In this study, a bidirectional MR analysis was conducted to investigate the relationship between RA and two outcomes, namely BNBAC and MNBAC. Eight MR methods were employed for the analysis. While some of the results obtained from different analysis methods showed inconsistencies, these discrepancies did not substantially impact our findings. Among the methods used, the random effects IVW approach exhibited greater statistical power, making it the primary analytical method employed in this study. Consequently, the findings from our investigation suggest a positive genetic causality between RA and MNBAC, implying that RA serves as a risk factor for MNBAC. However, no evidence of genetic causality was found between RA and BNBAC, RA and MNBAC, or MNBAC and RA.

The immune system plays a pivotal role in the pathogenesis of tumors, exerting multifaceted and intricate influences. Certain types of tumors exhibit a heightened incidence of chronic inflammation and infection, establishing a clear connection between tumor development and these immunological factors. RA, an autoimmune disease characterized by abnormal lymphocyte activity and the generation of autoantibodies against self-antigens, is associated with suppressed immune function. Consequently, dysfunctional immune surveillance and immunosuppression are recognized as risk factors for various types of cancer [31]. Moreover, the utilization of immunosuppressants is linked to an increased susceptibility to tumors. The etiology of tumor risk in RA patients may involve genetic predisposition and gene-environment interactions [7]. Furthermore, the usage of antirheumatic medications is associated with the tumor risk in RA patients [7]. Studies have demonstrated an augmented likelihood of severe infections and a dose-dependent escalation in malignancy risk among RA patients undergoing treatment with anti-tumor necrosis factor (TNF) antibodies [32]. Prolonged use of fostamatinib in patients with RA has also been shown to potentially increase the risk of malignancy [33]. Additionally, chemotherapy, a commonly employed therapeutic approach for cancer, is frequently implicated in immune system impairment and the subsequent elevated risk of autoimmune disorders such as RA. Although the underlying mechanisms remain unclear, it is plausible that genetic and environmental factors contribute to this process [34].

Estrogen metabolites have been implicated in RA and tumor development, and certain estrogen metabolites used for assessing cancer risk also play a significant role in RA. The precise pathway underlying RA-related malignancy remains elusive. One possible mechanism involves the enzymatic or nonenzymatic oxidation of estrogen, resulting in the formation of catechol estrogen metabolites through the semiquinone and quinone redox cycle. This process generates free radicals capable of inducing DNA modifications. These modifications alter the immunogenicity of DNA, triggering various immune responses that lead to elevated levels of tumor and RA antibodies [31]. It is imperative to recognize the variances in estrogen levels across different age groups when examining the potential association between estrogen, RA, and malignancy. As is widely acknowledged, the primary age of RA onset is typically between 30 and 50 years. However, many benign and malignant bone tumors, including osteosarcoma and Ewing’s sarcoma, predominantly manifest during adolescence. In addition, certain bone tumors manifest in middle to late adulthood; for instance, chondrosarcoma is more prevalent in the adult and elderly populations, while malignant lymphoma is commonly diagnosed in individuals aged 40 to 60 years. Additionally, myeloma is more frequently observed in those over the age of 40. Consequently, any estrogen hypothesis positing an association between RA and malignancy must carefully account for patient age, given the age-related variations in estrogen levels. RA patients exhibit a higher incidence of malignancies compared to the general population. RA-associated malignancies include lung cancer, skin cancer, myeloma, non-Hodgkin’s lymphoma and Hodgkin’s disease, lymphoma associated with TNF inhibitors, leukemia, breast cancer, colorectal cancer, and prostate cancer. These malignancies can be attributed to RA medications or the inflammation itself [31]. Disease-modifying anti-rheumatic drugs (DMARDs) currently represent the primary treatment for RA. These drugs modulate the normal immune pathway, influencing the growth and survival of malignant tumors. Although long-term immune dysregulation and inflammatory responses contribute to RA development, they may also increase the risk of cancer. Despite the elevated risk of certain tumors observed in RA patients, the exact mechanism remains unknown due to the complex etiology of the disease. In RA patients, prolonged and sustained activation of the immune system may drive the initiation and progression of cancer, potentially mediated by interleukin-6 (IL-6), which could serve as a common link between RA and cancer [35].

In the context of bone tumor age demographics, a preponderance of cases is observed among adolescents. Benign bone tumors, specifically osteoid osteoma, exhibit a predilection for manifestation in children and adolescents, while osteochondroma primarily afflicts individuals in the adolescent age group. Conversely, malignant bone tumors display distinct patterns: osteosarcoma demonstrates a proclivity towards occurrence in adolescent males, chondrosarcoma tends to affect adults and the elderly, with a male predilection, Ewing’s sarcoma is more frequently diagnosed in children, predominantly males, malignant lymphoma exhibits a peak incidence between the ages of 40 and 60, and myeloma typically presents in males above the age of 40. Although the spectrum of bone tumors is multifaceted, the most prevalent entities are osteosarcoma and Ewing’s sarcoma, both of which predominantly manifest in adolescent males. The general population’s annual incidence of osteosarcoma stands at 2–3 cases per million, although this figure escalates among adolescents, with the highest prevalence occurring within the 15–19 age group, reaching 8–11 cases per million annually. Notably, within this age cohort, osteosarcoma constitutes 15% of all solid extracranial malignancies. Males are afflicted by this condition 1.4 times more frequently than females [36]. Ewing’s sarcoma ranks as the second most prevalent bone tumor among children and adolescents. Data spanning from 1973 to 2004 in the USA documented an incidence rate of 2.93 cases per 1 million. Ewing’s sarcoma exhibits a higher prevalence in the white population, with a slight male predominance [37]. In contrast, RA, characterized as a systemic autoimmune disorder, displays a higher incidence among women. While RA can manifest at any age, its prevalence peaks between the ages of 30 and 50 [2]. The distinction between the demographics of bone tumors, primarily affecting adolescent males, and RA, primarily occurring in middle-aged females, underscores the absence of a discernible age and gender-related association between these two conditions. As our findings suggest, any potential link between RA and bone tumors likely resides at the genetic level.

In this study, our findings suggest a potential association between RA and an increased risk of MNBAC. While no MNBAC cases were observed among the tumor types associated with increased tumor risk in RA patients, the high prevalence of other tumors in this population contributes to the overall conclusion of this investigation. We postulate that the elevated incidence of MNBAC in RA patients may be attributed to the perturbed immune system in these individuals as well as the pharmacological interventions employed for RA treatment. As with any scientific inquiry, it is crucial to acknowledge the inherent limitations of this study. The presence of a limited number of genetic instruments or potential overlap in the sample between exposure and outcome variables may have introduced certain biases. Moreover, the utilization of GWAS summary data exclusively derived from European populations restricts the generalizability of the results to broader demographic groups.