Abstract
Objective. To determine cancer incidence in a large pediatric-onset systemic lupus erythematosus (SLE) population.
Methods. Data were examined from 12 pediatric SLE registries in North America. Patients were linked to their regional cancer registries to detect cancers observed after cohort entry, defined as date first seen in the clinic. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year–specific cancer rates. The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated, with 95% CI.
Results. A total of 1168 patients were identified from the registries. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years, resulting in a total observation period of 8839 years spanning the calendar period 1974–2009. During followup, fourteen invasive cancers occurred (1.6 cancers per 1000 person-yrs, SIR 4.13, 95% CI 2.26–6.93). Three of these were hematologic (all lymphomas), resulting in an SIR for hematologic cancers of 4.68 (95% CI 0.96–13.67). SIR were increased for both male and female patients, and across age groups.
Conclusion. Although cancer remains a relatively rare outcome in pediatric-onset SLE, our data do suggest an increase in cancer for patients followed an average of 7.6 years. About one-fifth of the cancers were hematologic. Longer followup, and study of drug effects and disease activity, is warranted.
Several reports have been published over the past decade examining malignancy risk in rheumatic disease populations. To date, the only cohort study published specifically on pediatric-onset systemic lupus erythematosus (SLE) was the preliminary report of our multicenter cohort1. The objective of our current report is to present the final updated analyses on cancer incidence in an expanded multicentered clinical population of pediatric-onset SLE, including previously analyzed data as well as data from 3 additional centers.
MATERIALS AND METHODS
Our analyses included 4 pediatric rheumatology clinics in Canada and 8 in the United States (Table 1). Patients were linked to their regional cancer registries to detect observed cancers occurring after cohort entry, defined as date first seen in the SLE clinic. The end of followup was defined as the date of cancer registry linkage, thus allowing the inclusion of subjects who reached adulthood. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year–specific cancer rates, and summing overall person-years of observation.
List of participating centers.
The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated for overall malignancies and for hematologic malignancies, along with 95% CI, based on the assumption of cancer occurrence as a Poisson-distributed variable. Results were also stratified by sex and age group of person-time (categorized into 0–19 and ≥ 20 yrs of age).
The study was approved by the ethics boards of all participating institutions including the McGill University Health Centre ethics review board (#GEN-06-031).
RESULTS
Across the 12 cohorts, there was a total of 1168 patients. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years (SD 6.4, interquartile range 3.4–10.0 yrs), resulting in a total observation period of 8839 years during the calendar period of 1974 to 2009. During the followup period, 14 invasive cancers occurred, compared with 3.39 expected (4.13, 95% CI 2.26–6.93). Three were hematologic malignancies [all non-Hodgkin lymphoma (NHL)], and the other cancers included 2 head and neck squamous cell carcinomas (tongue and nasopharynx) and 1 each of glioblastoma, thyroid cancer (papillary adenoma), breast cancer (infiltrating duct carcinoma), adenocarcinoma not otherwise specified, and 3 cancers whose morphology and histology codes were indeterminate. We did not detect multiple malignancies in the same subjects.
The SIR for NHL was increased at 18.6 (95% CI 3.84–54.4). One of the malignancies occurred in the first year of followup. Nevertheless, excluding all events and person-time in the first year of followup, the SIR for cancer remained elevated at 4.35 (95% CI 2.31–7.44).
Stratifying by sex, the SIR for all cancers was 6.26 (95% CI 1.29–18.28) in males and 3.78 (95% CI 1.89–6.76) in females. For cancer overall, stratifying results according to person-time contributed within age groups, the SIR was 3.29 (95% CI 0.68–9.62) for events and person-time occurring up to age 20, which was similar to the SIR for events and person-time occurring after the age of 20 (SIR 4.44, 95% CI 2.22–7.94).
DISCUSSION
Our present study contributes novel and compelling data on increased malignancy risk in pediatric-onset SLE. Comparing the cancer rates in 1168 patients from 12 centers, the data suggest a higher cancer risk in pediatric-onset SLE versus the general population, which confirms our earlier preliminary report1. The increase in cancer in pediatric-onset SLE appears in part to be driven by hematologic malignancies, which is similar to what is known in adults with SLE2. Of course, in absolute terms, this still translates into relatively few events (1.6 cancers per 1000 person-yrs), which is somewhat reassuring.
A limitation of our study is that patients may have developed cancer after relocating to another state or province, leading to underrepresentation of the true cancer incidence in this cohort. If that underrepresentation was present to a significant degree, it would likely bias the results toward the null. Thus, this potential limitation does not likely explain the results.
Unfortunately, we are unable to comment on the relative importance of SLE disease activity itself, versus the effect of therapeutic drugs. In adults with SLE, we have found mainly an association between lymphoma and cyclophosphamide, and possibly cumulative steroid use, though not specifically with disease activity3. We are also unable to evaluate the effects of race/ethnicity, or of SLE clinical factors such as type of organ involvement and cumulative disease activity, because those data were not available from all the centers participating in our study.
The few published case reports of malignancy in pediatric-onset SLE4,5,6 have documented Hodgkin lymphoma, NHL, and acute lymphoblastic leukemia (ALL). The 3 lymphoma cases in the literature occurred in teenagers after several years of SLE duration, while the fourth case (ALL) occurred in a 6-year-old within 1 year of SLE diagnosis. Two additional case reports described the simultaneous presentation of pediatric-onset SLE (fulfilling the American College of Rheumatology criteria) and ALL, at ages 3 and 77,8. As we noted in our earlier manuscript1, this suggests that there may be a bimodal age-related pattern of hematological malignancies in pediatric-onset SLE. Alternatively, the first peak might actually represent, at least in part, paraneoplastic presentations masquerading as pediatric-onset SLE. As noted, when we excluded the malignancies (and person-time) that occurred in the first year after the SLE diagnosis, the SIR remained elevated.
In terms of a comparison with what is known in adults, an increased hematologic cancer risk has also been demonstrated in adults with SLE (especially NHL, with an SIR 4.39, 95% CI 3.46–5.49 in adults2). Interestingly, in those analyses, adult patients with SLE with the highest cancer risk relative to the general population were in the youngest age group (below age 40 yrs), perhaps supporting the risk of cancer associated with the cumulative burden of SLE and its treatment. These data may also suggest moderating effects for age (of SLE onset) on cancer risk, with greater cancer risk in a developing child versus an adult.
In our pediatric-onset SLE population, the point estimate for the NHL SIR was higher than current estimates for NHL relative risk in adult-onset SLE. However, the 95% CI for our NHL SIR estimate was very wide, and so it is not possible to definitively conclude that the relative risk of NHL in pediatric-onset SLE is higher than in adult-onset SLE. Unlike many cancers in adults, childhood cancers are often not strongly linked to lifestyle or environmental risk factors, but instead may be more likely the result of genetic factors9. Though it is unlikely that a single genetic factor explains the link between NHL and SLE, we are beginning to understand some of the potential genetic links between malignancy and adult SLE10.
There is also current interest in malignancy risk for other pediatric-onset rheumatic diseases, including juvenile idiopathic arthritis (JIA). Using methods similar to the current study, we found rather different results in JIA, with 9 cancers observed in 5294 patients over 36,063 person-years, and an overall SIR that was not elevated11. Still, in those juvenile arthritis analyses, 3 of the 9 cancers were hematologic, potentially representing a signal for an increased risk of hematological cancer in juvenile arthritis, although it is not as striking as what we saw in our current analyses of pediatric-onset SLE.
In our analysis of the largest ever sample of patients with pediatric-onset SLE followed at 12 centers in North America, using tumor registry linkage, cancer was a relatively infrequent outcome. However, the analyses are consistent with an increased risk of cancer compared to the general population, which appears to be driven at least in part by hematologic risk. Longer followup of this population is necessary to accurately identify cancer risk in the later adult years. Additional efforts to evaluate the effects of race/ethnicity, or of clinical factors (such as type of organ involvement, disease activity, and drug exposures) on malignancy risk may help to better guide the care of patients with pediatric-onset SLE.
Footnotes
Funded by the Canadian Institutes of Health MOP-106431 and the National Institutes of Health 5R03CA149970-2.
- Accepted for publication June 7, 2017.
