Anti-TNF drugs for the treatment of CD appear to be associated with an increased risk of NHL. Although the increased risk is statistically significant when compared with the general population, the absolute risk remains small (6.1 per 10,000 patient-years). When compared with CD patients taking immunomodulators alone, there is a nonstatistically significant increased rate of NHL for those exposed to anti-TNF agents.
The baseline risk of NHL increases with age and is male-predominant.41
Therefore, when communicating the NHL risk to patients, conversations should be tailored for individuals. Although the SEER age categories are still fairly broad, it is possible to discuss more specific observed and expected rates for patients, depending on their age and gender, as opposed to our overall summary estimate.
We excluded the 2 studies with a greater than 15% dropout rate for the sensitivity analysis because we were concerned that these studies might not accurately represent the risk of lymphoma in their patient populations. Despite the fact that 6 of the observed lymphomas were then excluded, the disproportionate contribution of patient-years from the TREAT registry7
dramatically decreased the denominator, thereby increasing the NHL rate across all groups. Although statistical significance was only reached for one age category (men ages 55–64 had an SIR of 16.8), there is a dramatic increase in the absolute rate and SIR as patients get older. Because of infrequent anti-TNF use in older patients in the included studies, our analysis might be underpowered to detect a statistically significant difference in those older than 65 years.
Subgroup analyses were performed to determine whether the risk of lymphoma changed across different study designs. Patients in RCTs probably do not characterize the average patient receiving anti-TNF agents (ie, patients in early clinical trials might be sicker than those who received the medication after Food and Drug Administration approval), but they might correspond to a group at a higher risk of disease and treatment-related complications. On the other hand, clinical trials oftentimes exclude those with significant comorbidities, so it is unclear which direction the bias might favor. The case series might be more representative of patients treated with anti-TNF agents in clinical practice and embody a broad range of patients worldwide who have been treated in more diverse treatment settings. This subgroup had the highest rate of lymphoma, 18.8 per 10000 patient-years, which is nearly 2 per 1000 or 1 per 500 patient-years. This high rate was mostly driven by the study by Ljung et al,16
which had 3 cases in only 202 patient-years. This study is the outlier in contributing significantly to the heterogeneity among the included studies. Although the SIR for the case series is statistically significant, it is with wide CIs based on the relatively small sample.
These results contribute to the growing body of knowledge about the risk of NHL in patients with CD, but some confounding might be present. The disease itself does not appear to carry an increased risk of lymphoma,9,10
although this is controversial.42
It is important to note that almost all of the NHL patients had current or prior exposure to 6MP or azathioprine. Therefore, our rates of NHL are really reported rates of exposure to a combination of anti-TNF and immunomodulator therapy. Although numerically higher, this combination rate is not statistically higher than the Kandiel immunomodulator rate. This begs the question whether the major contributors to the increased risk are the immunomodulators or anti-TNF drugs. Patients in the study by Kandiel et al11
overall had a longer period of follow-up than those included in the 26 studies for this analysis. Although we do not know whether NHL risk accumulates over time, it is possible that our estimate for immunomodulator alone is an overestimate of what the 1-year incidence would be. However, a recent large French analysis of the lymphoma rate with immunomodulator exposure (but very little anti-TNF exposure) corroborates the possibility that immunomodulators are significantly contributing to the risk.43
On the basis of our analysis we cannot comment on the NHL risk associated with anti-TNF monotherapy. There simply have not been enough patients treated with anti-TNFs without immunomodulators to make any meaningful conclusions. Another possibility for confounding is radiation exposure. CD patients are potentially exposed to harmful levels of diagnostic radiation from repeated radiographic imaging,44
which might be associated with an increased risk of lymphoma.45
We were not able to ascertain the amount of radiation exposure in this analysis.
The most important limitation to this study is the lack of an ideal comparison group. Because the most common study design for anti-TNF agents includes an initial induction phase in which all patients receive active treatment, the control arms in the RCTs are not true placebo groups. A recent analysis compared adverse events between active and control arms in these anti-TNF RCTs and did not find a difference in lymphoma rates,46
but because of the above reason we do not believe that this was an adequate comparison to anti-TNF unexposed patients. The case series did not have controls by design, and although the cohort studies did have matched controls, the selective nature of patient enrollment is concerning. Although suboptimal, we chose SEER as a comparator on the basis of the knowledge that the largest study of lymphoma risk in CD patients did not show an increased baseline risk when compared with the general population.10
Because SEER is a US database and the included studies are international, we explored the variation of NHL rates worldwide. Although there is significant variation in the incidence of Hodgkin's lymphoma, the rate of NHL across continents is similar.47
Therefore, we believe that SEER is a reasonable representation for comparison.
The time horizon of 1 year was used to give enough time for adverse outcomes to develop, but we do not know whether the lymphoma risk will continue (or accumulate) as time progresses. Dosing data are incomplete, and the question of how much exposure is needed to increase the risk of lymphoma remains unanswered, but it is concerning that at least 4 of the patients had received only 1 infusion of an anti-TNF agent. This might mean that even 1 dose is enough to increase the lymphoma risk, or alternatively, it might raise questions about the biologic plausibility of these cases being attributed to a single episode of exposure.
We did not calculate quality scores for the included articles. Because our primary outcome was an objective event (eg, lymphoma), we did not believe that classic measures of quality such as blinded outcome assessment would have an impact on reporting. In addition, because we did not use the comparison groups from the studies, details of the randomization process seemed less relevant. Concerns regarding attrition were investigated by the sensitivity analysis, and although sampling bias related concerns regarding generalizability remain, the inclusion of multiple study designs might attenuate these problems. A formal analysis of publication bias was not performed because we believed that plotting a “treatment effect” against sample size was not practically relevant to our analysis of rare adverse events. However, we did have a range of included studies, with the smallest study having 13.3 patient-years and the largest having 10,796 patient-years. The smallest study that identified a case of lymphoma included 67.4 patient-years.
Patients, parents of patients, and physicians are concerned about the risk of lymphoma and have different thresholds for how much risk they are willing to accept.48–50
These results will help us understand the risk of NHL associated with anti-TNF and immunomodulator therapy and facilitate decisions about when it is most appropriate to use these agents. Although these estimates are a helpful step in determining treatment risks, further prospective data are necessary for a more accurate assessment. Large inception cohorts of patients with CD are being developed, and it will be critical to build monitoring of drug side effects into these programs.