Malignancies in systemic lupus erythematosus

Introduction

Many studies have shown unique cancer profiles for patients with autoimmune conditions such as rheumatoid arthritis (RA), Sjögren's syndrome, scleroderma, and systemic lupus erythematosus (SLE). Much of the data on cancer in SLE in general, and hematologic cancers specifically, comes from a very large (over 16,000 patients) multi-center international study of clinical SLE cohorts (which we will refer to later in this article). Although the 5-year survival rate of SLE patients now exceeds 90%, the age and sex adjusted standardized mortality ratio (SMR) in SLE patients still remains around three times higher compared to the general population. Some papers have ranked cancer as a significant factor contributing to the increased mortality and morbidity seen in people with SLE. However, not all cancers are increased in SLE; in fact, the incidence of some cancers, such as breast, are lower in SLE patients than in age-matched women. In particular, SLE patients have a reduced risk of breast, endometrial, and possibly ovarian and prostate cancers. In this article, we will begin by discussing some of the malignancies that are associated with higher cancer risk in SLE versus the general population, and then review some cases where malignancy risk appears to be lower in SLE.

Hematologic cancers

There is an increase in both the incidence and the mortality associated with lymphoma in SLE compared to the general population. The evidence of about a 3-fold increased risk for hematologic cancers is substantial, and this risk is particularly increased for nonHodgkin's lymphoma (NHL), where point estimates suggest at least a 4-fold increase in SLE versus the general population ( Table 48.1 ). Interestingly, investigators have also shown the correlate, that patients who develop NHL have a higher prevalence of SLE than would be expected by chance alone. Diffuse large B cell lymphoma (DLBCL) is the most frequent subtype of NHL and one study suggested that SLE patients were diagnosed at advanced stages and that their prognosis was worse. As in the general population, data suggest that lymphoma risk in SLE increases with age.

Some, though not all, of the potential pathways leading to hematological malignancies in SLE have been elucidated. Chromosomal abnormalities, such as juxtaposition of an oncogene next to a gene involved in immune cell function, can give rise to certain types of NHL. Some hypothesize that SLE patients with defects in regulation of lymphocyte proliferation may develop lymphoma through this mechanism. Another hypothesis concerns a cytokine implicated in SLE, A PRoliferating Inducing Ligand (APRIL), which is known to cause ongoing lymphocyte proliferation by prompting B cells to escape apoptosis. APRIL is strongly expressed in DLBCL in the general population and was detected at high levels in SLE lymphoma tissues, which may indicate the possibility of APRIL-mediated lymphoma development in this subset of patients , although the overexpression of APRIL may be associated with SLE itself.

DLBCL has been stratified by gene expression profiling into two major groups based on “cell of origin;” in the general population, the germinal center B-cell (GCB) subtype is more common. ^,16 However, in analyses of DLBCL arising in SLE, the majority (60%) were nonGBC. Non-GBC DLBCL are characterized by activation of the NF-κB and JAK-STAT pathways, which are both directly implicated in SLE through derangements of A20, tumor necrosis factor superfamily (TNFSF4), TNF-α, CD79, CARD11, and interleukin-1 receptor-associated kinase 1 (IRAK1) activity, as well as epigenetic modifications.

Interestingly, in primary Sjögren's syndrome, an autoimmune rheumatic disease at high risk for mucosa-associated lymphoid tissue (MALT) lymphoma, most MALT cases have either germline polymorphisms of TNFAIP3 , related to the A20 protein important in NF-κB activation, or somatic alterations of the gene within the lymphoma tissue. Moreover, polymorphisms of TNFAIP3 are common to RA (yet another condition linked with lymphoma) and Hodgkin's lymphoma. In previous genome wide association analyses, our group was unable to confirm a strong relationship with the lupus-related TNFAIP3 single nucleotide polymorphism (SNP) rs7749323 specifically for DLBCL, but this may be a sample size issue. In those analyses, the rs2205960 SNP, related to TNFSF4, was associated with an odds ratio (OR) per risk allele of 1.07, 95% CI 1.00–1.16, p value 0.0549. The OR for the SLE interferon regulatory factor risk allele rs12537284 (chromosome 7q32, gene) was 1.08, 95% CI 0.99–1.18, p value 0.0765. The STAT4 lupus risk SNP rs7582694 meanwhile was not clearly linked to DLBCL (again possibly a power issue). Our interpretation is that TNFAIP3, TNFSF4, and possibly interferon pathways are of high interest as potential mediators of the risk of DLBC (particularly non-GCB type) in SLE.

The role of IL-10 in B-cell lymphomagenesis has been entertained Serum IL-10, which has been correlated with SLE disease activity, was found to be a prognostic factor for NHL in the general population. Another hypothesis focuses on increased serum levels of type 1 interferons (IFNs), which are known to be associated with active SLE. Studies in mice models have confirmed that IFN-inducible p202 (and its human function homologue IFI16) in B cells is associated with increased susceptibility to developing B-cell malignancies. However, a better understanding of this pathway is needed to determine its important in lymphomas that arise in humans with SLE. Additionally, dysregulation of microRNAs is common to both SLE and NHL. For example, microRNA miR30a is involved in both the production of IgG autoantibodies and B cell proliferation in SLE, and also plays a crucial role in apoptosis, promoting NHL.

While disease activity has been linked with an increase in lymphoma incidence in RA, a case-cohort analysis within the large international multicenter SLE cohort (that we referred to in the introduction) was unable to determine links between disease activity and risk of lymphoma when medication exposures were accounted for. The analyses controlled for mean adjusted SLE Disease Activity Index scores over time, but residual effects of disease activity may still have been present. That study did find an increased risk associated with exposure to cyclophosphamide (lagged by 5 years). It is also important to stress that cyclophosphamide is an uncommon exposure, only used in the most severe SLE cases, and again, it is impossible to rule out residual confounding by disease activity. However, associations between cyclophosphamide and malignancy (particularly hematologic) are well known in the literature and are plausible given that this drug is an alkylating agent. On the other hand, data indicate that the highest risk of lymphoma is observed during the early stages of SLE, suggesting that cumulative exposure to immunosuppressive drugs does not explain all of the lymphoma risk in SLE. Indeed, many hematologic malignancies arise in SLE patients who have never been exposed to these drugs.

Though individual cohort studies were unable to demonstrate an increase in multiple myeloma (MM) in SLE, one study showed the frequency of monoclonal gammopathy to be higher than expected and a recent meta-analysis reported a moderate increased risk of MM in SLE with a pooled SIR of 1.48 (95% confidence interval (CI) 1.02–2.14). A review of SLE MM cases found that 80% occurred in black SLE patients, which could correlate with genetic factors, or SLE severity (which is often greater in blacks) and/or SLE treatment.

Regarding non-lymphoma hematologic cancers, myeloid leukemia types were found to be the most common among SLE patients, in contrast to lymphoid leukemia types, which are common in the general population. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been reported to occur more often in SLE than in the general population.

Given the hypothesis that chronic B lymphocytes stimulation can lead to lymphoma, it may be considered as surprising that SLE patients are at increased risk of myeloid leukemia. However, the mechanisms underlying the development of leukemia in SLE might be different from the mechanisms underlying lymphoma in SLE. A recent study compared 86 MDS and AML cases in patients with 27 different autoimmune diseases (including SLE) to controls matched for age, sex, and type of autoimmune disease. Azathioprine was associated with an increased risk for these cancers, and a strong trend was also seen for cyclophosphamide. No clear increased or decreased risk was seen for other agents, including steroids, methotrexate, or mycophenolate. These findings were unfortunately severely limited by the study's failure to adjust for disease duration, disease activity/severity, or calendar year, and whether SLE cases were clinically confirmed or just based on physician codes was unclear.