A review on SLE and malignancy

doi:10.1016/j.berh.2017.09.013

Best Practice & Research Clinical Rheumatology

Volume 31, Issue 3, June 2017, Pages 373-396

https://doi.org/10.1016/j.berh.2017.09.013 Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease characterized by autoantibody production, complement activation, and immune complex deposition. It predominantly affects young and middle-aged women. While improvements in the diagnosis and treatment of SLE have altered prognosis, morbidity and mortality rates remain higher than the general population. In addition to renal injury, cardiovascular disease, and infection, malignancy is known to be a significant cause of death in this population. There is increasing evidence to suggest that patients with SLE have a slightly higher overall risk of malignancy. The risk of malignancy in SLE is of considerable interest because the immune and genetic pathways underlying the pathogenesis of SLE and the immunosuppressant drugs (ISDs) used in its management may mediate this altered risk. Our current understanding of these and other risk factors and the implications for treating SLE and screening for malignancy is still evolving.

This review summarizes the association between SLE and malignancy. The first section discusses the risk of overall and site-specific malignancies in both adult- and pediatric-onset SLE. Next, we evaluate the risk factors and possible mechanisms underlying the link between malignancy and SLE, including the use of ISDs, presence of certain SLE-related autoantibodies, chronic immune dysregulation, environmental factors, and shared genetic susceptibility. Finally, we review guidelines regarding cancer screening and vaccination for human papilloma virus.

Section snippets

Overall risk of malignancy

Over the last four decades, there have been numerous studies examining the risk of malignancy in adult patients with systemic lupus erythematosus (SLE) compared to a matched general population. These studies are based either on observational clinical cohorts [1] or cohorts identified through administrative data such as hospital discharge [2] and national health insurance databases [3]; they are summarized in Table 1, and additional details are provided in Supplementary Table 1. In most of these

Immunosuppressive therapy and SLE disease activity

It remains unclear whether ISDs influence susceptibility to malignancy in patients with SLE. Mechanistically, ISDs may theoretically lead to the development of cancer by causing direct mutagenesis and cytotoxicity and by increasing susceptibility to or decreasing clearance of oncogenic viruses. The evidence on the risk of overall and site-specific malignancies, notably hematological and cervical neoplasia, with ISD exposure is summarized in Table 3.

As the use of ISDs is highly correlated with

Malignancy screening and HPV vaccination in SLE

Tessier-Cloutier et al. [110] recently reviewed the evidence regarding malignancy screening in SLE. Of the 25 research articles that suggested some form of screening strategy, most recommendations were rudimentary and based on cancer incidence data from observational cohort studies or a case–control design and none compared the value of alternative screening strategies. Eleven of these 25 studies promoted following the general population cancer screening guidelines, while the remaining 14

Summary

There is increasing evidence supporting the association between malignancy and adult-onset SLE. There is an increased risk for malignancy overall as well as for lung, liver, head and neck, thyroid, vulvar/vaginal, and anal malignancies and cervical dysplasia; a substantially increased risk for hematologic malignancies, particularly NHL, has been consistently observed. In contrast, a decreased risk of hormone-sensitive cancers such as breast and prostate has also been reported. Little is known

Conflict of interest

Dr. Clarke has received consulting fees from AstraZeneca/MedImmune and Exagen Diagnostics (less than $10,000).

Dr. Ramsey-Goldman has received consulting fees from Seattle Genetics, AstraZeneca, and Eli Lilly (less than $10,000).

Acknowledgments

Grant support: Dr. Clarke holds The Arthritis Society Research Chair in Rheumatic Diseases at the University of Calgary.

Dr. Ramsey-Goldman's work was supported by the NIH (grants 5UL1TR001422-02 formerly 8UL1TR000150 and UL-1RR-025741, K24-AR-02318, and P60AR064464 formerly P60-AR-48098).

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The objective of this study was to assess the risk and prevalence of oral cancer in patients with systemic lupus erythematosus (SLE) or discoid lupus erythematosus (DLE).
The review included observational cohort and cross-sectional studies that investigated the incidence or prevalence of oral cancer in adults with confirmed diagnoses of SLE or DLE. Studies were selected based on predefined eligibility criteria, including the use of specific diagnostic criteria for SLE and DLE. After searches in PubMed/MEDLINE, EMBASE, Scopus, Web of Science, LILACS, and LIVIVO databases and gray literature for relevant studies, the selection process was conducted by independent reviewers.
A total of 5,545 articles were identified. After screening, 8 studies met the inclusion criteria. The pooled risk estimate indicated a significantly increased risk of oral cancer in patients with SLE (risk ratio = 2.69; 95% confidence interval, 1.75 to 4.16; I² = 0%; P = .78) compared with the general population. The pooled prevalence of oral cancer in patients with DLE was 10% (95% ci, 0.03 to 0.13; I² = 59%; P = .12).
This review provides evidence supporting an elevated risk for individuals with SLE or DLE developing oral cancer. The findings highlight the importance of monitoring oral mucosa in patients with these conditions.
Identification of prognostic genes for breast cancer related to systemic lupus erythematosus by integrated analysis and machine learning
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Systemic Lupus Erythematosus (SLE) is an autoimmune disease with multi-organ involvement, and some studies have found that SLE has a reduced risk of breast cancer (BRCA). So, we tried to find prognostic genes for BRCA related to SLE by integrated analysis and machine learning.
First, we downloaded 2 SLE datasets from Gene Expression Omnibus (GEO) and BRCA data from the Cancer Genome Atlas (TCGA). Subsequently, we performed differentially expressed genes (DEGs) and functional enrichment analysis by Metascape in SLE. Genes that were differentially expressed in both datasets were the validated DEGs. And after constructing PPI network, genes with nodes >30 were intersected with survival genes in BRCA to obtain candidate genes. Then, the candidate genes were validated by lasso regression in both training and validation sets to obtain prognostic genes. Afterwards, we investigated the diagnostic potential of prognostic genes for SLE and the predictive efficacy for BRCA prognosis. Moreover, GSEA analysis and immune infiltration were performed for SLE and BRCA. Finally, we constructed a prognostic gene-miRNAs network and did functional enrichment of the shared genes.
DEGs for SLE were mainly enriched with neutrophil degranulation and IFN pathways. After the lasso model of BRCA was established, IRF7, IFI35 and EIF2AK2, were identified as prognostic genes for BRCA related to SLE and had good predictive ability for the prognosis of BRCA. Prognostic genes had excellent diagnostic potential for SLE, with IFI35 and EIF2AK2 positively associated with SLE activity and IRF7 positively associated with IFI35. GSEA showed that both SLE and BRCA were associated with ubiquitinated degradation. Immune infiltrates suggest that plasma cells, dendritic cells (DC), neutrophils and monocyte were elevated in SLE. DC, NK and CD8⁺ T cells were elevated in the BRCA low-risk group. Finally, 5 shared miRNAs were confirmed, which were mainly enriched in the IFN pathway.
IRF7, IFI35 and EIF2AK2, were identified as prognostic genes for BRCA related to SLE. IFN pathway played an important role in the etiology of SLE and the prognosis of BRCA.
Oral immune-mediated disorders with malignant potential/association: An overview
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Citation Excerpt :
The irregularity in the insulin-like growth factor 2 (IGF-2) or its receptor (IGF-2r) along with prolactin and growth hormone may lead to malignancy and activates the autoimmune system as well, which has been confirmed by the presence of abnormally high level of hormones in the patients with systemic lupus erythematosus.71–74 The autoantibodies related to the systemic lupus erythematosus are known for impairing DNA repair, leading to the accumulation of DNA, resulting in the increased probability of cancer development in these individuals.75,76 The interesting finding in these affected individuals is the occurrence of a sicca syndrome (which results in dry mouth and dry eyes), which is a similar finding in another autoimmune disease known as primary Sjogren's syndrome.
A group of oral disorders or conditions, which may result from, or could be triggered by an abnormality in the normal immune response of an individual are known as oral immune-mediated disorders. Some of these disorders have malignant potential, while others are associated with malignancy. In this overview, we will discuss a few of the oral diseases (such as oral lichen planus, primary Sjogren's syndrome, systemic lupus erythematosus, dermatitis herpetiformis, and linear immunoglobulin A bullous dermatosis, to name a few), which are caused due to irregularity in the immune system and are either associated with malignancy or capable of undergoing malignant transforming, thereby increasing the morbidity and mortality rate.
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Presence of cell-penetrating anti–double-stranded DNA is associated with a decreased risk of breast cancer [78]. Decreased risk of hormone-sensitive cancers may also be due to less exposure to endogenous and/or exogenous hormones, a result of earlier menopause, and/or avoidance of oral contraceptives or hormone-replacement therapy arising from concerns over adverse outcomes [79]. It is not known if the increased contact of lupus patients with the healthcare system leads to increased cancer surveillance, and potentially early detection of pre-malignant lesions, which may contribute to the decreased incidence of breast and prostate cancer.
Malignancy is a potential comorbidity in patients with systemic lupus erythematosus (SLE). However, risk by malignancy type remains to be fully elucidated. We evaluated the risk of malignancy type in SLE patients in a systematic review and meta-analysis.
MEDLINE and EMBASE were searched from inception to July 2018 to identify observational studies that evaluated malignancy risk in adult SLE patients compared with the general population. Random-effects models were used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Heterogeneity was quantified using the I² test.
Forty-one studies reporting on 40 malignancies (one overall, 39 site-specific) were included in the meta-analysis. The pooled RR for all malignancies from 3694 events across 80 833 patients was 1.18 (95% CI: 1.00–1.38). The risk of 24 site-specific malignancies (62%) was increased in SLE patients. For malignancies with ≥6 studies, non-Hodgkin lymphoma and Hodgkin lymphoma risk was increased >3-fold; myeloma and liver >2-fold; cervical, lung, bladder, and thyroid ≥1.5-fold; stomach and brain >1.3-fold. The risk of four malignancies (breast, uterine, melanoma, prostate) was decreased, whereas risk of 11 other malignancies did not differ between SLE patients and the general population. Heterogeneity ranged between 0% and 96%, and 63% were non-significant.
The risk of overall and some site-specific malignancies is increased in SLE compared with the general population. However, the risk for some site-specific malignancies is decreased or did not differ. Further examination of risk profiles and SLE patient phenotypes may support guidelines aimed at reducing malignancy risk.
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Calcium (optimal intake 1000–1200 mg/d) and vitamin D supplementation are recommended for patients with LN, as well as consideration for oral bisphosphonates according to individual risk assessment.684,685 Patients with SLE have increased risk of malignant tumors, including non-Hodgkin’s lymphoma, lung, liver, vulvar/vaginal, thyroid, nonmelanoma skin cancer, and the risk (especially with bladder cancer) is increased in patients with a history of exposure to cyclophosphamide.686,687 In general, the surveillance for malignancies in patients with LN follows the cancer-screening policies for the general population in the local community, and specific malignancy screening guidelines for patients with SLE are either lacking or largely opinion-based.688

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8A review on SLE and malignancy

Abstract

Section snippets

Overall risk of malignancy

Immunosuppressive therapy and SLE disease activity

Malignancy screening and HPV vaccination in SLE

Summary

Conflict of interest

Acknowledgments

J Autoimmun

The American journal of medicine

Reumatol Clin

Ann Oncol

Leuk Res

Autoimmun Rev

J Urol

Lung Cancer

Gynecol Oncol

Autoimmun Rev

J Pediatr

Autoimmun Rev

Rev Med Interne

Cancer risk in a cohort of patients with systemic lupus erythematosus (SLE) in California

Cancer Causes Control

High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: a long-term followup study in a Danish cohort

Arthritis Rheum

Increased cancer incidence in a Swedish cohort of patients with systemic lupus erythematosus

Scand J Rheumatol

Non-Hodgkin's lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus

Arthritis Rheumatol

Systemic lupus erythematosus and the risk of malignancy

Lupus

Increased risk of cancer in patients with systemic lupus erythematosus

Ann Rheum Dis

Increased risk of malignancy in patients with systemic lupus erythematosus

J Invest Med

Impact of head and neck malignancies on risk factors and survival in systemic lupus erythematosus

Acta Otolaryngol

Cancer incidence and type of malignancy in rheumatologic diseases in Korea: head-to-head comparison

Arthritis Rheum

Cancer complicating systemic lupus erythematosus–a dichotomy emerging from a nested case-control study

Lupus

Incidence of cancer among female patients with systemic lupus erythematosus in Korea

Clin Rheumatol

Occurrence of malignancies in Hungarian patients with systemic lupus erythematosus

Ann N Y Acad Sci

Risk of malignancy in women with systemic lupus erythematosus

J Rheumatol

Is there an association of malignancy with systemic lupus erythematosus? An analysis of 276 patients under long-term review

Rheumatology

Malignancies during follow-up in an epidemiologically defined systemic lupus erythematosus inception cohort in southern Sweden

Lupus

Risk of malignancy in an unselected cohort of Icelandic patients with systemic lupus erythematosus

Lupus

Mortality and cancer incidence in Korean patients with systemic lupus erythematosus: results from the Hanyang lupus cohort in Seoul, Korea

Lupus

Cancer in connective tissue disease

Arthritis Rheumatol

Malignancies associated with systemic lupus erythematosus in Taiwan: a nationwide population-based cohort study

Rheumatol Int

Malignancy in systemic lupus erythematosus

Arthritis Rheumatol

Lung, liver, prostate, bladder malignancies risk in systemic lupus erythematosus: evidence from a meta-analysis

Lupus

Systemic lupus erythematous and malignancy risk: a meta-analysis

PLoS One

Systemic lupus erythematosus and malignancies risk

J Cancer Res Clin Oncol

Description of malignancy rates in childhood-and adult-onset systemic lupus erythematous by proportional meta-analysis

JCR J Clin Rheumatol

The age-risk relationship of haematologic malignancies in female patients with systemic lupus erythematosus: a nationwide retrospective cohort study

Lupus

Non-lymphoma hematological malignancies in systemic lupus erythematosus

Oncology

Patients with systemic lupus erythematosus and haematological malignancy at a tertiary care centre: timing, histopathology and therapy

Lupus Sci Med

Effect of autoimmune diseases on risk and survival in histology-specific lung cancer

Eur Respir J

Increased risk of hepatobiliary cancers after hospitalization for autoimmune disease

Clin Gastroenterol Hepatol

8
A review on SLE and malignancy