Risk factors of neoplastic disease in patients with systemic rheumatic disorders

Abstract

Systemic inflammatory rheumatic disorders are associated with an increased risk of malignancy. The mechanism linking malignancy and rheumatic diseases is complex and multidirectional, and is only partially understood. This review focused on the incidence of neoplastic diseases in patients with the most common systemic rheumatic disorders. Rheumatoid arthritis is associated with a risk of malignancy that is about 10% higher than in the general population, and this is more related to the disease itself than to medication. Systemic lupus erythematosus is associated with an increased risk of neoplasms, particularly haematological malignancies such as non-Hodgkin lymphoma. The risk increases with long-lasting active disease. Systemic sclerosis is associated with an increased risk of lung and liver cancer, as well as malignancies of the haematological system. Men and patients with RNA polymerase III antibodies are at a higher risk. Dermatomyositis and polymyositis are subgroups of idiopathic inflammatory myopathy associated with a high risk of malignancy. Male gender and old age are additional risk factors. Other rheumatic diseases are also thought to be associated with an increased risk of cancer. Currently, the data are insufficient for a clear distinction to be made between subgroups at risk. Most patients with systemic autoimmune disorders are at enhanced risk of malignancy to some degree. The management of these patients should include procedures for the early detection of age- and population-specific malignancies, as well as those which are more prevalent in the patient population suffering from the individual rheumatic disease. It is important to note that an atypical disease course or increased treatment resistance for a rheumatic disorder may indicate that the observed changes are an expression of a paraneoplastic syndrome or that a new neoplasm is modifying the clinical course of an already diagnosed rheumatic disease.

Keywords

Rheumatoid arthritis / systemic lupus erythematosus / systemic sclerosis / idiopathic inflammatory myopathy / malignancy

References

[1] Szekanecz Z, Gomez I, Soós B, Bodoki L, Szamosi S, András C, et al. Eight pillars of oncorheumatology: Crossroads between malignancies and musculoskeletal diseases. Autoimmun Rev. 2020; 19: 102658.

[2] Szekanecz Z, Szekanecz E, Bakó G, Shoenfeld Y. Malignancies in autoimmune rheumatic diseases - a mini-review. Gerontology. 2011; 57: 3-10.

[3] Romão VC, Fonseca JE. Disease mechanisms in preclinical rheumatoid arthritis: A narrative review. Front Med (Lausanne). 2022; 9: 689711.

[4] Kundu JK, Surh Y. Emerging avenues linking inflammation and cancer. Free Radic Biol Med. 2012; 52: 2013-37.

[5] Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013; 13: 759-71.

[6] Tang P, Zha L, Ye C, Zhou L. Research progress on the carcinogenesis mechanism of inflammation in ulcerative colitis: a narrative review. Ann Palliat Med. 2021; 10: 11994-2002.

[7] Borm PJA, Tran L, Donaldson K. The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism. Crit Rev Toxicol. 2011; 41: 756-70.

[8] Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420: 860-7.

[9] Schulz N, Lange U, Klemm P. Therapeutic strategies in preclinical stages of rheumatoid arthritis. Pol Arch Intern Med. 2024; 134: 16766.

[10] van Delft MAM, Huizinga TWJ. An overview of autoantibodies in rheumatoid arthritis. J Autoimmun. 2020; 110: 102392.

[11] Turesson C, Rönnelid J, Kastbom A. Autoantibodies as prognostic markers in rheumatoid arthritis. J Transl Autoimmun. 2025; 10: 100291.

[12] Trier NH, Houen G. Anti-citrullinated protein antibodies as biomarkers in rheumatoid arthritis. Expert Rev Mol Diagn. 2023; 23: 895-911.

[13] Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015; 17: 212.

[14] Love T, Solomon DH. The relationship between cancer and rheumatoid arthritis: still a large research agenda. Arthritis Res Ther. 2008; 10: 109.

[15] Fujita S, Nakano K, Nagasu A, Hiramatsu-Asano S, Akagi T, Morita Y. Prognosis and prognostic factors of lung cancer complications in patients with rheumatoid arthritis. Int J Rheum Dis. 2024; 27: e15069.

[16] Kang HS, Kim J, Kim JH, Bang WJ, Choi HG, Yoo DM, et al. The Association of Chronic Periodontitis as a Potential Risk Factor with Rheumatoid Arthritis: A Nested Case-Control Study Using a Korean National Health Screening Cohort. Biomedicines. 2024; 12: 936.

[17] Raittio E, Nascimento GG, Lopez R, Baelum V. Exploring the Bidirectional Relationship Between Periodontitis and Rheumatoid Arthritis in a Large Danish Cohort. ACR Open Rheumatol. 2024; 6: 598-608.

[18] El Hasbani G, E Nassar J, Elsayed Ali AM, Uthman I, Jawad A. The impact of nicotine smoking on spondyloarthritis and rheumatoid arthritis. Reumatismo. 2024; 76: 78-86.

[19] Lai H, Liu Q, Ye Q, Liang Z, Long Z, Hu Y, et al. Impact of smoking cessation duration on lung cancer mortality: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2024; 196: 104323.

[20] Yan MK, Wang C, Wolfe R, Mar VJ, Wluka AE. Association Between Low-Dose Methotrexate Exposure and Melanoma: A Systematic Review and Meta-analysis. JAMA Dermatol. 2022; 158: 1157-66.

[21] Wadström H, Frisell T, Askling J; Anti-Rheumatic Therapy in Sweden (ARTIS) Study Group. Malignant Neoplasms in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors, Tocilizumab, Abatacept, or Rituximab in Clinical Practice: A Nationwide Cohort Study From Sweden. JAMA Intern Med. 2017; 177: 1605-12.

[22] Alten R, Kaine J, Keystone E, Nash P, Delaet I, Genovese MC. Long-term safety of subcutaneous abatacept in rheumatoid arthritis: integrated analysis of clinical trial data representing more than four years of treatment. Arthritis Rheumatol. 2014; 66: 1987-97.

[23] Simon TA, Smitten AL, Franklin J, Askling J, Lacaille D, Wolfe F, et al. Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment. Ann Rheum Dis. 2009; 68: 1819-26.

[24] Huss V, Bower H, Wadström H, Frisell T, Askling J; group A, et al. Short- and longer-term cancer risks with biologic and targeted synthetic disease-modifying antirheumatic drugs as used against rheumatoid arthritis in clinical practice. Rheumatology (Oxford). 2022; 61: 1810-8.

[25] Lauck KC, Ahmed A, Davis MJ, Council ML, Nehal K, Alam M. Cutaneous malignancy after biologic therapy for inflammatory disease: An active comparator, retrospective cohort study. J Am Acad Dermatol. 2025;S0190-962202184-X.

[26] Singh N, Li CI. Impact of rheumatoid arthritis and biologic and targeted synthetic disease modifying antirheumatic agents on cancer risk and recurrence. Curr Opin Rheumatol. 2021; 33: 292-9.

[27] Molina-Collada J, Alonso F, Otero L, Bohórquez C, Torné CD, García CP, et al. Cancer risk with biologic and targeted synthetic DMARDs in patients with rheumatic diseases and previous malignancies: Results from the BIOBADASER register. Semin Arthritis Rheum. 2024; 64: 152341.

[28] Wadström H, Pettersson A, Smedby KE, Askling J. Risk of breast cancer before and after rheumatoid arthritis, and the impact of hormonal factors. Ann Rheum Dis. 2020; 79: 581-6.

[29] Hoi A, Igel T, Mok CC, Arnaud L. Systemic lupus erythematosus. Lancet. 2024; 403: 2326-38.

[30] Apor E, O’Brien J, Stephen M, Castillo JJ. Systemic lupus erythematosus is associated with increased incidence of hematologic malignancies: a meta-analysis of prospective cohort studies. Leuk Res. 2014; 38: 1067-71.

[31] Dreyer L, Faurschou M, Mogensen M, Jacobsen S. High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: a long-term followup study in a Danish cohort. Arthritis Rheum. 2011; 63: 3032-7.

[32] Ni J, Qiu L, Hu L, Cen H, Zhang M, Wen P, et al. Lung, liver, prostate, bladder malignancies risk in systemic lupus erythematosus: evidence from a meta-analysis. Lupus. 2014; 23: 284-92.

[33] Volkmann ER, Andréasson K, Smith V. Systemic sclerosis. Lancet. 2023; 401: 304-18.

[34] Kucharz EJ, Kopeć-Mędrek M. Systemic sclerosis sine scleroderma. Adv Clin Exp Med. 2017; 26: 875-80.

[35] Giannini M, Ellezam B, Leclair V, Lefebvre F, Troyanov Y, Hudson M, et al. Scleromyositis: A distinct novel entity within the systemic sclerosis and autoimmune myositis spectrum. Implications for care and pathogenesis. Front Immunol. 2023; 13: 974078.

[36] Onishi A, Sugiyama D, Kumagai S, Morinobu A. Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies. Arthritis Rheum. 2013; 65: 1913-21.

[37] Kuo CF, Luo SF, Yu KH, Chou IJ, Tseng WY, Chang HC, et al. Cancer risk among patients with systemic sclerosis: a nationwide population study in Taiwan. Scand J Rheumatol. 2012; 41: 44-9.

[38] Szekanecz É, Szamosi S, Horváth Á, Németh Á, Juhász B, Szántó J, et al. Malignancies associated with systemic sclerosis. Autoimmun Rev. 2012; 11: 852-5.

[39] Carbonell C, Marcos M, Guillén-Del-Castillo A, Rubio-Rivas M, Argibay A, Marín-Ballvé A, et al.; RESCLE Investigators, Autoimmune Diseases Study Group (GEAS). Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE). Autoimmun Rev. 2022; 21: 103167.

[40] Lepri G, Catalano M, Bellando-Randone S, Pillozzi S, Giommoni E, Giorgione R, et al. Systemic Sclerosis Association with Malignancy. Clin Rev Allergy Immunol. 2022; 63: 398-416.

[41] Kim JS, Woods A, Gutierrez-Alamillo L, Laffoon M, Wigley FM, Hummers LK, et al. Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course. Arthritis Rheumatol. 2024; 76: 68-77.

[42] Wallwork RS, Shah AA, Casciola-Rosen L. Association between anti-SSSCA1 antibodies and cancer in systemic sclerosis. Rheumatology (Oxford). 2023; 62: 2539-43.

[43] Xu GJ, Shah AA, Li MZ, Xu Q, Rosen A, Casciola-Rosen L, et al. Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer. Proc Natl Acad Sci U S A. 2016; 113: E7526-34.

[44] Connolly CM, Gupta L, Fujimoto M, Machado PM, Paik JJ. Idiopathic inflammatory myopathies: current insights and future frontiers. Lancet Rheumatol. 2024; 6: e115-27.

[45] Didona D, Solimani F, Caposiena Caro RD, Sequeira Santos AM, Hinterseher J, Kussini J, et al. Dermatomyositis: a comprehensive review of clinical manifestations, serological features, and therapeutic approaches. Ital J Dermatol Venerol. 2023; 158: 84-98.

[46] Kardes S, Gupta L, Aggarwal R. Cancer and myositis: Who, when, and how to screen. Best Pract Res Clin Rheumatol. 2022; 36: 101771.

[47] Kilinc OC, Ugurlu S. Clinical features of dermatomyositis patients with anti-TIF1 antibodies: A case based comprehensive review. Autoimmun Rev. 2023; 22: 103464.

[48] Tonutti A, Ceribelli A, Gremese E, Colafrancesco S, Santis MD, Selmi C. Cancer in connective tissue disease. Front Immunol. 2025; 16: 1571700.

[49] Luo R, Xia D, Yu S. A meta-analysis of melanoma risk in idiopathic inflammatory myopathy patients. Z Rheumatol. 2024; 83: 299-304.

[50] Oldroyd AGS, Callen JP, Chinoy H, Chung L, Fiorentino D, Gordon P, et al. International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening: an International Myositis Assessment and Clinical Studies Group (IMACS) initiative. Nat Rev Rheumatol. 2023; 19: 805-17.

[51] Ansari N, Salesi M. The association between primary Sjogren’s syndrome and non-Hodgkin’s lymphoma: a systematic review and meta-analysis of cohort studies. Clin Rheumatol. 2024; 43: 2177-86.

[52] Zhong H, Liu S, Wang Y, Xu D, Li M, Zhao Y, et al. Primary Sjögren’s syndrome is associated with increased risk of malignancies besides lymphoma: A systematic review and meta-analysis. Autoimmun Rev. 2022; 21: 103084.

[53] Gandolfo S, Bombardieri M, Pers J, Mariette X, Ciccia F. Precision medicine in Sjögren’s disease. Lancet Rheumatol. 2024; 6: e636-47.

[54] Kapsogeorgou EK, Voulgarelis M, Tzioufas AG. Predictive markers of lymphomagenesis in Sjögren’s syndrome: From clinical data to molecular stratification. J Autoimmun. 2019; 104: 102316.

[55] Wyatt NE, Derebail VK, Falk RJ, Jain K. Antineutrophil Cytoplasmic Antibodies (ANCAs): Role in Diagnosis, Disease Monitoring, and Prognosis. J Am Soc Nephrol. 2025; 36: 1428-38.

[56] Nocturne G, Virone A, Ng W, Guern VL, Hachulla E, Cornec D, et al. Rheumatoid Factor and Disease Activity Are Independent Predictors of Lymphoma in Primary Sjögren’s Syndrome. Arthritis Rheumatol. 2016; 68: 977-85.

[57] Ungprasert P, Sanguankeo A, Upala S, Knight EL. Risk of malignancy in patients with giant cell arteritis and polymyalgia rheumatica: a systematic review and meta-analysis. Semin Arthritis Rheum. 2014; 44: 366-70.

[58] Toker M, Ghersin H, Khanna U, Schwartz R, Kumthekar A, Wu B. IgA vasculitis and malignancy: A systematic review. J Eur Acad Dermatol Venereol. 2024; 38: e41-4.

[59] Yu L, Yan Y, Liu W, Huang S, Sun L, Ruan S. Association of ankylosing spondylitis with the risk of cancer: a meta-analysis of cohort studies. Rheumatology (Oxford). 2025; 64: 440-54.

[60] Deng C, Li W, Fei Y, Li Y, Zhang F. Risk of malignancy in ankylosing spondylitis: a systematic review and meta-analysis. Sci Rep. 2016; 6: 32063.

[61] Ao Y, Wen Y, Li Y, Peng H, Wu X, Wang Z, et al. Ankylosing Spondylitis and the Risk of Lung Cancer: A Meta-Analysis and Mendelian Randomization. Front Genet. 2022; 13: 861984.

[62] Fischer S, Meisinger C, Freuer D. Autoimmune diseases and female-specific cancer risk: A systematic review and meta-analysis. J Autoimmun. 2024; 144: 103187.

[63] Zhou J, Fu R, Zhang J, Zhang S, Lin Z, Lin Z, et al. Association between serum uric acid and colorectal cancer risk in European population: a two-sample Mendelian randomization study. Front Oncol. 2024; 14: 1394320.