Mechanistic and clinical insights at the scleroderma-cancer interface

Shah, Ami A.; Casciola‐Rosen, Livia

doi:10.5301/jsrd.5000250

Cited by 24 publications

(19 citation statements)

References 65 publications

(97 reference statements)

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“…It is beyond the scope of this article to review the mechanistic link between cancer and the development of SSc. 37 However, we cannot fail to mention that the close temporal relationship between cancer and SSc among anti-RNAP3+ patients led to the hypothesis that SSc could represent a para-neoplastic disorder in this patients’ subset. 38,39 This hypothesis was supported by the presence of genetic abnormalities (missense mutations or loss of heterozygosity) in the RPC155/POLR3A gene in the cancer tissues from anti-RNAP3+ SSc patients, but not in cancers from other SSc patients.…”

Section: Introductionmentioning

confidence: 86%

Anti-RNA polymerase III antibodies in patients with suspected and definite systemic sclerosis: Why and how to screen

Lazzaroni

Airò

2018

Journal of Scleroderma and Related Disorders

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Anti-RNA Polymerase III antibodies are the most frequent anti-nuclear antibodies in systemic sclerosis, after anticentromere and anti-Topoisomerase I. Considering their specificity for systemic sclerosis, they have been included in 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis. They were first identified in 1993 using an immunoprecipitation method; the subsequent diffusion of commercial assays, based on the enzyme-linked immunosorbent assay or multiplex line immunoblot techniques, has allowed an increasing number of systemic sclerosis patients to be tested for this autoantibody; nevertheless, the diffusion of this test in systemic sclerosis patients is probably still sub-optimal. Anti-RNA Polymerase III antibodies have been associated with important clinical manifestations: rapid and diffuse cutaneous involvement, joint contractures, scleroderma renal crisis, gastric antral vascular ectasia and malignancies synchronous to systemic sclerosis onset. Moreover, other possible clinical associations, including pulmonary hypertension, still need confirmation. Since the correct approach for screening for anti-RNA Polymerase III antibodies in patients with suspected or definite systemic sclerosis is still debated, possible strategies are proposed here. Moreover, issues that are still controversial are discussed, including the interpretation of multiple simultaneous positivity for anti-RNA Polymerase III antibodies and other autoantibodies in line immunoassay, and the possible relevance of anti-RNA Polymerase III antibodies titre.

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Section: Introductionmentioning

confidence: 86%

Anti-RNA polymerase III antibodies in patients with suspected and definite systemic sclerosis: Why and how to screen

Lazzaroni

Airò

2018

Journal of Scleroderma and Related Disorders

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“…Second, the origins of SSc aAbs, that is, the molecular events that initiate their production and the subsequent mechanisms that perpetuate their biosynthesis during the disease course, are important but separate issues that are not addressed herein. 34,40,41 Third, this review does not encompass several other aAbs associated with SSc manifestations such as anti-U3RNP and anti-U11/12RNP or occurring primarily in the setting of an overlap connective tissue disease. 42,43 In addition, this review focuses on aAbs with a well-established molecular specificity rather than using broad generic terms such as anti-endothelial cell (EC) aAbs.…”

Section: Caveatsmentioning

confidence: 99%

Pathogenic roles of autoantibodies in systemic sclerosis: Current understandings in pathogenesis

Senécal

Hoa

Yang

et al. 2019

Journal of Scleroderma and Related Disorders

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The potential pathogenic role for autoantibodies in systemic sclerosis has captivated researchers for the past 40 years. This review answers the question whether there is yet sufficient knowledge to conclude that certain serum autoantibodies associated with systemic sclerosis contribute to its pathogenesis. Definitions for pathogenic, pathogenetic and functional autoantibodies are formulated, and the need to differentiate these autoantibodies from natural autoantibodies is emphasized. In addition, seven criteria for the identification of pathogenic autoantibodies are proposed. Experimental evidence is reviewed relevant to the classic systemic sclerosis antinuclear autoantibodies, anti-topoisomerase I and anticentromere, and to functional autoantibodies to endothelin 1 type A receptor, angiotensin II type 1 receptor, muscarinic receptor 3, platelet-derived growth factor receptor, chemokine receptors CXCR3 and CXCR4, estrogen receptor α, and CD22. Pathogenic evidence is also reviewed for anti-matrix metalloproteinases 1 and 3, anti-fibrillin 1, anti-IFI16, anti-eIF2B, anti-ICAM-1, and anti-RuvBL1/RuvBL2 autoantibodies. For each autoantibody, objective evidence for a pathogenic role is scored qualitatively according to the seven pathogenicity criteria. It is concluded that anti-topoisomerase I is the single autoantibody specificity with the most evidence in favor of a pathogenic role in systemic sclerosis, followed by anticentromere. However, these autoantibodies have not been demonstrated yet to fulfill completely the seven proposed criteria for pathogenicity. Their contributory roles to the pathogenesis of systemic sclerosis remain possible but not yet conclusively demonstrated. With respect to functional autoantibodies and other autoantibodies, only a few criteria for pathogenicity are fulfilled. Their common presence in healthy and disease controls suggests that major subsets of these immunoglobulins are natural autoantibodies. While some of these autoantibodies may be pathogenetic in systemic sclerosis, establishing that they are truly pathogenic is a work in progress. Experimental data are difficult to interpret because high serum autoantibody levels may be due to polyclonal B-cell activation. Other limitations in experimental design are the use of total serum immunoglobulin G rather than affinity-purified autoantibodies, the confounding effect of other systemic sclerosis autoantibodies present in total immunoglobulin G and the lack of longitudinal studies to determine if autoantibody titers fluctuate with systemic sclerosis activity and severity. These intriguing new specificities expand the spectrum of autoantibodies observed in systemic sclerosis. Continuing elucidation of their potential mechanistic roles raises hope of a better understanding of systemic sclerosis pathogenesis leading to improved therapies.

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“…The association of SSc and cancer is not fortuitous and the temporal clustering observed in some patients raises the possibility of SSc as a paraneoplastic syndrome in some patients, as described in other autoimmune conditions such as dermatomyositis (6, 8). However, the connections between the two are more complex than once imagined, and may result from many and diverse mechanisms (9). While immunosuppressants used to treat this autoimmune condition may lead to cancer development (10, 11), cytotoxic anti-cancer therapies have been associated with the development of scleroderma-like features such as Raynaud phenomenon, digital ischemia and fibrosis (12–15).…”

Section: Introductionmentioning

confidence: 99%

Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors

et al. 2019

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Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis. An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer. Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions.

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Mechanistic and clinical insights at the scleroderma-cancer interface

Cited by 24 publications

References 65 publications

Anti-RNA polymerase III antibodies in patients with suspected and definite systemic sclerosis: Why and how to screen

Anti-RNA polymerase III antibodies in patients with suspected and definite systemic sclerosis: Why and how to screen

Pathogenic roles of autoantibodies in systemic sclerosis: Current understandings in pathogenesis

Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors

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