We found an increased incidence of malignancy among children with JIA when compared to children without JIA. Our results are comparable to those of some, but not all, prior studies. A recently published study by Simard, et al
used extensive linkage of Swedish national registers to estimate the relative risk of incident malignancy associated with JIA versus a matched general population comparator cohort (22
). The authors reported that among all 5,296 children diagnosed with JIA since 1987, there was an adjusted relative risk of overall malignancy of 2.3 (1.2–4.4). The authors of this study could not examine medication exposures in a detailed fashion. However, when follow-up was censored in 1999 (to coincide with the introduction of TNF inhibitor therapy) the results were similar, which implies that the observed increased malignancy rate cannot be solely attributed to TNF inhibitor therapy. Using a database of commercial insurance claims from the United States, Harrison, et al
preliminarily reported a hazard ratio of 2.8 (0.9–8.3) for overall malignancy among 3,605 children diagnosed with JIA who had not been exposed to TNF inhibitors or other biologics compared to matched children without JIA (28
). Hence, both of these studies using different data sources reported results similar to those of our study. In contrast, Bernatsky, et al
estimated a SIR of 0.12 (0.0–0.70) for overall malignancy among 1,834 children diagnosed with JIA at 3 major Canadian pediatric rheumatology centers versus expected rates generated from tumor registries (21
). The explanation for this different result is unclear. Prior to these recent studies, Thomas, et al
reported no increased rate of overall malignancy among children in Scotland diagnosed with juvenile chronic arthritis, though this study was limited to 896 children with resultant wide confidence intervals surrounding the estimates (29
Thus, most but not all studies addressing this question have identified an increased risk of malignancy in children with JIA. There are several plausible reasons to believe that JIA may be associated with an increased risk of malignancy. First, there is precedence in that RA is associated with an increased risk of malignancy, particularly lymphoma (15
). Medications that are used to treat JIA suppress the immune system, which would be expected to potentially increase the risk of selected malignancies, though we also found an increased rate of malignancies among children not treated with systemic immunosuppression. On the other hand, it is possible that children with JIA undergo more careful screening for cancer and that the observed association is due to a detection bias. However, given that few childhood cancers remain undiagnosed for extended periods of time, this seems a less plausible explanation. Finally, because malignancy, in particular acute leukemia, may initially be mistakenly clinically diagnosed as JIA (30
), the potential for misclassification bias exists. We attempted to decrease the possibility of misclassification by requiring a 6 month lag period between the first disease ICD-9 code and the start of follow-up observation. Nevertheless, some misdiagnoses may have occurred.
Among 1,484 children with JIA with 2,922 person-years of observation following exposure to TNF inhibitors, we did not find a strong association between TNF inhibitors and malignancy and we did not identify any cases of lymphoma. When we restricted our outcome definition to probable and highly probable incident malignancies, there were no malignancies identified following exposure to TNF inhibitors. The FDA’s study of TNF inhibitors did not report disease-specific malignancy rates based on the indication for TNF inhibitor therapy (11
). However, the authors did report drug-specific malignancy rates, and treatment with etanercept in clinical practice can be assumed to have been largely for children diagnosed with JIA. Among all children exposed to etanercept in the United States, the authors reported no increased rate of overall malignancy (6 malignancies identified) but an approximate 5-fold increase in the rate of lymphoma (3 lymphomas identified). Harrison, et al
combined preliminary data from 3 prospective JIA biologics registries and estimated a SIR for overall malignancy of 3.7 (0.5–13.4) for children with JIA exposed to etanercept compared to the general population of children without JIA (32
). This SIR is similar to the estimate that we and others have found among all JIA patients irrespective of treatment compared to children without JIA and does not suggest a strong association between TNF inhibitor therapy and malignancy.
Our study had limitations common to observational studies of administrative claims data. We did not have access to medical records. Accordingly, we could not directly verify the diagnoses of JIA or malignancy. However, we required 2 or more JIA ICD-9 codes separated in time, a methodology that has been commonly used in studies of adult RA (33
). Furthermore, concurrent treatment with MTX or TNF inhibitors in the setting of physician ICD-9 codes for JIA can be expected to be reasonably specific for this diagnosis. Some individuals with remote past exposures to MTX or TNF inhibitors prior to their appearance in MAX data may have been misclassified as not being exposed. To ascertain the certainty of incident malignancy and perform sensitivity analyses of the outcome, comprehensive review of the entire claims history was performed by two expert clinicians. Our estimates of probable and highly probable incident malignancy rates for the comparator cohorts of children without JIA approximated those reported in the SEER data, suggesting reasonable accuracy for true incident malignancy. We could not directly estimate or adjust for JIA disease activity or severity. Therefore, medication channeling by prescribers with resultant confounding between TNF inhibitor use and malignancy is possible (i.e., “sicker” patients received TNF inhibitors and were also more likely to develop malignancy). This confounding, if present, would have strengthened the association between TNF inhibitors and malignancy and we did not observe a strong association in our study. The time window of potential increased risk of malignancy following initiation or cessation of MTX or TNF inhibitors is not known. Accordingly, we simply classified children as “ever exposed” to these medications. Though a conservative approach, this assumption may potentially result in an underestimate of the malignancy rate if the true risk of malignancy returns to baseline quickly after cessation of treatment. However, the majority of children in the MTX without TNF inhibitor and any TNF inhibitor medication exposure groups continued their therapies and had a corresponding outpatient pharmacy claim within 60 days of the end of their study follow-up (58% for MTX and 50% for TNF inhibitors). The mean duration of study follow-up following known exposure to TNF inhibitors was 24 months. This duration of follow-up may be insufficient to capture the long-term or cumulative effects of TNF inhibitors. Finally, despite using the largest available claims database in the United States, our sample size still resulted in relatively wide confidence intervals, indicative of the rarity of incident malignancy in childhood.
It is not known how enrollment in Medicaid may affect the incidence of malignancy or the treatment of JIA. Nevertheless, all children in this study were enrolled in Medicaid and therefore low socioeconomic status cannot be a potential confounder in the determination of relative rates of malignancy. We used an internal comparator of children with ADHD to attenuate concerns about the method of identification of malignancy outcomes in the MAX data.
We assumed that ADHD and childhood asthma were not associated with a different incidence of malignancy compared to the general population, though there is evidence to suggest that this assumption may not be true among adults with asthma (34
). Nevertheless, we used the malignancy rates of the ADHD cohort to determine the SIR results presented in the manuscript, and the results generated using the asthma cohort were similar.
More recent data were not available to us at the time of this study owing to the lag time and financial cost inherent in the creation and release of national MAX files by CMS. Compared to the JIA cohort, we had access to fewer calendar years of data for the comparator cohorts but many more person-years of follow-up. None of the cohorts were intended to be incident diagnosis cohorts, and all follow-up time after the index date was considered equal for all subjects. There was no anticipated calendar effect on malignancy rates, and all rates of malignancy were standardized to the age distribution of the entire JIA cohort. We hope to conduct future analyses of more recent MAX data to provide more definitive estimates of the incidence of malignancy in children with JIA.
Prior to the FDA’s new warning of an increased rate of malignancy among children receiving TNF inhibitors compared to children in the general population, there was relatively little scientific study of a possible increased risk of malignancy attributable to JIA. To our knowledge, the only published formal analysis was the previously mentioned small study of children with juvenile arthritis that largely pre-dated the methotrexate era of treatment (29
). Concern of a possible increased risk of lymphoma associated with methotrexate therapy was later raised (20
), but was never systematically studied. The results of our current study highlight the critical importance of appropriate comparator groups when evaluating the safety of new therapeutic agents and strengthen the case for the proposed inception of a disease-based (rather than medication-based) consolidated safety registry for children with JIA (35
In summary, we found a significantly increased rate of incident malignancy among children diagnosed with JIA compared to children without JIA. JIA treatment, including TNF inhibitors, did not appear to be significantly associated with the development of malignancy. Larger and longer-term studies of the association between malignancy and JIA and its treatment are needed to confirm our findings.