Journal of Pediatric Gastroenterology & Nutrition:
Pediatric Inflammatory Bowel Diseases and the Risk of Lymphoma: Should We Revise Our Treatment Strategies?
Cucchiara, Salvatore*; Escher, Johanna C†; Hildebrand, Hans‡; Amil-Dias, Jorge§; Stronati, Laura*; Ruemmele, Frank M||,¶
*Pediatric Gastroenterology Unit, University of Rome La Sapienza, University Hospital Umberto I, Rome, Italy
†Department of Pediatric Gastroenterology, Sophia Children's Hospital-Erasmus Medical Center, Rotterdam, The Netherlands
‡Department of Women and Child Health, Astrid Lindgren Children's Hospital, Stockholm, Sweden
§Department of Pediatrics, Pediatric Gastroenterology, Hospital S. João, Porto, Portugal
||AP-HP, Hôpital Necker-Enfants Malades, Department of Pediatrics, Pediatric Gastroenterology
¶Université Paris-Descartes, Faculté de Médecine Necker, INSERM U793, Paris, France
Received 27 May, 2008
Accepted 4 September, 2008
Address correspondence and reprint requests to Prof Frank M. Ruemmele, MD, PhD, Hôpital Necker Enfants Malades, Pediatric Gastroenterology, 75015 Paris, France (e-mail: email@example.com).
Inflammatory bowel diseases (IBDs) are lifelong inflammatory gastrointestinal diseases starting in about one third of patients during childhood. Treatment strategies aim to control this chronic inflammatory process. Owing to recent advances in the understanding of IBD, immunosuppressive agents (mainly against TNFα directed) as well as biological drugs are more and more often used. This therapeutic approach clearly improved the clinical condition of the majority of patients with IBD. However, with this more aggressive treatment strategy, safety concerns clearly arise. Recently, the description of a series of a particularly severe form of T cell lymphoma in pediatric and young adult patients with IBD under immunomodulator and biological combination therapy raised the question of the risks of treatment-induced side effects or complications. As reviewed in the present article, there is a slightly increased risk of not only lymphoma development in IBD patients, potentially related to the inflammatory process, but also to the use of immunosuppressive therapies. On the basis of the literature data, we reanalyzed current treatment strategies for children with moderate-to-severe IBD, who are candidates to receive immunomodulator and/or biological agents potentially accelerating the risk of lymphoma development. Comparative clinical studies in IBD are still missing; however, it is prudent to think about adapting immunosuppressive therapies to the inflammatory process of the underlying disorder and if possible to reduce them to monotherapy. Alternative treatment strategies for heavy immunosuppression exist (eg, enteral nutrition in Crohn disease or colectomy in patients with ulcerative colitis) and should be considered whenever appropriate. There is a major need for comparative studies before evidence-based guidelines can be established for safest and best treatment strategies of pediatric patients with IBD.
Inflammatory bowel diseases (IBDs) include 3 major entities, Crohn disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC). They have a chronic course with frequent relapses and a high morbidity despite continuous pharmacological treatment. The latter traditionally comprises aminosalicylates, antibiotics, corticosteroids, and immunomodulators (IMs). None of these agents have been shown to alter the natural course of the disease, particularly of CD, though IMs such as azathioprine (AZA) or 6-mercaptopurine (6-MP) and methotrexate (MTX) have been successful in neutralizing corticosteroid dependency and in maintaining remission (1,2). Despite IMs represented a significant breakthrough in the treatment of IBD and have become an integral component of the drug armamentarium for this disease, their use has been associated with serious complications in several organs, and the long-term immunosuppressive effect has been thought to carry an increased risk of lymphoma in patients with IBD (3,4). Although lymphoma in the setting of immunosuppression has been well documented, different studies with regard to IBD have produced conflicting results and uncertainty on which extent disease severity and duration itself contribute to the risk of malignancy in IBD (5).
The improved understanding of the pathogenetic mechanisms of IBD has led to the development of targeted immune modulators, commonly referred to as biological agents (biologics) (6). They include natural or modified biological compounds (vaccines, hormone extracts), recombinant proteins or peptides, monoclonal antibodies, fusion proteins, and antisense oligonucleotides. Infliximab (IFX), a chimeric monoclonal IgG1 antibody against tumor necrosis factor-alpha (TNF-α) has been widely used over the past 12 years in the management of moderate to severely active CD (and, more recently, UC), unresponsive to traditional anti-inflammatory agents or immunosuppressive agents (7). Large randomized controlled trials have confirmed the efficacy of IFX for the induction and the maintenance of remission in both CD and UC, in adults as well as in children. In May 2006, the FDA, in the United States, and in June 2007 the European Medicines Agency, in Europe, approved the use of IFX in children >6 years who continue to have active disease despite treatment with conventional therapies. There is no official approval of the drug in pediatric UC; however, IFX has been used and is under investigation through controlled trials in children and adolescents with active and refractory UC.
Although side effects related to IFX (and other biologics; ie, early infusion reactions and adverse events such as autoimmune phenomena, opportunistic infections, tuberculosis, and sepsis) have clearly been described in clinical trials, it is still uncertain to what extent the long-term use of anti-TNF-α may be associated with an increased risk of malignancy (8). Recent reports of increasing numbers of mainly adolescents and young adults with an aggressive and commonly fatal form of lymphoma, a hepatosplenic T cell lymphoma (HSTCL), has raised great concern among pediatric gastroenterologists caring for patients with IBD (9). Description of these cases seems to influence the therapeutic attitude in the management of severe cases of IBD in children and widely accepted strategies (ie, combination of IMs and biologics) are now questioned (10).
In the present review, we discuss the pathogenesis and risk of lymphoma in patients with IBD either treated or not with immunosuppressive drugs and biologics. We aim to outline different therapeutic strategies for children with moderate-to-severe IBD, who are candidates to receive IMs agents and/or biologics.
EPIDEMIOLOGY AND PATHOBIOLOGY OF LYMPHOMA
Lymphomas are a group of cancers of the lymphatic system that can start in almost any organ of the body. Recently, the worldwide incidence of malignant lymphomas has dramatically increased, partially related to AIDS-related lymphomas. In the United States, non-Hodgkin lymphoma (NHL) represents today the fifth most commonly occurring cancer (∼3.4% of cancer deaths) with 19 new cases per 100,000 people per year, more often in whites than in blacks and about 50% more common among men than women (11). Aggressive lymphomas are commonly diagnosed in adolescents and young adults, whereas both aggressive and indolent neoplasms are more common in patients older than 50 years (12). Malignant lymphomas include an array of heterogenous malignancies (Table 1): the 2 main types are NHL (90% of all lymphomas) and HL (10%) (13). The World Health Organization (WHO) classifies NHL according to morphological, immunophenotypical, and molecular features into B cell, T cell, and natural killer (NK) cell neoplasms (14). The disease comprises close to 40 subtypes. In Western countries, the most common NHL are diffuse large B cell lymphomas and follicular lymphoma, representing 30% and 20% of cases, respectively; all other NHL subtypes have a frequency of <10% (15).
T cell lymphomas manifest the immunophenotypic features of postthymic T lymphocytes, being derived from, according to their T cell receptor (TCR), αβ, or γδ cells. The rare form of HSTCL is a systemic disease derived from functionally immature innate effector cells, most often of γδT cell origin (11). γδT cells comprise fewer than 5% of all normal T cells and show a restricted distribution, being found mainly in splenic red pulp, intestinal epithelium, and other epithelial sites (16).
IBD AND THE RISK OF LYMPHOMA
Since the first descriptions of lymphoma occurring in the setting of UC, in 1928, and in CD, in 1955, it was of major concern to know whether patients with IBD have an increased risk of developing lymphoma (17,18). The evidence that immunosuppressive medications may increase the incidence of lymphoma in transplant recipients as well as in patients with rheumatoid arthritis (RA) has produced similar concern among gastroenterologists caring for patients with IBD. Over the years, the relation between lymphoma and IBD has been assessed in 3 forms: case reports and case series in a retrospective fashion and studies reporting the incidence of lymphoma in IBD patient cohorts with a specific subanalysis addressing the role of the immunosuppressive therapy in tumor development using case-control studies (19).
Two main factors can be involved in the development of lymphoma in IBD: the inflammatory process itself and the use of IMs (AZA/6-MP and MTX) that are widely used for prolonged periods. A critical role of inflammation as a promoter of the development of neoplasms has been reported for patients with RA (20). A recent matched case-control study of 378 consecutive RA Swedish adult patients, in which malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of more than 74,600 patients), and 378 controls has shown that the risk of lymphoma is significantly increased in the subset of patients with the most severe disease, thus suggesting that inflammatory activity, rather than its treatment, may be a major risk for development of lymphoma (70-fold increased lymphoma risk in patients with high disease activity). No similarly designed studies in patients with IBD evaluating the role of disease activity have yet been performed.
The major problem in assessing the risk of lymphoma in IBD is that a relatively rare event (IBD) may be complicated by a second uncommon event (lymphoma). One of the largest population-based study included 17,000 IBD adult subjects (>6000 patients with CD and >10,000 with UC) and more than 60,000 controls, matched for age and primary care practice with >1 year follow-up (21). The authors have used the General Practice Research Database (GPRD), which comprises the computerized records of 2000 general practitioners and 8 million patients. In the present study, the incidence of lymphoma in IBD was not statistically different from the general population. The relative risk (RR) of lymphoma in patients with IBD was 1.2, which was not different from the RR in controls (95% confidence interval [CI] 0.7–2.1). However, the study does not make clear whether immunosuppressive and/or biological agents increase the lymphoma risk in IBD. A large population-based study analyzed prospectively data from different regional cohorts of IBD in Sweden (22). The authors examined the occurrence of hematopoietic disease during the course of IBD in 2 regional population-based cohorts of patients with UC and CD (>8000 patients) diagnosed between 1955 and 1990, in addition to a nationwide inpatient register of 45,000 patients diagnosed between 1964 and 2000. Patients from the 2 cohorts were analysed separately revealing an independent nonsignificant borderline increase of lymphoma in CD and of myeloid leukemia in UC. Interestingly, the lymphoma risk occurred during the first 5 years of CD and most of the observation period was before the era of biological treatment. In general, there was a lack of information on the pharmacotherapy of these patients.
Earlier population-based cohort studies from Sweden, Denmark, Minnesota, and Italy did not reveal an increased risk of lymphoma in CD or UC (23–25). Two studies from the United States including 1227 patients with CD and 734 patients with UC and from Europe including 1655 patients with CD and 3121 patients with UC produced contrasting results (26,27). Although the latter did not show an increased risk of lymphoma in IBD, the North American study revealed an approximately 6-fold increased frequency of NHLs and a 3-fold increased number of Hodgkin disease in both types of patients with IBD compared with age- and sex-matched population data. However, the authors suggest that this increase cannot reflect the true cancer risk because of a bias in referral and ascertainment in comparing retrospective charts from a tertiary referral center with a normal population survey. Recently, Loftus et al (28) from the IBD Center at the Mayo Clinic in Rochester, Minnesota, highlighted the difficulties and limitations of these epidemiological studies: they observed a total of 61 lymphomas (85% NHL) in 15,000 hospitalized patients with IBD, whereas a population-based study in the same area including 454 patients with IBD with 6662 person-years follow-up, presented in the same report, did not find a significant increase in the incidence of lymphoma in IBD. Similarly, a previous study by Persson et al (29), analyzing 1251 patients with CD, did not note an increase in risk of lymphoma in IBD.
Recently, Aithal and Mansfield (30) commented that studies on IBD populations give somewhat conflicting results, with studies on the basis of large cohorts followed in highly specialized tertiary reference centers showing an increase in lymphoma incidence, contrary to population-based studies. As specialized referral centers drain the most complicated and complex patients, this may overestimate the real lymphoma risk.
IMMUNOSUPPRESSIVE THERAPY IN IBD AND THE RISK OF LYMPHOMA
The thiopurine agents 6-MP, AZA, and somewhat less often MTX are used in adult and pediatric patients with CD and UC who are resistant to or dependent on corticosteroids as steroid-sparing drugs in those subjects. Thioguanine metabolites inhibit T lymphocyte proliferation and presumably induce apoptosis of TCR and cosignal activated T cells (31). The interference with effector T cell survival and function may be on one hand the principal mechanism of the beneficial effect of AZA and 6-MP, but on the other hand this may also cause a defective T cell immunosurveillance promoting the development of lymphoproliferative disorders (19). It is important to note that the use of immunosuppressors in the treatment of IBD increased considerably during the past 15 years (32). Kandiel et al (33) recently performed a meta-analysis on the basis of 6 individual studies addressing the question of whether the most commonly used drugs, AZA and 6-MP, may increase the risk of lymphoma among patients with CD and UC. The overall conclusion of this meta-analysis was that AZA/6-MP enhances approximately 4-fold the risk to develop a lymphoma (mainly NHL). This increased risk is consistent with the RR estimates observed in earlier studies on patients with RA. Six studies met the inclusion criteria for the meta-analysis: after combining all patient data (a total of 3891 patients), the pooled RR was 4.18 (95% CI 2.07–7.51) with 11 cases of lymphoma (9 NHL), although only 2.63 were expected. However, it is important to note that the individual studies showed significant heterogeneity; moreover, because the data were obtained from observational studies, it was not possible to exclude that the increased risk of lymphoma was related to the severity of the underlying disease, rather than to the chronic use of IMs. A subgroup analysis in the study of Lewis et al (21) on 17,000 patients with IBD revealed that in 837 patients with CD and 628 patients with UC treated with AZA/6-MP no lymphoma for CD and 1 Hodgkin lymphoma in a patient with UC was noted, resulting in an incidence ratio of 1.57 for both groups together. Farrell et al (34) reported 4 cases of NHL in a small cohort of 238 patients with IBD who had received IM: 2 patients were diagnosed with NHL 9 and 14 months after beginning AZA; 2 other patients received MTX alone or MTX plus cyclosporine. The calculated RR of NHL in the group under IM was 59 times higher than the general population; however, because of the small sample size this study produced a less precise estimate of the RR than other studies.
Methotrexate is less frequently used as first-line IM in patients with IBD, but often when patients are intolerant of or unresponsive to AZA/6-MP (35–37). There is little information on the relation between MTX and lymphoma in IBD. Of the 796 adult patients at the St James's Hospital in Dublin, Farrell et al (34) reported that 31 patients received MTX and 2 of them developed an NHL (1 also had cyclosporine). This high incidence is of concern; however, definite conclusions cannot be drawn from such a small cohort. To obtain stronger data on the risk of lymphoma in subjects with IBD on MTX, it is helpful to examine the results in the treatment of other disorders such as RA. As in IBD, it is difficult to distinguish the effects of the IM administration from those due to the severity of the underlying disorder. A large observational study of more than 18,000 adults with RA enrolled in the National Data Bank for Rheumatic Diseases gives encouraging observations on MTX and lymphoma (38). This study reports that the standardized incidence ratio (SIR) for lymphoma overall was 1.9 (95% CI 1.3–2.7). For patients taking MTX, the SIR was 1.7 (95% CI 0.9–3.2), compared with 1.0 (95% CI 0.4–2.5) for those not receiving MTX or biologics.
TNF-α ANTAGONISTS IN IBD AND THE RISK OF LYMPHOMA
The increasing use of new IM, such as anti-TNF-α–directed drugs, further amplifies the fear of an increased risk of lymphoma in patients with IBD, either by these drugs alone or by the commonly used combination of anti-TNF-α antibodies and IM (AZA/6-MP or MTX) (39).
Retrospective analyses and case-control studies suggest that IFX does not increase the overall cancer risk in patients with CD, but it is widely recommended to extend follow-up surveillance, because the balance between benefit and risk of concomitant administration of immunosuppressive and biological therapies in subjects with long-lasting severely active CD is still unknown (8). In a retrospective survey of 117 patients with CD receiving IFX (400 infusions in total, mean follow-up of 52 weeks, 14–864 days), no cases of lymphoma or other cancers were reported (40). A large single-center observational study on more than 500 consecutive adults with CD receiving IFX (median follow-up 17 months, 86% taking concomitant immunosuppressive drugs) showed occurrence of lymphoma in 2 cases only (1 NHL and 1 HL), 1 of which was judged as potentially related to IFX (41). In a Swedish study by Ljung et al (42), 212 adults with IBD were followed up for a median period of 28 months (more than 50% taking concomitant IM, mean of 2.6 infusions): NHL occurred in 3 cases, with an incidence rate higher than that reported in other studies. The authors emphasized the need for vigilant surveillance with respect to this malignant complication in patients with IBD requiring IFX. In a multicenter, matched-pair study data from 404 patients with CD treated with IFX were matched with 404 patients with CD who had never received IFX: the frequency of newly diagnosed cancers did not differ significantly between IFX-treated and IFX-naïve patients (43).
As emphasized by Vermeire et al (44), analyzing CD and RA IFX trials, 6 lymphomas were diagnosed for a follow-up of 4148 patient-years vs 0 for 691 placebo patient-years. All lymphomas occurred in patients treated with concomitant IM. Four of these lymphomas occurred in patients with RA (in which the background incidence of lymphoma is increased in comparison with the general population).
Therapy, Resource, Evaluation and Assessment Tool (TREAT) is a FDA-mandated patient registry, established to study long-term safety of IFX and other therapies in CD. At the 2007 Digestive Disease Week (DDW) meeting in Washington, DC, results of 6273 enrolled patients were presented: 3334 received IFX (10,796 patient-years; 86.5% ≥2 infusions) and 2929 other therapies (45). The incidence of lymphoma in the 2 groups was similar (0.04/100 patient-years in IFX group vs 0.05 in non-IFX patients [RR: 0.8, 95% CI 0.22–2.99]).
Siegel et al (46) constructed a decision analytic model to determine the risks and benefits of IFX when compared with standard therapy in a hypothetical cohort of patients. The analysis simulated 2 cohorts of 100,000 patients each, with one arm receiving IFX and the other on standard therapy. Model inputs of the risk of lymphoma were taken from controlled trials, single-center cohorts of consecutively enrolled patients, and population-based cohorts. The analysis showed that at the end of 1 year (out of 100,000 patients), IFX use would lead to 12,216 more patients in remission, 4255 fewer surgeries, and 33 fewer deaths from flares of disease. However, the model also suggests that this gain would be obtained at the cost of 201 more lymphomas and 249 more deaths related to complications from IFX. The methodology used in this study has received a lot of criticism, mainly due to the decision not to use data from the TREAT registry of more than 6000 patients. Furthermore, the authors may also underestimate the risk of the standard therapy group by assuming that the rates of steroid use were equivalent in both arms.
Studies from the use of biologics in chronic diseases other than IBD give somewhat more robust results. In observational studies of adult patients with RA, SIR for lymphoma in subjects receiving anti-TNF-α was higher than in patients not receiving this therapy (47). In the study by Wolfe and Michaud (38), the estimated SIR for lymphoma in patients taking IFX was 2.6 (95% CI 1.4–4.5). An observational study conducted in southern Sweden compared 2 cohorts of patients with RA (one arm of 757 patients receiving anti-TNF-α agents, another arm of 800 patients on conventional regimens) (48). The SIRs for total tumor RR for the anti-TNF-α group and the comparison group were 1.1 (95% CI 0.6–1.8) and 1.4 (95% CI 1.1–1.8), respectively; the lymphoma RR was 11.5 (95% CI 3.7–26.9) and 1.3 (95% CI 0.2–4.5), respectively. A possible contribution of anti-TNF-α treatment to the lymphoma incidence in this study must be interpreted with caution. The anti-TNF-α–treated arm likely represents a group of patients with RA with a supposedly up to 25-fold increased lymphoma incidence due to a long-standing severe inflammatory disease. The current finding of an 11.5 increased lymphoma risk in anti-TNF-α–treated patients with RA and a tendency for an increased risk when adjusting for disease severity is disturbing and deserves further study. In a recently published systematic review and meta-analysis of randomized, placebo-controlled trials of IFX and adalimumab used for ≥12 weeks in patients with RA, 3493 patients receiving anti-TNF-α and 1512 taking either nonbiological agents or placebo were examined (49). The trials included in this analysis were heterogeneous with respect to the intervention and control groups. The authors have calculated a pooled odds ratio (OR) for malignancies and infections (using methods with a continuity correction for sparse data). The pooled OR for all malignancies was 3.3 (95% CI 1.2–9.1). An analysis for lymphoma was not made, but a total of 10 lymphomas were seen in the group on anti-TNF-α and none in the control group (6 of 10 were not included in the analysis because they occurred beyond the trial period). For IBD, current evidence from clinical trials, retrospective analyses, and postmarketing surveillance indicates a small increased risk of lymphoma in patients with IBD receiving IFX or other biologics (5,8), but this risk has not clearly quantified.
HEPATOSPLENIC T CELL LYMPHOMA AND IBD
Hepatosplenic T cell lymphoma is a rare form of peripheral NH lymphoma, first reported in 1981 in 3 patients having an aggressive lymphoma labeled as erythrophagocytic Tγ lymphoma (50). Since then, about 150 cases have been described in the literature, but unfortunately this has not led to improvement in the treatment because the lymphoma has a fatal outcome in most patients within 2 years of diagnosis. The disease has a predilection to develop in adolescents and young adults and manifests with splenomegaly (in 98%) and hepatomegaly (in 80%), without lymphadenopathy, and with general symptoms such as unexplained fever, weight loss, and night sweats; hematological abnormalities are common (thrombocytopenia in 85%, anemia in 84%, leukocytopenia in 45%), elevated LDH are found in 62%, and elevated liver parameters are found in 43%. The course of disease is aggressive despite the treatment (51,52).
In 1990, HSTCL was recognized as a distinct lymphoma entity, characterized by expression of 1 or 2 T cell receptor phenotypes and classified as either hepatosplenic γδ or αβ T cell lymphoma, with no evidence of Epstein-Barr virus infection in the malignant cells (53). Most HSTCL tumors have a γδ phenotype. A unique cytogenetic feature of the γδT cell lymphoma cells is the presence of isochromosome 7q and trisomy 8.
Diagnosis of the disease may be complicated in some cases by misleading symptoms such as isolated thrombocytopenia (misinterpreted as idiopathic thrombocytopenic purpura), circulating blast-like lymphoma cells (misinterpreted as acute lymphoblastic leukemia blasts), or clinical symptoms leading to the assumption of a viral infection (52). More difficulties may result from not considering this rare entity in the differential diagnosis. The diagnosis is established by splenectomy or liver biopsy, but as bone marrow involvement is a constant feature at presentation, bone marrow biopsy is an adequate and easily feasible procedure (53). The true incidence of HSTCL in childhood is unknown. The expected incidence of NHL in pediatric age is in the range of 1 out of 100,000 or nearly 800 cases per year in the United States (13). More than 50% of NHLs in childhood are aggressive mature B cell tumors, whereas 25% to 30% are T cell lymphomas, usually of precursor T cell type. Mature T cells NHLs are rarely observed (<5% of all pediatric NHLs in the United States): one may expect 1 case of HSTCL in a child per year in the United States (54). In long-term renal transplant patients, γδ-HSTCL was first described as an unusual form of T cell posttransplant lymphoproliferative disease (PTLD); T cell PTLDs constitute up to 14% of all PTLD cases (55). The interval between organ transplantation and the occurrence of T cell PTLD ranges from 4 to 26 years (10). Prolonged immunosuppression as used after transplantation seems to play an important role, but it is unknown why the reported T cell PTLD cases seem to be disproportionately (in 76%) concentrated in long-term renal transplant recipients (56).
HSTCL in Inflammatory Bowel Disease
The association of this subtype of lymphoma with IBD is recent (9). The literature describes few cases of IBD with HSTCL, who had never received biologics, but were treated with AZA or 6-MP. Lemann et al (57) recently described in abstract form a cohort of patients with steroid-refractory CD treated with intravenous cyclosporine, 1 of which was maintained in remission for 4 years with AZA and developed an HSTCL with a fatal course. Another case of such lymphoma with a leukemic course has been described by Navarro et al (58) in a patient with CD who had received AZA for 5.5 years. Mittal et al (59) have described a case of γδ-HSTCL in an 18-year-old man with long-standing CD who received, since the age of 9 years, AZA for 6 years. At the ESPGHAN meeting in 2007 a case of HSTCL was reported in a 15-year-old boy with chronically active UC treated with AZA for 9 years (60). The last 2 cases had a fatal course.
As of October 2007, HSTCL was described in 11 patients with IBD treated with IFX, ages from 12 to 31 years (in 6 cases the range was between 12 and 19 years). In all 11 cases, AZA or 6-MP was given concomitantly with IFX (length of administration of IM ranged from 2.5 to 7 years) (10). Exposure to IFX ranged from 1 single infusion up to maintenance therapy of approximately 4 years. However, as of May 2008, the number of reported cases of HSTCL increased to 14 patients under IM/biologics therapy. Table 2 reports data for each patient. Nine of the 14 patients died as a consequence of their lymphoma. Unfortunately, the number of patients with IBD under sole IM without biologics developing into HSTCL during the same time period is not available.
OPTIMAL TREATMENT STRATEGIES IN IBD
The natural course of IBD is characterized by recurrent bouts of symptoms leading to severe morbidity and impairment of quality of life. Although some patients have prolonged periods of remission, intermingled with episodes of flare-ups, others may have continuous active disease (61). Data gathered prospectively from the Pediatric IBD Collaborative Research Group Registry in the United States indicate 31% of children with CD and 45% of those with UC exhibit at 1-year follow-up a certain degree of corticosteroid dependency, despite concomitant use of IM; furthermore, corticosteroid refractoriness develops in 11% of children with CD. In pediatric CD despite classical treatment with corticosteroids and 5-ASA agents, surgical intervention occurs in 30% to 78% within 10 to 15 years of diagnosis (62,63). These observations strongly indicate the need for strategies aimed at interrupting or delaying the natural evolution of the disease. This is of great importance for pediatric patients, because young age at onset is thought to be a variable associated with a complicated course of the disease (64). To control the inflammatory reactions and to maintain clinical remission, different IM and biologics now have a well-established place in the treatment of CD. However, at present there are still unsettled issues on the use of IM in pediatric IBD, such as the optimal duration and the “exit strategy” from the start. Particularly, as highlighted in this review, potential complications and side effects of IM treatment should be minimized by appropriate and optimal treatment algorithms. Until recently, an apparently widely agreed attitude has supported the combined use of IM and IFX in both inducing and maintaining remission of IBD (65). In the REACH multicenter study, in evaluating the safety and the efficacy of IFX in children with moderate-to-severe active CD, concomitant IMs were required in the recruited patients (66). The recent postmarketing report of 11 cases of HSTCL mainly occurring in young patients with IBD who had received IFX has raised a lot of concern on the policy of combining IFX and IM (Centocor Data on file, ML_IFX62_Hepatosplenic_Lypmhoma_extended version_r02_30NOV07).
Description of these cases seems to have caused a critical revision of the well-established strategy of combining IM and biologics, although no cases of HSTCL have been reported in all of the published trials in rheumatology and gastroenterology, in which IFX has been given in combination with IM (67). Our recent survey among ESPGHAN members showed that in fact, since 2007, treatment algorithms were changed in the majority of IBD centers. This is rather surprising, because no objective data suggesting different treatment strategies were available and this issue was not addressed in any trial at that moment. This ESPGHAN survey revealed that before 2007, 97% of pediatric patients with CD were on combined IM/IFX medication. However, since the reports of HSTCL in patients with CD under combined medication, two thirds of pediatric gastroenterologists have stopped AZA in these patients and switched to either IFX monotherapy or have started to combine IFX with MTX.
How Should We Use Immonomodulator and Biologics in Pediatric IBD?
How should we use biologics and IM in the clinical setting? Different options can be considered for long-term administration of biologics, such as IFX: as scheduled therapy, that is, for IFX every 8 weeks as monotherapy or every 8 weeks with concomitant IM; episodic administration with IM; as a bridge to IM.
There is no doubt that after induction of remission with a baseline infusion of IFX (0, 2, 6 weeks), a scheduled every 8 week administration of IFX is an excellent regimen. Adult and pediatric controlled trials have shown that this planned strategy is associated with lower rates of immunogenicity, better mucosal healing, and stronger improvement in quality of life (68,69). However, one may ask the question if this effect is attributable to the combination of an IM to IFX or if it is the sole effect of IFX, indicating that a monotherapy may be sufficient.
The combined administration of IM has been widely advocated because it seemed to be associated with a reduction in immunogenicity and in infusion-related side effects (70); in this sense it has been postulated that the use of IM helps to obtain a more prolonged therapeutic effect by protecting from the formation of anti-infliximab antibodies (ATI) that are related to loss of efficacy for IFX (71). However, there are clinical arguments and recent observations that tend to support the chronic use of IFX (or other humanized antibodies, such as adalimumab or certuliximab) as monotherapy (72): because almost all patients who are receiving IFX have received a long-lasting course of IM (mainly AZA/6MP) that finally failed to stabilize the clinical course. It may be advisable to interrupt these insufficiently active agents and give IFX as sole medication.
* There is clear evidence that the combination therapy with biologics and IM is associated with increased toxicity (increased risk for opportunistic infections and potentially also malignancy).
* No clear data support the concept that the combination of IFX and IM as maintenance therapy does add any advantage as compared with scheduled IFX monotherapy with regard to ATI formation as well as clinical and endoscopic remission. Recent data from Belgium indicate that in adult patients with IBD, IM may be stopped after 6 months without the risk for earlier relapse (73). In this study there was no difference in IFX dose adjustments or discontinuation between patients receiving IFX monotherapy and those receiving combination therapy; moreover, if mucosal healing at 2 years was taken into account, there was no difference between patients receiving combination therapy vs monotherapy. However, there was a significant difference between the groups when analyzing median IFX levels: patients who remained on combination therapy adding an IM had higher levels of IFX over time compared with patients receiving IFX monotherapy. There was also a difference in the development of antibodies to IFX, but this did not translate into any difference in clinical efficacy. An interesting subgroup analysis of ACT I and II trials and the ACCENT trial was presented at the 2007 DDW: there was no difference in clinical efficacy between patients who were receiving IFX alone vs patients who were receiving IFX and IM (74–76).
* It is not clearly or unequivocally demonstrated that loss of response to IFX is due to occurrence of ATI: indeed, changes in the profile of proinflammatory molecules at the level of intestinal mucosa have also been advocated (77). It is of interest to observe that both adalimumab and certolizumab (a pegylated humanized Fab′ fragment with a high binding affinity for TNF-α) induce a higher response rate in IFX-naïve patients than in those with previous IFX failure. This would suggest that with time TNF-α has less of a protagonist role in the mucosal inflammatory milieu (78,79).
If patients are partial or insufficient responders to IFX or other biologics, the additional use of alternative IM, such as the antimetabolite MTX may be considered (35–37). However, the recent report of Feagan et al (DDW 2008) questions this attitude. In an RCT comparing IFX monotherapy versus IFX + MTX, no benefit of bi-therapy was found with regard to disease control or ATI formation. Further comprehensive data are needed before any firm conclusions on combination therapy can be drawn.
The recently available fully humanized anti-TNF-α antibody adalimumab has been shown in well-conducted trials in adults with CD to be effective in inducing and maintaining remission in moderate-to-severe disease. Because of the lower immunogenicity and an easier way of administration it could rapidly become an alternative to anti-TNF-α drug for patients with IBD. Interestingly, in the CHARM adalimumab maintenance study, there was no apparent difference, at weeks 26 and 56, between patients who were receiving monotherapy with adalimumab versus those who were receiving adalimumab combined to an IM (78). These observations strengthen the use of adalimumab as monotherapy. Similar observations also ensue from the PRECiSE2 data on certolizumab pegol (79).
We should never forget that in children and adolescents with moderate-to-severe IBD, there are alternative forms of efficacious therapy to a continuous pharmacological bombing using a combination of immunosuppressive and biological agents, that is, nutritional therapy for CD and elective precocious total colectomy for UC. There are impressive data on the efficacy and safety of nutritional therapy alone, consisting of either polymeric or elemental formulae, in inducing and maintaining remission in severe forms of CD (80): nutritional therapy has been shown to dramatically promote mucosal healing and then influence the course of CD (81,82). On the contrary, it is admissible to wonder whether in cases of severe chronically active UC, it is justified to manage these patients with potentially harmful combinations of IM, biologics, and courses of CS (without serious chances of modifying the disease course) instead of planning elective colectomy.
The introduction of biological therapy, and particularly the use of anti-TNF-α agents, has provided a powerful tool in the treatment and management of IBDs, mainly CD. A growing body of evidence suggests that the benefits of anti-TNF-α therapy extend beyond just the measure of clinical efficacy, with the theoretic potential to alter the natural history of the disease. Thus, these recent medical advances in IBD have made our treatment expectations more ambitious. At present, several issues on biological therapy remain unsolved and will represent the objective for future studies: the exit strategy or the stopping rules, the long-term use of monotherapy versus combination with IM, the early use of biological therapy as a bridge to classical IM, and the identification of patient subgroups based on phenotype and genotype markers that make them suitable for biological therapy. However, safety issues are the priority for all patients, especially children. And undoubtedly, important prospective data concerning the safety of biologics, either combined with IM or alone, must be gathered using large registries. These data will constitute the basis for future indications and treatment recommendations for children, as well as adult patients with IBD. As reviewed, there is a slightly increased risk to develop malignancies for patients with IBD. However, to date we do not really know if this increased risk is related to severity and chronicity of the inflammatory reaction characterizing IBD or to the prolonged use of immunosuppression—or perhaps a combination of both. Only large population-based studies and accurate registries will help to clarify this issue.
1. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007; 369:1641–1657.
2. Hyams JS, Markowitz JF. Can we alter the natural history of Crohn disease in children? J Pediatr Gastroenterol Nutr 2005; 40:262–272.
3. Gearry RB, Barclay ML. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol 2005; 20:1149–1157.
4. Nguyen GC, Harris ML, Dassopoulos T. Insights in immunomodulatory therapies for ulcerative colitis and Crohn's disease. Curr Gastroenterol Rep 2006; 8:499–505.
5. Jones JL, Loftus EV Jr. Lymphoma risk in inflammatory bowel disease: is it the disease or its treatment? Inflamm Bowel Dis 2007; 13:1299–1307.
6. D'Haens G, Daperno M. Advances in biologic therapy for ulcerative colitis and Crohn's disease. Curr Gastroenterol Rep 2006; 8:506–512.
7. Veres G, Baldassano RN, Mamula P. Infliximab therapy in children and adolescents with inflammatory bowel disease. Drugs 2007; 67:1703–1723.
8. Biancone L, Calabrese E, Petruzziello C, et al
. Treatment with biologic therapies and the risk of cancer in patients with IBD. Nat Clin Pract Gastroenterol Hepatol 2007; 4:78–91.
9. Mackey AC, Green L, Liang LC, et al
. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 44:265–267.
10. Rosh JR, Gross T, Mamula P, et al
. Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale? Inflamm Bowel Dis 2007; 13:1024–1030.
11. Alexander DD, Mink PJ, Adami HO, et al
. The non-Hodgkin lymphomas: a review of the epidemiologic literature. Int J Cancer 2007; 120(Suppl 12):1–39.
12. McNally RJ, Parker L. Environmental factors and childhood acute leukemias and lymphomas. Leuk Lymphoma 2006; 47:583–598.
13. Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Hematology Am Soc Hematol Educ Program
14. Hagenbeek A, Bischof Delaloye A. Editorial perspective—advances in B-cell non-Hodgkin's lymphoma. Leuk Lymphoma 2003; 44(Suppl 4):S1–S4.
15. Chiu BC, Weisenburger DD. An update of the epidemiology of non-Hodgkin's lymphoma. Clin Lymphoma 2003; 4:161–168.
16. Fisher SG, Fisher RI. The epidemiology of non-Hodgkin's lymphoma. Oncogene 2004; 23:6524–6534.
17. Bargen JA. Chronic ulcerative colitis associated with malignant disease. Arch Surg 1928; 17:561–576.
18. Hughes RK. Reticulum cell sarcoma: a case possibly originating in regional enteritis. Ann Surg 1955; 21:770–773.
19. Kwon JH, Farrell RJ. The risk of lymphoma in the treatment of inflammatory bowel disease with immunosuppressive agents. Crit Rev Oncol/Hematol 2005; 56:169–178.
20. Baecklund E, Iliadou A, Askling J, et al
. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 2006; 54:692–701.
21. Lewis JD, Bilker WB, Brensinger C, et al
. Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 2001; 121:1080–1087.
22. Askling J, Brandt L, Lapidus A, et al
. Risk of haematopoietic cancer in patients with inflammatory bowel disease. Gut 2005; 54:617–622.
23. Persson PG, Karlén P, Bernell O, et al
. Crohn's disease and cancer: a population-based cohort study. Gastroenterology 1994; 107:1675–1679.
24. Karlén P, Löfberg R, Broström O, et al
. Increased risk of cancer in ulcerative colitis: a population-based cohort study. Am J Gastroenterol 1999; 94:1047–1052.
25. Palli D, Trallori G, Bagnoli S, et al
. Hodgkin's disease risk is increased in patients with ulcerative colitis. Gastroenterology 2000; 119:647–653.
26. Greenstein AJ, Gennuso R, Sachar DB, et al
. Extraintestinal cancers in inflammatory bowel disease. Cancer 1985; 56:2914–2921.
27. Ekbom A, Helmick C, Zack M, et al
. Extracolonic malignancies in inflammatory bowel disease. Cancer 1991; 67:2015–2019.
28. Loftus EV Jr, Tremaine WJ, Habermann TM, et al
. Risk of lymphoma in inflammatory bowel disease. Am J Gastroenterol 2000; 95:2308–2312.
29. Persson PG, Karlén P, Bernell O, et al
. Crohn's disease and cancer: a population-based cohort study. Gastroenterology 1994; 107:1675–1679.
30. Aithal GP, Mansfield JC. Review article: the risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment. Aliment Pharmacol Ther 2001; 15:1101–1108.
31. Mudter J, Neurath MF. Apoptosis of T cells and the control of inflammatory bowel disease: therapeutic implications. Gut 2007; 56:293–303.
32. Carvalho R, Hyams JS. Diagnosis and management of inflammatory bowel disease in children. Semin Pediatr Surg 2007; 16:164–171.
33. Kandiel A, Fraser AG, Korelitz BI, et al
. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005; 54:1121–1125.
34. Farrell RJ, Ang Y, Kileen P, et al
. Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low. Gut 2000; 47:514–519.
35. Uhlen S, Belbouab R, Narebski K, et al
. Efficacy of methotrexate in pediatric Crohn's disease—a French multicenter study. Inflamm Bowel Dis 2006; 12:1053–1057.
36. Turner D, Grossman AB, Rosh J, et al
. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease. Am J Gastroenterol 2007; 102:2804–2812.
37. Ravikumara M, Hinsberger A, Spray CH. Role of methotrexate in the management of Crohn disease. J Pediatr Gastroenterol Nutr 2007; 44:427–430.
38. Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum 2007; 56:1433–1439.
39. Blonski W, Lichtenstein GR. Safety of biologic therapy. Inflamm Bowel Dis 2007; 13:769–796.
40. Kinney T, Rawlins M, Kozarek R, et al
. Immunomodulators and “on demand” therapy with infliximab in Crohn's disease: clinical experience with 400 infusions. Am J Gastroenterol 2003; 98:608–612.
41. Colombel JF, Loftus EV Jr, Tremaine WJ, et al
. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology 2004; 126:19–31.
42. Ljung T, Karlén P, Schmidt D, et al
. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004; 53:849–853.
43. Biancone L, Orlando A, Kohn A, et al
. Infliximab and newly diagnosed neoplasia in Crohn's disease: a multicentre matched pair study. Gut 2006; 55:228–233.
44. Vermeire S, van Assche G, Rutgeerts P. Review article: altering the natural history of Crohn's disease—evidence for and against current therapies. Aliment Pharmacol Ther 2007; 25:3–12.
45. Lichtenstein GR, Cohen RD, Feagan BG, et al
. Safety of infliximab and other Crohn's disease therapies—Treat™ Registry data with nearly 20,000 patient-years and follow-up. Gastroenterology 2007; 132:A178.
46. Siegel CA, Hur C, Korzenik JR, et al
. Risks and benefits of infliximab for the treatment of Crohn's disease. Clin Gastroenterol Hepatol 2006; 4:1017–1024.
47. Symmons DP. Lymphoma rheumatoid arthritis—again. Rheumatology (Oxford) 2007; 46:1–2.
48. Geborek P, Bladstrom A, Turesson C, et al
. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005; 64:699–703.
49. Bongartz T, Sutton AJ, Sweeting MJ, et al
. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295:2275–2285.
50. Kadin M, Kamoun M, Lamberg J. Erythrophagocytic Tγ lymphoma: a clinicopathologic entity resembling malignant histiocytosis. N Engl J Med 1981; 304:648–653.
51. Belhadj K, Reyes F, Farcewt J-P, et al
. Hepatosplenic γδT-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood 2003; 102:4261–4269.
52. Jaffe ES. Pathobiology of peripheral T-cell lymphomas. Hematology Am Soc Hematol Educ Program
53. Gaulard P, Bourquelot P, Kanavaros P, et al
. Expression of the alpha/beta and gamma/delta T-cell receptors in 57 cases of peripheral T-cell lymphomas: identification of a subset of γδT-cell lymphomas. Am J Pathol 1990; 137:617–628.
54. Percy C, Smith M, Linet M, et al. Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al (editors). Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975–1995
. Bethesda, MD: National Cancer Institute, SEER Program. NIH Pub. No. 99–4649; 1999:35–50.
55. Rajakariar R, Bhattacharyya M, Norton A, et al
. Post transplant T-cell lymphoma: a case series of four patients from a single unit and review of the literature. Am J Transplant 2004; 4:1534–1538.
56. Wu H, Wasik MA, Przbylski G, et al
. Hepato-splenic gamma-delta T-cell lymphoma as a late onset posttransplant lymphoproliferative disorder in renal transplant recipients. Am J Clin Pathol 2000; 113:487–496.
57. Lemann M, de La Valussiere G, Bouhnik Y, et al
. Intravenous cyclosporine for refractory attacks of Crohn's disease (CD): long-term follow-up of patients [abstract]. Gastroenterology 1998; 114:A1020.
58. Navarro JT, Ribera JM, Mate JL, et al
. Hepatosplenic T-gamma delta lymphoma in a patient with Crohn's disease treated with azathioprine. Leuk Lymphoma 2003; 44:531–533.
59. Mittal S, Milner BJ, Johnston PW, et al
. A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab. Eur J Haematol 2006; 76:531–534.
60. Keller KM, Magdefrau C, Bohl L, et al
. Hepatosplenic T-cell-lymphoma in a 15-year-old boy with ulcerative colitis treated with azathioprine for 9 years. J Pediatr Gastroenterol Nutr 2007; 44:e259.
61. Carvalho R, Hyams JS. Diagnosis and management of inflammatory bowel disease in children. Semin Pediatr Surg 2007; 16:164–171.
62. Markowitz J, Hyams J, Mack D, et al
, Pediatric IBD Collaborative Research Group. Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease. Clin Gastroenterol Hepatol 2006; 4:1124–1129.
63. Hyams J, Markowitz J, Lerer T, et al
, Inflammatory Bowel Disease Collaborative Research Group. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol 2006; 4:1118–1123.
64. Biank V, Broeckel U, Kugathasan S. Pediatric inflammatory bowel disease: clinical and molecular genetics. Inflamm Bowel Dis 2007; 13:1430–1438.
65. Rutgeerts P, Van Assche G, Vermeire S. Review article: infliximab therapy for inflammatory bowel disease—seven years on. Aliment Pharmacol Ther 2006; 23:451–463.
66. Hyams J, Crandall W, Kugathasan S, et al
, REACH Study Group. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007; 132:863–873.
67. Clark M, Colombel JF, Feagan BC, et al
. American gastroenterological association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease, June 21–23, 2006. Gastroenterology 2007; 133:312–339.
68. Loftus EV Jr. Biologic therapy in Crohn's disease: review of the evidence. Rev Gastroenterol Disord 2007; 7(Suppl 1):S3–S12.
69. Veres G, Baldassano RN, Mamula P. Infliximab therapy in children and adolescents with inflammatory bowel disease. Drugs 2007; 67:1703–1723.
70. Hanauer SB. Immunosuppressive therapy in the formation of antibodies to infliximab in Crohn's disease. Curr Gastroenterol Rep 2007; 9:487–488.
71. Vermeire S, Noman M, Van Assche G, et al
. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease. Gut 2007; 56:1226–1231.
72. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007; 369:1641–1657.
73. Van Assche G, Magdelaine-Beuzelin C, D'Haens G, et al
. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008; 134:1861–1868.
74. Lichtenstein GR, Diamond RH, Wagner C, et al
. Infliximab administered as 3-dose induction followed by scheduled maintenance therapy in IBD: comparable clinical outcomes with or without concomitant immunomodulators [abstract]. Gastroenterology 2007; 132:A146.
75. Rutgeerts P, Sandborn WJ, Feagan BG, et al
. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462–2476.
76. Hanauer SB, Feagan BG, Lichtenstein GR, et al
, ACCENT I Study Group. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359:1541–1549.
77. Bamias G, Nyce MR, De La Rue SA, et al
, American College of Physicians; American Physiological Society. New concepts in the pathophysiology of inflammatory bowel disease. Ann Intern Med 2005; 143:895–904.
78. Colombel JF, Sandborn WJ, Rutgeerts P, et al
. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007; 132:52–65.
79. Sandborn WJ, Feagan BG, Stoinov S, et al
, PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med 2007; 357:228–238.
80. Ruemmele FM, Roy CC, Levy E, Seidman EG. Nutrition as primary therapy in pediatric Crohn's disease: Fact or fantasy? J Pediatr 2000; 136:285–291.
81. Borrelli O, Cordischi L, Cirulli M, et al
. Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn's disease: a randomized controlled open-label trial. Clin Gastroenterol Hepatol 2006; 4:744–753.
82. Day AS, Whitten KE, Sidler M, et al
. Systematic review: nutritional therapy in paediatric Crohn's disease. Aliment Pharmacol Ther 2008; 27:293–307.
This article has been cited 9 time(s).
Annals of Nutrition and MetabolismInfluence of Exclusive Enteral Nutrition Therapy on Bone Density and Geometry in Newly Diagnosed Pediatric Crohn's Disease PatientsAnnals of Nutrition and Metabolism
Monatsschrift KinderheilkundeTNF alpha-inhibitor therapy - Assessment of cancer riskMonatsschrift Kinderheilkunde
ViszeralmedizinConservative Therapy: Step Up or Top Down?Viszeralmedizin
Digestive DiseasesImmunomodulation with Methotrexate: Underused and Undervalued?Digestive Diseases
Mutation Research-Reviews in Mutation ResearchMechanisms of intestinal inflammation and development of associated cancers: Lessons learned from mouse modelsMutation Research-Reviews in Mutation Research
American Journal of GastroenterologyEfficacy of Adalimumab in Moderate-to-Severe Pediatric Crohn's DiseaseAmerican Journal of Gastroenterology
Pharmacology & TherapeuticsRational development and utilization of antibody-based therapeutic proteins in pediatricsPharmacology & Therapeutics
International Journal of Paediatric DentistryPaediatric gastrointestinal conditions and their oral implicationsInternational Journal of Paediatric Dentistry
Journal of Pediatric Gastroenterology and NutritionLymphomatoid Granulomatosis: A Unique Complication of Crohn Disease and Its Treatment in PediatricsJournal of Pediatric Gastroenterology and Nutrition
Anti-TNF; Biologicals; Crohn; Inflammatory bowel disease; Lymphoma; Pediatric
© 2009 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read