Review article: explaining risks of inflammatory bowel disease therapy to patients

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1 Alimentary Pharmacology and Therapeutics Review article: explaining risks of inflammatory bowel disease therapy to patients C. A. Siegel Section of Gastroenterology and Hepatology, Inflammatory Bowel Disease Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. Correspondence to: Dr C. A. Siegel, Section of Gastroenterology and Hepatology, Inflammatory Bowel Disease Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 3756, USA. Publication data Submitted 6 August 21 First decision 31 August 21 Resubmitted 29 September 21 Accepted 3 September 21 EV Pub Online 26 October 21 This commissioned review article was subject to full peer-review. SUMMARY Background Medical treatment for inflammatory bowel disease (IBD) has advanced significantly over the past decade, but it is important to communicate effectively the balance of benefits and risks of therapy to patients to facilitate informed medical decisions. Aim To review the available data describing the risk of side effects of IBD medications and to describe effective methods for communicating risk. Methods To identify relevant articles for this review, a PubMed search was conducted using relevant key words and phrases. In addition, reference lists from identified manuscripts were searched and recent abstracts from National meetings were reviewed. Results The steroid-sparing medications used for the treatment of IBD all carry risks of both common and rare adverse events. Trade-offs need to be made between the risks of these medications vs. the risks of poorly treated disease and corticosteroids. There has been significant research on how best to present risk data to patients, which is summarized in this review. Conclusions To ensure that our patients understand their choices and feel comfortable with their treatment, we need to communicate risk data to patients clearly. Patients comprehend absolute numbers better than relative risk, and when available, pictorial representations of data are preferred over solely presenting numerical outcomes. Aliment Pharmacol Ther 211; 33: doi:1.1111/j x

2 C. A. Siegel INTRODUCTION Significant progress has been made for the treatment of inflammatory bowel disease (IBD) over the past decade. In addition to the introduction of biological therapy, we are learning to optimize the available medications better. The treatment algorithm of starting with safe but weaker medications early in the disease course, and only advancing to more potent medications when those treatments fail, has been challenged. The top-down treatment strategy for Crohn s disease showed us that use of infliximab in combination with azathioprine early in their disease course led to remission, steroid sparing and endoscopic healing more often than patients treated in a standard step-up fashion. 1 In SONIC, patients with a relatively short disease duration who were naïve to immunomodulators and biologics were randomized to receive azathioprine, infliximab or combination infliximab and azathioprine therapy. The combination therapy group clearly showed superiority for inducing remission and mucosal healing. 2 It is becoming clearer that certain subgroups of patients will respond to therapy and attain remission with this more aggressive approach of using effective medications before complications occur, and before patients become dependent on corticosteroids. However, the risk associated with these treatments needs to be considered. Although the perceived risk of treatment may be much higher than the actual risk, patients, parents and many providers are hesitant to use these medications before it may seem warranted by the current level of disease activity. To help all of those involved in decisions for treatment, we need to understand better the predicted response to therapy and how the chance of adverse events is related to the treatment or the disease itself. Although determining the expected benefit and risks of therapy is the first step in helping us to educate our patients, a critical component is in developing methods for clearly communicating these complex data. This review aims to report the available data on the risks of corticosteroids, immunomodulators and biologics when used for the treatment of IBD, to discuss the challenges associated with communicating risk, and to describe techniques for communicating risk to patients and their families more effectively. METHODS To identify relevant articles for this review, a PubMed search was conducted using the following key words and phrases: risk, adverse events, medical decision making, risk communication, Crohn s, ulcerative colitis, inflammatory bowel disease, patient comprehension. Reference lists from identified manuscripts were searched for further publications. Relevant abstracts from the most recent American Gastroenterological Association and American College of Gastroenterology were also reviewed. RESULTS Risk of adverse events associated with IBD therapy The risk of an event is based on two important components: the probability of that event occurring, and the consequences if the event occurs. 3 The probability is simply the numerical estimate of how often an event occurs over a defined period. The consequence is the severity or outcome of that event. For example, the probability of nausea occurring when taking methotrexate is high, but consequences are low as these symptoms are typically self-limited. In contrast, the risk of lymphoma associated with anti-tnf therapy is low, but there is a significant consequence if this occurs. Data on risk are usually reported as probability, and the consequence is typically inferred. Patients will perceive both of these components differently depending on their individual understanding of chance, preconceptions about treatment, level of worry and prior experiences. There are limitations to the available data for the risks of IBD therapies. The probability of the occurrence of common adverse events is fairly well established and consistent across clinical trials and cohort studies, but the frequency of rare events is more difficult to determine. Fortunately, serious and life-threatening events are so rare that they are not typically seen in clinical trials and therefore we must rely on cohort- and populationbased studies, which have their own biases and limitations. Meta-analyses have been completed for some, but not all important adverse events related to therapy. Although point estimates are available for the chance of experiencing many of the concerning adverse events associated with treatment, confidence intervals are typically wide and their reliability uncertain. With this understanding, these estimates provided are the current best guess for the rate of adverse events associated with IBD therapy. Corticosteroids. Corticosteroids are commonly used for the treatment of IBD. They can be very effective in the short-term, but over the long-term, most patients either require surgery or become steroid-dependent. 4 Side effects are frequent, and 55% of patients have some adverse event leading to cessation of steroid therapy Aliment Pharmacol Ther 211; 33: 23 32

3 Review: communicating risks of IBD therapy Table 1 shows the estimated frequency of a number of common adverse events associated with corticosteroid therapy. Other rarer side effects include avascular necrosis of the hip, adrenal suppression and life-threatening opportunistic infections. The frequency of occurrence of these events remains unknown, but due to the significant impact on quality of life if they do occur, they should be presented to patients. Furthermore, the use of corticosteroids is a risk factor for disabling disease, 9 and appears to be a predictive factor for developing complications such as stricturing and perforating disease. 1 Table 1 Corticosteroid side effects Event Any side effect leading to stopping prednisone Estimated frequency 5 8 (%) 55 Ankle oedema 11 Facial swelling 35 Easy bruising 7 Acne 5 Memory problems 7 Psychosis confusion agitation 1 Infections 13 Cataracts 9 Increased eye pressure 22 Hypertension 13 Osteoporosis 33 Other serious side effects include diabetes, severe hip damage and poor function of adrenal glands Uncertain frequency Immunomodulators. Immunomodulators used for the treatment of IBD include mercaptopurine (MP) and its pro-drug azathioprine and methotrexate. MP and azathioprine have similar side-effect profiles. Approximately 11% of patients need to stop these medications due to some adverse event. Common events associated with MP and azathioprine include allergic reactions, nausea, elevated liver tests and pancreatitis (Table 2). These events are self-limited and resolve when stopping therapy. More concerning are possible life-threatening side effects including serious infections (approximately 5% of patients) and the occurrence of non-hodgkin s lymphoma (NHL). Estimates for the frequency of NHL are approximately 4 9 per 1 treated patients over the course of one year. 11, 12 A proposed mechanism for this increased rate of NHL appears to be related to proliferation of Epstein Barr Virus (EBV). 13 Patients with IBD treated with MP or azathioprine are at an approximately 2 5 times increased risk of developing NHL compared 11, 12 with patients never exposed to these medications. Methotrexate is proven effective for the treatment of Crohn s disease, but has not been adequately studied to understand its use in ulcerative colitis. In the sentinel induction study showing efficacy of methotrexate for Crohn s disease, 17% of patients withdrew from the study due to adverse events (as compared to 2% in the placebo group). Table 2 displays side effects that occurred more often in the methotrexate group including nausea (42%), headache (17%) and fatigue (16%). 14 The follow-up maintenance study showed a similar frequency of events. 15 Methotrexate infrequently suppresses the white blood cell count, and serious infections may occur less often than with MP azathioprine. More serious events associated with the use of methotrexate include hepatotoxicity and hypersensitivity pneumonitis. Although hepatotoxicity has been described clearly in patients with psoriasis, 16 this has not been demonstrated in IBD patients. In one study, 2 IBD patients received methotrexate and all underwent liver biopsy. Only one patient had significant fibrosis, and this patient had Table 2 Common side effects associated with inflammatory bowel disease medications Event Mercaptopurine and azathioprine 8 Stop therapy due to adverse event 11 Allergic reactions 2 Nausea 2 Hepatitis abnormal liver tests 2 Pancreatitis 3 Serious infections 5 14, 15 Methotrexate Stop therapy due to adverse event 17 Nausea 43 Headache 17 Fatigue 2 Anti-TNF 8 Stop therapy due to an adverse event 1 Infusion or injection site reactions 3 21 Drug-related lupus-like reactions 1 Serious infections 3 Estimated frequency (annual, %) Aliment Pharmacol Ther 211; 33:

4 C. A. Siegel multiple contributing factors including diabetes, obesity and other concomitant potentially hepatotoxic medications. 17 Approximately 1% of patients with rheumatoid arthritis receiving methotrexate may develop hypersensitivity pneumonitis. Risk factors in these patients include diabetes, older age and pre-existing rheumatoid lung disease. 18 Hypersensitivity pneumonitis has been reported in patients with IBD, but only in case reports. 19, 2 Lymphoma has rarely been reported with the use of methotrexate in patients with IBD; 21 however, there are more data in rheumatoid arthritis suggesting that lymphoma may also develop as a result of EBV proliferation. 22 Anti-TNF therapy. Approximately 1% of patients stop anti-tnf therapy related to some adverse event. 23 Although a number of adverse events have been reported in association with anti-tnf agents, the most common and well documented are summarized in Table 2. Infusion or injection site reactions are one of the most common events, ranging from 3% to 21% depending on the drug delivery and definition of a reaction. 23 Although anti-nuclear antibodies and double-stranded deoxyribonucleic acid are commonly seen in IBD patients treated with anti-tnf therapy, drug-related lupus-like reactions only occur in approximately 1% of patients. 24 Serious infections occur in approximately 3% of patients in clinical trials, 23 and death related to serious adverse events has been reported to occur as frequently as 1 in 25 treated patients. 25 However, the average age of patients who have died is older than 6, and typically they have associated comorbidities and concomitant corticosteroid use. 25, 26 This does not mean that young patients are protected from life-threatening complications as a result of treatment, but they are likely at a far lower risk. The risk of lymphoma associated with anti-tnf monotherapy is not known simply because there are no sufficient numbers of patients worldwide with IBD who have been treated with anti-tnf therapy without prior exposure to immunomodulators. A recent meta-analysis estimates the rate of NHL in patients with Crohn s disease treated with anti-tnf therapy (almost all with prior or concomitant use of MP azathioprine). 27 The absolute rate was reported to be 6 per 1 treated patients over the course of 1 year. Compared with the expected rate in the general population (Surveillance, Epidemiology, End Results registry), this is 3.2 times higher than expected (95% CI: ) and 1.7 times higher (95% CI:.5 7.1) than was reported in a cohort of Crohn s disease patients treated with immunomodulators alone. As estimates for the frequency of developing NHL with MP azathioprine monotherapy are so close to those with combination anti-tnf therapy, it is likely that immune suppression at the level used in IBD leads to a fairly uniform (and low) risk. The risk of NHL in IBD patients taking any steroid-sparing immune suppressive agents is approximately 4 9 per 1 patient-years. Hepatosplenic T-cell lymphoma (HSTCL) is a subtype of NHL, which unfortunately has nearly universal fatal outcomes. Although a handful of cases had been reported in IBD patients receiving immunomodulators alone, a series of patients exposed to anti-tnf therapy quickly accumulated since December of Most patients are male, the average age is in the mid late 2s, and all patients with IBD who have developed this condition while receiving anti-tnf therapy also had prior exposure to immunomodulators. The rate of occurrence of HSTCL has not been determined, as an accurate denominator of patients at risk is difficult to define. Risk of combination vs. monotherapy. Despite publication of the SONIC trial showing superiority of combination anti-tnf and azathioprine therapy compared with either drug on its own, 2 controversy still remains regarding the value of using two drugs based on the possible increased risk. Intuitively, using two immune suppressive medications puts patients at a higher risk of adverse events than one. However, we have not seen this in clinical trials or other outcome reports. In SONIC, which included patients with an median age of 34 years and a median disease duration of 2 years, the rate of serious infections (about 6%) was equal across all three groups. Similar findings were seen in COMMIT (study comparing infliximab monotherapy to infliximab therapy combined with methotrexate) with patients who were about the same age, but had an average disease duration of 1 years. 29 The Crohn s Therapy, Resource, Evaluation and Assessment Tool (TREAT) study evaluated the risk of infliximab. 3 Although there was an increased risk of serious infection and death when infliximab was used in combination with corticosteroids or narcotics, this was not seen when used in combination with immunomodulators (OR:.78, 95% CI: for serious infection; OR:.72, 95% CI: for death). A retrospective analysis from the Mayo Clinic reported the risk of opportunistic infections with different combinations of immune suppressant therapies. 31 They did see an increased risk of infections when more than one drug was used; however, this was almost completely driven by the combination of MP azathioprine and corticosteroids. There was actually only one case of an opportunistic 26 Aliment Pharmacol Ther 211; 33: 23 32

5 Review: communicating risks of IBD therapy infection with combination anti-tnf and MP azathioprine, which did not show statistical significance. Overall, other than HSTCL, data are lacking to confirm that anti- TNFs in combination with MP azathioprine have any increased risk over anti-tnf alone. Natalizumab. Natalizumab is a monoclonal antibody against alpha-4 integrin that inhibits leucocyte adhesion and migration into inflamed tissue. It is approved in the United States for the treatment of Crohn s disease and is effective in maintaining remission. It is used more frequently for the treatment of multiple sclerosis, and most data on risk come from these patients. The most concerning adverse event associated with this medication is progressive multifocal leucoencephalopathy (PML). PML is a degenerative brain disease caused by the John Cunningham (JC) virus. To date, PML has been reported in just one patient with Crohn s disease who was a subject in one of the early clinical trials. 32 There have been over 7 patients exposed to natalizumab worldwide, most of whom have multiple sclerosis, and the rate of PML has remained stable around 1 per 1 patient-years of exposure. 33 Antibody testing is being developed to identify patients who are at higher risk of developing PML. Communicating risk Even with improved confidence of our estimates of the risks associated with IBD therapies, there still remains the difficult problem of clearly communicating these data to patients. To understand how to communicate better with patients, it is instructive to review where mistakes can be made in conveying information. First, very small numbers and comparisons between these numbers are difficult to conceptualize. In one study assessing numeracy (quantitative literacy), half of patients could not convert 1% to 1 per 1, and 8% of patients were unable to convert 1 per 1 to.1%. 34 Furthermore, patients had a difficult time determining which was higher, 1 in 27 vs. 1 in 37. Medical students did not fare much better in a separate study on the same topic. 35 Second, providers can inadvertently (or perhaps purposefully) frame data in such a format that can influence a patient s decision. This was nicely demonstrated in a survey study where twice as many patients agreed to take a hypothetical cholesterol lowering medication that would lead to a 34% relative risk reduction of myocardial infarction than a medication yielding a 1.4% absolute reduction in the risk. 36 Even though these represented exactly the same numerical benefit, patients preferred the larger, albeit relative number. Studies have been conducted comparing different formats of data in an effort to minimize framing. In a randomized cross-sectional survey, patients were best able to interpret benefits of treatment when relative risk reduction was presented along with a given baseline risk of disease. 37 Absolute risk was also easy to interpret. The number needed to treat was the most often misinterpreted format. A meta-analysis on this topic showed that presenting relative risk led to a more favourable assessment of outcomes due to the higher numerical value. 38 This perception probably also leads to patients over-representing risk, as a relative increase of 3 4 times a very small probability of occurrence is still a very small risk. Based on this work and others, there are some general principles for effective patient communication (Table 3). 39, 4 Verbal description alone of risk should be avoided. Descriptive words such as rare or common can be interpreted in such a wide range that they can be misleading. For example, a British study compared the estimates of students interpretation of descriptive words that have been assigned by the European Commission as recommended verbal descriptors. 41 The European Commission intended the term common to represent a side-effect frequency of 1 1%, but the students mean quantification of common was 45%. Similarly, the European Commission defines rare as.1.1% and very rare as <.1%, but study participants estimated these terms to be a probability of 8% and 4% respectively. The authors concluded that these descriptive terms result in significantly higher levels of perceived risk and a lower likelihood of a patient taking the medication. It is better to use multiple formats in presenting risk, including numbers and graphs. Pictorial displays of data are helpful when available. When numbers are presented, a consistent denominator should be used (4 of 1 vs. 5 of 1) as opposed to trying to decipher the difference between 1 in 25 and 5 per 1. To avoid misrepresentation, absolute risks should be presented as opposed to relative risks, and the number needed to treat should be Table 3 Recommendations for clear communication of 39, 4 risk Do not use vague descriptive words (e.g. rare, common) Use multiple formats (e.g. numbers, graphs) for presentation Show pictorial representations if available Present comparisons with a common denominator Use absolute as opposed to relative numbers Avoid small percentages (.6%); use 6 per 1 instead Individualize estimates if possible Aliment Pharmacol Ther 211; 33:

6 C. A. Siegel avoided. Percentages <1% should be presented as a frequency (6 of 1 ) as opposed to a very small number (.6%). When able, patients better retain information if it is individualized for them, as opposed to a generic description (e.g. a discussion on HSTCL should be different for young males from that for females). Dealing with uncertainty Physicians and patients are typically uncomfortable with the idea of uncertainty of reported data. All point estimates have associated confidence intervals, and although there is an ethical obligation to admit uncertainty, we do not want to confuse our audience. It has not been well established how to report uncertainty to patients, but some work has defined how uncertainty may be interpreted by patients and offers ideas on how to clarify this issue better. 42 Presenting disease risk as a numerical range as opposed to a point estimate leads to lower trust in the data, and a heightened perception of these risks. This response, known as ambiguity aversion has been shown to reduce people s interest in therapeutic interventions. One study evaluated how the presentation of data influenced subjects perception of their risk of developing colorectal cancer. 43 Respondents had heightened cancerrelated worry when a range (confidence interval) was presented as opposed to a point estimate. When presented as a visual format (picture or figure), the sense of ambiguity aversion was lower, and worry was also decreased in patients who were characterized as optimistic, as opposed to those who were characterized as pessimistic. Patients have a right to know that there is uncertainty in our estimates, but we need to be careful in how to present this so as not to increase their concern, confuse the message, and possibly dissuade patients from using appropriate therapies. The best way to communicate uncertainty of data to patients is to admit that all reports of benefit and risk of therapies are based on estimates from the currently available evidence, and it is possible that these estimates can change over time. How much risk are patients willing to take, and how much do they want to know? The amount of risk patients are willing to accept when taking IBD-related medications has been studied. In a web-based survey study of over 5 subjects, patients with Crohn s disease were presented a series of conjoint trade-off tasks to determine their maximal acceptable risk of specific side effects. 44 Specifically, they were asked how much risk they were willing to accept of dying from sepsis, lymphoma or PML in exchange for either responding to a medication or achieving remission from different levels of disease activity. A few interesting results were noted. First, as might be anticipated, patients were willing to accept higher risks for a greater expected benefit from therapy. Second, patients were more risk averse for unfamiliar risks (PML) than for familiar risks (sepsis and lymphoma). Next, patients in general were willing to accept a much higher level of risk (almost a 1% annual risk of lymphoma in some scenarios) than has been reported in the literature. Taken together, based on these results, it appears that patients are willing to take the known risks associated with IBD therapies; however, they accept risk more readily if they feel that they are sick enough to deserve the therapy and that they will receive substantial benefit from the treatment. The survey was repeated with parents of patients with Crohn s disease. 45 Parents showed similar risk thresholds to adult patients; however, they were even more risk taking when the child was sick and more risk averse when the child had only mild-to-moderate disease. This raises an interesting question whether patients and parents will be willing to accept a top-down treatment strategy if the disease is in its early stages and has not yet declared itself as severe. Ziegler and colleagues studied the question of how much information about adverse events patients want to know. With a large survey of 25 adults, they found that 76% of respondents desired to be told about all possible adverse events, no matter how rare. Very few (.4%) responded that they were not interested in any information. A desire for more information was correlated with a lower educational level and previous experience with adverse events. Subjects were asked whether a physician is ever justified in withholding information about adverse events. Seventy-three per cent of all individuals answered no, and 68% thought that physicians should give the same information to all patients as opposed to giving as much information as he she thinks best for the individual patient. A recent study directly related to IBD asked patients about their needs for information soon after diagnosis. 46 The information rated most often (91% of subjects) as very important was that related to possible side effects of medications. Although it is striking that a high proportion of patients is interested in hearing about every possible adverse event, there is certainly an impracticality of this approach. Patients may have the expectation of hearing it all, but the numerous possible side effects associated with almost every treatment are likely to be overwhelming. Furthermore, as time pressure increases during a typical office 28 Aliment Pharmacol Ther 211; 33: 23 32

7 Review: communicating risks of IBD therapy visit, this leaves less time to discuss expected outcomes, comprehension of dosing regimens and a clear follow-up plan. More work is needed in understanding what patients truly want and need to hear about side effects and how to communicate this effectively. Do patients need to understand the exact risk to make decisions? Much of the work on patient communication has focused on how to educate patients properly about the precise quantitative benefit or risk. A competing idea called the Fuzzy Trace Theory proposed by Valerie Reyna argues that patients may better comprehend data if given as the bottom-line meaning, or gist, when making judgments for decision making. 47 Gist is a crude mental representation of the risk, as opposed to verbatim that refers to the precise number, whether presented verbally or visually. For example, the verbatim risk of lymphoma associated with combination anti-tnf and immunomodulator therapy is.6%. The gist is that this is a very low risk, which is very unlikely to occur. Reyna describes that if given a memory test, verbatim is the important data representation. However, patients actual decision making is not necessarily affected by their knowledge, and the memory independence effect states that reasoning accuracy is independent of memory accuracy. Gist is not simply the vague representation of the risk, but the distillation of the meaning of past experiences and new information into a meaningful bottom-line understanding. As decision making is more about reasoning than memory, allowing patients to make a gist-based representation will probably improve their ability to make better preference-based decisions. No matter how we get patients to understand risk, whether it is verbatim, gist, or some combination of these, for a patient to be involved in a decision with their physician, they need to be activated to engage in the trade-off of risks and benefits. Activation refers to patients taking an active role in managing one s own health and health care. 48 Patients who are more activated are likely to understand the consequences of their choices, and are likely to be more motivated to make better, highquality choices for their medical care. Activation helps both low numeracy and low health literacy groups, and may be able to help these patients compensate for lack of knowledge. If we can help patients understand what is at stake in a given medical decision, then they may be more motivated to be engaged, and activated to comprehend and process the information which they are given. Developing tools to help IBD patients understand risk A majority of patients with IBD (81%) believe that it is very important to be actively involved in the decisionmaking process. 49 However, patients and parents of Ten Thousand People pictures to help you see yours odds Risk of lymphoma with immune suppression The Paling Palette of 1, People Risk Communication Format@John Paling 21 See We can only show you estimates. It is impossible to be certain weather your results will be positive or negative. Figure 1 Risk of lymphoma associated with immune suppression. Visual representation of the annual risk of non- Hodgkin s lymphoma associated with the use of immune suppressive therapy for patients with inflammatory bowel disease. The risk is likely to be similar for immunomodulators and immunomodulators combined with anti-tnf therapy, and is estimated to be between 4 and 9 per 1 patient-years. 11, 27 Nine people are highlighted to demonstrate this absolute risk. Aliment Pharmacol Ther 211; 33:

8 C. A. Siegel Azathioprine 6 had serious infections, 94 did not Anti-TNF 5 had serious infections, 95 did not Combination 4 had serious infections, 96 did not Figure 2 Risk of serious infections with monotherapy or combination therapy. Visual representation of the risk of serious infections in the SONIC trial. 2 The risk is approximately equal across all three treatment groups, as demonstrated by the number of highlighted faces. patients with IBD have misperceptions of both the benefits and risks associated with IBD therapies. 5, 51 Therefore, effective methods to communicate benefit and risk will help allow patients and parents obtain accurate information and become more activated in their care. Tools have been developed to display benefits and risks of IBD therapy numerically and graphically to allow for rapid and clear communication with patients. 8 One example is shown in Figure 1, where a risk palette displays an estimate of the frequency of lymphoma in IBD patients treated with immune suppressive therapy. Figure 2 uses a standard 1 faces picture to demonstrate the risk of serious infections across the three treatment groups in the SONIC trial. Other tools are available as an online supplement to a recently published review, 8 and are currently being tested with patients to make sure that these tools are effective in delivering a clear message Risk of complication Overall HR 1.6 Risk at 3 years Risk at 1 month Personal characteristics Input age at Dx SB input ASCA A input Gender input Months since Dx 3 Disease location LB input UT input PA input Serologic inputs ASCA G input CBir1 input OmpC input panca input Genetic inputs Genetic information SNP8 input SNP12 input SNP13 input Treatment options 25 Immunomodulators Anti-TNF Corticosteroids 1 Treatment option = 1: treatment within 9 days from diagnosis. Treatment option = 2: Treatment after 9 days from diagnosis Year from present Without treatment With treatment Figure 3 Crohn s disease risk prediction tool. The graph shows the model output, which predicts the risk of a Crohn s disease complication (either stricturing or internal penetrating disease) for a specific patient. The example patient is an 18-year-old female with a recent diagnosis, small bowel and perianal disease and elevated serological markers. Her risk of a complication of Crohn s disease at 3 years is 84%. The predicted response to anti-tnf treatment administered within 9 days of diagnosis is also displayed. Dx, diagnosis; SB, small bowel; LB, large bowel; UT, upper tract; PA, perianal; ASCA, anti-saccharomyces cerevisiae antibody; anti-cbir1, anti-flagellin; OmpC, anti-outer membrane porin C of Escherichia coli; panca, perinuclear anti-neutrophil antibody; SNP, single-nucleotide polymorphism; TNF, tumour necrosis factor; IM, immunomodulator. 3 Aliment Pharmacol Ther 211; 33: 23 32

9 Review: communicating risks of IBD therapy regarding IBD therapy. Additionally, a real-time interactive tool to predict an individual patients risk of developing disease-related complications from Crohn s disease and their response to therapy has been developed and is being validated. 1 Using the technique of System Dynamics Analysis, this tool can be used at the point of care to display graphically the probability of a patient experiencing a disease-related complication over a 3-year period (Figure 3). More work is to be carried out in the future to create and test different formats of patient communication tools for IBD patients. CONCLUSION Current treatments for IBD in the biological era are allowing us to treat patients more effectively, but bring with them the responsibility of understanding the risks associated with these therapies and developing appropriate strategies to ensure that patients understand the trade-off between these benefits and risks. As providers, we need to feel comfortable discussing risk and uncertainty, and have efficient methods of communicating this to patients. We also need to understand that not all patients are willing to accept these risks, despite how rare. We have learnt that the patients with IBD who are at the most overall risk are those with poorly controlled disease and those receiving corticosteroids. 52 Although there are measurable risks associated with immune suppressant therapies, in most patients (but not all), the benefits of treatment leading to an improved disease course outweigh these risks. If we are to improve the quality of life of our patients and ultimately decrease this overall risk, we need to be able to help patients make good decisions about which medications are right for them. On the other hand, some patients are at a low risk of experiencing complications of their disease, and they should not assume additional risk of treatment if it is not warranted. An important part of our job as clinicians is to educate our patients on the risks of their disease and the benefits and risks of therapy so that they can make good decisions that are in line with their personal preferences for treatment. ACKNOWLEDGEMENTS Dartmouth-Hitchcock Medical Center and Cedars-Sinai Medical Center have a United States patent pending on the Crohn s disease risk prediction tool, filed March 24, 21. Dr Siegel is an inventor. Declaration of personal interests: The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. Dr Siegel has served as a consultant, on the advisory board, and developed and delivered CME material for Abbott Labs, Elan Pharmaceuticals and UCB. Declaration of funding interests: Dr Siegel is supported by a CCFA career development award and by Grant Number K23DK78678 from the National Institute of Diabetes and Digestive and Kidney Diseases. REFERENCES 1. D Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn s disease: an open randomised trial. Lancet 28; 371: Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn s disease. N Engl J Med 21; 362: Lipkus IM. Numeric, verbal, and visual formats of conveying health risks: suggested best practices and future recommendations. Med Decis Making 27; 27: Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 21; 121: Present DH. How to do without steroids in inflammatory bowel disease. 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