Pediatric Cancer Survivors at High Risk for Autoimmune Disease

Jennifer Garcia

November 11, 2015

Survivors of childhood cancer are at an increased risk of developing autoimmune disease later in life, according to a new study published online November 10 in the Annals of the Rheumatic Diseases.

"Cure is no longer a sufficient goal in childhood cancer care," Anna Sällfors Holmqvist, MD, from Skåne University Hospital, Lund University, Sweden, and fellow researchers write. "As the vast majority of these patients survive, attention must be paid to their long-term quality of life and health challenges."

Dr Holmqvist and colleagues evaluated registry data for 20,361 patients from Denmark, Iceland, and Sweden who were diagnosed with childhood cancer at between 0 and 19 years of age who survived for at least 1 year after their diagnosis. Registry information dating from the 1940s and 1950s through December 31, 2008, was evaluated. Data for comparison subjects (n = 125,794) of the same age, sex, and country of residence who were cancer-free between 0 and 19 years of age were included in the analysis. Participants were followed for a median of 15 to 19 years.

The researchers found that survivors had a 40% increased risk of developing autoimmune disease, expressed as a standardized hospitalization rate ratio (SHRR; the difference between the expected and excess number of cases of autoimmune disease). The SHRR was 1.40 (95% confidence interval [CI], 1.3- - 1.52) for all 33 investigated autoimmune diseases combined. In particular, the diseases associated with the highest SHRRs were autoimmune hemolytic anemia (16.3), Addison's disease (13.9), and polyarteritis nodosa (5.8).

Similarly, cases of rheumatic heart disease, scleroderma, idiopathic thrombocytopenic purpura, Hashimoto's thyroiditis, pernicious anemia, sarcoidosis, Sjögren's syndrome, and diabetes were all significantly higher in cancer survivors than in patients without a cancer history.

The researchers also calculated the absolute excess risk for the development of autoimmune disease in this cohort and found it to be 67 per 100,000 person-years, "representing an excess of seven survivors with a hospital contact for an autoimmune disease for every 1000 patients followed for 10 years." The absolute excess risks were highest for insulin-dependent diabetes mellitus and Addison's disease, at 23 and 13 per 100,000 person-years, respectively. The researchers note that the risk for all autoimmune diseases combined was similar, regardless of the patient's age at the time of the cancer diagnosis.

With the exception of Sjögren's syndrome, Hashimoto's thyroiditis, and chronic rheumatic heart disease, there was no difference in SHRRs between men and women.

When patients were stratified according to cancer type, the authors found that patients who had been diagnosed with leukemia, Hodgkin's lymphoma, renal tumors, and central nervous system neoplasms were 40% to 60% more likely to develop an autoimmune disorder later in life when compared with subjects who had not had childhood cancer.

The authors note that they cannot rule out that the increase in diagnosis of autoimmune disease among childhood cancer survivors may be a consequence of closer medical monitoring, rather than a true increased risk for disease. However, several factors argue against that possibility, including the persistent excess risk for up to 30 years after the cancer diagnosis for most conditions, and up to 50 years later for some conditions. In addition, the excess risk described in the current study refers to inpatients, not the outpatient setting where one would expect closer surveillance to play a bigger role in detection.

"[P]ersistent immune abnormalities after treatment with chemotherapy predispose to the development of autoantibodies, which are central to the pathogenesis of many autoimmune diseases," write Dr Holmqvist and colleagues, which may explain why survivors may have an increased risk for autoimmune disease.

"Both the cancer itself and the immunosuppressive treatment, as well as the increased number and types of infections during cancer treatment, could alter the immune system as a whole and also result in immunologically different antigens, leading to the production of autoantibodies," they add.

The authors also suggest that radiotherapy may also have an effect on the development of autoimmunity, although there were insufficient data available to investigate the effects of chemotherapy and radiation on future risk of autoimmune disease.

Funding for this study was provided by a grant from the Danish Council for Strategic Research. The authors have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online November 10, 2015. Full text


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