Numerous studies have demonstrated that patients with SLE had an increased overall cancer risk compared with the general healthy age and sex matched population, especially Non-Hodgkin’s Lymphoma, thyroid cancer, lung cancer and vulva cancer. The mechanism remains unclear, it is speculated that various factors including medication exposure, the activated auto-immune system, viral infection, overlap syndrome, as well as traditional lifestyle cancer risk factors may all contribute to the increased cancer risk in SLE [24, 25]. To the best of our knowledge, only a handful of studies have been done to explore the association between cancer and the drugs used in SLE, and the results were inconsistent [18-21]. In this large nested case-control study, we found that the SLE patients with cancer had lower disease activity, and that HCQ was negatively associated with cancer risk in SLE patients.
Both SLE and cancer have been associated with immune dysfunction [26]. In SLE patients, the impaired immune system is not able to discriminate between self and non-self antigens, leading to aberrant production of autoantibodies causing host tissue damage. On the contrary, cancer formation is caused by compromised host’s immune system that cannot recognize cancer antigens. It has been previously reported that the immunogenicity of cancer cell could induce the production of a wide range of auto-antibodies including ANA, anti-dsDNA, anti-Sm, anti-SSA, anti-SSB, anti-Rib and anti-nRNP [27]. The level of ANA has been reported to be elevated in 31.5% lymphoma patients relative to the control group [12]. While it is well established that anti-dsDNA is highly specific for SLE, it has been found in patients with different malignancies and may serve as a prognostic indicator for cancer. The association between anti-dsDNA and cancer was firstly demonstrated in bronchogenic carcinoma [28]. One study suggested that this antibody may play a role in the pathogenesis of lymphoma and thymoma [29]. It has been hypothesized that the presence of anti-dsDNA autoantibodies in patients with colorectal cancer might indicate better disease outcome [15]. Our current study evaluated the significance of disparities in the levels of ANA, anti-dsDNA, anti-Sm, anti-RO52, anti-RO60, anti-SSB, anti-Nuc, anti-His, anti-Rib and anti-nRNP antibodies between the cancer group and the cancer free control group at the time of cancer diagnosis. Our results demonstrated there were no significant difference in the levels of these factors between the cancer group and the control group at the time of cancer diagnosis.
The organ damage and disease activity in SLE patients with or without cancers were investigated, and the results were inconsistent, likely due to the differences in inclusion criteria, race, and scoring systems. For instance, a mean SLICC/ACR damage score of 1.9 and 1.7 has been reported for the cancer group and the control group respectively, suggesting that organ injury was more severe in the cancer group [18]. A different study did not find statistically significant differences in the adjusted mean SLEDAI-2K between a lymphoma group and a control group [19]. It should be noted that while SLICC/ACR mainly evaluates organ damage [30], the adjusted mean SLEDAI-2K reflects the mean disease activity after onset [31]. Our results indicate that SLE with different malignancies had lower SLEDAI scores, lower rates of renal involvement and low level of complement compared with the control group. The SLEDAI mainly reflects the disease activity within ten days [23]. Taken together, these data indicate that SLE patients with cancers have lower disease activity at the time of cancer diagnosis.
The role of immunosuppressant in cancer development in SLE patients remains controversial. One study showed that immunosuppressant therapy was not associated with overall cancer risk in patients with SLE but might contribute to an increased risk of hematological malignancy [18]. A different research reported that exposure to CTX might contribute to a higher lymphoma risk in SLE patients [19], although this was contradicted by a different report showing that the use of CTX and AZA did not contribute to lymphoma risk [20]. It has been demonstrated that CTX increases cancer risk in SLE patients in a dose-dependent manner [21]. Therefore, more investigations looking at a larger number of participants is needed. In fact, numerous studies have demonstrated that the activated auto-immune system may contribute to the increased cancer risk in patients with SLE, especially on-Hodgkin’s Lymphoma. The probable mechanism is the detective immune surveillance system. By virtue of the disease, SLE patients have impaired immune surveillance system due to the activated auto-immune system. In healthy immune system, aberrant cells produced during cell replication are eliminated to prevent them from becoming malignant. In SLE patients, this regulation process may be impaired, making patients more vulnerable to develop cancers. At the same time, the abnormal apoptotic process inherent in SLE may enhance this process [32, 33]. In the scenario of lymphomas occurring in SLE patients, besides the mechanism mentioned above, there is a further aspect that has to be taken into account: these malignancies arise from the immune system itself. The activated lymphocytes in SLE are prone to potentially dangerous genetic events during their maturation, such as recombination or hypermutation in B cells, which eventually promote the development of lymphoma, particularly Non-Hodgkin’s lymphoma [34, 35].
HCQ is extensively used in SLE treatment. Besides its well-established effects on the skin and joint symptoms, several studies have indicate that HCQ has important long-term effects on lupus, including reduced long-term accrual damage and decreased long-term mortality [36, 37]. A protective function of antimalarial against cancer in SLE patients has been proposed [38]. Hsu et al. found that HCQ decreased cancer risk in a dose-dependent manner [21]. Our current large-scale study has also elucidated a negative association between HCQ and cancer.
It has been proposed that HCQ might modulate autophagy by impacting lysosomal acidification and blocking the fusion of auto-phagosomes with lysosomes [39]. Chloroquine may trigger the expression of Tp53 which may protect the cells from genotoxic stimuli [40]. In addition, the antimalarial may inhibit unlimited replication of cancer cells via their strong DNA intercalating properties [41]. Chloroquine may promote DNA repair following DNA damage as a result of alkylating therapy [42]. Multiple preclinical and clinical trials have demonstrated a synergistic anticancer effect of HCQ with chemotherapies and targeted therapies [43]. For instance, cytotoxicity of tamoxifen against breast cancer cells has been shown to be enhanced by combination therapy with HCQ [44]. In addition, HCQ is effective against hepatocellular carcinoma and pancreatic ductal adenocarcinoma [45, 46], as well as hematologic cancer like chronic myeloid leukemia, myeloma and lymphoma [47-49]. Taken together, these reports suggest that HCQ may decrease the cancer risk in SLE patients.
In the SLE cohort included in this study, thyroid cancer, cervical cancer and lung cancer were the top three cancer types. Studies suggest an increased risk of cervical cancer among SLE patients compared with the general population [50, 51]. It has been reported that immunosuppressant increases the risk of cervical neoplasia in SLE patients and this is attributable to decreased HPV clearance [50, 52]. This suggests that SLE patients under immunosuppressive agents should undergo regular screening for cervical dysplasia.
This retrospective study of a large cohort of SLE patients examined the odds of being diagnosed with cancer in SLE patients. Our results suggest that SLE patients with cancers have lower disease activity at the time of cancer diagnosis. In addition, a negative association between HCQ administration and cancer risk in SLE patients was unveiled, highlighting a novel potential cancer prevention strategy for SLE patients.