Systemic lupus erythematosus (SLE) is an inflammatory disease mediated by immunological mechanisms with a complex genetic basis. Interaction between genes and environmental factors favouring this disease have resulted in a progressively more self-aggressive immune system with a greater capacity for harming the body's own organs and systems. This complex gene-environment interaction is associated with a diverse phenotype expression and comorbid consequences that shorten life expectancy and quality of life in SLE patients. Although the accelerated atherosclerosis experienced by patients with lupus and other inflammatory disorders is one of the late consequences that has received most attention, neoplasms have also received the attention of many researchers. However, the results of research on this latter aspect are not entirely homogenous.1,2 This disparity is probably due in part to the methods used in the various studies, as well as to the very essence of the mechanisms involved in the development of cancer and SLE. For instance, we know that genes involved in the development of lupus vary between one population and another, as too does the incidence of cancer between different geographical areas, mainly due to environmental factors, though genetic factors also play a part.3,4 In Spain this aspect is poorly known and has never been examined with controlled studies. The aim, therefore, of this study was to determine the incidence of cancer in a cohort of SLE patients from southern Spain and compare the result with a similar population without SLE.

This prospective, controlled dynamic cohort study was undertaken between February 1990 and December 2006 in a population over 14 years of age seen at the Hospital Universitario Virgen de la Victoria in Malaga, Spain. This tertiary referral hospital for cancer and autoimmune diseases covers 475,017 inhabitants from the western part of the province of Malaga. The SLE cohort was hospital based and started in 1990. Data from a few patients treated in our unit until then were collected retrospectively. However, the follow-up was fully prospective since 1990 and an established protocol for the collection of data and biological samples was used. Patients have been followed up in outpatient clinics and in the hospital as inpatients. The study was approved by the hospital ethics and research committee.

The cohort comprised 175 SLE patients included between November 1989 and December 2006. Table 1 summarizes the descriptive data of the cohort. Most patients were younger than 40 years of age at the end of the follow-up and there was no male patient aged over 65 years. Proportionally more men than women abandoned the follow-up [7 (40%) vs. 22 (14%); P=.018].

Concerning immunosuppressive therapy, 96 patients (55%) received at some time at least one immunosuppressive drug, mostly bolus cyclophosphamide, followed by methotrexate and azathioprine.

This study suggests that the incidence rate of cancer in our SLE patients is almost four times greater than expected for our hospital area of western Malaga. This finding was seen after observation of our cohort of SLE patients for 1370.5 patient-years, which is no different clinically or analytically from the large SLE series.1,14–19 Although the crude rate of cancer in the SLE patients was higher than that of the controls, the significance was lost after standardizing the rates. This is very likely due to the small sample size as compared with large multicentre studies. Another methodological factor that could influence in higher cancer rate of the SLE patients was a greater chance of detecting cancer in a prospective hospital cohort compared with controls that came freely. The same reason could be behind the observation that none of our lupus patient died from cancer.

The relation between cancer and immunologically mediated inflammatory diseases, including SLE, has been the subject of great debate for some time, and it has, consequently, been examined by many authors in several different countries. In 2005, Bernatsky et al. published the largest multicentre study, comprising 9547 patients from 23 centres in six different areas (Canada, United States, United Kingdom, Sweden, Korea and Iceland) and representing 76,948 patient-years, with a mean follow-up of 8 years.1 Like us, these authors also found an increased risk of cancer among SLE patients, though the risk was lower than in our study as they estimated a SIR of 1.15 (95% CI, 1.05–1.27). Prior to this study, many others had been done, with conflicting results. Some studies found a higher risk of cancer in patients with SLE,1,2,18 whereas several others failed to find this association,20,21 showing that this topic remains unresolved. This great variation in the results may have several explanations, including, importantly, the different distribution of the risk of cancer among the various countries (and even within the same country). Accordingly, it is even more important for each country to undertake its own studies on cancer incidence.

Another factor possibly influencing the variation in the results in cancer incidence concerns the study method employed. Some studies have involved a clinical group with no external control group, whereas others did use an external control group, either from a statistics centre,20,21 or a national/provincial cancer registry,17,18 and even a hospital registry,2 like that used by us.

The mean time between diagnosis of SLE and diagnosis of cancer in our cohort was 5 years. Bernatsky et al.,1 in a cohort of 9547 SLE patients, found that most of the cancers occurred after the first year of diagnosis of SLE. Nevertheless, considering that tumours have a very variable, prolonged subclinical period of development, the presence of SLE can hardly be held responsible solely for this greater incidence. This is so even though there is always a delay between the onset of lupus symptoms and its diagnosis, particularly in patients whose cancer is diagnosed during the initial years of SLE, which has led several authors to suggest that SLE may be considered a paraneoplastic syndrome in these patients.22 The genetic and immunological changes giving rise to SLE may also play a fundamental role in the development of malignant tumours many years before the disease is clinically expressed. To this extent, changes in immune vigilance and loss of tolerance may share certain mechanisms. In fact, cancer incidence was associated with chronic inflammation as determined by ESR in our patients. This association has been also observed in patients with rheumatoid arthritis.23 By contrast, the temporal association between cancer and thrombosis observed in our study could be explained by a dual mechanism, i.e., by the relationship between thrombosis and antiphospholipid antibodies in SLE and by thrombophilic state induced by the cancer as “second hit” that triggers thrombosis.24 Although we have not found an association between cancer and immunosuppressants, such as azathioprine or cyclophosphamide, it is worth mentioning that this association has been observed by others.25

The spectrum of malignant tumours in SLE patients is very variable. Almost all types of tumours have been reported,26 though the disease has most commonly been associated with haematological malignancies, mainly non-Hodgkin's lymphoma.1,14,19 The types of neoplasia that we observed were those expected for age and sex in general population. In our cohort we only found one pretumour haematological disorder, a myelodysplastic syndrome, which we did not include among the malignant tumours as it did not progress to acute leukaemia. Thus, we found no relation between SLE and haematological tumours, not even non-Hodgkin's lymphoma, as in other studies.18,21 Three main reasons may explain this lack of association. As Zintzaras et al. point out in their meta-analysis,27 the SIR has become lower over the years (in 1992 it was 44.40, in 1995 it was 27.10, and in 2001 it was 7.42), which would explain why our series, despite being an open observational study from 1992, found no lymphomas. Secondly, non-Hodgkin's lymphoma is usually more common in men28 and only 10% of our cohort was male. The third reason for the lack of association between SLE and haematological tumours relates to the association between lymphoma and inflammation. The improved control in SLE activity attained over recent years has contributed to lymphoma becoming an increasingly rarer complication, and sustained activity is related with the appearance of neoplasms and greater associated mortality.23

We want to emphasize that an important limitation of our study concerns the restricted number of patients, though not the observation period, which covered 17 years and resulted in a total observation of 1370.5 patient-years. Nevertheless, to reduce instability in the calculation of the stratum-specific rates associated with the observation of such a low number of events, we standardized the SIR by an indirect method, which assigned weights according to the stratum size of the SLE cohort, making them less susceptible to random variation. This aspect is important, because we saw that the SLE patients belonging to the younger age strata were those who had higher incidence rates of cancer, a finding not seen in other studies.21,29,30

In conclusion, the crude incidence rate of cancer in our cohort of SLE patients was almost four times greater than that seen in the equivalent population without SLE. Our results support the hypothesis that patients with SLE have a greater risk of cancer. A chronic increase in the ESR and the presence of thrombosis were associated with a greater risk of cancer in our SLE patients.

The authors declare no conflict of interest.