SEARCH

SEARCH BY CITATION

Keywords:

  • methotrexate;
  • anti-TNF agents;
  • lymphoma;
  • ulcerative colitis;
  • Crohn's disease;
  • infliximab;
  • Purine Analogues

Abstract

  1. Top of page
  2. Abstract
  3. IBD AND THE RISK OF LYMPHOMA
  4. PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  5. MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  6. TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  7. SUMMARY
  8. REFERENCES

With the increasingly widespread use of immunosuppressive and biologic agents for the treatment of Crohn's disease and ulcerative colitis come concerns about potential long-term consequences of such therapies. Disentangling the potential confounding effects of the underlying disease, its extent, severity, duration, and behavior, and concomitant medical therapy has proven to be exceedingly difficult. Unlike the case in rheumatoid arthritis, the overwhelming preponderance of population-based evidence suggests that a diagnosis of inflammatory bowel disease (IBD) is not associated with an increased relative risk of lymphoma. However, well-designed studies that evaluate the potential modifying effect of IBD severity have yet to be performed. Although the results from hospital- and population-based studies have conflicted, the results of a recent meta-analysis suggest that patients receiving purine analogs for the treatment of IBD have a lymphoma risk ≈4-fold higher than expected. Analyses of lymphoma risk in patients receiving biologic agents directed against tumor necrosis factor-alpha are confounded by concomitant use of immunosuppressive agents in most of these patients. Nevertheless, there may be a small but real risk of lymphoma associated with these therapies. Although the relative risk of lymphoma may be elevated in association with some of the medical therapies used in the treatment of IBD, this absolute risk is low. Weighing the potential risk of lymphoma associated with select medical therapies against the risk of undertreating IBD will help physicians and patients to make more informed decisions pertaining to the medical management of IBD.

(Inflamm Bowel Dis 2007)

Crohn's disease (CD) and ulcerative colitis (UC) are the 2 major subtypes of idiopathic inflammatory bowel disease (IBD). In CD, untreated transmural bowel inflammation can lead to the development of intra-abdominal abscess, peritonitis, internal or enterocutaneous fistula formation, and bowel obstruction.1–5 Up to 80% of patients with CD will require at least 1 operation during the course of their disease.6 Without treatment, patients with IBD can experience significantly impaired quality of life. It is thought that IBD occurs as a result of an interplay between genetic predisposition and initiation of a dysregulated immune response through exposure to luminal antigens.7 Both animal and human data support the hypothesis that luminal bacterial antigens are the most likely trigger of this aberrant immune response.7–12

Improved understanding of the immunopathogenesis of this disease has lead to an explosion in research related to the use of immunosuppressive and biologic agents. A number of these novel therapies have been shown to be particularly effective at inducing and maintaining remission in IBD.13–18 Over the past 15 years the emphasis of the medical management of IBD has shifted to earlier and more aggressive use of immunosuppressive and biologic agents.19 Immunosuppressive agents with proven efficacy in the treatment of IBD include azathioprine (AZA), 6-mercaptopurine (6-MP), and methotrexate (MTX).13, 17, 18 Infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha (TNF-α), is widely used in the management of moderate to severely active and/or fistulizing CD unresponsive to traditional antiinflammatory agents or a single immunosuppressive agent.15, 16 Additionally, multicenter, randomized, placebo-controlled clinical trials have proven the efficacy of infliximab for the induction and maintenance of remission in moderate to severely active UC.20 Adalimumab, a recombinant human antibody to TNF-α, is effective for inducing and maintaining remission in CD, and is now commercially available in the US for these indications.21, 22 Certolizumab pegol (CDP870), a pegylated humanized Fab' antibody fragment, has also been shown in clinical trials to be effective in inducing and maintaining remission in CD, but this agent is not yet commercially available.23, 24

As experience with the use of these agents increases, new concerns regarding potential infectious and malignant sequelae related to the long-term immunosuppressive effects of these drugs have emerged. Particularly controversial is the degree to which IBD patients on immunosuppressive agents are at risk for the development of lymphoma.25, 26 There is confusion related to the conflicting results of studies in the medical literature, and uncertainty regarding how disease severity and duration, as well as the degree of immunosuppression, contribute to the risk of lymphoma in this patient population.

IBD AND THE RISK OF LYMPHOMA

  1. Top of page
  2. Abstract
  3. IBD AND THE RISK OF LYMPHOMA
  4. PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  5. MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  6. TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  7. SUMMARY
  8. REFERENCES

The putative role IBD plays in the development of lymphoma has generated a great deal of controversy.27–34 Patients with IBD have long been suspected of being at increased risk of lymphoma. Indeed, almost 80 years ago a case of “lymphosarcoma” was noted in the first published case series of colorectal cancer occurring in the setting of UC.35 Over the years, numerous case reports and case series have been published that describe the development of lymphoma in the setting of IBD.36–38 As none of these reports were prospective in nature, no causal inferences can be made. However, it is interesting to note that most of the lymphomas described in these cases arose from the gastrointestinal tract; the implication being that chronic inflammation may increase the potential for malignant change.

Observational studies evaluating the relationship between IBD and lymphoma come in the form of case reports or case series,36, 38–41 hospital-based,42, 43 or larger population-based cohort studies.44–51 One of the largest population-based studies (Table 1)47 utilized the General Practice Research Database (GPRD), which is comprised of the computerized medical records of 2000 general practitioners and 8 million patients (6% of the population of the UK). All patients coded with a diagnosis of UC or CD as per the Oxford Medical Indexing System were eligible for the study. In total, over 6000 patients with CD and 10,000 patients with UC, as well as more than 60,000 age-, sex-, and primary practice-matched subjects randomly selected from the non-IBD patient population in the database were included in the analysis. All patients having developed lymphoma within 1 year of the index date were excluded. The duration of follow-up was at least 1 year. The primary outcome of interest was an incident diagnosis of Hodgkin's disease or non-Hodgkin lymphoma (NHL). The relative risk (RR) of lymphoma in patients with CD or UC compared to their matched controls was 1.20 (95% confidence interval [CI], 0.67–2.06)—stated another way, there was a 20% increased risk noted, but this elevation was not statistically significant.47 The incidence rate of lymphoma in the CD and UC groups was not significantly different from the expected rate in the general population.47 The largest population-based study to date was performed by Askling et al,52 in which prospectively recorded data, assembled from multiple regional cohorts of IBD (the Uppsala cohort, Stockholm County cohort, Stockholm pancolitis register, and the Swedish inpatient register), were analyzed. Over 47,000 Swedish patients with CD and UC were included.52 The RR of lymphoma was estimated using standardized incidence ratios (SIR, observed cases divided by expected cases). The SIR of all lymphomas was 0.8 (95% CI, 0.5–1.3) among the UC regional cohorts (n = 4,467) and 1.0 (95% CI, 0.8–1.2) in the UC inpatient register cohort (n = 26,036).52 In the CD regional cohorts (n = 3,561), the SIR of lymphoma was 1.3 (95% CI, 0.8–2.0), while it was 1.3 (95% CI, 1.0–1.7) in the Crohn's inpatient register (n = 19.024).52 In a combined analysis, the SIR for malignant lymphoma in UC was 1.0 (95% CI, 0.8–1.3) and the SIR for lymphoma in CD was 1.3 (1.0–1.6).52 This minimal elevation of lymphoma risk for CD was limited to the first 5 years of follow-up from time of Crohn's diagnosis. Even after adjusting for extent of disease, hospitalization, and surgery, no significant differences in the RR estimates were identified.52

Table 1. Overall Risk of Lymphoma in Inflammatory Bowel Disease: Population-Based Studies
ReferenceSettingPatientsRelative Risk (95% CI)
  1. CD, Crohn's disease; UC, ulcerative colitis; CI, confidence intervals.

Ekbom et al.50Uppsala, SwedenCD 16550.4 (0–2.4)
  UC 31211.2 (0.5–2.4)
Persson et al.44Stockholm, SwedenCD 12511.4 (0.4–3.5)
Karlen et al.49Stockholm, SwedenUC 15471.2 (0.3–3.5)
Loftus et al.46Olmsted County, USACD 2162.4 (0.1–13)
  UC 2380 (0–6.4)
Palli et al.43Florence, ItalyCD 2312.5 (0.3–9)
  UC 6899.3 (2.5–24)
Bernstein et al.51Manitoba, CanadaCD 28572.4 (1.2–5)
  UC 26721.0 (0.5–2.2)
Lewis et al.47General Practice Research Database, United KingdomCD 66051.4 (0.5–3.4)
  UC 103911.2 (0.7–2.1)
Winther et al.34Copenhagen County, DenmarkUC 1160Not elevated
Jess et al.43Copenhagen County, DenmarkCD 374Not elevated
Askling et al.52Multiple Swedish cohortsCD 201201.3 (1.0–1.6)
  UC 275591.0 (0.8–1.3)

Three earlier population-based cohort studies from Sweden failed to reveal significantly elevated RRs of lymphoma in CD or UC (Table 1).44, 49, 50 Similarly, population-based cohort studies from Denmark, Minnesota, and Italy failed to demonstrate an increased risk of lymphoma.45, 46, 48 Only 1 population-based, retrospective, matched cohort study utilizing population-based IBD and cancer registries demonstrated an increased risk of lymphoma, limited to patients with CD.51 Further subgroup analysis indicated that the increased risk was observed only in male patients with CD. Although most hospital-based cohort studies have reported an increased risk of lymphoma in patients with IBD, these risk estimates are likely distorted as a result of referral bias.42, 43

One issue that has not been adequately addressed in studies of IBD is whether or not disease severity influences the risk of lymphoma. In the rheumatoid arthritis (RA) literature, a fairly strong and consistent association between disease activity and risk of lymphoma has been demonstrated.53, 54 Indeed, the elevated lymphoma risk associated with poorly controlled inflammation in RA is used as an argument in favor of the institution of early and aggressive immunosuppression. In 1998, Baecklund et al54 performed a nested case-control study of RA-associated lymphoma using a previously described population-based cohort of over 11,000 RA patients from the Uppsala health care region of Sweden. Forty-one lymphoma cases and 113 RA controls were evaluated, with lymphoma risk reported as odds ratios (OR). High inflammatory activity was the most prominent risk factor for lymphoma (OR, 5.8; 95% CI, 3.1–213).54 Very few patients were treated with immunosuppressive drugs, and no association between any specific drug and the risk of lymphoma was found. A study with a similar nested case-control design in a population-based cohort of over 74,000 Swedish individuals with RA consisted of 378 patients with lymphoma (cases) and 378 RA controls without lymphoma. This study confirmed the relationship between severity of inflammatory activity and lymphoma risk.53 Compared with low disease activity, medium activity was associated with a 7-fold increased risk and high disease activity was associated with more than a 70-fold increased lymphoma risk. Similarly designed studies in IBD (i.e., that evaluate the role of disease severity) have not been performed.

PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD

  1. Top of page
  2. Abstract
  3. IBD AND THE RISK OF LYMPHOMA
  4. PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  5. MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  6. TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  7. SUMMARY
  8. REFERENCES

A number of single-center and population-based cohort studies investigating the association between the use of immunosuppressive agents and lymphoma in patients with IBD have been published (Table 2).47, 55–60 In a 2001 cohort study utilizing the GPRD, a subgroup analysis of 1465 IBD patients treated with thiopurine antimetabolites did not demonstrate a significantly different RR of lymphoma from that of the general population.47 The SIR for lymphoma in this subgroup was 1.57 (95% CI, 0.04–8.75). The single case of lymphoma that did develop, a Hodgkin's lymphoma, occurred in a UC patient within 10 months of receiving a single prescription for AZA.47 A hospital-based study from Oxford, UK, found that the incidence rate for lymphoma in AZA-treated patients did not differ significantly from the rate observed in IBD patients not receiving immunosuppressive therapy.59 Farrell et al58 conducted a retrospective cohort study of 782 IBD patients who attended a tertiary referral center in Ireland and received immunosuppressive agents between 1990 and 1999. Two hundred twelve patients (30%) received AZA 2–2.5 mg/kg daily for a median of 1.8 years. Overall, there was an increase in the rate of NHL, with an SIR of 31.2 (95% CI, 2.0–85; P < 0.001).61 In total, 4 patients developed B-cell lymphomas. Two of these 4 cases had received AZA for therapy of steroid-refractory disease. The patients were ages 34 and 53 at the time of lymphoma development, with an IBD duration of 2 and 5 years, respectively. Glazier et al60 published a 10-year, single-center experience with 6-MP whereby the medical records of over 285 IBD patients treated with 6-MP were reviewed. The mean daily dose of 6-MP in 188 patients was 0.84 mg/kg/day and the mean duration of treatment was 27 months. Malignancies occurred in 2 patients and included 1 melanoma and 1 colonic lymphoma. The single lymphoma was confirmed as a large B-cell lymphoma in a 44-year-old male with a 6-year history of refractory Crohn's colitis.60 In a recent review of cohort studies of this topic, it was estimated that 14 cases of lymphoma have been identified among 4770 IBD patients receiving AZA or 6-MP, MTX, and/or cyclosporine, and that these patients had been followed for ≈17,000 person-years.62 Unfortunately, the results of hospital-based and cohort studies have yielded conflicting results, most likely due to inadequate sample size, poor follow-up, differences in immunosuppressive dose and duration, and other flaws in study design. Recently, Kandiel et al63 performed a meta-analysis utilizing data from 6 of these cohort studies. The authors were able to pool calculated SIRs from all studies. When data were pooled across all studies, there were 11 observed lymphomas out of an expected 2.63 cases, resulting in an SIR of 4.18 (95% CI, 2.07–7.51).63 Due to significant variability in SIR estimates between the studies, sensitivity analyses were performed whereby each study was excluded from the group and SIR was recalculated. These demonstrated a persistent increase in the SIR, with estimates ranging from 3.49 to 5.21. The authors concluded that IBD patients on thiopurines seemed to have a 4-fold increased risk of lymphoma, but whether this risk was due to the medications themselves or the underlying disease severity could not yet be elucidated.63

Table 2. Risk of Lymphoma in IBD Patients Treated with Azathioprine or 6-Mercaptopurine
ReferenceSettingNObservedExpectedSIR (95% CI)
  1. SIR, standardized incidence ratio; GPRD, General Practice Research Database; NA, not applicable.

Kinlen53UK32120.1612.5 (1.2–46)
Connell, et al.56London75500.520
Korelitz, et al.57New York City, USA48630.614.9 (0.9–14.5)
Farrell, et al.61Dublin, Ireland23820.0537.5 (3.5–138)
Lewis, et al.69GPRD,UK146510.641.6 (0.001–9)
Fraser, et al.59Oxford, UK62630.654.6 (0.9–13.7)
Kandiel, et al.63Pooled Analysis3891112.634.2 (2.1–7.5)
Glazier, et al.60New Jersey, USA2851NANA

It is well documented that solid organ transplant recipients are at increased risk of developing immunosuppression-related NHL and posttransplant lymphoproliferative disorders (PTLD).27–29 In most cases, these disorders have been associated with Epstein-Barr virus (EBV) infection.30 In the nontransplant setting, EBV-related lymphoproliferation occurs with less frequency.31–33 Several case reports and case series have pointed to a potential association between the use of thiopurines in IBD and the EBV-related lymphomas.64, 65 Larvol et al64 reported a case of EBV-related lymphoma in a patient with CD that regressed after stopping AZA. Dayharsh et al65 identified 18 IBD patients diagnosed with lymphoma at the Mayo Clinic in Rochester, Minnesota, between 1985 and 2000. Six patients diagnosed with lymphoma were on AZA or 6-MP. Pathology specimens were retrieved and tissue was tested for evidence of EBV by means of in situ hybridization. Interestingly, 5 of the 6 patients treated with thiopurine had evidence of EBV in lymphoma tissue (83%), compared to only 2 of the 10 patients not on immunosuppressive agents (20%).65 In addition to this, EBV DNA and EBV gene products have been observed in the mucosal samples of patients with IBD who have gastrointestinal lymphomas.66–68 These findings have raised concerns regarding the role of immunosuppressive medications in the development of EBV-related lymphomas in patients with IBD.

Despite these concerns, immunosuppressive therapies remain effective treatment options for patients with moderate to severe disease. Lewis et al69 utilized a Markov decision analysis model to quantify the risks and benefits of various management strategies in CD patients whose disease activity was sufficiently active to warrant treatment with AZA for maintenance of remission following corticosteroid-induced remission. The AZA treatment strategy produced an overall increase in quality-adjusted life expectancy of 0.6 months. Although this benefit appeared to decrease with increasing age, it was estimated that the overall risk of NHL with the AZA treatment strategy would have to be nearly 10 times higher than alternative strategies for the overall quality-adjusted life expectancy to be reduced.69 As described earlier, most of the published literature has not reported this level of risk.

MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD

  1. Top of page
  2. Abstract
  3. IBD AND THE RISK OF LYMPHOMA
  4. PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  5. MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  6. TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  7. SUMMARY
  8. REFERENCES

As with the thiopurines, concerns exist in relation to the increased risk of lymphoma in IBD patients receiving therapy with MTX. However, very little information concerning the association between MTX and lymphoma in the IBD patient population has been published. One must examine the use of MTX in other diseases to obtain more robust estimates of lymphoma risk. As in the case with IBD, it is difficult to disentangle the effects of RA itself from use of medications such as MTX and the biologics when attributing lymphoma risk. The increased risk of lymphoma in RA has been well documented31, 55, 70, 71 and has been attributed to both disease severity and EBV status.53, 54, 72 As with thiopurines and IBD, spontaneous case reports have described the regression of lymphoma with discontinuation of MTX, providing a temporal association between the drug and the development and subsequent regression of lymphoma.73 In a large observational study of over 18,000 RA patients in a national registry, the SIR for lymphoma overall was 1.9 (95% CI, 1.3–2.7).70 (Expected rates in this study were derived from the Surveillance, Epidemiology, and End Results [SEER] database, which is maintained by the Centers for Disease Control and Prevention.) For patients on MTX, the SIR was 1.7 (95% CI, 0.9–3.2), compared to 1.0 (95% CI, 0.4–2.5) for those not receiving MTX or any other biologic therapies. Although there is a suggestion of an association between MTX use and lymphoma in this study, one cannot determine if this association is due to the severity of underlying RA (leading therefore to the prescription of MTX) or to the drug itself.70

To date, there are no published studies that rigorously investigate the risk of lymphoma in IBD patients treated with MTX. The potential association was examined indirectly in the hospital-based study from Dublin by Farrell et al58 described previously. In this study, only 31 IBD patients had received MTX, 2 of whom developed NHL. One of these patients was also on cyclosporine. Meaningful conclusions cannot be drawn from such a small cohort of subjects.

TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD

  1. Top of page
  2. Abstract
  3. IBD AND THE RISK OF LYMPHOMA
  4. PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  5. MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  6. TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  7. SUMMARY
  8. REFERENCES

We have seen how there may be a slightly increased risk of lymphoma associated with CD itself and how thiopurines and MTX are associated with an increased lymphoma risk. Therefore, evaluation of the safety of the TNF-α antagonists, which are often used in conjunction with thiopurines and MTX, becomes exceedingly difficult, especially for a low-frequency event such as lymphoma.74 Furthermore, much of the data on lymphoma risk associated with these agents is based on patients with RA, which, as mentioned previously, is known to be associated with lymphoma.53, 54

Infliximab, a chimeric monoclonal IGg1 antibody to TNF-α, has been shown in multiple large, randomized-controlled clinical trials to be efficacious for the induction and maintenance of remission in patients with moderate to severely active CD not responsive to conventional therapy, fistulizing CD, and for moderate to severely active UC not responsive to conventional therapy.15, 16, 20 In 1998, infliximab was approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severely active CD, and the indication for UC was approved in 2005.75 Other biologic agents directed against TNF-α (i.e., adalimumab and certolizumab pegol) have been shown in clinical trials to be efficacious for CD,21–24, 76 and in 2007 adalimumab was approved by the FDA for moderate to severely active CD with inadequate response to conventional therapy.77

In clinical trials of infliximab for all indications, patients treated with infliximab had a higher incidence rate of lymphoma (0.11 cases per 100 person-years) than patients treated with placebo (0 cases).78 After commercial release, an increasing number of lymphomas were reported to the FDA,79 and in 2003 this led an FDA advisory committee on the safety of biologics in RA to mandate an estimate of the RR using SIRs, with the expected numbers derived from the general population from the SEER database. The SIR for lymphoma in patients treated with infliximab is ≈4.78

In the largest, single-center experience in IBD to date, the medical records of over 500 consecutive patients receiving infliximab treatment for CD were reviewed.80 The patients received a median of 3 infusions and were followed for a median of 17 months. Eighty-six percent of patients were taking concomitant immunosuppressive therapy (11% MTX and 75% AZA). Two patients developed lymphoma (0.4%), of which 1 was NHL and the other was Hodgkin's lymphoma.80 Only 1 of these cases was rated as potentially related to infliximab treatment. In a population-based cohort study from Stockholm County, Sweden, 212 IBD patients who received therapy with infliximab were followed for a 28-month period.81 Patients had received a mean of 2.6 infusions of infliximab. Over half of the patients were receiving concomitant therapy with AZA, 6-MP, or corticosteroids, and ≈25% were receiving both. The authors reported the development of NHL in 3 patients (1.4%), all of whom had CD, and 1 of whom was on concomitant AZA.81 Death from lymphoma occurred in 2 of these cases. The incidence rate of lymphoma reported by Ljung et al80, 81 was significantly higher than that reported in previous clinical trials as well as that reported in the experience from the Mayo Clinic (0.2%). In contrast, observational data from the large Crohn's Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry are somewhat reassuring with respect to lymphoma risk.82, 83 As of August 2005, this FDA-mandated registry contains over 6000 CD patients, about half of whom have received infliximab, and almost 15,000 patient-years of follow-up. The incidence of lymphoma was reported as 0.06 per 100 patient-years in infliximab-treated patients compared to 0.05 per 100 patient-years in patients not receiving infliximab (RR, 1.3; 95% CI, 0.4–5.0).83

In clinical trials and open-label follow-up of patients treated with adalimumab for any condition, the observed incidence of lymphomas has been 0.12 cases per 100 person-years of follow-up, which is 3.5 times higher than what would have been expected based on SEER data.84 In postmarketing surveillance for RA (which is based on spontaneous reporting and should thus be considered an underestimate), ≈0.04 cases of lymphoma per 100 person-years of follow-up have been reported.77, 84

In observational studies of RA patients, SIRs for lymphoma in those receiving anti-TNF agents are significantly higher than those RA patients not receiving such therapy.70, 85 In the previously cited observational study of over 18,000 American RA patients, Wolfe and Michaud70 estimated the SIR for lymphoma in patients treated with infliximab at 2.6 (95% CI, 1.4–4.5). A large observational study from southern Sweden compared 2 cohorts of RA patients for cancer risk, 1 group of 757 patients treated with anti-TNF agents, and another group of 800 patients receiving conventional therapy.85 The observed rates of malignancies were compared to expected rates. The RA patients on standard therapy had a lymphoma incidence similar to that expected, while those treated with anti-TNF therapy had over 11 times more lymphomas that expected.85 However, given the known association between RA and lymphoma, and RA disease severity and lymphoma,53, 54 it is impossible to determine if these elevated risks are due to the TNF blocker or due to the underlying disease severity.

As noted above, the observational studies have provided conflicting data regarding the risk of lymphoma with TNF blockade, and these studies likely will never answer the question definitively due to the aforementioned confounders of disease severity and concomitant medications. However, a recently published meta-analysis of 9 randomized trials of infliximab and adalimumab in RA focused on the risk of malignancy and has received a great deal of attention.86 Theoretically, the process of randomization should have eliminated any confounding by disease severity. The trials included in the analysis required treatment with infliximab or adalimumab (with or without other disease-modifying antirheumatic drugs [DMARDs]), and the control arms consisted of either placebo or DMARD alone. The study ultimately included 9 clinical trials. These clinical trials were quite heterogeneous with respect to the intervention and control groups. Eight of the 9 trials included RA patients with severe disease activity. Utilizing fixed-effects modeling for rare event data, the authors pooled the data from these trials to estimate the odds of malignancy and serious infection in those treated with anti-TNF therapy (intervention arms) compared to those who were not (control arms). A continuity correction was used to deal with imbalances in patient numbers between study arms and zero-event data. The pooled OR for all malignancies (including nonmelanoma skin cancers) was 3.3 (95% CI, 1.2–9.1). The authors calculated a number needed to harm (NNH) of 154 for 1 additional malignancy within a treatment period of 6–12 months. The estimate of odds of malignancy after omission of nonmelanoma skin cell cancer did not change significantly (OR, 4.5; 95% CI, 1.3–14.9). A separate analysis of lymphoma risk was not made, but a total of 10 lymphomas were observed in the anti-TNF-treated patients and none were observed in the patients in the control arms; 6 of the 10 were not included in the meta-analysis because they had occurred in follow-up after the trials had ended.86 In a reply to letters to the editor, these estimates were updated to include data from 2 additional RA trials, and the OR for malignancy overall remained significant (OR, 2.4; 95% CI, 1.2–4.8), but a revised OR excluding nonmelanoma skin cancers was not reported.87 There has also been debate about whether the meta-analysis should have accounted for person-years of follow-up.88 Future meta-analyses should directly assess lymphoma risk, should include trials of patients with CD, and should include trials of all relevant anti-TNF therapies, including certolizumab pegol.

In May 2006, the black-box warning for infliximab was amended to include information about the risk for hepatosplenic T-cell lymphoma in adolescent and young adult patients with CD.78 There have only been 150 cases of this rare form of lymphoma reported worldwide since the condition was first recognized in the early 1990s. As of October 2006, 8 cases of this rare, aggressive peripheral T-cell lymphoma in young patients using infliximab had been reported to the FDA's MedWatch.89 All 8 patients had IBD, all were on concomitant immunosuppression with thiopurines, and 6 patients died. At least 1 case of hepatosplenic T-cell lymphoma occurring in the setting of AZA alone (i.e., without anti-TNF therapy) has been reported in CD.90 At present, it is not yet clear whether the apparent increased risk for this malignancy is due to infliximab, thiopurines, or a combination of the 2.90 Although these developments have reportedly changed clinical practice for many pediatric gastroenterologists, many of whom are no longer prescribing concomitant immunosuppressive therapy when infliximab is indicated, certainly no consensus has developed on this point yet. Although concerning, it is impossible at this point to assign causation to therapy with infliximab. The potential confounding effects of underlying disease severity and duration and concomitant immunosuppression in a younger patient population are not easy to disentangle. Likewise, these factors may be synergistic.

Siegel et al91 recently published a provocative decision analysis that attempted to evaluate the risks and benefits of infliximab compared with standard therapy for the treatment of moderate to severely active CD in a hypothetical cohort of 35-year-old patients. The primary outcomes of interest were deaths, number of lymphomas, changes in clinical status, and gain or loss in the average quality-adjusted life years (QALYs) per patient over the course of 1 year. Model inputs of the risk of lymphoma were derived from controlled clinical trials, single-center cohorts of consecutive patients, and population-based cohorts. Spontaneous postmarketing surveillance reports and voluntary patient registries were excluded. The estimated benefit of infliximab was derived from the ACCENT I study.15 Model results showed that at the end of 1 year (out of 100,000 patients), infliximab use would result in 12,216 more patients in remission, 4255 fewer surgeries, and 33 fewer deaths from disease flares. The gain in average QALYs per patient was also higher in the infliximab group compared to standard therapy (0.77 versus 0.75 QALYs/patient, respectively). However, the model suggested that this benefit would be obtained at the cost of 201 more lymphomas and 271 more overall deaths. Although patients in the infliximab-treated group suffered fewer disease-related deaths, the overall death rate was higher, largely sepsis-related. Some of the methodology utilized in this study has received criticism.92 The decision not to utilize data from the recently published TREAT registry of more than 6000 patients has been criticized, given the reassuring results that have endured over time. However, one cannot overlook the potential impact of nonresponse bias on the degree to which such risk estimates are truly representative of the patient population of interest. The authors may also have underestimated the risk of the standard therapy arm by assuming that the rates of corticosteroid use were equivalent in both treatment groups. The model, designed as a decision tree, has also been criticized for not accounting for time spent in each health state. Additionally, crossover, which was allowed for infliximab failures but not standard therapy failures, may have biased the results in favor of the infliximab group. Although such criticisms serve to outline the limitations of these models, the glaring absence of more robust, prospective, long-term data leaves a void which can only be filled through the use of such techniques.

SUMMARY

  1. Top of page
  2. Abstract
  3. IBD AND THE RISK OF LYMPHOMA
  4. PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  5. MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  6. TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  7. SUMMARY
  8. REFERENCES

The issue of assigning causality when describing the relationship between lymphoma and IBD in the context of increased disease activity and administration of immunosuppressant therapy is complex. The data, taken as a whole, do not support the hypothesis that IBD alone is a risk factor for the development of lymphoma. However, it remains unclear as to whether or not IBD patients with more severe and prolonged disease activity are at greater risk than those with less severe disease. Although not conclusive, the preponderance of data in the literature has established that IBD patients treated with AZA and 6-MP are at greater risk of developing lymphoma than the general population. Although potential confounders such as age and sex have been controlled for in some of these studies, other potentially critical variables including disease activity, duration of disease, and coadministration of other immunosuppressive agents have not consistently been taken into account. Few studies have compared the risk of lymphoma in AZA- or 6-MP-treated IBD patients to those not treated with these agents, resulting in questionable risk comparisons. To date, there are no published epidemiologic data investigating the risk of lymphoma in IBD patients treated with MTX. However, the results of a recently published large cohort study in the RA literature are somewhat reassuring in that the study could not detect a significantly increased risk of lymphoma in patients receiving therapy with MTX compared to expected rates. There appears to be a small, but real, increase in the risk of lymphoma in IBD patients receiving anti-TNF-α therapy, but this risk has not been clearly quantified. Although the largest population-based study to date reported lymphoma incidence rates surpassing those previously reported in clinical trials, single-center experiences, and registries, the results should be interpreted cautiously. To date, the literature pertaining to the risk of lymphoma in IBD patients lacks the sophisticated study design that would assist in understanding the complex and probably synergistic relationships between IBD disease severity and duration, and concomitant use of immunosuppressives and biologic agents, and how these factors relate to the development of lymphoma.

REFERENCES

  1. Top of page
  2. Abstract
  3. IBD AND THE RISK OF LYMPHOMA
  4. PURINE ANALOGS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  5. MTX AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  6. TUMOR NECROSIS FACTOR ANTAGONISTS AND THE RISK OF LYMPHOMA IN PATIENTS WITH IBD
  7. SUMMARY
  8. REFERENCES