes, but in the absence of physical clinics it has become harder for gastroenterologists to ensure that their patients are optimally managed. Endoscopies and regular clinics had to be postponed or cancelled. Post lockdown, physical appointments are starting again, but patients will remain wary of presenting themselves for fear of catching or spreading the virus. Also, whilst all this has been going on, many patients will be experiencing stress-induced relapses and flares. We spoke to a gastroenterologist recently, who described the situation as “a nightmare”.

A digital revolution?

So where are the positives in all this? When the dust settles, some things will have changed, probably for the better. One such example is the acceleration in remote patient management. Prior to the lockdown, phone and video clinics were rare. Now, they are common. The situation has required a rapid evolution in the way that patients are managed. Healthcare providers have been forced to get to grips with technology that can facilitate virtual meetings between doctors and patients. The efficiency savings that such appointments should offer both patients and the NHS mean that they are likely to remain common and exist in partnership with physical appointments when they are required.

Figure 1 Mobile apps offer patients the chance to take more responsibility for their disease and provide data for clinicians to help spot flares before they happen.

The shift towards fewer physical appointments will also speed up the adoption of the increasingly common mobile apps that are being developed for IBD and other chronic diseases. Generally, these apps are designed to help patients track their symptoms, allowing better management of medication, lifestyle and mental health, with the aim of avoiding triggers that can make symptoms worse. Some apps allow patients to share this data with their doctors, potentially allowing clinicians to monitor disease more closely, offering a chance to catch and treat flares earlier.

The modernisation of patient management and a shift towards increased personal responsibility for patients when it comes to disease management was already slowly happening. Like many other areas, the pandemic has pushed these things forward, making them a reality for thousands of patients in just a few months.

Biosimilars – an opportunity to take the top-down approach

Prior to the current digital renaissance, new biologic drugs had already made a huge difference to the treatment of IBD patients. These powerful antibody drugs target the factors responsible for inflammation more precisely than traditional medicines, such as corticosteroids. However, this revolution in treatment has not been cheap, with recent studies showing that biologics have now become the^2,3 in both the US and Europe. In the case of Crohn’s disease, as much as 50% of the cost of treatment now comes from biologics.

Things are changing though – biologics do come off patent, leading to the availability of cheaper generic “biosimilars”. Biosimilar drugs have the same therapeutic activity as the original molecules, just with small structural changes.. The RAND corporation predicted in 2017 that across all disease areas, biosimilars could save the US $54 billion over the following decade⁴. In the case of IBD, anti-TNF biologics such as  Adalimumab and Infliximab are now available as biosimilars.   With rapidly decreasing costs, it is increasingly feasible for clinicians to prescribe these treatments, which is an opportunity to realise the potential benefits of the top-down approach^5–7.

A lack of precision could cancel out the benefits

Whilst offering potentially huge benefits, without careful deployment remote patient management and biosimilars can pose risks. For example, fewer physical appointments could lead to doctors missing signs that patients are heading for relapses, resulting in flares being treated later, increasing the risk of bowel damage and the need for surgery. In the case of biosimilars, just like their brand-name counterparts, these powerful drugs can come with unpleasant side effects, necessitating their judicious use, ideally in the patients who will benefit most.

IBD patients who present with similar clinical risk factors can go on to experience very different disease courses. Around a third of patients experience a mild disease course, with few or no relapses, and half suffer more frequent flares and require intensified treatment⁸ (Figure 2)

Figure 2 Case studies demonstrate the hugely different disease course that can be experienced by IBD patients who present with very similar clinical risk factors.

Patients who will experience mild disease are likely to benefit most from less aggressive treatment, as this will not expose them to the risks and potential side-effects of stronger immunosuppressive therapies. These patients could also be safely monitored less closely, making them ideal candidates for remote management. Conversely, patients predicted to suffer more severe disease with frequent flares are most likely to benefit from top-down treatment with biologics/biosimilars and closer monitoring by clinicians. A one size fits all therapeutic pathway will not realise the potential benefits of remote management and biosimilars. Instead, a precision medicine approach is required, with patients at the highest risk of severe disease identified at diagnosis and treated and monitored aggressively.

PredictSURE® IBD – a prognostic test that can make precision medicine a reality for IBD patients

Clinical criteria such as age at diagnosis and early need for steroids, have been reported to associate with outcome, but these perform poorly when tested⁹, making it difficult to identify patients at high risk of severe disease. The last decade has provided insights into the impact of the immunological state known as T-cell exhaustion on disease course in IBD patients^10,11. This has led to the development of PredictSURE® IBD, the first fully validated, CE marked whole blood prognostic test for Crohn’s disease and ulcerative colitis¹². Using qPCR, PredictSURE IBD measures the expression of 17 genes and a proprietary algorithm to sort patients into subgroups at high- and low-risk of multiple relapsing disease.

Figure 3 The PredictSURE IBD prognostic blood test stratifies patients into high- and low-risk subgroups

The clinical validation of the test shows that 91% of patients identified as high-risk required multiple treatment escalations in the first 12 months of follow up (sensitivity). Conversely, 98% of those patients identified by the test as low-risk did not have multiple treatment escalations in the same time period (negative predictive value, NPV). PredictSURE IBD allows clinicians to identify which patients are likely to benefit from more aggressive biosimilar therapies at the point of diagnosis, and to have more confidence in managing patients remotely who are likely to experience milder disease.

We think that taken together, the advances in digital healthcare, biosimilar drugs and the prognostic capability of PredictSURE IBD offer great potential to improve the long-term outcomes for IBD patients. Let’s not miss the opportunity to make the “the new normal” a better future.

References

(1)          Bezzio, C.; Saibeni, S.; Variola, A.; Allocca, M.; Massari, A.; Gerardi, V.; Casini, V.; Ricci, C.; Zingone, F.; Amato, A.; Caprioli, F.; Lenti, M. V.; Viganò, C.; Ascolani, M.; Bossa, F.; Castiglione, F.; Cortelezzi, C.; Grossi, L.; Milla, M.; Morganti, D.; Pastorelli, L.; Ribaldone, D. G.; Sartini, A.; Soriano, A.; Manes, G.; Danese, S.; Fantini, M.; Armuzzi, A.; Daperno, M.; Fiorino, G. Outcomes of COVID-19 in 79 Patients with IBD in Italy: An IG-IBD Study. Gut 2020. https://doi.org/10.1136/gutjnl-2020-321411.

(2)          Burisch, J.; Vardi, H.; Schwartz, D.; Friger, M.; Kiudelis, G.; Kupčinskas, J.; Fumery, M.; Gower-Rousseau, C.; Lakatos, L.; Lakatos, P. L.; D’Incà, R.; Sartini, A.; Valpiani, D.; Giannotta, M.; Arebi, N.; Duricova, D.; Bortlik, M.; Zammit, S. C.; Ellul, P.; Pedersen, N.; Kjeldsen, J.; Midjord, J. M. M.; Nielsen, K. R.; Andersen, K. W.; Andersen, V.; Katsanos, K. H.; Christodoulou, D. K.; Domislovic, V.; Krznaric, Z.; Sebastian, S.; Oksanen, P.; Collin, P.; Barros, L.; Magro, F.; Salupere, R.; Kievit, H. A. L.; Goldis, A.; Kaimakliotis, I. P.; Dahlerup, J. F.; Eriksson, C.; Halfvarson, J.; Fernandez, A.; Hernandez, V.; Turcan, S.; Belousova, E.; Langholz, E.; Munkholm, P.; Odes, S.; Turk, N.; Cukovic-Cavka, S.; Nicolaou, A.; Lukas, M.; Shonová, O.; Blichfeldt, B.; Marker, D.; Carlsen, K.; Weimers, P.; Aalykke, C.; Kudsk, K.; Vind, I.; Thorsgaard, N.; Skamnelos, A.; Politis, D.; Vegh, Z.; Demenyi, P.; Kramli, S. N.; Piaz, G. D.; Santini, A.; Girardin, G.; Kupcinskas, L.; Jonaitis, L.; Valantiene, I.; Zykus, R.; Kucinskiene, R.; Lazar, D.; Nikulina, I.; Castro, L. de; Pineda, J.-R.; Pereira, S.; Martinez-Cadilla, J.; Sanroman, L.; Figueira, M.; Ares, D. M.; Rodriguez-Prada, J.-I.; Carmona, A.; Gonzalez-Portela, C.; Widen, U.-B.; Myers, S.; Ashton, K.; Whitehead, E. Health-Care Costs of Inflammatory Bowel Disease in a Pan-European, Community-Based, Inception Cohort during 5 Years of Follow-up: A Population-Based Study. Lancet Gastroenterol. Hepatol. 2020, 5 (5), 454–464. https://doi.org/10.1016/S2468-1253(20)30012-1.

(3)          Park, K. T.; Ehrlich, O. G.; Allen, J. I.; Meadows, P.; Szigethy, E. M.; Henrichsen, K.; Kim, S. C.; Lawton, R. C.; Murphy, S. M.; Regueiro, M.; Rubin, D. T.; Engel-Nitz, N. M.; Heller, C. A. The Cost of Inflammatory Bowel Disease: An Initiative From the Crohn’s & Colitis Foundation. Inflamm. Bowel Dis. 2020, 26 (1), 1–10. https://doi.org/10.1093/ibd/izz104.

(4)          Mulcahy, A. W.; Hlavka, J. P.; Case, S. R. Biosimilar Cost Savings in the United States: Initial Experience and Future Potential https://www.rand.org/pubs/perspectives/PE264.html (accessed Jul 14, 2020).

(5)          Panchal, H.; Wagner, M.; Chatterji, M.; Taouli, B.; McBride, R.; Patterson, J. R.; Ungaro, R.; Dubinsky, M.; Cho, J.; Sachar, D. B. Earlier Anti-Tumor Necrosis Factor Therapy of Crohn’s Disease Correlates with Slower Progression of Bowel Damage. Dig. Dis. Sci. 2019, 64 (11), 3274–3283. https://doi.org/10.1007/s10620-018-5434-4.

(6)          Peyrin-Biroulet, L.; Oussalah, A.; Williet, N.; Pillot, C.; Bresler, L.; Bigard, M.-A. Impact of Azathioprine and Tumour Necrosis Factor Antagonists on the Need for Surgery in Newly Diagnosed Crohn’s Disease. Gut 2011, 60 (7), 930–936. https://doi.org/10.1136/gut.2010.227884.

(7)          Frolkis, A. D.; Lipton, D. S.; Fiest, K. M.; Negrón, M. E.; Dykeman, J.; deBruyn, J.; Jette, N.; Frolkis, T.; Rezaie, A.; Seow, C. H.; Panaccione, R.; Ghosh, S.; Kaplan, G. G. Cumulative Incidence of Second Intestinal Resection in Crohn’s Disease: A Systematic Review and Meta-Analysis of Population-Based Studies. Am. J. Gastroenterol. 2014, 109 (11), 1739–1748. https://doi.org/10.1038/ajg.2014.297.

(8)          Solberg, I. C.; Vatn, M. H.; Høie, O.; Stray, N.; Sauar, J.; Jahnsen, J.; Moum, B.; Lygren, I.; IBSEN Study Group. Clinical Course in Crohn’s Disease: Results of a Norwegian Population-Based Ten-Year Follow-up Study. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2007, 5 (12), 1430–1438. https://doi.org/10.1016/j.cgh.2007.09.002.

(9)          Loly, C.; Belaiche, J.; Louis, E. Predictors of Severe Crohn’s Disease. Scand. J. Gastroenterol. 2008, 43 (8), 948–954. https://doi.org/10.1080/00365520801957149.

(10)        McKinney, E. F.; Lyons, P. A.; Carr, E. J.; Hollis, J. L.; Jayne, D. R. W.; Willcocks, L. C.; Koukoulaki, M.; Brazma, A.; Jovanovic, V.; Kemeny, D. M.; Pollard, A. J.; MacAry, P. A.; Chaudhry, A. N.; Smith, K. G. C. A CD8 + T Cell Transcription Signature Predicts Prognosis in Autoimmune Disease. Nat. Med. 2010, 16 (5), 586–591. https://doi.org/10.1038/nm.2130.

(11)        Lee, J. C.; Lyons, P. A.; McKinney, E. F.; Sowerby, J. M.; Carr, E. J.; Bredin, F.; Rickman, H. M.; Ratlamwala, H.; Hatton, A.; Rayner, T. F.; Parkes, M.; Smith, K. G. C. Gene Expression Profiling of CD8+ T Cells Predicts Prognosis in Patients with Crohn Disease and Ulcerative Colitis. J. Clin. Invest. 2011, 121 (10), 4170–4179. https://doi.org/10.1172/JCI59255.

(12)        Biasci, D.; Lee, J. C.; Noor, N. M.; Pombal, D. R.; Hou, M.; Lewis, N.; Ahmad, T.; Hart, A.; Parkes, M.; McKinney, E. F.; Lyons, P. A.; Smith, K. G. C. A Blood-Based Prognostic Biomarker in IBD. Gut 2019, 68 (8), 1386–1395. https://doi.org/10.1136/gutjnl-2019-318343.