Elsevier

Autoimmunity Reviews

Volume 9, Issue 4, February 2010, Pages 195-199
Autoimmunity Reviews

Malignancies in systemic lupus erythematosus

https://doi.org/10.1016/j.autrev.2009.07.004Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease, characterized by a wide array of symptoms and organ involvements, leading to varying disease courses and outcome, and ranging from mild to severe types. In patients with SLE, the incidence and risk of malignancy development is increased, and mostly non-Hodgkin's lymphoma (NHL), cervical cancer, as well as bronchial carcinomas occur. Besides others, the common genetic predisposition, chronic antigen stimulus, disproportional immune responses, as well as the chronic administration of immunosuppressive medications can contribute to the development of malignancies in lupus.

In this review we present the molecular pathology, as well as the epidemiological and clinical aspects of malignancies in patients with SLE.

Introduction

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease, which encompasses mild to moderate forms, and also severe, progressive variants. Through the disease course several organs and organ-systems can be affected, amongst others the cardio-vascular, musculoskeletal, excretory, respiratory and nervous systems [1]. Due to the modern management and increasing novel therapeutical regimes, the prognosis of the disease is better; the survival in lupus has increased [2]. In consequence of increasing life expectancy in SLE, chronic organ damages and late complications, such as malignancy, have become key determinants of both morbidity and mortality [3]. There is a clear change in the major causes of death in SLE, namely the previous, directly lupus-related mortality is reduced, while the frequency of chronic complications, such as cardio-vascular, infectious and malignancy-associated mortality seems to be increasing in lupus patients [2], [3]. The expanding occurrence of malignancies can be associated with the common pathogenetic pathways in lupus and the development of neoplasms. This phenomenon is reinforced by the following notions: generally, in autoimmune diseases malignancies occur with high frequencies; in neoplastic disorders, autoimmune diseases can develop, as part of the paraneoplastic syndrome; also, immunosuppressive treatment in autoimmune diseases increases the development of malignancies [4], [5], [6], [7], [8].

Another link between lupus and malignant diseases can be served by antiphospholipid antibodies (aPL), frequently present in SLE and cancer as well. A recent publication indicates that aPL can be a risk factor both for thrombotic processes and cancer development [9].

A pooled analysis of reported autoimmune conditions and the risk of non-Hodgkin's lymphoma (NHL) based on 29,423 participants indicated several important correlations: Sjögren's syndrome (SS) was associated with a 6.5-fold increased risk of acquiring NHL, there was a 1000-fold increased risk of parotid gland marginal zone (MZ) lymphoma development and also diffuse large B-cell lymphoma (DLBCL) showed association with SS. SLE was associated with a 2.7-fold increased risk of DLBCL and MZ lymphomas [10]. Taken these findings together we assume that in SLE patients with secondary SS the probability of NHL development may be increased even further, therefore this clinical condition poses danger and this special subset of lupus patients requires thorough follow-up and regular screening for malignancies.

From the etiopathogenic point of view, lupus and various malignancies have common pathogenic background; the genetic predisposition, mutual provoking factors (UV light), viral infection (Epstein–Barr virus), also lifestyle-related risk factors (smoking, obesity). Besides, hormonal factors may represent a link between autoimmunity and malignancy, including insulin-like growth factor (IGF), prolactin, estrogen and growth hormone (GH) [11], [12], [13].

The long-term, in many instances aggressive immunosuppressive treatment in lupus is evidently related to the development of malignant transformations and manifest tumors. Besides these common extrinsic etiological factors, the intrinsic errors of the immune system contribute to the development of both disease entities [11]. In many systemic autoimmune diseases, where disproportional humoral autoimmune responses are pivotal in the pathogenesis (e.g. SLE and SS), exaggerated B-cell processes exist, resembling B-cell malignancies [14], [15]. Both conditions are characterized by cell-cycle regulation abnormalities, which affect lymphocyte survival, proliferation and differentiation, as well. In parallel, programmed cell death is affected, and the longevity of B-cells is apparent [14], [16]. In these processes various cytokines and soluble mediators, such as IL-6, IL-10 and B-cell activating factor (BAFF/BLyS) have been shown to play a major role [14], [17]. Due to chronic antigenic stimulation, B cells contribute to the enhanced levels of circulating BAFF, and also APRIL. The aberrant up-regulation of these cytokines may initiate a vicious cycle, in which enhanced levels of BAFF and proliferation-inducing ligand (APRIL) reinforce the systemic activation of the humoral immune system [18]. Very similar pathogenic machinery has been introduced in B-cell malignancies too [19], which presumes the common pathogenic background behind lupus and malignant transformations. Recent data indicate the importance of CD8+ cytotoxic T lymphocytes (CTL) in limiting the expansion of autoreactive B cells. The CTL population is down regulated in lupus, but mechanisms critical in CTL expansion may differ in SLE from those observed in other conditions, e.g. tumors and infections [20].

We have previously assessed cancer-related morbidity and mortality, the type of malignancies in lupus patients, and analyzed association with immune-suppressive therapy, disease duration, and age based on 860 SLE patients between 1970 and 2004 [21]. A total of 37 patients presented with cancer, reflecting 4.3% cancer-associated morbidity. Patients were 47 (20–73) years old at the onset of malignancy, which appeared 13 (1–45) years later than SLE. Cancer prevalence was the highest in the first 5–10 years of lupus. We found breast cancer was the most common malignancy followed by gastrointestinal tumors, cervix cancer and hematologic malignancies, bronchial cancer, followed by bladder, skin, and ovarian cancer. Standardized incidence ratio was the highest for non-Hodgkin's lymphoma and cervix cancer. Although 76% of patients with cancer received immune-suppressive therapy besides corticosteroids, no direct correlation could be confirmed between therapy and malignancy. In this study, the cancer-associated mortality was 11%, which peaked during the last 4 years of the study period [21].

In the multi-center study, conducted by Bernatsky et al., the incidence of cancer in 9547 SLE patients was assessed, compared with that in the general population (Table 1). Within the average follow-up of 8 years, 431 cancers occurred. The data confirmed an increased risk of cancer among patients with SLE. For all cancers combined, hematologic malignancies, non-Hodgkin's lymphoma, was the leading cause of death. The data also suggested an increased risk of lung cancer and hepatobiliary cancer [22] (Table 2).

Section snippets

Non-Hodgkin's lymphoma and SLE

As previously described, the incidence of NHL in SLE appears to be 3–4× higher, than in the average population (Table 2). Clinically, the identification of NHL in patients with lupus is difficult, since both diseases share similar characteristic features (lymphadenopathy/lymphadenomegaly, fever, weight-loss, hepato-splenomegaly, cytopenia, positive anti-nuclear antibody/ANA), therefore the correct differential diagnosis requires thorough investigations and regular checkup in SLE. Generally, in

Immunosuppressive medications and malignancy development in SLE

Since the pathogenic role of immunosuppressive treatment could contribute to the development of malignancies in SLE, a case-cohort study was performed within a multi-site international SLE cohort; the hazard ratio (HR) was calculated for cancer after exposure to immunosuppressive drugs (e.g. anti-malarial drugs, systemic glucocorticoids, non-steroidal anti-inflammatory drugs/NSAIDs, aspirin). Results were assessed based on 246 cancer cases and 538 controls without cancer. The adjusted HR for

Tumor markers in SLE

The assessment of tumor-associated antigens (TAAs) in the sera of 40 SLE patients indicated that significantly more patients had elevated levels of carcinoembryonic antigen (CEA), cancer antigen (CA)19-9, CA125 and CA72-4. The mean absolute serum levels of CEA and CA15-3 were also significantly higher in SSc compared to controls. Serum CA72-4 correlated with central nervous system involvement, while CA125 correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI);

Conclusions

In patients with SLE, the incidence and risk of malignancy development is increased, and mostly NHL, cervical cancer, as well as bronchial carcinomas occur. The risk of neoplasm development in lupus is the highest in the first year, while in the subsequent years, the prevalence of malignancy is further rising, as a consequence of its general increase in the average population. Based on our survey, the survival of patients from the time of identification of the neoplasm is approximately

Take-home messages

  • Malignancies develop in about 4.5% of lupus patients.

  • The standardized incidence ratio is the highest for non-Hodgkin's lymphomas, Hodgkin's disease, cervical, bronchial and breast cancers.

  • Shared etiopathogenic factors–common genetic predisposition, infections (EBV, STDs), hormonal status (estrogen), lifestyle-related factors (smoking, obesity), UV-light–and the use of immune suppressive agents may explain the increased risk for cancer development in lupus.

  • Over-expression of B-cell activating

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