Reassessing Crohn's Disease After Anti-TNF Therapy
Treatment of moderate to severe CD has been revolutionised by anti-TNF therapy. In the UK, NICE mandates yearly reassessment with a view to demonstrating ongoing requirement for treatment. While the data regarding the success of withdrawal of anti-TNF therapy in patients in remission are sparse, identifying who should withdraw from treatment and when to do so remains a major question in IBD. In addition, while data in general support the relative safety of anti-TNF therapy, however, it remains an expensive treatment accounting for approximately two-thirds of all healthcare costs for people with CD in one recent study. Unfortunately, endoscopic, radiological and biochemical remission, in combination with lack of symptoms, is only achieved in a small proportion of patients and the limited data available suggest that this is the group of patients who are most likely to maintain remission after withdrawal of therapy.
We report that relatively few patients in our cohort (15% (11/73)) achieved our locally defined criteria after at least 12 months treatment. However, in the cohort in whom it was possible to apply the criteria, more patients (37% (19/52)) fulfilled favourable parameters for withdrawal identified in the STORI trial. However, it must be noted that in this study, being a 'real world' cohort, there were many differences to the patients included in the STORI trial. For example, unlike in STORI, some of our patients were on adalimumab, not all were taking concomitant azathioprine, many had clinical characteristics that would have precluded their inclusion in STORI and, finally, only a small number had FC measured. This highlights the difficulties of using criteria derived from a well-defined cohort of patients in a clinical trial in clinical practice. Indeed, when considering withdrawal of anti-TNF therapy, other factors also need to be taken into account, including length of sustained remission, patient wishes, adequate ongoing immunosuppression and pretreatment morbidity. Despite the reassuring data regarding successful retreatment in patients withdrawn from anti-TNF therapy, risk of relapse is often a contraindication to trial of withdrawal particularly for personal reasons such as work, education or a desire to become pregnant. It is perhaps, therefore, unsurprising that some patients have concerns regarding withdrawal of anti-TNF therapy.
NICE guidance has brought the debate of how and when to withdraw anti-TNF therapy to the fore. The recent EPACT-II update advises that withdrawal of therapy may be attempted after 2 years for those in clinical and endoscopic remission, and 4 years after clinical remission alone. However, these recommendations are largely based on expert consensus opinion highlighting the lack of evidence available. The STORI trial was the first major study to address the issue of anti-TNF withdrawal. It prospectively investigated withdrawal of IFX in patients achieving steroid-free remission and demonstrated that 50% of patients relapsed within 1 year despite ongoing immunomodulation. However, investigators were able to define a group at low risk of relapse making up 29% of patients in the study, of whom only 15% relapsed at 1 year. The STORI trial identifies an FC <300 μg/g as being associated with a favourable prognosis. However, there remains an understandable clinical wariness over FC outwith the normal range and further studies are required to validate this.
The NICE guidance is not accompanied by criteria for the assessment of remission. The minimal requirement is to demonstrate need for ongoing anti-TNF therapy; however, standardisation of the reassessment process would be useful. Reassessment must be flexible, tailored to the individual, acceptable to patients and cost-effective. Although yearly colonoscopy and MRE give comprehensive information on disease status, these are expensive and time-consuming, and colonoscopy is invasive. Furthermore, inter-reporter variation in endoscopic and MRE surveillance can cloud reassessment, and standardisation of reporting methods using scoring systems would increase utility for reassessment. FC can demonstrate, yet does not accurately quantify, disease activity, and in isolation in some patients might be sufficient to demonstrate ongoing need for anti-TNF therapy. However, the optimum mode and interval for reassessment and restaging of CD is yet to be defined and requires further prospective study.
Defining the criteria for withdrawal of anti-TNF therapy, therefore, remains problematic. Even the best data available, the STORI data, come from a relatively small, uncontrolled trial which is yet to be externally validated. Therefore, the criteria we adopted in our patients may have been too harsh and excluded some patients who may have had a reasonable chance of successfully withdrawing therapy. However, it is important to note that the cohort described is a tertiary referral cohort and therefore may represent a group of patients with more refractory disease who were less likely to tolerate withdrawal of anti-TNF therapy. Finally, use of anti-TNF therapy has recently increased in patients with a short disease duration who tend to have a better response to therapy and are therefore more likely to achieve criteria for remission than those with longer standing disease. Such patients represent a small proportion of this cohort and it is unknown if they are more likely to be able to withdraw from therapy than those with a longer disease duration.
This study has several limitations. Case-note review is dependent on the quality and maintenance of case-notes and interpretation of endoscopy reports from a range of operators. However, all patients treated with anti-TNF in our unit are reviewed in a multi-disciplinary meeting on an 8-weekly basis allowing an element of standardisation. In addition, the vast majority of the endoscopic evaluation of patients with CD is performed by three consultants who specialise in IBD. To minimise inter-reporter variation of MRE, we used a scoring system which was applied by a single radiologist.
Anti-TNF therapy is not a panacea, and a significant proportion of patients have ongoing disease activity; that the majority of patients in our cohort fell into this category, despite steroid-free clinical remission, shows that reassessment is not just important for withdrawal of therapy, but also identifies active disease, which in some cases may require treatment escalation.
Discussion
Treatment of moderate to severe CD has been revolutionised by anti-TNF therapy. In the UK, NICE mandates yearly reassessment with a view to demonstrating ongoing requirement for treatment. While the data regarding the success of withdrawal of anti-TNF therapy in patients in remission are sparse, identifying who should withdraw from treatment and when to do so remains a major question in IBD. In addition, while data in general support the relative safety of anti-TNF therapy, however, it remains an expensive treatment accounting for approximately two-thirds of all healthcare costs for people with CD in one recent study. Unfortunately, endoscopic, radiological and biochemical remission, in combination with lack of symptoms, is only achieved in a small proportion of patients and the limited data available suggest that this is the group of patients who are most likely to maintain remission after withdrawal of therapy.
We report that relatively few patients in our cohort (15% (11/73)) achieved our locally defined criteria after at least 12 months treatment. However, in the cohort in whom it was possible to apply the criteria, more patients (37% (19/52)) fulfilled favourable parameters for withdrawal identified in the STORI trial. However, it must be noted that in this study, being a 'real world' cohort, there were many differences to the patients included in the STORI trial. For example, unlike in STORI, some of our patients were on adalimumab, not all were taking concomitant azathioprine, many had clinical characteristics that would have precluded their inclusion in STORI and, finally, only a small number had FC measured. This highlights the difficulties of using criteria derived from a well-defined cohort of patients in a clinical trial in clinical practice. Indeed, when considering withdrawal of anti-TNF therapy, other factors also need to be taken into account, including length of sustained remission, patient wishes, adequate ongoing immunosuppression and pretreatment morbidity. Despite the reassuring data regarding successful retreatment in patients withdrawn from anti-TNF therapy, risk of relapse is often a contraindication to trial of withdrawal particularly for personal reasons such as work, education or a desire to become pregnant. It is perhaps, therefore, unsurprising that some patients have concerns regarding withdrawal of anti-TNF therapy.
NICE guidance has brought the debate of how and when to withdraw anti-TNF therapy to the fore. The recent EPACT-II update advises that withdrawal of therapy may be attempted after 2 years for those in clinical and endoscopic remission, and 4 years after clinical remission alone. However, these recommendations are largely based on expert consensus opinion highlighting the lack of evidence available. The STORI trial was the first major study to address the issue of anti-TNF withdrawal. It prospectively investigated withdrawal of IFX in patients achieving steroid-free remission and demonstrated that 50% of patients relapsed within 1 year despite ongoing immunomodulation. However, investigators were able to define a group at low risk of relapse making up 29% of patients in the study, of whom only 15% relapsed at 1 year. The STORI trial identifies an FC <300 μg/g as being associated with a favourable prognosis. However, there remains an understandable clinical wariness over FC outwith the normal range and further studies are required to validate this.
The NICE guidance is not accompanied by criteria for the assessment of remission. The minimal requirement is to demonstrate need for ongoing anti-TNF therapy; however, standardisation of the reassessment process would be useful. Reassessment must be flexible, tailored to the individual, acceptable to patients and cost-effective. Although yearly colonoscopy and MRE give comprehensive information on disease status, these are expensive and time-consuming, and colonoscopy is invasive. Furthermore, inter-reporter variation in endoscopic and MRE surveillance can cloud reassessment, and standardisation of reporting methods using scoring systems would increase utility for reassessment. FC can demonstrate, yet does not accurately quantify, disease activity, and in isolation in some patients might be sufficient to demonstrate ongoing need for anti-TNF therapy. However, the optimum mode and interval for reassessment and restaging of CD is yet to be defined and requires further prospective study.
Defining the criteria for withdrawal of anti-TNF therapy, therefore, remains problematic. Even the best data available, the STORI data, come from a relatively small, uncontrolled trial which is yet to be externally validated. Therefore, the criteria we adopted in our patients may have been too harsh and excluded some patients who may have had a reasonable chance of successfully withdrawing therapy. However, it is important to note that the cohort described is a tertiary referral cohort and therefore may represent a group of patients with more refractory disease who were less likely to tolerate withdrawal of anti-TNF therapy. Finally, use of anti-TNF therapy has recently increased in patients with a short disease duration who tend to have a better response to therapy and are therefore more likely to achieve criteria for remission than those with longer standing disease. Such patients represent a small proportion of this cohort and it is unknown if they are more likely to be able to withdraw from therapy than those with a longer disease duration.
This study has several limitations. Case-note review is dependent on the quality and maintenance of case-notes and interpretation of endoscopy reports from a range of operators. However, all patients treated with anti-TNF in our unit are reviewed in a multi-disciplinary meeting on an 8-weekly basis allowing an element of standardisation. In addition, the vast majority of the endoscopic evaluation of patients with CD is performed by three consultants who specialise in IBD. To minimise inter-reporter variation of MRE, we used a scoring system which was applied by a single radiologist.
Anti-TNF therapy is not a panacea, and a significant proportion of patients have ongoing disease activity; that the majority of patients in our cohort fell into this category, despite steroid-free clinical remission, shows that reassessment is not just important for withdrawal of therapy, but also identifies active disease, which in some cases may require treatment escalation.
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