Malignancies and soluble tumor antigens in rheumatic diseases

doi:10.1016/j.autrev.2006.03.007

Autoimmunity Reviews

Volume 6, Issue 1, November 2006, Pages 42-47

https://doi.org/10.1016/j.autrev.2006.03.007 Get rights and content

Abstract

Paraneoplastic symptoms, caused by a malignancy, but not directly related to invasion by the tumor or its metastases are the result of a wide variety of tumor-derived biologic mediators like hormones, peptides, antibodies, cytotoxic lymphocytes, autocrine and paracrine mediators. Recognition of paraneoplastic syndromes is important, as it may lead to an early diagnosis of cancer. There is some evidence that systemic inflammatory diseases, such as rheumatoid arthritis (RA), lupus, scleroderma or dermatomyositis may increase the risk for the development of malignancies, predominantly lymphoproliferative disorders. However, reports are somewhat controversial. Immunosuppressive and cytotoxic drugs used in antirheumatic therapy, such as methotrexate, cyclophosphamide, azathioprine or anti-TNF biologicals may also lead to the development of such tumors. Tumor-associated antigens may be produced by inflammatory cells and their production may be increased in RA and other autoimmune diseases.

Introduction

There are various aspects of the association of rheumatic diseases with cancer: 1) Musculoskeletal symptoms and syndromes may develop as paraneoplastic diseases during the presence of malignancies; 2) there may be an increased incidence of tumors in certain systemic inflammatory and autoimmune diseases; 3) some immunosuppressive agents, including DMARDs, may increase the risk for cancer, and 4) circulating tumor markers may be elevated in the sera of patients with arthritis. (Primary or metastatic tumors developing within the musculoskeletal system will not be discussed).

Section snippets

Paraneoplastic syndromes

In the case of paraneoplastic rheumatic disorders, the tumor is at distance from the joints, and the articular and periarticular regions are not affected by the cancer. The symptoms may present as well defined autoimmune and anti-inflammatory disorders that usually occur without malignancy or they can be seen as vasculitis or other joint, bone, muscle or soft tissue diseases. Paraneoplastic musculoskeletal symptoms may precede the development of malignant disease with years but the two

Risks of developing malignancies in rheumatic diseases

There have been numerous reports of the association between rheumatic diseases and the development of tumors, particularly lymphoproliferative disorders (Table 2). Several factors including the autoimmune disease itself, viral factors (e.g. EBV) and others have been implicated in the pathogenesis of tumor development. However, it is difficult to separate disease-derived mechanisms from the potential oncogenic properties of immunosuppressive drugs used in these autoimmune-inflammatory diseases

Immunosuppressive and cytotoxic agents associated with tumor development

Numerous medications used to treat arthritis and autoimmune diseases modulate the immune system. Therefore, these agents may directly or indirectly be associated with the subsequent development of malignancies. Such drugs may confer the risk through direct DNA mutagenesis, generalized immunosuppression increasing the risk of EBV-associated lymphomas or through toxic injury as seen in the urinary bladder when using cyclophosphamide. Longer treatment has been associated with increasing risk of

Soluble tumor antigens in rheumatic diseases

There have been scattered reports, that some tumor-associated antigens (TAA) may, apart from cancer cells, become expressed on the surface of inflammatory cells. We and others have detected carcinoembryonic antigen (CEA)-related antigens (CD66b and CD66c) on neutrophils and monocyte/macrophages. In addition, there is an increased expression of CD66 in the RA synovial tissue in comparison to normal synovia [29], [30]. CEA is present mostly on colorectal and gastric carcinomas, CA15-3 on breast

Conclusions

There is an increasing recognition that neoplasia is associated with a wide range of rheumatic disorders and symptoms. Parts of these are of paraneoplastic origin, but the rheumatic disease itself or immunosuppressive and cytotoxic therapy may also increase the risk for the development of various types of malignancies. Paraneoplastic symptoms may precede the diagnosis of the tumor, and can be predictive of a malignant disease. In certain cases the paraneoplastic symptoms point to the tumor

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In SLE, CA72-4 correlated with central nervous system (CNS) involvement, whereas CA125 correlated with the SLEDAI activity index [51]. Studies by us and others have suggested that these TAAs may also be involved in the adhesive processes of leukocytes, as well as tumor cells [1,50,51]. The lesson for daily clinical practice is that blood levels of sTAA should be evaluated with caution in patients with RMDs!
Oncorheumatology is the meeting point of tumor formation and rheumatic musculoskeletal diseases (RMD). Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. Within the first group, secondary malignancies may be associated with rheumatic diseases. Mostly sustained inflammation is responsible for transition into cancer. Tumor-associated antigens (TAA) with adhesive properties are present on tumor cells. These molecules may also be expressed by inflammatory leukocytes and soluble TAA levels may be elevated in RMDs. There has been continuous debate with respect to the possible carcinogenicity of conventional and targeted antirheumatic drugs. Very recent data from registries suggest that neither biologics, nor JAK inhibitors increase cancer risk in arthritis patients. The issue of physiotherapy in rheumatic patients with recent or current cancer has also been controversial. Some modalities, primarily exercise, may be safely applied to patients with RMD and cancer. The second large topic includes paraneoplastic syndromes. Musculoskeletal paraneoplasias are triggered by tumor-derived mediators. These syndromes are sometimes slightly different from the classical RMDs. Various chemotherapies may also be associated with autoimmune side effects. Recently, these immune-related complications have also been observed in cancer patients treated with immune-checkpoint inhibitors. Sex hormone-deprivation therapies, such as aromatase inhibitors and anti-androgens are widely used for the treatment of breast and prostate cancer, respectively. These compounds may induce bone loss and lead to osteoporosis. Finally, primary and secondary malignancies of the musculoskeletal system may also interest rheumatologists. In this review, the clinical, practical aspects of these eight pillars of oncorheumatology will be discussed.
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Malignancies and soluble tumor antigens in rheumatic diseases

Abstract

Introduction

Section snippets

Paraneoplastic syndromes

Risks of developing malignancies in rheumatic diseases

Immunosuppressive and cytotoxic agents associated with tumor development

Soluble tumor antigens in rheumatic diseases

Conclusions

Rheum Dis Clin North Am

Rheum Dis Clin North Am

Semin Nucl Med

Leuk Res

Eur J Cancer

Am J Med

Clin Immunol Immunopathol

Rheumatic syndromes associated with malignancy

Curr Opin Rheumatol

Rheumatic syndromes: clues to occult neoplasia

Curr Opin Rheumatol

Cancer-associated neuromusculoskeletal syndromes

Postgrad Med

Rheumatic manifestations of neoplasia

Curr Opin Rheumatol

Polymyositis

Berl Klin Wochenshr

Dermatomyositis sine myositis: association with malignancy

J Rheumatol

Elevated cancer incidence in patients with dermatomyositis: a population based study

J Rheumatol

A novel antinuclear antibody associated with a lupus-like paraneoplastic syndrome

Ann Intern Med

Rheumatic diseases and malignancy—is there an association?

Scand J Rheumatol

Prevalence of rheumatic manifestations and antineutrophil cytoplasmic antibodies in haematological malignancies

Rheumatology

Palmar fasciitis and polyarthritis associated with gastric carcinoma: complete resolution after total gastrectomy

Int Med