REVIEW OF THE LITERATURE
Disease States Other than IBD
The immunomodulator and anti-TNF drugs currently prescribed for IBD are also used to treat a number of other disease states with substantially larger patient populations. Reviewing the evidence linking these therapies to malignancy in non-IBD patient populations (Tables 1 and 2) is helpful not only in predicting the specific types of therapy-associated neoplasms that are likely to be observed in patients with IBD but also in furthering our understanding of the underlying pathogenetic mechanisms.
Lessons Learned from Transplant Medicine
Much of the early evidence supporting an association between immunosuppressive therapy and cancer comes from studies of organ transplant recipients. This is particularly true for azathioprine, which has been used to prevent graft rejection in transplant recipients since the 1960s. It is well-established that transplant recipients have an elevated risk of malignancy compared with the general population50 and that this risk has a dose-dependent and time-dependent relationship with immunosuppressive therapy. Furthermore, once cancer has developed, immunosuppressants can accelerate tumor growth and metastasis.51 Transplant recipients have been shown to be at increased risk of a wide range of malignancies, including non-Hodgkin's lymphoma (NHL), posttransplant lymphoproliferative disorder (PTLD), nonmelanoma skin cancer (NMSC), melanoma, Kaposi's sarcoma, and tumors of the cervix, vulva, liver, lung, kidney, bladder, and thyroid. The risks of breast, pancreatic, and colorectal cancers, on the other hand, are only slightly or not at all increased following transplantation.51 There are 3 major classes of mechanisms involved in the pathogenesis of immunosuppressant-associated malignancies: (1) decreased immunosurveillance of oncogenic viruses, (2) direct oncogenic effects of the drugs themselves, and (3) decreased immunosurveillance of emerging cancers.51
The role of oncogenic viruses in the pathogenesis of immunosuppressant-associated neoplasia is perhaps best illustrated by PTLD, the most common malignancy seen during the first year after transplant when immunosuppressive regimens are most intensive.51 The vast majority of cases of PTLD are associated with Epstein–Barr virus (EBV) infection of B lymphocytes.52 During primary infection with EBV, typically acquired during childhood through infected saliva or breast milk, the virus infects, transforms, and immortalizes host B cells. The infected B cells then typically remain in a latent state, and the host becomes a permanent carrier of the virus. EBV infection is extremely common, and it is estimated that >90% of humans worldwide are carriers of the virus.53 Viral proteins drive proliferation of EBV-infected B cells and prevent their death by apoptosis, but in immune-competent individuals, this B-cell proliferation is kept in check by a T-cell–mediated immune response. When T-cell function is inhibited by immunosuppressive agents, however, EBV can induce uncontrolled B-cell expansion, ultimately leading to PTLD. In transplant recipients, EBV-positive PTLD can develop as the result of primary infection, reactivation of latent EBV, or when an EBV-seronegative patient receives an organ from a seropositive donor. Transplant recipients at highest risk for PTLD include EBV-seronegative patients and those who receive more intensive immunosuppressive regimens. Fortunately, the majority of cases of PTLD undergo spontaneous remission once the intensity of immunosuppressive therapy is reduced.52
Experience with transplantation has shown that azathioprine directly promotes the development of cancer through several different mechanisms. Azathioprine is a purine analogue; its active metabolite, 6-mercaptopurine, is incorporated into cellular DNA, where it inhibits purine nucleotide synthesis and interferes with RNA synthesis and metabolism. Its direct oncogenic effects are well modeled by the pathogenetic mechanisms underlying the increased rate of NMSC in transplant recipients. Overall, NMSC is the most frequent posttransplant malignancy in countries with predominantly Caucasian populations, and the risk of NMSC is 12 to 90 times higher in organ transplant recipients compared with the general population.51 The risks of both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are increased in transplant recipients, but the excess risk of SCC is much greater. One population-based study of renal transplant recipients in Ireland treated with triple immunosuppression (azathioprine, cyclosporine, and corticosteroids) reported a SIR of 82 (95% confidence interval [CI], 73–91) for SCC and 16 (95% CI, 14–18) for BCC compared with a nontransplanted population.54 Intensity and duration of immunosuppression appear to be correlated with the risk of NMSC,51 and several different pathogenetic mechanisms have been identified. First, 6-thioguanine, a metabolite of azathioprine, interacts with ultraviolet (UV) A radiation to produce reactive oxygen species, which induce DNA damage in skin cells and result in abnormal cutaneous photosensitivity.55 It has also been demonstrated that azathioprine significantly reduces the repair of UV-induced DNA lesions in keratinocytes.56 Furthermore, there is evidence that azathioprine may cause mutations in PTCH, a tumor suppressor gene that is frequently mutated in BCC, independent of sun exposure.57 Finally, it has been suggested that impaired immunosurveillance of epidermodysplasia verruciformis–associated human papillomavirus (HPV) may also play a role in NMSC development in transplant recipients.51
An additional oncogenic effect of azathioprine has been identified by researchers studying the increased risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in transplant recipients. A large study conducted by Offman et al found that the relative risks for AML/MDS in transplant recipients compared with matched controls were 5.5 (95% CI, 4.0–7.7) for heart/lung recipients and 2.1 (95% CI, 1.6–2.7) for kidney recipients, the majority of whom received azathioprine with or without cyclosporine A and steroids. Furthermore, the authors found a correlation between the frequency of AML/MDS and azathioprine dosage; the incidence of AML/MDS in patients receiving 2.0 to 3.0 mg/kg/d was significantly higher than that of the patients who received <1.0 mg/kg/d (P = 0.031). The authors proposed that azathioprine selects for myeloid cells with defective DNA mismatch repair mechanisms that enable the cells to escape cytotoxic drug effects and proliferate. Absent or diminished activity of the DNA mismatch repair system significantly increases spontaneous mutation rates, and clonal expansion of these defective cells ultimately leads to AML/MDS.58
The risks of many types of malignancies with no known viral etiology are elevated in transplant recipients compared with the general population, including melanoma and tumors of the lung, liver, kidney, bladder, and thyroid. It is known that in immune-competent individuals, lymphocytes help protect against the formation of carcinogen-induced neoplasia, prevent the development of spontaneous tumors, and defend against metastasis.59 While the exact mechanisms underlying the pathogenesis of these nonviral malignancies in transplant recipients have not yet been well characterized, it seems likely that impaired immunosurveillance of cancer secondary to immunosuppressive therapy plays a significant role, although direct oncogenic effects of the immunosuppressive drugs may also be involved.
Additional Evidence from Rheumatology, Dermatology, and Neurology
The association between azathioprine use and the increased risk of malignancy observed in transplant recipients is supported by evidence from studies of rheumatological and neurological patients exposed to the drug. A population-based matched case–contol study conducted by Baecklund et al7 found that the risk of malignant lymphoma in patients with RA treated with azathioprine was >4 times that of patients with RA never exposed to the drug. This finding was consistent with the results of an earlier British study, which examined a cohort of patients with RA followed from 1964 to 1984. Compared with the general population, the rate of lymphoma was found to be 10-fold higher in patients with RA who were treated with azathioprine compared with a 5-fold elevation in patients with RA not exposed to the medication.60 The excess risk of lymphoma in azathioprine-naive RA patients compared with the general population is believed to be due to the chronic inflammatory state produced by the disease, thus those patients with the highest degree of disease activity are at the greatest risk of developing lymphoma.54 Finally, a French study of patients with multiple sclerosis reported a progressive elevation in overall risk of malignancy related to duration of exposure to azathioprine. Although these results did not quite reach statistical significance, they were suggestive of a dose–response relationship with no significant risk during the early years of treatment and a possible increased risk after 10 years of continuous therapy (OR = 4.4, 95% CI, 0.9–20.9).23
Evidence regarding the relationship between methotrexate exposure and oncogenesis in non-IBD patient populations is relatively scarce and inconsistent (Tables 1 and 2). A review of the psoriatic literature reveals conflicting results. One study involving 1380 psoriasis patients from 16 university medical centers across the United States found that patients who received high-dose methotrexate (≥4 years of exposure or a cumulative dose ≥3 g) had a 2-fold risk of SCC compared with patients who received low-dose or no methotrexate.25 A follow-up study by the same author reported that high-dose methotrexate patients also had an elevated risk of lymphoma compared with the general population, whereas those patients who received low-dose or no methotrexate were not at increased risk.14 In contrast, a Finnish study found no evidence of methotrexate-associated increases in the rates of SCC or lymphoma in patients with psoriasis during >77,000 person-years of follow-up.22
Examination of the rheumatological literature yields similarly mixed results. An Australian study of patients with RA involving 4145 person-years of follow-up reported a 50% excess risk of malignancy in methotrexate-treated patients compared with the general population, with a 5-fold increase in the risk of NHL and approximately 3-fold increases in the risks of lung cancer and melanoma.13 However, as this study did not include a control group of methotrexate-naive RA patients, it could not be determined how much of the excess malignancy risk was attributable to the drug itself. The authors of a 3-year prospective study of patients with RA in France found no excess risk of NHL in patients treated with methotrexate but did report a significantly increased risk of Hodgkin's lymphoma. Of note, 3 of the 18 cases of NHL observed in this study were EBV positive, as were 5 of the 7 cases of Hodgkin's lymphoma. Among the 8 patients whose lymphomas were treated with methotrexate withdrawal alone, 3 underwent spontaneous remission, supporting a causal role for methotrexate in the development of these malignancies.11 In contrast, several studies of American, Canadian, and Swedish RA patient populations, an American cohort of patients with juvenile idiopathic arthritis, and a multisite international cohort of patients with systemic lupus erythematosus found no evidence of a significant relationship between methotrexate exposure and risk of lymphoma or any other malignancies.4,5,7,12,18,21
TNF is a monocyte-derived cytokine that possesses both anti-oncogenic and pro-oncogenic properties. TNF can promote tumor necrosis by stimulating apoptosis, yet it is also capable of facilitating the survival and proliferation of neoplastic cells through induction of the nuclear factor κB cascade.61 Thus, the relationship between anti-TNF therapy and oncogenesis is unpredictable and incompletely understood. Numerous studies have examined the risk of malignancy associated with the use of anti-TNF agents in non-IBD patient populations (Tables 1 and 2). Although it appears that anti-TNF therapy has, at most, only a modest association with increased overall cancer risk in these patients, there is evidence to suggest a specific association with NMSC.
A meta-analysis of randomized placebo-controlled trials of infliximab and adalimumab in patients with RA reported an elevated rate of cancer overall (pooled OR = 3.3, 95% CI, 1.2–9.1) and identified a dose-dependent relationship between anti-TNF therapy and malignancy risk. The authors reported the number needed to harm was 154 (95% CI, 91–500) for an additional malignancy within a treatment period of 6 to 12 months.17 In contrast, several other meta-analyses and numerous observational studies involving patients with RA, juvenile idiopathic arthritis, and psoriasis have not shown evidence of a significantly increased overall risk of malignancy associated with anti-TNF therapy.1,2,6,8,10,15,16,18–20,62 As previously mentioned, patients with RA have an increased risk of lymphoma independent of medication exposure, but numerous studies have found that this risk does not appear to be significantly elevated further by the use of infliximab, etanercept, or adalimumab.1–6,8,10 The data from a recent study evaluating the influence of anti-TNF therapy on the incidence of cancer in patients with RA with a history of malignancy is also reassuring. The authors of this national prospective observational study used data from the British Society for Rheumatology Biologics Register to identify a cohort of patients with RA with previous malignancy and compared 177 of those patients treated with anti-TNF therapy with 177 patients receiving traditional disease-modifying antirheumatic drugs. The incident rate of malignancy in the anti-TNF cohort was 25.3 events per 1000 person-years compared with 38.3 events per 1000 person-years in the traditional disease-modifying antirheumatic drugs cohort, which translated into an adjusted incidence rate ratio of 0.58 (95% CI, 0.23–1.43) for the anti-TNF cohort compared with the disease-modifying antirheumatic drugs cohort.63
The evidence linking anti-TNF therapy to increased rates of NMSC is somewhat more consistent, although not definitive. Two large meta-analyses, one involving only patients with RA and another that included patients with any condition treated with anti-TNF agents, reported statistically significant relative risks of NMSC in anti-TNF–exposed patients of 1.45 (95% CI, 1.15–1.76) and 2.02 (95% CI, 1.11–3.95), respectively.1,15 A population-based study conducted by Chakravarty et al21 reported that patients with RA treated with either an anti-TNF agent or methotrexate alone had a slightly increased risk of NMSC that did not reach statistical significance, but when any anti-TNF agent was used in combination with methotrexate, the HR for developing NMSC became statistically significant at 1.97 (95% CI, 1.51–2.58). The excess risk of SCC associated with anti-TNF therapy may be greater than that of BCC: one phase 3 clinical trial investigating the safety and efficacy of etanercept in patients with psoriasis noted that while patients treated with etanercept had no elevated risk of BCC (SIR = 0.69, 95% CI, 0.28–1.42 compared with the general population of Arizona), the incidence of SCC was increased almost 4-fold compared with the general population of Minnesota (SIR = 3.91, 95% CI, 1.07–10.01), although it was still less than that of the general population of Arizona (SIR = 1.59, 95% CI, 0.43–4.08). This suggests that even if anti-TNF therapy does increase the risk of SCC in patients with psoriasis to some degree, their absolute risk of SCC still remains lower than that of anti-TNF–naive subjects who live in environments with high levels of UV radiation.62 Unfortunately, the majority of patients included in all of these studies have a history of prior or concurrent exposure to other classes of immunosuppressive medications, and little data are available regarding the underlying risk of NMSC in these patient populations independent of medication exposure. Thus, it is impossible to definitively conclude whether the increased risk of NMSC observed with anti-TNF therapy is the result of the medications themselves, the chronic state of increased inflammatory activity from the underlying diseases, or a combination of both.
Natalizumab is a relatively new biological immunomodulator approved for use in the treatment of multiple sclerosis and CD. It is a humanized monoclonal antibody that targets α4-integrin and inhibits leukocyte migration into inflamed tissues. As of June 2009, 2 cases of primary central nervous system lymphoma and 1 case of BCC had been reported over the course of approximately 63,900 person-years of natalizumab exposure, consistent with the expected background rate in the general population.64,65 Thus far, postmarketing experience has not revealed any evidence of increased risk of lymphoproliferative disorders or other malignancies associated with the drug.
Do Patients with IBD Have an Increased Risk of Cancer Independent of Therapy?
It is challenging to assess the baseline risk of malignancy in patients with IBD because the majority of studies addressing this subject involve patients who have a history of exposure to at least one class of immunosuppressants, making it difficult to separate disease effects from medication effects. It is well known that CD and UC are associated with increased risks of gastrointestinal malignancies, including colorectal carcinoma (particularly in UC), cancers involving the hepatobiliary system, and carcinoma of the small intestine (CD only).66 The baseline risk of other extraintestinal solid tumors and hematologic malignancies in patients with IBD is less clear.
A recent meta-analysis of population-based cohort studies assessing the risk of extraintestinal cancer in IBD by Pedersen et al found that, compared with the general population, patients with CD had increased risks of SCC (SIR = 2.35, 95% CI, 1.43–3.86), and cancers of the stomach (SIR = 2.05, 95% CI, 1.06–3.97), lung (SIR = 1.82, 95% CI, 1.18–2.81), and urinary bladder (SIR = 2.03, 95% CI, 1.14–3.63). A borderline significant increase in the risk of lymphoma (SIR = 1.42, 95% CI, 0.95–2.12) among patients with CD was also noted. Patients with UC, on the other hand, were found to have an increased incidence of leukemia (SIR = 2.00, 95% CI, 1.31–3.06), whereas their risk of pulmonary cancer was significantly lower than that of the general population (SIR = 0.39, 95% CI, 0.20–0.74).67 It is likely that the differences in the rates of pulmonary, bladder, and skin cancers observed between the 2 groups are largely attributable to differences in smoking habits between the patient populations, although it is impossible to rule out medication-related and disease-related effects.
The increased risk of hematologic malignancies in IBD reported by Pedersen et al is supported by evidence from a Swedish population-based cohort study of 47,679 patients with CD or UC, which found a significantly increased risk of myeloid leukemia in UC (SIR = 1.8, 95% CI, 1.2–2.6) and a borderline significant increase in the risk of lymphoma in patients with CD (SIR = 1.3, 95% CI, 1.0–1.6). The risk of lymphoma in patients with CD was not correlated with proxy markers of disease activity and appeared to be confined to the first few years of follow-up, with little evidence of a long-term increase in risk.68 A large population-based study of patients with IBD in Manitoba found that, compared with a matched non-IBD cohort, male patients with CD had an increased risk of lymphoma (incidence rate ratio [IRR] = 3.63, 95% CI, 1.53–8.62), which did not appear to be related to immunomodulator use.66 Not all studies are in agreement, however; Herrinton et al30 reported that patients with IBD observed for nearly 6 years without a recorded dispensing of thiopurine or anti-TNF were not at increased risk of lymphoma (SIR = 1.0, 95% CI, 0.96–1.1) relative to the general Kaiser Permanente population. Similarly, a population-based study by Lewis et al34 involving 6605 patients with CD and 10,391 patients with UC in the United Kingdom found no significantly increased risk of lymphoma associated with either disease.
With regard to nonhematologic extraintestinal malignancies, the available data are relatively scarce and inconsistent. While Pedersen et al67 reported an increased risk of SCC in patients with CD, Singh et al found no evidence of an elevated risk of SCC in patients with CD or UC in a cohort of 9618 patients with IBD. However, the authors did report an increased risk of BCC in male patients with CD who had never been exposed to immunosuppressants (HR = 1.68, 95% CI, 1.21–2.34), with no evidence of an increased risk of BCC in female patients with CD or patients of either gender with UC.40 Finally, there is some evidence to suggest an increased risk of abnormal cervical cytology in women with IBD, but this remains controversial43,45,46 (see Medication-associated Malignancies in IBD: Extraintestinal Solid Tumors section). Independent of medication exposure, no other types of nonhematologic extraintestinal malignancies appear to be more prevalent in patients with IBD compared with the general population based on the currently available evidence.
Medication-associated Malignancies in IBD
While the overall risk of malignancy does not appear to be significantly elevated in patients with IBD regardless of medication exposure (Table 4),31,33,35,37,44,47 the risks of several types of site-specific cancers do appear to be increased by certain IBD therapies (Tables 3 and 4). There is evidence to suggest that the risk of certain types of lymphoma and skin cancer may be elevated in patients who receive thiopurine or anti-TNF therapy, particularly when used in combination. Rates of abnormal cervical cytology in women with IBD may also be increased by exposure to immunosuppressive therapy. Currently, there is little evidence to suggest an association between IBD therapies and any other types of hematologic malignancies or extraintestinal solid tumors.
There are a relatively large number of studies examining the relationship between thiopurine exposure and the risk of hematologic malignancies in patients with IBD (Table 3). Many of these were based out of single medical centers, making them prone to referral bias and limiting their generalizability.35–37,48,49,69–71 For the purposes of this review, we will focus primarily on the population-based studies and meta-analyses that address this topic.
To date, there have been 5 population-based studies examining the risk of lymphoproliferative disorders in patients with IBD exposed to thiopurines. The earliest of these, conducted by Lewis et al, was a retrospective cohort study using the General Practice Research Database and included 6605 patients with CD and 10,391 patients with UC followed for an average of 4 years. Among the 1465 patients with IBD who were exposed to thiopurines, only one case of Hodgkin's lymphoma was identified, which occurred in a patient with UC who had received azathioprine 10 months earlier.34 Nine years later, Armstrong et al used the same database to perform a nested case–control study of patients with IBD comparing azathioprine use among patients with diagnosed malignancies and those without any known cancer. Patients who had ever used azathioprine were found to have a >3-fold increase in risk of lymphoma compared with azathioprine-naive IBD patients.31 Beaugerie et al conducted a prospective observational cohort study of 19,486 patients with IBD followed for 49,713 person-years and identified a total of 23 cases of lymphoma (22 cases of NHL and 1 case of Hodgkin's lymphoma), 17 of which occurred in patients with past or current thiopurine exposure. This translated into a multivariate-adjusted HR of 5.28 (95% CI, 2.01–13.9) for patients currently using thiopurines compared with thiopurine-naive patients. Patients who had discontinued their use of thiopurines had no significant increase in lymphoma risk compared with thiopurine-naive patients.32 Similarly, the 2 most recent population-based studies reported that, compared with the general population, patients with IBD currently taking thiopurines had an elevated incidence of lymphoproliferative disorders, whereas exposed patients who had discontinued use of thiopurines did not.29,30
Two meta-analyses have addressed the risk of lymphoma among patients with IBD treated with thiopurines. Kandiel et al analyzed 6 cohort studies and obtained a pooled SIR of 4.18 (95% CI, 2.07–7.51) for lymphoma. Three of the 6 studies provided sufficient data to directly compare thiopurine-exposed and thiopurine-naive IBD patients, yielding a combined relative risk of 2.92 (95% CI, 1.05–8.13) for lymphoma associated with thiopurine exposure.28 The second meta-analysis found no significant increase in the risk of lymphoma in patients with IBD exposed to immunosuppressants (thiopurines, methotrexate, cyclosporine, or tacrolimus); however, the authors were unable to stratify risk by medication type. Furthermore, 6 of the 9 studies included in this meta-analysis lacked control groups of patients with IBD not exposed to immunosuppressants. In the analysis of these 6 studies, the authors used a population of patients with IBD in Canada with a low rate of immunosuppressant exposure (8%) as a substitute control group, which raises some question regarding the validity of their results.27
Several studies have specifically addressed the association between EBV-positive lymphomas and thiopurine exposure in patients with IBD. Dayharsh et al evaluated all patients with IBD at the Mayo Clinic Rochester who developed lymphoma between 1985 and 2000 and determined the EBV status of each case of lymphoma. Six of the 18 identified lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine, and 5 of those 6 were EBV positive (compared with only 2 of the 12 lymphomas that occurred in patients not treated with thiopurines).72 The aforementioned population-based study by Beaugerie et al32 also found that the majority of lymphoproliferative disorders observed in patients with IBD receiving thiopurines were EBV positive, whereas only a small minority of the lymphoproliferative disorders occurring in patients who had discontinued or never received thiopurine therapy were associated with EBV. Similarly, a recent Dutch study identified 44 cases of lymphoma among 17,384 patients with IBD, and of the 33 lymphomas for which EBV status could be determined, 11 of 12 EBV-positive lymphomas occurred in patients treated with combination thiopurines, 5-aminosalicylates, and prednisone, whereas only 4 of 21 EBV-negative lymphomas occurred in patients not receiving thiopurines. No cases of lymphoma were observed in patients receiving anti-TNF therapy.73
Extremely little data are currently available regarding the risk of hematologic malignancy in patients with IBD exposed to methotrexate. One Irish single-center study conducted by Farrell et al identified 4 cases of NHL in a cohort of 238 patients with IBD receiving immunosuppressants. Two of the 4 cases occurred in methotrexate-exposed patients, 1 of whom was also treated with cyclosporine. The risk of NHL in the immunosuppressed cohort was significantly elevated compared with the general population (SIR = 59, P = 0.0001), but the risk was not stratified by medication type, and the power of this outlier study was limited by small sample size.36
Currently, there are 3 anti-TNF agents approved for use in IBD: infliximab, adalimumab, and certolizumab pegol. Assessing the relationship between malignancy and anti-TNF therapy itself in IBD is difficult because very few patients have been treated with anti-TNF therapy without current or prior exposure to immunomodulators. To date, 2 meta-analyses have addressed the risk of anti-TNF–associated malignancy in IBD. Peyrin-Biroulet et al analyzed the evidence pertaining to the safety and efficacy of anti-TNF therapy for patients with CD from 21 placebo-controlled trials, which included a total of 3341 patients in the anti-TNF groups. There was no difference in the frequency of malignancies between the anti-TNF and control groups, although lymphoma was not assessed separately. Of note, a total of only 16 malignancies were identified in the anti-TNF and control groups combined, and the median duration of follow-up was only 24 weeks.39 A meta-analysis by Siegel et al examined the risk of NHL in adult patients with CD exposed to anti-TNF therapy and included a total of 8905 patients with 21,178 patient-years of follow-up from 26 studies. Thirteen cases of NHL were reported among anti-TNF–exposed patients (6.1 per 10,000 patient-years), the majority of whom had previously been exposed to immunomodulators. Compared with the general population, patients treated with anti-TNF had a >3-fold risk of NHL, but they were not found to be at significantly increased risk compared with a group of patients with CD treated with immunomodulators alone (SIR = 1.7, 95% CI, 0.5–7.1).26
Herrinton et al used the Kaiser Permanente IBD Registry to assess the lymphoma risk in relation to medication use. Among 16,023 patients with IBD followed for an average of 5.8 years, there were 43 cases of lymphoma, 5 of which occurred in patients exposed to anti-TNF agents. Compared with the general Kaiser Permanente population, while the risk of lymphoma was elevated among users of thiopurines alone (SIR = 1.4, 95% CI, 1.2–1.7 for current use; SIR = 0.3, 95% CI, 0.2–0.4 for past use), exposure to anti-TNF therapy was even more strongly associated with lymphoma risk (SIR = 4.4, 95% CI, 3.4–5.4 for current use; SIR = 5.5, 95% CI, 4.5–6.6 for past use). However, as the majority of patients treated with anti-TNF therapy had previous or concurrent exposure to thiopurines, it could not be determined how much of this elevation in risk was attributable to anti-TNF therapy alone.30 No hematologic malignancies were observed within a cohort of 651 Danish patients with IBD treated with infliximab during 1999 to 2005,33 and within a French matched-pair cohort of patients with CD, the only hematologic malignancies observed among 404 infliximab-treated patients were 1 case of Hodgkin's lymphoma and 1 case of leukemia.47 Taken as a whole, this evidence suggests that the risk of hematologic malignancies in patients with IBD is likely increased by anti-TNF therapy to some degree, particularly when used in combination with immunomodulators, but the absolute rate remains quite low.
Hepatosplenic T-cell Lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is a rare, aggressive, and almost universally fatal extranodal lymphoma that primarily affects males aged 35 years and younger. Between 1996 and 2011, 36 cases of HSTCL occurring in patients with IBD were reported, the majority of which occurred in male patients with CD. Sixteen of those patients had received thiopurine monotherapy, whereas the remaining 20 patients received combination therapy with thiopurines and anti-TNF agents (all 20 had been exposed to infliximab, 4 had also received adalimumab, and 1 had received adalimumab and natalizumab).74 The authors estimated the absolute risk of HSTCL in all patients receiving thiopurines to be roughly 1:45,000 while the estimated risk for men younger than 35 years was 1:7404. The absolute risk of HSTCL for all patients receiving concomitant thiopurine and anti-TNF therapy has been estimated to be slightly <1:22,000, and the estimated risk for men younger than 35 years on combination therapy is approximately 1:3534.74,75 These estimates are helpful; however, significant educated guesses had to be made regarding the denominator of “at-risk” patient populations.
Extraintestinal Solid Tumors
There is substantial evidence supporting an association between thiopurine exposure and an increased risk of NMSC in patients with IBD. In a nested case–control study evaluating the effects of different medication exposures on NMSC within a cohort of 53,377 patients with IBD, Long et al42 reported that patients with persistent exposure to thiopurines (≥365 days) had a >4-fold elevation in their risk of NMSC compared with patients with IBD not taking immunosuppressants, and even patients with only recent thiopurine use (≤90 days) were at significantly increased risk (OR = 3.56, 95% CI, 2.81–4.50). A French prospective observational cohort study including 19,486 patients with IBD found that while patients never exposed to thiopurine therapy had no increased risk of NMSC compared with the general population (SIR = 0.73, 95% CI, 0.24–1.72), both current and past thiopurine exposure were associated with significant increases in the risk of NMSC (HR = 5.9, 95% CI, 2.1–16.6 and HR = 4.1, 95% CI, 1.3–13.3, respectively).76 The excess risk of SCC associated with thiopurine use in patients with IBD may be much greater than that of BCC. Singh et al40 reported a >5-fold elevation in risk of SCC associated with thiopurine use in patients with IBD, whereas the risk of BCC did not appear to be significantly increased by thiopurine exposure.
Anti-TNF therapy may also be associated with an increased risk of NMSC in patients with IBD, particularly when used in combination with immunosuppressants. In the same nested case–control study conducted by Long et al, patients with CD who had either recent (≤90 days) or persistent exposure (≥365 days) to adalimumab or infliximab had a >2-fold risk of NSMC compared with those receiving no medications. This excess risk was further increased when anti-TNF agents were used in combination with immunosuppressants (thiopurines, calcineurin inhibitors, mycophenolate mofetil, or methotrexate); patients with CD with persistent exposure to combined immunomodulator and anti-TNF therapy had an almost 7-fold risk of NMSC compared with those receiving no medications, and those who had only recent exposure to combination therapy with these agents had a nearly 6-fold increase in their risk of NMSC.42 Because of overlapping diagnostic codes, this study was not able to distinguish between SCC and BCC. Another limitation of the study was that the majority of patients in the anti-TNF subgroup had previously been exposed to other nonbiological immunomodulators, which the authors attempted to address through a backward elimination strategy using a change in estimate approach.
Finally, the use of methotrexate alone does not appear to significantly increase the risk of NMSC in patients with IBD. Singh et al reported that methotrexate exposure did not increase the risk of NMSC in patients with CD or UC compared with methotrexate-naive non-IBD controls, although the authors acknowledged that their analysis of methotrexate effect was limited by the small sample size of the subgroup of patients exposed to the drug (n = 350).40 This finding was consistent with the results of a larger population-based study that reported no increased risk of NMSC associated with methotrexate use in patients with CD.42
Interestingly, Farrell et al reported a significantly increased incidence of melanoma (SIR 21.9, P = 0.0001) in patients with IBD exposed to immunosuppressants (azathioprine, methotrexate, and/or cyclosporin) compared with the general population. However, this was based on only one observed case of melanoma in a small cohort (n = 238) of immunosuppressant-exposed patients.36 A much larger and more recent retrospective cohort and nested case–control study that included 108,518 patients with IBD found a significantly increased incidence of melanoma in patients with IBD overall compared with a non-IBD cohort (IRR = 1.29, 95% CI, 1.09–1.53), with significantly increased risk for CD (IRR = 1.45, 95% CI 1.13–1.85) but not for UC (IRR = 1.13, 95% CI 0.89–1.42). When Cox proportional hazards modeling was used to adjust for health care utilization and comorbidities (but not medication exposure), the risk was no longer significantly elevated in the overall IBD population compared with non-IBD patients (adjusted HR = 1.15, 95% CI, 0.97–1.36), but a borderline increased risk remained for patients with CD (adjusted HR = 1.28, 95% CI, 1.00–1.64). In the overall IBD population, use of any anti-TNF medication was associated with melanoma (adjusted OR = 1.88, 95% CI, 1.08–3.29), whereas there was no significant association with thiopurine or 5-aminosalicylate use.38
Abnormalities of the uterine cervix
Whether immunosuppressive therapy is associated with an elevated rate of abnormal cervical cytology in female patients with IBD remains controversial. Thus far, only 3 studies have specifically addressed this question. One retrospective matched case–control cohort study involving 116 patients with UC or CD demonstrated that women with IBD were more likely to have abnormal Pap smears compared with non-IBD controls (18% versus 5%, P = 0.004), but no significant associations between cervical abnormalities and the use of medications (thiopurines, corticosteroids, 5-aminosalicylates, or infliximab) were identified.46 A later study by Kane et al confirmed the finding that women with IBD were more likely to have abnormal Pap smears compared with non-IBD controls (42.5% versus 7%, P < 0.001) and also found that women with IBD were more likely to have higher-grade lesions than controls (OR = 3.1, P < 0.001). However, in contrast to the previous study, the authors reported that women exposed to immunomodulators (prednisone, thiopurine, and/or infliximab) for at least 6 months had an almost 2-fold increase in their risk of having an abnormal Pap smear compared with nonexposed women with IBD. Higher-risk abnormalities were also more likely in immunomodulator-exposed patients compared with nonexposed women with IBD (OR = 6.5, 95% CI, 1.43–30.1), and all the higher-risk lesions were found to be HPV positive.45 The third study, a population-based, nested case–control study that was conducted in Manitoba and included 525 women with IBD, found that women with UC had no increased risk of cervical abnormalities compared with healthy controls. Women with CD were only at increased risk if they received 10 or more prescriptions for oral contraceptives over the 5 years preceding the cervical abnormality. Neither immunomodulators (thiopurines or methotrexate) nor corticosteroids alone were associated with an increased risk of cervical abnormalities, but women exposed to both immunomodulators and corticosteroids (not necessarily concurrently) during the 5 years leading up to the study did have a significantly increased risk (OR = 1.41, 95% CI, 1.09–1.81) compared with nonexposed controls.43
All 3 of these studies had significant limitations, making it difficult to draw any definitive conclusions about either the baseline risk of abnormal cervical cytology in women with IBD or potential therapy-related effects. The first 2 studies were conducted at single tertiary care centers, creating the potential for referral bias and limiting their generalizability. Both collected some information retrospectively through subject interviews, creating potential recall bias. Neither studies took into account the duration of the follow-up period or differences in frequency of Pap smears between patients with IBD and controls, which could have resulted in detection bias because women with longer follow-up and/or more frequent cervical cancer screening have a higher likelihood of having an abnormal Pap smear.45,46 The third study, on the other hand, did not directly control for lifestyle or reproductive factors, such as smoking, parity, and sexual factors. It also lacked data about the incidence of HPV infections, making it impossible to explore the relationship between immunosuppressants and HPV infection in cervical carcinogenesis.43 Clearly, further studies are needed before we can assess the relationship between IBD, abnormal cervical cytology, and medication effects with any degree of confidence.
Some studies showed an increased risk of gastrointestinal cancers, specifically colon, rectal, and anal cancers (Table 4). However, in these studies, the comparison group was the general population, and we know that these types of gastrointestinal malignancies occur more often in patients with IBD due to their persistent inflammatory burden. Therefore, it is not clear if immune suppression has any association with increasing risk of gastrointestinal malignancies. In the non-IBD patients, the risk of gastrointestinal malignancy is not elevated (Table 2), supporting the argument that the gastrointestinal malignancies in patients with IBD are disease, not treatment, related.
Although immunomodulators (thiopurines and methotrexate) and biological agents (anti-TNF agents and natalizumab) can be very effective for the treatment of IBD, there is mounting concern among patients and clinicians that these therapies may cause cancer. Immunosuppressive therapy has the potential to facilitate oncogenesis through decreased immunosurveillance of both oncogenic viruses and emerging cancers and through direct oncogenic effects of the immunosuppressive medications themselves. Evaluating the risk of malignancy associated with the therapies currently used in IBD is challenging, in large part because most patients included in the studies addressing this topic have a history of exposure to multiple classes of medications. This not only makes it difficult to assess the baseline risk of malignancies in patients with IBD independent of therapy but also limits our ability to separate out the effects of individual drugs. It is well known that patients with IBD are at increased risk of certain types of gastrointestinal malignancies independent of medication exposure, so in this review, we have focused primarily on the question of whether IBD therapies are associated with increased risks of hematologic malignancies and extraintestinal solid tumors.
With regard to hematologic malignancies, there is some evidence that at baseline, UC may be associated with a slightly increased risk of myeloid leukemia,67,68 and although the majority of literature does not support an elevated risk of lymphoma in IBD, several studies suggest that patients with CD, particularly males, may have a small elevation in their lymphoma risk independent of therapy.66–68 It is now clear that ongoing thiopurine exposure is associated with an elevated risk of lymphoma in patients with IBD.28–30,32,66 Many of these lymphomas are EBV positive,32,72,73 suggesting that decreased immunosurveillance of the virus plays a central role in their pathogenesis. Combination immunomodulator and anti-TNF therapy appears to increase the risk of NHL in patients with CD, but the absolute incidence remains low (estimated to be 6.1 per 10,000 patient-years by one meta-analysis).26 Male patients younger than 35 years appear to be at particular risk of HSTCL, especially when exposed to combination immunomodulator and anti-TNF therapy, but again, the estimated absolute risk is extremely low (1:3534).74 Whether or not the risk of leukemia in IBD is increased by medication exposure remains unclear.
Regarding extraintestinal solid tumors, there is substantial evidence supporting an association between NMSC, particularly SCC, with both current and past exposure to thiopurines.38,40,42,76 This persistent risk appears to be largely attributable to direct oncogenic effects of these drugs: it has been established that thiopurine metabolites interact synergistically with UV-A radiation to induce DNA damage in keratinocytes,55 and it appears that azathioprine also reduces the repair of these UV-induced mutations.56 Combination therapy with immunomodulators and anti-TNF agents also increases the risk of NMSC in IBD,42 but the effect of anti-TNF monotherapy on this risk is not yet clear. Anti-TNF therapy has recently been linked to increased rates of melanoma in patients with IBD.38 Finally, the risk of abnormal cervical cytology in women with IBD may be increased by immunosuppressive therapy, but this remains controversial.43,45,46
The relationships between methotrexate, natalizumab, and malignancy in IBD have not been adequately studied. There is some evidence from the psoriatic literature that high-dose methotrexate exposure may increase the risk of SCC and lymphoma.14,25 Studies involving patients with RA treated with methotrexate have also suggested an association with EBV-positive lymphoma.11,13 There is a clear need for future studies specifically designed to assess the risk of methotrexate-associated malignancy in patients with IBD. Similarly, although postmarketing surveillance has not revealed any evidence to suggest that natalizumab is associated with a risk of malignancy in any patient population, there have not yet been any studies conducted specifically assessing the effect of natalizumab on malignancy rates in IBD.
In conclusion, although there is substantial evidence that IBD therapies increase the risk of certain malignancies in patients with UC and CD, particularly lymphoma, HSTCL, and NMSC, the absolute rates of these malignancies remain low. Patients and clinicians should weigh these risks carefully against the significant potential benefits offered by these medications. Further studies designed to specifically assess the risk of cancer associated with use of methotrexate, anti-TNF monotherapy, and natalizumab in IBD are clearly needed to further facilitate better-informed treatment decisions.9,24,41
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Keywords:© Crohn's & Colitis Foundation of America, Inc.
inflammatory bowel disease; thiopurine; methotrexate; anti–tumor necrosis factor; malignancy