Julian Panés MD is Professor of Medicine, former chief of the department of gastroenterology at Hospital Clinic de Barcelona and head of the hospital’s inflammatory bowel disease unit. Here, he discusses the impact and management of ulcerative colitis and Crohn’s, and the findings of the recent VEGA study.
Dr Panés has devoted his career to gastroenterology. His department at Hospital Clinic de Barcelona aims to provide holistic care to patients with inflammatory bowel disease (IBD). The hospital is also an academic centre and, together with a scientific team, he is active in translational research studies, focusing on both molecular targets and biomarkers to improve disease monitoring and to develop predictors of response to therapies in IBD.
Understanding IBD
As Dr Panés explained, IBD comprises two main conditions: Crohn’s disease and ulcerative colitis. He added that ‘both have a genetic predisposition, which has contributed to our understanding of the disease.’ The disease itself is polygenic and there have been over 200 genes already identified as predisposing to IBD. While most of us carry some of these genes, ‘the median number of genes carried by those with IBD is around 50 compared with 42 in the general population.’ Monogenic forms that manifest as very early onset and severe disease have also been identified.
This genetic predisposition, coupled with exposure to environmental factors, interact with the gut microbiome to orchestrate ‘an aberrant immune response that leads to the development of inflammation in the intestine.’ The underlying cause of IBD remains unclear and unravelling the nature of the genetic–environmental–microbiome interaction is both challenging and puzzling.
For instance, as he explained: ‘we know that smoking is clearly a predisposing factor in Crohn’s disease but it is a protective factor for ulcerative colitis.’ This difference, he said, has been revealed in studies of genetically identical twins, noting how if one sibling is a smoker, they develop Crohn’s whereas the non-smoker succumbs to ulcerative colitis.
Once the disease is initiated it becomes chronic and is characterised by periods of exacerbation or flares and periods of remission. However, as Dr Panés continued, ‘there is a broad spectrum of disease course over time; some patients have few flares but at the other extreme, some patients have continuous inflammation.’
Dr Panés explained how ulcerative colitis is restricted to the colon, affecting the mucosal layer but disease only extending to the submucosa in severe cases. In contrast, Crohn’s disease can occur along any part of the gastrointestinal tract, although it typically affects the ileum and the colon. In addition, Crohn’s disease is transmural; in other words, it is present in all layers of the gut, which probably explains how it is also associated with deep ulceration that completely extends through the colon, forming fistulas or channels between other areas of the intestine or even the skin.
The role of diet in IBD
Much of the epidemiological evidence points to a role for diet and lifestyle factors as important and potential triggers for the development of IBD. For an unknown reason, IBD is much more prevalent in developed countries. Moreover, this higher prevalence is not simply due to poor reporting or under-diagnosing within less well-developed countries because, as such countries become more advanced, there is a commensurate increase in the risk of developing IBD.
Dr Panés mentioned how the Mediterranean diet appeared to be protective against the development of IBD and that specific dietary factors, such as a high fat content and intake of emulsifiers, have become recognised risk factors for the disease, as has exposure to antibiotics during the early stages of life.
Although a Mediterranean diet appears protective, Dr Panés described how the value of adopting of such a diet once the disease becomes established is less clear and the current evidence is equivocal. Nevertheless, he explained that any potential benefits to following a Mediterranean diet are really only helpful for those with mild disease and are unlikely to help individuals with severe disease.
Ulcerative colitis symptoms
Dr Panés described how, typically, patients with ulcerative colitis experience increased stool frequency, diarrhoea, and rectal bleeding, which is a particularly alarming symptom that prompts individuals to seek medical advice. Another and perhaps more disturbing symptom is faecal urgency which often necessitated a considerable degree of lifestyle adaptation. In more severe disease, he explained, urgency can lead to incontinence, which has a significant impact on patients’ quality of life. Additionally, patients with more severe disease may also have abdominal pain fever or even anaemia.
In the absence of a specific disease marker, a holistic assessment that combines symptoms, findings from colonoscopy and a biopsy, is needed to make a diagnosis of ulcerative colitis.
In contrast, diagnosing Crohn’s disease is more difficult because diarrhoea is not always present, although abdominal pain is the most common symptom but often leads to a delay in patients being diagnosed.
Prevalence and disease severity
Dr Panés mentioned that ulcerative colitis affects around four in 1000 patients in Europe which equates to around 1.5 million sufferers. He added that around half of these patients will have mild to moderate disease and among those with moderate to severe disease, roughly one third will require hospitalisation at some point.
The onset of the disease he said, ‘typically occurs around adolescence or early adulthood’ although it can occur at any age. He added how one of the more alarming findings from epidemiological studies is that the prevalence of IBD appears to be on the increase at both ends of the age spectrum. As he continued: ‘it was very rare 25 years ago to diagnose IBD in a patient older than 60 or 70 and also paediatric cases were very infrequent.’ The increasing prevalence within the early-onset group, he described as both monogenic or polygenic in nature and more severe.
Disease severity in ulcerative colitis is, as Dr Panés described, based on both the intensity of an individual flare as well as disease course over time. For example, ‘more severe disease is characterised by more stools per day and more prominent bleeding, with the intensity of bleeding being an important determinant of severity.’ Typically, those with severe disease might have more than 8 episodes of passing stools throughout the day but in those with the most severe disease, this can be as high as 25 episodes. Clinical signs associated with more severe disease include anaemia and hypoalbuminaemia, and which are factors warranting hospitalisation.
Healthcare burdens associated with ulcerative colitis
The noticeable increasing disease prevalence has a huge impact on healthcare expenditure given how management requires input from a multi-disciplinary team including nurses, physicians, psychologists and surgeons.
Furthermore, though the episodic nature of the disease is characterised by intermittent flares, teams still need to be ready and able to rapidly respond to a patient’s needs, because, as Dr Panés explained ‘if treatment is not started quickly, the patient can deteriorate rapidly.’ He added that despite the effectiveness of current therapies, around “20% of patients at some point have uncontrolled disease and require surgery.’
A further and longer-term consequence of ulcerative colitis is an increased risk of cancer, especially when the disease has been present for 8–10 years and in those with chronic and active disease. The risk of cancer in ulcerative colitis is further increased among patients with primary sclerosing cholangitis.
As Dr Panés said, ‘the risk in patients who also have primary sclerosing cholangitis is so high that patients have an annual colonoscopy check-up.’ Even among those without this co-morbidity but with chronic and active disease that has been present for eight to 10 years, colonoscopy is still warranted but performed only every three to five years.
Treatments for mild to moderate IBD
Amino-salicylates are the preferred first-line treatment option in milder disease and which are used with an initial high dose of 4g/day for induction (which can last six to eight weeks) and then reduced during maintenance therapy. This strategy he finds, seems to be more effective than using the regime intermittently. As Dr Panés explained, ‘if patients do not continue with treatment, there is a 40% risk of a disease flare the following year, which reduces to around 20% if they maintain treatment.’
He added that an amino-salicylate regime is both very effective and well tolerated by patients and advises patients to ‘maintain the treatment long-term because it has been associated with a reduced risk of cancer.’
Second-line treatments for those who still experience symptoms would be oral corticosteroids which again are initially given at a higher dose and slowly tapered off before returning the patient to amino-salicylates.
Treatment adherence for long-term conditions invariably reduces over time and, as Dr Panés noted, ‘there may be a temptation for patients who have been in remission for a long time to test what happens if they stop treatment.’
Although treatments can be stopped, he stressed the need for patients to discuss this with the physician, rather than experimenting on their own. He believes that treatment adherence is likely to be relatively high (and stressed by nursing members of the multi-disciplinary team) for those with ulcerative colitis given the strong desire to avoid a disease flare.
Treatments for severe ulcerative colitis
Amino-salicylates are no longer effective once ulcerative colitis becomes more severe and he suggested that when presented with patients who had very severe disease, particularly if they required hospitalisation, his approach would be to start them on a course of intravenous corticosteroids.
Such patients, he said, require very close monitoring over the next few days and if they fail to respond to second and third-line treatments including immunosuppressants or an anti-tumour necrosis factor (anti-TNF) agent, then a colectomy is warranted to avoid more serious complications, for example, a colonic perforation.
Dr Panés believes that the introduction of biologics has had a profoundly positive impact on the management of ulcerative colitis, both in the short- and long-term. He described how the first anti-TNF agent, infliximab, proved to be an effective treatment for those who had failed to adequately respond to other therapies.
However, a limitation was that initially the drug was only approved for induction therapy and he observed that while effective, ‘the majority of patients had a relapse two to three months later.’ Fortunately, later studies showed that the drug was effective as a maintenance treatment prompting a change in its approval. As a result, he said that now, any biologic is developed and studied for use in both induction and maintenance.
The VEGA study
Once the anti-TNF drugs had proven their worth in ulcerative colitis, other biologics were developed which had other targets. For example, vedolizumab inhibited a4b7 integrin and was an effective agent with a rapid onset of action.
Another recognised target was the p40 subunit of interleukin 12 and 23 which is blocked by ustekinumab. More recently, he added, JAK inhibitors such as tofacitinib and S1P modulators such as ozanimod have also been approved. But despite this wider range of therapeutic options, Dr Panés said that it seems ‘we have reached a ceiling of efficacy that is around 30% of patients being in remission one year after starting treatment.’ In other words, the majority of patients in receipt of monotherapy are not completely free of symptoms.
As a clinician, he feels that the overarching aim of any treatment is that ‘the patient is completely in remission and without symptoms because even mild symptoms can lead to a deterioration in their quality of life so that they underperform in all aspects of life.’
He mentioned how some 20 years ago, it was found that the combination of infliximab with azathioprine provided superior relief of symptoms compared to monotherapy. Despite this positive result, it seemed to have become lost in antiquity and no subsequent studies have examined the efficacy of combination therapy in ulcerative colitis. He felt that with the introduction of guselkumab (which targets interleukin 23) and golimumab, which is an anti-TNF, an opportunity has opened to test a combination of these two drugs even before guselkumab was formally approved.
The aim of the study as he put it was to ‘test whether combination therapy with an anti-TNF and an anti-IL 23 was more effective than either monotherapy alone.’ The study included patients with moderate and severe ulcerative colitis and randomised them to monotherapy or combination induction therapy.
The findings, he says, were impressive, showing that the number of patients achieving all of the endpoints tested, including clinical remission, i.e. the complete absence of symptoms ‘was doubled (48% vs 23%) by the combination therapy relative to each monotherapy alone’ and for each of the outcomes assessed.
The study also examined the safety of treatment as biologics are known to suppress the immune system and thus increase the risk of infection. Fortunately, as Dr Panés explained, there were no safety concerns identified and the incidence of adverse effects was no higher with combination therapy than for each monotherapy.
The next steps
While VEGA represented a ‘proof of concept’ study, clearly demonstrating the benefit of combination induction therapy, Dr Panés said that it was now important to progress towards Phase III trials. In fact, he says that the aim of these studies is to ‘compare the efficacy and safety of combination therapy for one year.’ His believes that using the combination therapy over an extended period of time will afford a greater clinical benefit for patients. Nevertheless, he feels that there are still several unanswered questions.
For instance, it is necessary to define the best strategy for induction and equally important, is the identification of predictive biomarkers that can be used to identify which patients will respond to either mono- or combination therapy. As Dr Panés explained, ‘two patients with almost identical disease severity might not respond equally to the same therapy’ and it is therefore necessary to have some guidance as to which approach would best suit an individual patient.
The impact of the findings from the VEGA study is likely to be significant and lead to changes in clinical practice. However, there is still much to be achieved, especially the identification of prognostic treatment biomarkers, but it seems highly likely that in the coming years, a larger number of patients with ulcerative colitis will be able to achieve clinical remission that will enable them to lead as normal a life as possible.
