Inflammatory Bowel Diseases:
Pediatric Review Article
Balancing and Communicating the Risks and Benefits of Biologics in Pediatric Inflammatory Bowel Disease
Dulai, Parambir S. MD*; Siegel, Corey A. MD*; Dubinsky, Marla C. MD†
*Inflammatory Bowel Disease Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire; and
†Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California.
Reprints: Marla C. Dubinsky, MD, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Suite 1165W, Los Angeles, CA 90048 (e-mail: Marla.Dubinsky@cshs.org).
C. A. Siegel serves on the advisory board, as a consultant, and received grant support from Abbott Labs, Janssen, and UCB. He is also supported by Grant number K23DK078678 from the National Institute of Diabetes and Digestive and Kidney Diseases and Grant number 1R01HS021747-01 from the Agency for Healthcare Research and Quality. M. C. Dubinsky serves as a consultant to Abbott, Janssen, UCB, and Takeda. P. S. Dulai has nothing to disclose.
Received April 10, 2013
Accepted May 07, 2013
Abstract: Anti–tumor necrosis factor agents are now considered to be a vital component of the treatment algorithm for pediatric inflammatory bowel disease. Despite the clear benefit of these agents and the realignment of treatment goals to achieve early mucosal healing, the decision to initiate therapy is often delayed due to uncertainties regarding risks and benefits. The purpose of this review was to summarize the currently available data regarding anti–tumor necrosis factor agents in pediatric inflammatory bowel disease. Specifically, we review their expected efficacy in both Crohn’s disease and ulcerative colitis and the likelihood of side effects associated with these agents. In addition, we address the barriers physicians face when communicating these data and help to identify how pediatric patients and their parents can be more involved in a shared decision-making process. Through the creation of a new decision aid (Option Grid), we hope to allow for a more clear line of communication at the bedside when helping patients and parents make these difficult treatment decisions.
Inflammatory bowel disease (IBD) is a chronic relapsing, remitting illness that presents during childhood or adolescence in up to 25% of patients. The global incidence of pediatric IBD also seems to be on the rise.1–3 The significant impact of this disease on growth, development, and health-related quality of life,4,5 along with an enhanced understanding of disease mechanisms, has led to the realignment of treatment strategies toward early initiation of biological therapy for better lifetime control.6–9
Despite the clear impact of biologics on disease outcomes, this “top-down approach” is often met with uncertainty by patients and parents. With parents often underestimating benefit and overestimating risk,10 the decision to initiate biologics can frequently be delayed until patients are felt to be “sick” enough to warrant the risks of therapy.11 For parents and patients to make informed, balanced, and timely decisions, they must be able to understand not only the chance of responding to therapy but also the risk for significant side effects and alternative treatment options as well. For physicians to effectively communicate these outcomes, after understanding the data, we need to develop tools that can be used with parents and patients to allow for a more open and clear discussion in the clinic.
This review will first discuss the safety, efficacy, and durability of biologics in pediatric IBD. Next, we will further discuss the role of parents and children in medical decision making, factors impacting those decisions, and methods through which to effectively communicate risks and benefits. Finally, through the creation of an “Option Grid,” we will provide a tool to efficiently review expected outcomes with patients and parents at the bedside.
EFFICACY OF BIOLOGICS IN PEDIATRIC IBD
Initial retrospective studies helped to establish the safety and efficacy of single-dose infliximab (IFX) induction therapy for Crohn’s disease (CD), demonstrating significant improvements in symptoms at 4-week and 12-week follow-up.12 Later prospective studies, using more objective measures of response (Pediatric Crohn’s Disease Activity Index [PCDAI]), demonstrated remission in >50% of patients at some point of treatment.13,14 Although these studies helped to solidify the role of IFX in pediatric CD and identified 5 to 10 mg/kg to be the most beneficial dosage, this single-dose induction protocol was associated with a significant rate of relapse (42%–78%). In an attempt to prolong response to therapy by using a 3-dose induction regimen at 0, 2, and 6 weeks, Cezard et al15 achieved significantly higher rates of remission at 4 weeks (90%) and 12 weeks (76%). Relapse rates, however, remained high at 90%, with the majority (74%) relapsing within 6 months of the initial treatment. Borrelli et al16 showed similar outcomes 8 weeks after induction therapy, but in this study, 8 of 18 parents allowed for continuation of therapy with maintenance IFX every 8 weeks. At 6-month follow-up, the mean PCDAI was significantly lower in the maintenance group as compared with those treated with 3-dose induction alone (10.5 ± 1.41 versus 18.8 ± 4.54; P < 0.05).
The REACH trial, a randomized multicenter open-label trial, evaluated the outcomes of induction therapy with IFX in 112 patients. They achieved clinical response and remission, as defined by the PCDAI score, in 88% and 59% of patients, respectively, at 10 weeks. When evaluating the subgroup of patients with fistulizing disease at baseline (n = 22), 41% of patients attained partial or complete response 2 weeks after the initial infusion and 68% achieved complete response by week 54.17,18 This study addressed the necessity of an Q8 week dosing interval by randomizing patients responding to IFX induction therapy to either Q8 week or Q12 week maintenance. The Q8wk group had an increased likelihood for maintaining response (63.5% versus 33.3%, P = 0.002) and remission (55.8% versus 23.5%, P < 0.001) at 1 year.18 When further comparing episodic or “on demand” treatment intervals to scheduled maintenance therapy, Ruemmele et al19 again showed that scheduled Q8 therapy was the superior treatment protocol at 1-year follow-up, and Crombe et al20 demonstrated it to be the superior treatment protocol as far as 3 years after inducing remission. During the open-label extension of the REACH trial, approximately 80% of patients continued to have minimal to no disease activity up to 3 years after the initiation of IFX.21
Adalimumab (ADA) has been to shown to induce and maintain response in adult patients with CD who are naive, intolerant, or no longer responsive to IFX.22,23 Its use in pediatric patients has largely been off-label for refractory disease.24–29 The IMAgINE 1 study, a phase 3, multicenter, randomized, open-label induction double-blind maintenance trial, recently evaluated the efficacy of ADA in patients refractory to conventional therapy (PCDAI > 30, 40% previously treated with IFX).29 They demonstrated that ADA was well tolerated and a response to induction was seen in 82% of patients, with >50% maintaining response at 6-month and 12-month follow-up. Of the 36 patients with fistulas, 26 had improvement at 1 year with 11 having complete closure. This study demonstrated that IFX-naive patients had higher rates of response and remission to ADA than those previously exposed to IFX (only secondary nonresponders were included), achieving rates comparable with those seen in the REACH trial, which included only anti–tumor necrosis factor (anti-TNF)–naive patients.18 Although ADA is currently not Food and Drug Administration approved for pediatric CD, taken together, these data suggest that outcomes may be comparable with that of IFX.
Unlike pediatric CD, data on the use of IFX in pediatric ulcerative colitis (UC) is limited largely to 2 prospective cohort studies and several small retrospective case series. Turner et al30 described a cohort of 128 patients with UC hospitalized for a severe flare, 33 of whom underwent treatment with IFX for disease refractory to steroids. Short-term response (Pediatric Ulcerative Colitis Activity Index <35) was seen in 76% of patients, with 55% maintaining long-term response and remaining colectomy free. Patients with new onset disease and those with a shorter duration of disease activity were more likely to respond to IFX than those with a longer disease history. In the largest pediatric UC study to date (n = 332), Hyams et al31 treated a mixed cohort of steroid refractory patients (34 of 52, 65%) and steroid-dependent patients (18 of 52, 35%) with maintenance or episodic therapy and achieved short-term response (3 month—Physician Global Assessment) in 36% of patients. The likelihood of remaining colectomy-free after IFX treatment was 75%, 72%, and 62% at 6, 12, and 24 months of follow-up, respectively.31
Biologics Affect on Growth and Development
With nearly 25% of patients with IBD presenting during childhood or adolescence, and the majority of this being around puberty, the impact of disease activity on growth and development is significant. The principal determinants of impairment are chronic nutritional deficiencies, secondary to malabsorption and reduced intake, along with chronic inflammation, resulting in interruption of the insulin like growth factor (IGF-1) growth hormone axis (interleukin 6, 1β, IGF-1, TNF).32 The greatest consequence seems to be in pediatric CD, where nearly half of all patients have a reduction in growth velocity before diagnosis compared with only 3% to 10% in UC.33,34 There is now strong evidence to support the improvement of linear growth with IFX independent of steroid dose reduction or progression through puberty.35,36
The REACH study demonstrated significant improvements in height z-scores (mean baseline z-score: −1.5) at 30-week follow-up (mean improvement in z-score of 0.3; P < 0.001) and 54-week follow-up (mean improvement in z-score of 0.5; P < 0.001).18 This improvement in linear growth was related to inhibition of TNF-alpha effects on osteoblasts and coupling of bone formation and resorption and continued through the open-label extension, with a median change from baseline of 0.82, 1.01, and 1.56 at 1, 2, and 3 years, respectively.21,37 The patients benefiting most from this improvement were those on steroids at enrollment and those with at least 1-year delay in bone age. These growth benefits also seem to be significantly more pronounced in children with severe CD treated either before the onset of puberty or in its early stages (Tanner I–III), reconfirming the role for early initiation of biological therapy.35
In summary, IFX is an effective treatment option for both pediatric CD and UC. In patients with UC suffering from an acute severe flare, early IFX induction is recommended in patients with a Pediatric Ulcerative Colitis Activity Index score of >45 on hospital day 3 or >65 on hospital day 5 to avoid the substantial morbidity and mortality associated with delayed treatment of this population.38 IFX should also be considered in children with persistently active or steroid-dependent UC, uncontrolled by 5-aminosalicylic acid, and thiopurines.39 ADA is an effective alternative in patients with CD intolerant or no longer responsive to IFX therapy. The role of ADA in pediatric UC still remains unclear, and large multicenter trials are needed.
SAFETY IN PEDIATRIC IBD
Immunogenicity and Infusion Reactions
The formation of antibodies to IFX has been seen in 3% to 35% of IFX-treated pediatric patients and is thought to impact clinical efficacy and increase the risk for both acute infusion reactions (AIR) and delayed type III hypersensitivity reactions (serum sickness).18,40–45 It should be mentioned that the REACH study, which only detected antibodies to IFX in 3% of pediatric patients, had inconclusive results in 77% of patients due to the presence of circulating IFX, limiting the conclusions that can be drawn.18
AIR can be either immune-mediated (type I hypersensitivity) or non-immune mediated (rate-related). Symptoms of AIR commonly include shortness of breath, flushing, rash, headaches, and tachycardia.46 Rarely, these patients suffer from anaphylaxis and shock. Pooling data from 32 cohort studies for pediatric patients with IBD undergoing treatment with IFX, 149 of 1550 patients (9.6%) receiving more than 13,940 infusions experienced a total of 184 AIR (1.3%), with nearly a quarter of these being severe in nature (41 of 184, 22%).12–21,30,31,47–73 When expressed based on the duration of IFX exposure, the overall incidence for infusions reactions was 147 per 1000 patient-years of exposure with an incidence of 33 per 1000 patient-years of exposure for severe reactions (Table 1). Forty-two patients required discontinuation of further treatment (2.7%) with no patient deaths secondary to AIR. Five patients developed symptoms consistent with a delayed hypersensitivity reaction (0.3%, 0.22 per 100 patient-years of follow-up [PYF]).
Female gender, immunosuppressive use for less than 4 months, and a previous infusion reaction have been found to be risk factors for AIR in children.45,74,75 Episodic treatment has been shown to increase the rate of severe delayed infusion reactions among adult patients, but one publication suggests that this does not seem to be the case in children.45 This may be partially explained by the fact that adult patients undergoing episodic treatment with lengthy intervals between infusions are at a higher risk for development of antibodies to IFX compared with children.41 Premedication with antihistamines or corticosteroids does not seem to prevent the development of initial infusion reactions in children.76,77 Although premedication was not used or commented on routinely throughout the studies, our review suggests that it does seem to possibly prevent repeat reactions in those patients who continue on treatment after an initial AIR and therefore should be considered for patients continuing on therapy.41
Pediatric data on the formation of antibodies to ADA are limited to the IMAgINE 1 study, which detected antibodies to ADA in 3% of patients.29 Adult data have reported the formation of antibodies to ADA in 3% to 17% of patients, but unlike IFX, these antibodies only seem to impact clinical efficacy and not adverse reactions.78,79
Of the 250 IFX-treated patients in whom anti–nuclear antibody testing was performed, 17% (n = 43) developed positive anti–nuclear antibodies, 4% (n = 10) developed anti–double-stranded antibodies, and 2% (n = 5) developed anti-tissue antibodies. These antibodies often disappear within 6 months of treatment discontinuation,15 making the significance of these asymptomatic antibodies unclear. Drug-induced clinical lupus was rare and only occurred in 2 patients, with 1 of these having negative serology.51,61 The patient with negative serology was successfully retreated with 2 more infusions and the rash was thought to be associated with drug-induced lupus that resolved over 6 months. The other was switched to ADA with no further autoimmune phenomenon reported. Other autoimmune disorders described include vascular purpura (n = 2) that resolved with discontinuation of IFX, Henoch–Schonlein purpura (n = 1), and an anti-neutrophil cytoplasmic antibody-associated vasculitis involving the fingers (n = 1), which was felt to likely be related to the underlying IBD.20,61,65 To date, there are no reported cases of autoimmune disorders developing after treatment with ADA, but there are far fewer data as compared with IFX.
Pooled data for both IFX and ADA show an overall infection rate of 17.7%, with 2.8% of treated patients suffering from serious infections.80 Expressed by the length of patient follow-up, the incidence of infections per 1000 PYF was 132 overall and 20 for serious infections. Given the potential for underreporting in retrospective studies, data were reanalyzed limiting this evaluation to prospective studies (n = 15 studies, 1186 patients with 1901 PYF). The incidence was 177 per 1000 PYF for all infections (n = 337) and 17 per 1000 PYF for serious infections (n = 33).
The majority of pediatric infections with IFX were upper respiratory tract in origin (41%) or nonsevere nonspecified illnesses (25%). Other common infections included zoster/varicella (5%), pneumonia (3%), fevers with or without septicemia (3%), abscesses (5%), and fungal infections (2%).14,15,18–21,30,31,48,51–53,55,56,58,61,63,65,67–69 There have been a few cases reported of other infections in patients taking IFX, including positive PPD without CXR findings (n = 1), otitis media (n = 1), oral herpes (n = 1), molluscum contagiosum (n = 1), pseudomonas cellulitis at a gastrotomy site (n = 1), osteomyelitis (n = 1), listeria meningitis (n = 1), appendicitis (n = 2), and clinical reactivation of Epstein–Barr virus (n = 3).14,18–20,48,51,56,65,68 Of the 429 patients reviewed on ADA treatment, reported infections included abscesses (n = 8), staff folliculitis (n = 1), Clostridium difficile (n = 1), scarlet fever (n = 1), disseminated histoplasmosis (n=1), H1N1 (n = 1), unspecified viral illnesses (n = 1), Yesinia enterocolitica (n = 1), device-related sepsis (n = 1), Aeromonas spp. (n = 1) and sinusitis (n = 1).24–29 Only one potentially treatment-related infectious death occurred with IFX in an 11-year-old boy who became septic from an abscess located near a colonic stenosis in the setting of malnutrition and leukopenia associated with azathioprine.70 Two potentially treatment-related infectious deaths occurred with ADA, both with sepsis in the setting of central line placement.25
Overall, biological therapy in pediatric patients seems to be safe and well tolerated. Attempts at reducing the incidence of potentially severe complications should be focused on exposure prevention, screening, and vaccination where appropriate. Treatment should be avoided in those with acute infections, and patients with abscesses should have surgical drainage before treatment. Those undergoing concomitant treatment with immunosuppressive therapy should be carefully monitored for neutropenia and leucopenia to avoid life-threatening opportunistic illnesses.
Concern arises for the occurrence of malignancy given adult studies demonstrating an increased incidence of non–Hodgkin's lymphoma with the use of anti-TNF agents and immunomodulators.81 In our review, only 1 patient developed Hodgkin’s lymphoma, resulting in an incidence rate of 3.8 per 10,000 PYF.80 This is numerically, but not statistically, different than the rates seen with thiopurine monotherapy (4.4 per 10,000 PYF; standardized incidence ratio = 0.84, 95% confidence interval = 0.016–16.1) or the expected baseline rate in the general pediatric population for all lymphoid neoplasias (0.58 per 10,000 PYF; standardized incidence ratio = 6.3, 95% confidence interval = 0.14–51.9) and Hodgkin’s lymphoma specifically (0.12 per 10,000 PYF; standardized incidence ratio = 37.8, 95% confidence interval = 0.48–2693).80,82 With 73% of patients being treated concomitantly with thiopurines, including the 1 patient who developed Hodgkin’s lymphoma, it is unclear if this potential risk still exists with anti-TNF monotherapy in the pediatric population. Adult pooled data have suggested that IFX monotherapy carries no additional risk of lymphoma beyond that seen with placebo, but further studies are needed in adult and pediatric patients.83
Another particularly serious type of lymphoma, hepatosplenic T-cell lymphoma, has been reported in patients with IBD. At the time of Kotlyar’s 2011 publication on this topic,84 36 cases had been reported between the ages of 12 and 58 years: 20 of whom had received IFX and thiopurine combination therapy and the remaining 16 receiving thiopurine monotherapy. Four patients received ADA after IFX therapy. All except 2 were male patients.84 Because there is no accurate method to determine the number of male patients within this age range who have been exposed to anti-TNF agents or thiopurines, it is not possible to confidently determine a denominator of “at risk” patients. Therefore, the incidence of hepatosplenic T-cell lymphoma cannot be accurately calculated. This risk with thiopurines seems to be duration and gender dependent, with male patients exposed for >2 years being at highest risk.84 Postulated mechanisms for this risk include dose-dependent and duration-dependent rates of thiopurine-induced DNA damage, resulting in abnormalities of chromosome 7, 8, 13, and Y.85
Based on our review, and adult literature, IFX therapy does not seem to significantly impact the rate of lymphoma in pediatric patients. To date, there have been no reported cases of Hodgkin’s lymphoma or hepatosplenic T-cell lymphoma occurring with anti-TNF monotherapy, and therefore, attempts at reducing the risk for lymphoma may be accomplished through discontinuation of thiopurines after an initial response is seen or transitioning to alternative immunosuppressants, such as methotrexate. Large population-based studies, however, are required to more accurately understand the relationship of lymphoma development with biologics in pediatric patients with IBD.
Other Reactions and Adverse Events
In our review, other reported adverse events attributable to IFX included psoriasis (n = 1) or psoriasiform lesions (n = 12), anemia (n = 11), neutropenia (n = 3), transaminitis (n = 6), arthralgias/joint pain (n = 5), suicide attempt (n = 2), pancreatitis (n = 1), basal cell carcinoma (n = 1), bradycardia (n = 1), cardiac insufficiency (n = 1), cardiomyopathy (n = 2), and prolonged QTc resulting in death (n = 1).14,18–20,30,48,51,56,61,65,69 The psoriasiform lesions were easily treated with topical steroids, and transaminitis typically resolved despite continued therapy. Of the 3 patients with neutropenia, 2 of these patients were on concomitant immunosuppressive therapy and 1 patient resolved after discontinuation of azathioprine.
Of the 2 cardiomyopathies noted in our review, one was found to have a familial cardiomyopathy after IFX was initiated and the other was found to have a cardiomyopathy with pericardial effusion that resolved after discontinuation of therapy.30,56 The patient with prolonged QTc who unfortunately died had suffered a near cardiac death from an arrhythmia before IFX therapy, which questions the association with IFX at all.69 The risk of cardiotoxicity with anti-TNF agents has been well described. The ATTACH trial evaluated the use of biologics in adult patients with NYHA Class III-VI Heart Failure and demonstrated that when compared with placebo, IFX resulted in a 3-fold increased risk for the combined outcomes of death from any cause and hospitalization for heart failure.86 A pediatric pilot study investigated the role of electrocardiographic and echocardiographic monitoring of heart function during IFX therapy in patients with IBD. Twenty-six patients were enrolled, 12 patients with IBD undergoing IFX therapy and 14 age-matched and sex-matched controls. Asymptomatic ultrasound evidence of cardiac involvement was present in 7 of the 12 patients with IBD after initiation of IFX therapy. Although no differences were found in heart rate variability indexes when compared with controls, the investigators commented on the presence of a positive correlation between QT dispersion, left ventricular diastolic dimension, and left ventricular systolic dimension, which they felt suggested an increased risk for development of cardiac dysrrhythmias.87 Taken together, patients should be screened clinically for features of heart failure or familial syndromes that may predispose them to adverse events. At the current time, there are no recommendations for screening or monitoring average risk adult or pediatric patients with an electrocardiography or echocardiography.
BALANCING RISK AND REWARD—STEP-UP, TOP-DOWN, MONOTHERAPY, OR COMBINATION THERAPY?
Traditionally, pediatric patients with IBD undergo a step-up strategy for treatment. It has recently been demonstrated in adult patients with CD that this pyramidal approach may be reversed to allow for earlier initiation of biologics with improved efficacy and long-term outcomes.88 In adult patients with CD, the SONIC trial demonstrated that combined therapy was most beneficial in immunosuppressive naive patients.89 Despite various studies demonstrating that pediatric patients with CD and UC treated earlier in their disease course have improved outcomes, data comparing a step-up with a top-down treatment strategy in pediatric patients are limited.13,30,52,58,60
A retrospective study compared 3 treatment strategies in 36 newly diagnosed pediatric patients with CD. At 1-year follow-up, patients treated initially with IFX and azathioprine had lower rates of relapse (as defined by a PCDAI >10) compared with those initially treated with steroids + azathioprine (23% versus 62%, P = 0.047) or steroids + mesalamine (23% versus 80%, P = 0.012).64 At 2 years, relapse rates were 39%, 77%, and 90%, respectively. Similarly, in pediatric UC, patients with new onset disease and those with a shorter duration of disease activity were found to be more likely to respond to IFX, suggesting that earlier initiation of biologics would result in improved outcomes.30
In summary, the adult literature supports the concept of the early use of combination therapy, and although this may also apply to pediatric patients, data are lacking to currently endorse this approach. However, as described above, the risks associated with anti-TNF therapy are really not significantly different as compared with thiopurine therapy and perhaps in some cases safer. Therefore, we should be moving closer to the idea of using anti-TNF therapy early, with or without an immunomodulator. In the sickest patients, combination therapy probably adds benefit, and then once in remission, consideration can be given for stopping one of the medications, more likely the thiopurine.
BEYOND THE DATA: WHO’S MAKING TREATMENT DECISIONS AND WHO’S QUALIFIED TO DO SO?
Although the treatment benefit and safety profile of anti-TNF treatment is becoming clearer in pediatric patients with IBD, there is still a strong emotional and communication barrier for patients and parents ultimately choosing to use these medications. The decision for treatment is significantly influenced by the data we present to patients and parents and the manner in which we present it. It has been demonstrated that parents of children with IBD are accepting risks related to therapies but require significant benefit to make this tradeoff.90,91 As patients and parents of patients perceive risks and benefits differently,10 it is vital to understand the barriers to communication and to develop informative yet simple communication tools to overcome these misperceptions.
Health Literacy and Health Care Decisions—Barriers to Success
Various factors influence the perception of risk and benefit, but none more so than health literacy. Health literacy, defined as a set of skills that are required to function well in the health care or public health setting, is a well-recognized critical component of a high-quality health care system.92 A large proportion of parents in the United States, however, nearly 1 in 4, have limited health literacy skills.93 This low parental literacy has been shown to correlate with worse health outcomes in pediatric patients,92,93 likely through a combination of perceived barriers to communication or health care access, difficulty understanding written material, particularly medication labels, and feelings of exclusion from the decision making process.92–94 The ultimate result of this is a decreased participation in shared decision making by parents, greater perceived burden from the child’s illness, and increased reliance of physicians to dictate therapy.94,95
Adolescent health literacy seems to significantly impact health outcomes as well. Those with lower-than-average literacy rates seemed to have increased risk-taking or violent behaviors92 and were less likely to participate in their own medical care and therefore more likely to be nonadherent with treatment.96,97 This noninvolvement results in adolescents not implementing the necessary level of self-care activities, particularly when transfer of care occurs to adult specialists. This further worsens health care outcomes and creates barriers to communication between adult physicians and now adult patients.92,93
Traditionally, we have been very poor at assessing health literacy and readiness for transition of care from parent to child.98 It is thus paramount to assess both parents and children for deficiencies in health literacy and identify high-risk patients, particularly during the transition phase from adolescence to adult medicine. These deficits can then be overcome through a combination of written material and counseling with a variety of tools, such as the My Health Passport for IBD, activity books, Option Grids (described below), or simply asking children about involvement.92,97,99
Children and Medical Decisions—What Do They Want and When Should They Get It?
The effort to make adolescent health care more patient-centered must also include a clear understanding of patient preferences and priorities. Only through this can we effectively communicate the benefits of therapy and improve patient satisfaction and compliance. Furthermore, involvement of the child may promote a sense of control, which, in turn, may correlate to positive adjustment, increased adherence, and ultimately improved outcomes. Much like adults, children prefer a high degree of involvement in the medial decision-making process. A recent survey demonstrated that the factors most important to adolescents with chronic illnesses were sense of respect and trust, assessment of pain, and direct communication with the physician as opposed to through their parents.100,101 The technical aspects of care, such as experience of the physician, also ranked highly but having a sense control over health care decisions seemed to be the most important feature of a good relationship. It also important to note that not all patients want to participate in shared decision making, and this should be assessed on an individual basis.
Concerns arise for when to initiate these discussions and how to assess for readiness of involvement. Earlier literature has shown us that, children as young as 9 years seem to have the capacity to express their preferences regarding treatment. Those aged 14 years and older do not differ significantly from adults in regards to reasoning and understanding treatment options.102 Therefore, although this will be variable, early involvement of children in the shared decision-making process is not only feasible but creates a sense of responsibility and improved communication, resulting in improved outcomes and quality of life.
SHARED DECISION MAKING IN PEDIATRIC IBD—A NEW TOOL IN OUR ARMAMENTARIUM
Shared decision making is the process through which physicians inform and recommend treatment options to patients with the overall goal of enhancing patient involvement and facilitating “evidence-based patient choice.” To effectively communicate these data, physicians rely on “decision aids”—balanced presentations of particular treatment options for a decision that needs to be made by the patients with their provider.11 These can be as simple as paper handouts to as complex as web-based videos, which can be updated regularly and allow for a broader distribution. A 2011 Cochrane analysis of more than 80 patients’ decision aids showed that these tools can have a positive effect on patient–provider communication, increase people's involvement, and improve knowledge and realistic perception of outcomes.103
One type of decision aid that is recently gaining popularity is an Option Grid. An Option Grid is a 1-page summary table answering frequently asked questions comparing head-to-head treatment options. It is designed to be used quickly and efficiently in a face-to-face clinical encounter to help a patient through a specific treatment decision. When studied, clinicians believed that Option Grids made it easier to explain treatment options to patients and found that it enhanced patient involvement in collaborative decision making.104 An Option Grid has previously been created using adult data for patients with CD comparing thiopurine monotherapy to anti-TNF monotherapy to combination therapy (http://www.optiongrid.co.uk/resources/Crohns_disease_treatment-Option_Grid.pdf).
To help summarize the vast amount of pediatric data presented above, we have adapted the adult CD Option Grid for pediatric patients. It is specifically focused on the question of using thiopurine monotherapy versus anti-TNF monotherapy versus combination therapy (Fig. 1). Data presented in the Option Grid include REACH,18,21 IMAgINE 1,29 pooled data from our analysis regarding the risk of side effects, and expert opinion of the authors and 2 external reviewers. Due to a paucity of biological and comparative benefit and risk data for pediatric UC, we did not create an Option Grid for UC. Option Grids should not be used in isolation instead of careful conversation with patients but as a tool to facilitate a discussion over benefits and risks and to promote an informed shared medical decision. We hope that this Option Grid will help providers better communicate with patients and their parents and will motivate others to develop and use such tools.
The use of anti-TNF agents has transformed the way in which we care for pediatric patients with IBD. It has resulted in not only improved disease control but also patient growth and quality of life. Although these drugs carry the potential for serious adverse events, such as infections and malignancy, overall biological therapy in pediatric patients seems to be safe and well tolerated. Through careful patient selection and screening, the use of appropriate scheduled treatment protocols, and avoidance of prolonged immunomodulator use, we can keep the balance in favor of reward over risk. Irrespective of these presented data, the greatest barrier to success with biologics still lies in our ability to effectively communicate these outcomes to parents and patients in a simple yet informative manner. We hope that through the creation of our Option Grid providers will be able to not only address parent and patient concerns and misperceptions but also enhance the shared decision-making process, allowing for improved parent and patient satisfaction, adherence, and ultimately long-term outcomes.
The authors thank Dr. Jim Markowitz and Dr. Joel Rosh for their thoughtful review of the Option Grid.
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pediatric inflammatory bowel disease; Crohn’s disease; ulcerative colitis; anti-TNF; risk; shared decision making; Option Grid
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