Excess cancer incidence and mortality among patients with systemic lupus erythematosus: a population-based study in New Zealand

Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disorder caused by immuno-dysregulation and presence of autoantibodies. This can result in widespread inflammation and damage to various organs, including the skin, joints, kidneys, heart and lungs.¹ In New Zealand, the age-standardised prevalence rate of SLE is 65.2 per 100,000 for women and 8.5 per 100,000 for men.² SLE predominantly affects women, with over 80% of those diagnosed being female. The majority of SLE cases are identified in individuals aged 15–45 years.^2,3 The outcomes of SLE can be highly variable, with the disease manifesting in a spectrum from complete and lasting remission to severe, life-threatening complications. Approximately 30% of SLE patients in New Zealand die of this disease.⁴ Overall, patients with SLE experience worse outcomes compared to the general population, with a standardised mortality ratio (SMR) of 4.0 (95% confidence interval [CI] 3.7–4.3) in New Zealand.⁴ Additionally, younger patients with SLE have higher SMRs compared with their older counterparts.⁴

Research has shown that patients with SLE have an increased risk of cancer compared to the general population.^5–8 A systematic review of 48 cohort studies involving 247,575 SLE patients found that the relative risk of overall cancer in this group is 1.62 (95% CI 1.47–1.79).⁹ It is reported that SLE is a risk factor for 17 site-specific cancers, including six digestive cancers (oesophageal, colon, anal, hepatobiliary, liver and pancreatic), five haematologic cancers (lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, leukaemia and multiple myeloma) and cancer in lung, larynx, cervix, vagina/vulva, kidney, bladder, skin and thyroid.^5–9 The underlying reasons for the association between SLE and an increased risk of cancer remain unclear. Several factors may contribute to this relationship, including chronic inflammation, use of certain immunosuppressive medications, genetic factors and the interaction between immune system dysregulation and cancer biology.^5–9 The impact of immunosuppressive medications on cancer development in patients with SLE remains controversial.^8,9 However, some research indicates that SLE patients may have a reduced risk of certain hormone-sensitive cancers, including breast, ovarian and endometrial cancers,^8,9 and antimalarial drugs might be protective factors for cancer in SLE.¹⁰

SLE patients not only face higher cancer incidence rates but also experience increased cancer mortality rates compared to the general population. The relative risk of cancer-related death in SLE patients compared to the general population is 1.52 (95% CI 1.36–1.70).⁹ In New Zealand, cancer represents the third most frequent cause of death among SLE patients, contributing to 19% of all deaths in this group.⁴ This highlights the significant impact of cancer on the survival of SLE patients and underscores the need for targeted cancer screening and preventive measures within this vulnerable population. The incidence and mortality rates of cancer among patients with SLE have not yet been studied in New Zealand. This study represents the first effort to address this knowledge gap. It aims to investigate cancer incidence and mortality among SLE patients within New Zealand.

Methods

Study design, participants and data sources

This is a retrospective cohort study, including prevalent SLE patients in 2010–2021 in New Zealand. These patients were identified by searching the National Minimum Dataset (NMDS) and the Mortality Collection using the International Statistical Classification of Diseases 10th revision (ICD-10) code “M32” and by searching death certificates with the keyword “systemic lupus erythematosus”. More details on patient selection and verification have been reported previously.⁴ The NMDS is a national database that compiles discharge information from both public and private hospitals, including coded clinical data for both same-day and multi-day inpatient stays. The Mortality Collection contains coded mortality data (date and cause of death), while death certificates record the latest uncoded mortality information. The date of initial SLE identification was determined as the earliest occurrence of an inpatient event with the ICD-10 code “M32” in the NMDS, or the first outpatient event recorded in the National Non-Admitted Patient Collection (NNAPC) within a rheumatology department or renal service. NNAPC includes event-based purchase units associated with medical and surgical procedures in outpatient settings, as well as emergency department events. SLE cases were then linked to the New Zealand Cancer Registry (NZCR) to identify when and what cancer was diagnosed, using patients’ National Health Index (NHI) numbers. The NHI number is a unique identifier for individuals accessing health and disability services in New Zealand. The NZCR is a population-based register of all primary malignant diseases diagnosed in New Zealand.

Statistical analyses

The characteristics, including cancer site, ethnicity (Māori and non-Māori) and age at cancer diagnosis (0–24, 25–44, 45–64, 65–74 and 75+ years), of SLE patients who were diagnosed with cancer in 2010–2021 were described by sex (women and men). In New Zealand, sex and ethnicity data in national administrative datasets are self-identified by patients when they engage with health services. The cancer incidence rate among patients with SLE was stratified by sex and age-standardised to the general population in New Zealand as of the year 2019. This was because detailed cancer incidence data categorised by cancer site and age group for the general population were only available for 2019 for comparisons with the age-standardised cancer incidence rate among SLE patients, and such data were not updated beyond this year.¹¹ The age-standardised registration rates of cancer have been stable in New Zealand, so it was reasonable to use the 2019 data for comparison. The relative risk of developing cancer among SLE patients compared to the general population was also computed. This measure indicates how much more likely SLE patients are to develop cancer relative to the general population. Along with the relative risk, a 95% CI was calculated for each cancer site, age group and ethnicity.

The Mortality Collection provides the underlying cause of death, which is indicated and coded using ICD-10 codes. However, this underlying cause is not explicitly stated on the death certificates, which list up to seven causes of death. To determine the primary cause of death, the causes listed on the death certificates were examined by the authors to identify the underlying cause. The underlying cause of death is defined by the World Health Organization as “(a) the disease or injury which initiated the train of events leading directly to death, or (b) the circumstances of the accident or violence which produced the fatal injury.”¹² The underlying causes of death were classified into two groups: cancer deaths and non-cancer deaths. Characteristics of patients who died from cancer were described by sex. The overall cancer death rate among SLE patients, stratified by sex and ethnicity, was age-standardised to the general population based on the 2019 cancer mortality data. The relative risk of cancer death for SLE patients compared to the general population was calculated, with adjustments made for age and ethnicity. The data analyses were conducted using R 4.0 (R Institute, Vienna, Austria). Approval for the study’s ethics was obtained from the Northern B Health and Disability Ethics Committee, with the reference number 2022 EXP 13741.

Results

Patient characteristics

During the study period, 2,656 prevalent SLE patients were identified, including 2,305 women and 353 men. The total person-years of follow-up were 20,591 for women and 2,721 for men (Table 1). There were 187 new cancer cases identified among women and 53 among men. The most common cancer diagnosed among SLE patients was non-Hodgkin lymphoma (33, 13.8%), followed by breast cancer (28, 11.7%), lung cancer (25, 10.4%), colorectal cancer (24, 10.0%) and melanoma (19, 7.9%) (Table 2). In total, haematologic cancer (including leukaemia, lymphomas, multiple myeloma and malignant plasma cell neoplasms, other specified and unspecified malignant neoplasms of lymphoid, haematopoietic and related tissue) accounted for 20% of cancer cases identified (38 cases among women and 10 cases among men). Fifteen percent of the cancers were identified among Māori patients, and 85.0% were found among non-Māori patients. Half of the cancers were diagnosed at under 65 years of age, including 10.4% at the age of 25–44 years and 40.8% at the age of 45–64 years. Women were diagnosed with cancer at a younger age than men. Specifically, 12.3% of cancers in women were diagnosed between the ages of 25 and 44, while 18.7% were diagnosed at age 75 or older. In contrast, for men, these figures were 3.8% and 32.1%, respectively.

Cancer incidence

The age-standardised cancer incidence rate was 797 per 100,000 person-years for patients with SLE, compared to 541 for the general population in 2019 (Table 3). Male patients with SLE (1,209 per 100,000 person-years) had a higher cancer incidence rate than female patients (742 per 100,000 person-years), while there was no substantial difference between sex in the general population. Overall, the relative risk of cancer incidence for SLE patients compared to the general population was 1.47 (95% CI 1.30–1.67) for all SLE patients, 1.48 (95% CI 1.28–1.71) for women and 2.08 (95% CI 1.59–2.73) for men. The relative risk was 1.52 (95% CI 1.10–2.11) for Māori and 1.46 (95% CI 1.27–1.68) for non-Māori patients. There were differences in relative risk by cancer sites. For example, the relative risk was 5.41 (95% CI 3.82–7.65) for non-Hodgkin lymphoma, 1.70 (95% CI 1.14–2.52) for lung cancer, 4.55 (95% CI 1.70–12.19) for leukaemia and 3.03 (95% CI 1.43–6.40) for thyroid cancer. Greater disparity in cancer incidence was observed in younger patients, with a relative risk from 2.48 (95% CI 1.67–3.68) for those aged 25–44 years to 1.35 (95% CI 1.03–1.77) for patients aged 75 years or older.

Cancer mortality

In 2010–2021, 100 SLE patients died of cancer, including 78 women and 22 men (Table 4). Six patients died of cancer before the age of 25 years and 31 at the age of 25–44 years. Lung cancer (20.0%) was the most common cancer death, followed by non-Hodgkin lymphoma (17.0%), colorectal cancer (9.0%), breast cancer (7.0%) and leukaemia (6.0%). The relative risk of cancer death for SLE patients compared to the general population was 1.70 (95% CI 1.39–2.07) for all SLE patients, 1.75 (95% CI 1.40–2.19) for women and 2.27 (95% CI 1.49–3.44) for men (Table 5). The difference in cancer deaths between SLE patients and the general population was observed in patients under the age of 75 years with a relative risk from 4.11 (95% CI 1.83–9.24) for those aged 25–44 years to 2.20 (95% CI 1.58–3.07) for patients aged 65–74 years, but not in those aged 75 years or older (relative risk 1.17, 95% CI 0.80–1.69). SLE patients had a much greater risk of dying of haematologic cancer than the general population, with a relative risk of 4.99 (95% CI 3.38–7.37). Non-Hodgkin lymphoma contributed most of the differences, with a relative risk of 8.53 (95% CI 5.24–13.89).

Discussion

This is the first comprehensive study examining the cancer incidence and mortality among patients with SLE in New Zealand. Patients with SLE experience a significantly higher risk of developing cancer and cancer mortality compared to the general population. These findings align with existing research conducted in other countries.^9,13–15 Specifically, the relative risks calculated in this study reveal that patients with SLE in New Zealand have a cancer incidence risk of 1.47 and a cancer mortality risk of 1.70. Similarly, a Finnish study comparing 1,006 SLE patients and 3,005 population controls estimated an incidence rate ratio for any malignancy of 1.41 (95% CI 1.08–1.85) and an adjusted hazard ratio for death of 1.68 (95% CI 1.17–2.43).¹³ These findings underscore the critical need for awareness of cancer risk and enhanced cancer screening to SLE patients, as well as the potential benefits of early detection and tailored treatment strategies to improve survival outcomes in this vulnerable group.

The increased risk of cancer in patients with SLE is influenced by several factors, including chronic inflammation, the use of immunosuppressive medications and genetic predispositions.^5–9 Chronic inflammation can promote tumour growth, while immunosuppressive therapies weaken the immune system’s ability to detect and eliminate cancer cells.^5–9 High cumulative cyclophosphamide dose increases the risk of cancer.¹⁶ When using cyclophosphamide, careful monitoring and consideration for alternate therapies are recommended. In contrast, hydroxychloroquine was reported to be a protective factor for cancer in SLE patients.^10,16 It is important for SLE patients to use preventative measures, including smoking cessation, vaccines and regular cancer screening programmes (particularly in cervical cancer).^17,18 Future research should explore treatment regimens for SLE that minimise cancer risk without compromising disease control.

The risk of cancer among patients with SLE varies substantially by cancer type, with certain malignancies showing increased incidence, while others may be less common. It has been found that the risk of non-Hodgkin lymphoma and Hodgkin lymphoma was increased by over threefold, while the risk for myeloma and liver cancer was more than doubled.^19,20 Additionally, the risk for cervical, lung, bladder and thyroid cancers was elevated by at least 1.5-fold, and stomach and brain cancers showed a greater than 1.3-fold increase.^19,20 A Canadian study also reported a four-fold increased risk specifically for non-Hodgkin lymphoma and a three-fold increased risk of haematologic cancers among SLE patients.¹⁴ These are consistent with what we found in our study, which showed that non-Hodgkin lymphoma was the most common cancer diagnosed among SLE patients (33% of all cancers), with a relative risk of 5.41 compared to the general population. Additionally, patients with SLE faced a relative risk of 3.39 for developing haematologic cancers overall. Our study also identified an elevated risk of certain cancer types, such as lung cancer, leukaemia and thyroid cancer. Lung cancer ranked as the third most common cancer and was the leading cause of cancer-related death among SLE patients in New Zealand. SLE patients had a 78% higher risk of dying from lung cancer.⁴ These findings are consistent with prior research indicating that autoimmune rheumatologic conditions, such as SLE, rheumatoid arthritis and scleroderma, are associated with an elevated risk of not only developing lung cancer but also dying from it.^14,21

It has been reported that the cancer-specific standardised mortality ratio was higher in younger SLE patients,²² a finding consistent with our study. This increased risk suggests that younger SLE patients are more likely to die of cancer compared with their counterparts in the general population. This may be partly because younger patients had a higher relative risk of developing cancer (2.48 for those aged 25–44 years compared with 1.35 for those aged 75+ years in our study). Other contributing factors may include more severe disease manifestations in younger patients, leading to the need for aggressive treatments like immunosuppressive therapies, which can weaken the immune response and elevate cancer risk. While we lacked information on the disease severity of the SLE patients in our study, our prior research indicated that younger patients were over 10 times more likely to have SLE listed as the underlying cause of death.⁴ This finding suggests that younger patients may experience more severe forms of the disease.

Our study demonstrated a higher relative risk of both developing and dying from cancer for male patients compared with females. A meta-analysis also showed a slightly higher relative risk for men (1.59, 95% CI 1.18–2.14) than women (1.49, 95% CI 1.15–1.93).⁸ However, the gap was much greater in our study, with a relative risk of 2.08 (95% CI 1.59–2.73) for men and 1.48 (95% CI 1.28–1.71) for women. This may be related to the different clinical characteristics between male and female SLE patients, including more renal and haematological involvement in male patients.²³ Male patients were also reported to be diagnosed with more late-onset SLE, which may lead to increased reliance on immunosuppressive therapies that compromise their immune systems.²⁴

This study has some strengths. This is the first population-based study examining the cancer incidence among SLE patients in New Zealand. The linkage of multiple national datasets through the unique NHI numbers allowed for a thorough analysis of cancer incidence and mortality among patients with SLE compared to the general population. The analyses with detailed stratification by cancer site, sex, age group and ethnicity also revealed specific patterns and disparities in cancer risk. Such insights are crucial for developing targeted screening and prevention strategies to improve outcomes for diverse patient populations. Despite the valuable information provided by this study, there are notable limitations that need to be acknowledged. One limitation is the relatively small number of cancer cases available for analysis, especially when data were further stratified by cancer site, sex, age group and ethnicity. This small sample size can lead to greater variability and uncertainty in the cancer incidence/mortality rates and relative risk estimates. Another limitation is the lack of data on smoking, body mass index/obesity, disease activity and medications received by these SLE patients, limiting our ability to adjust for their potential effects. Future research with more comprehensive data is needed to address these factors. We did not have data on cancer screening uptake in our cohort either. Previous research showed less uptake of cancer screening by SLE patients, e.g., not having regular cervical screening etc.²⁵

Conclusions

Patients with SLE in New Zealand experience a higher cancer burden compared to the general population, with greater disparity among younger patients and male patients. Haematologic cancers were especially prevalent among SLE patients. It is crucial to stay alert for the possibility of cancer and carefully evaluate any new symptoms that might indicate its presence, even in younger patients. Further research is needed to explore potential associations between SLE treatments and cancer risk.

View Table 1–5.