Adalimumab is a fully human monoclonal antibody that specifically targets and blocks the binding of TNF-α to its receptors. This mechanism of action inhibits the release of pro-inflammatory cytokines, reduces systemic inflammation, and helps to slow the progression of cartilage and bone damage (Filippini et al., 2010). Due to its targeted action, adalimumab is considered a key therapeutic option for patients with EORA. Clinical studies demonstrate that in patients aged ≥65 years, adalimumab achieves a 38.8% improvement in DAS28 scores, comparable to the 37.5% improvement observed in patients aged 18–65 years (p > 0.05). However, improvements in functional scores (HAQ) tend to be somewhat lower in elderly patients (see Table 1), which may be attributed to factors such as delayed treatment initiation, age-related immune system decline, and the greater burden of comorbidities (Veerasubramanian et al., 2024). While adalimumab is highly effective in halting bone damage and improving quality of life, its safety profile in elderly patients—especially those with compromised immune function—remains a significant concern. The most commonly reported adverse effects of adalimumab include an increased risk of infections, such as reactivation of tuberculosis and fungal infections, as well as malignancies, including skin cancer and lymphoma. These risks are particularly pronounced in older individuals who may already be immunosuppressed (Cometi et al., 2020). Studies indicate that the relative risk of severe infections in elderly patients treated with TNF-α inhibitors is 1.59 (95% CI: 1.45–1.76), with heightened risk in patients with underlying cardiovascular disease or a history of malignancy (Pavlov-Dolijanovic et al., 2023). Additionally, secondary treatment failure frequently occurs, with initial efficacy often diminishing over time, leading to eventual discontinuation of therapy. The discontinuation rate of adalimumab in elderly patients (21.8%) is significantly higher than in younger patients (16.9%, p < 0.05). This difference is primarily attributed to side effects, poor treatment tolerance, and the high costs associated with biologic therapies (Gossec et al., 2024). From a clinical management perspective, adalimumab is most suitable for patients with high disease activity but relatively low risks of infection and malignancy. For patients at an elevated risk of infection, alternative biologic agents such as abatacept or tocilizumab should be prioritized (Jiang et al., 2024; Choi et al., 2023). Given the potential for serious side effects, long-term monitoring of elderly patients on adalimumab therapy should focus on assessing disease activity (DAS28, HAQ), inflammatory markers (CRP, ESR), and any adverse events. Treatment regimens should be adjusted accordingly to balance efficacy and safety, with careful consideration given to dosing intervals and potential modifications based on individual patient response.

Etanercept is a soluble tumor necrosis factor receptor fusion protein that binds competitively to TNF-α, thereby inhibiting its interaction with cell surface receptors. This mechanism effectively suppresses inflammation and delays joint and bone damage (Filippini et al., 2010). Etanercept has shown sustained efficacy in preventing bone destruction and improving inflammatory markers. Its relatively lower risk of infections provides a therapeutic advantage in elderly patients. However, some studies have reported suboptimal functional improvement (e.g., in HAQ scores) among elderly patients, which may be attributed to the burden of comorbidities and delayed treatment initiation. Regarding safety, the primary adverse effects associated with etanercept include infections (such as pneumonia and reactivation of tuberculosis) and injection site reactions. Etanercept is associated with a lower risk of infections than adalimumab (OR = 0.79, 95% CI: 0.46–1.34), and is generally better tolerated (D'Arcy et al., 2021). Nevertheless, etanercept may still be linked to an increased risk of skin cancer and lymphoma, requiring regular monitoring of the skin and lymphatic system in patients. The discontinuation rate of etanercept is primarily influenced by infection risks and injection site reactions, with the high cost of treatment also contributing to reduced patient adherence. Despite these challenges, etanercept typically demonstrates a higher drug retention rate in EORA patients compared to adalimumab, particularly in those with high disease activity but a lower risk of infections (Jiang et al., 2024). Overall, both adalimumab and etanercept are effective TNF-α inhibitors that improve DAS28 scores and slow bone damage in EORA patients. However, they differ significantly in terms of safety profiles and patient suitability. Adalimumab carries a higher risk of infections and malignancies (see Table 1), making it more appropriate for patients with a low risk of infection. In contrast, etanercept, with its lower infection risk and better tolerability, is generally better suited for elderly patients with fewer comorbidities. Although injection site reactions are more common with etanercept, its overall tolerability is superior to that of adalimumab. Long-term follow-up should focus on dynamically monitoring disease activity (e.g., DAS28 and HAQ scores), inflammatory markers, and adverse events. Treatment regimens should be adjusted based on individual patient responses to minimize the cumulative impact of potential side effects.

Tofacitinib is an oral Janus kinase (JAK) inhibitor that modulates the JAK-STAT signaling pathway, effectively reducing both joint and systemic inflammation in patients with EORA. This mechanism makes it a valuable therapeutic option for patients who have not responded adequately to conventional DMARDs or TNF-α inhibitors. Clinical studies have shown that tofacitinib provides comparable improvements in DAS28 scores in elderly patients as it does in younger individuals, demonstrating its effectiveness in disease control. However, concerns about its safety, especially in the elderly, have emerged. Compared to younger patients, elderly individuals (≥65 years) receiving tofacitinib have a significantly higher risk of serious adverse events (SAEs) — 17.56 per 100 patient-years versus 8.44 per 100 patient-years in younger cohorts. Additionally, elderly patients are at twice the risk of herpes zoster infections (6.40 vs 3.76 per 100 patient-years), and face elevated risks of venous thromboembolism and malignancy, particularly at the 10 mg dose. Notably, the risk of venous thromboembolism in this group is substantially increased, with a hazard ratio (HR) of 5.02 (95% CI: 1.44–17.47) (Shih et al., 2024). Given these risks, careful monitoring is essential when using tofacitinib, especially in elderly patients who typically have a reduced immune response and multiple comorbidities. The oral formulation of tofacitinib offers convenience, particularly for older patients who may struggle with adherence to injectable therapies. However, when compared to other JAK inhibitors, like upadacitinib, tofacitinib shows somewhat weaker effects in improving quality of life and reducing morning stiffness (Duran et al., 2022). Especially in patients with higher disease activity, clinical practice requires balancing effective treatment with monitoring for potential safety concerns. Adjustments to treatment, including dose modifications or closer monitoring for infections and thromboembolic events, may be necessary to ensure that the benefits of tofacitinib outweigh the risks (Wang et al., 2024). In summary, while tofacitinib represents a promising therapeutic option for EORA patients, its potential safety issues necessitate vigilant monitoring and individualized treatment strategies to mitigate risks while optimizing outcomes.

Baricitinib is a selective inhibitor of Janus kinases 1 (JAK1) and 2 (JAK2) that modulates the JAK-STAT signaling pathway, effectively reducing both joint and systemic inflammation in patients with EORA. It has demonstrated significant efficacy in patients with high disease activity, particularly in those who have not responded adequately to conventional DMARDs. Long-term studies show that both 2 mg and 4 mg doses of baricitinib consistently improve DAS28 scores and ACR20 response rates, with a notable advantage in controlling inflammation (Taylor et al., 2022). However, despite its strong therapeutic benefits, safety concerns with baricitinib should be carefully considered. In elderly patients, the incidence of serious infections is 5.5 cases per 100 patient-years, compared to 2.1 cases per 100 patient-years in younger patients. Pneumonia (0.6 cases per 100 patient-years) and herpes zoster (0.3 cases per 100 patient-years) are the most common infections observed. Additionally, there is an increased risk of venous thromboembolism (VTE), with deep vein thrombosis occurring at a rate of 0.49 cases per 100 patient-years and pulmonary embolism at 0.26 cases per 100 patient-years. The incidence of major adverse cardiovascular events (MACE) is 0.5 cases per 100 patient-years, highlighting the need for close monitoring of infection and thrombotic risks when using baricitinib (Keystone et al., 2015). Compared to tofacitinib, baricitinib carries a more pronounced risk of lipid abnormalities, especially in elderly patients who may require more frequent monitoring of lipid profiles. Despite these safety concerns, the rapid onset of action and stable long-term efficacy of baricitinib make it an important option for treating patients with high disease activity in EORA. In clinical practice, it is crucial to monitor not only infection risks but also lipid levels and cardiovascular health throughout treatment to ensure an optimal balance between efficacy and safety. Baricitinib is particularly well-suited for patients with higher quality-of-life demands, as it is especially effective in alleviating morning stiffness and joint pain (Genovese et al., 2016). This makes it complementary to other JAK inhibitors, such as upadacitinib, which may target different aspects of the disease. Ultimately, treatment with baricitinib requires individualized dosing (2 mg or 4 mg), tailored to each patient’s specific risk profile, along with regular monitoring of relevant blood parameters and infection indicators. By doing so, clinicians can maximize the therapeutic benefits of baricitinib while minimizing potential safety risks (Virtanen et al., 2024).

Upadacitinib is a novel, selective JAK1 inhibitor that, due to its high selectivity, significantly reduces the risk of off-target adverse effects. In multiple clinical trials, upadacitinib has shown a rapid onset of action and potent anti-inflammatory effects, particularly in improving pain, morning stiffness, and overall quality of life, outperforming adalimumab. The SELECT-MONOTHERAPY trial results showed that upadacitinib monotherapy significantly increased the ACR20 response rate at 14 weeks (68% vs 41%, p < 0.001), with a corresponding improvement in DAS28-CRP scores (Kiełbowski et al., 2024). Furthermore, the SELECT-EARLY trial revealed that upadacitinib outperformed methotrexate (MTX) monotherapy in both efficacy and radiographic improvements, highlighting its potential as an early treatment option for EORA (Strand et al., 2021). Compared to baricitinib, upadacitinib shows superior efficacy in relieving morning stiffness and pain, along with significant improvements in both ACR20 and DAS28 scores. These factors make it a competitive option for patients with high disease activity in EORA. However, safety concerns with upadacitinib should not be overlooked. Its primary adverse events include infections (including upper respiratory infections and herpes zoster) and liver dysfunction (see Table 1). Research showns that the incidence of serious adverse events is 4.7%, with venous thromboembolism occurring in 0.6% of patients and liver function abnormalities in 0.8% (Fleischmann et al., 2019). While upadacitinib may present a slightly lower infection risk than tofacitinib and baricitinib, pneumonia and lipid abnormalities still require close monitoring, particularly in elderly patients. To minimize adverse reactions, reducing the dose from 30 mg to 15 mg and regularly monitoring liver function, blood lipids, and infection risks are recommended. This approach can help optimize long-term therapeutic efficacy while minimizing safety concerns (Smolen et al., 2019). Consequently, upadacitinib is particularly suited for EORA patients with higher quality-of-life demands, especially those seeking better control over morning stiffness and joint pain. However, clinical use should be individualized, with close monitoring to maintain a balance between efficacy and safety based on each patient’s specific risk profile.

Secukinumab is a fully humanized monoclonal antibody that targets interleukin-17A (IL-17A). It works by blocking the binding of IL-17A to its receptor, thereby inhibiting the release of pro-inflammatory cytokines and reducing joint and systemic inflammation in patients with EORA. In treating EORA, secukinumab not only effectively controls disease activity but also offers an important alternative for patients who do not respond to or cannot tolerate traditional TNF-α inhibitors (Sato et al., 2006). Clinical studies have consistently demonstrated secukinumab’s significant efficacy in treating EORA. For example, a Phase III trial showed that after 12 weeks of treatment, secukinumab significantly increased the ACR20 response rate to over 60%, outperforming the placebo group. Further meta-analyses revealed that in patients with inadequate response to TNF-α (TNF-IR), secukinumab achieved ACR50 and ACR70 response rates that were 1.94 and 2.11 times higher than those of the placebo group, respectively (p < 0.01). Importantly, this efficacy was sustained over the long term, leading to substantial improvements in disease remission and functional recovery (Wu et al., 2019; Genovese et al., 2010). These findings highlight secukinumab’s potential not only in improving short-term symptoms but also in playing a critical role in long-term disease management strategies for EORA patients. In terms of safety, secukinumab has shown good tolerability, particularly concerning infection risk. The most common adverse events are mild infections (such as upper respiratory tract infections) and injection site reactions (see Table 1), while the incidence of severe infections remains relatively low—around 2.5%–3.0%, which is lower than the infection rates typically seen with TNF-α inhibitors. This relatively lower infection risk makes secukinumab an attractive option for elderly EORA patients (Kunwar et al., 2016; Chabaud et al., 1999). However, injection site reactions remain a frequent reason for discontinuation, highlighting the importance of targeted management and patient education to improve adherence and overall treatment experience. Secukinumab’s value in the treatment of EORA lies in its favorable balance between efficacy and safety. It is particularly well-suited for patients with high disease activity and a low infection risk. In clinical practice, selecting the appropriate patients and addressing injection site reactions can further enhance both the treatment’s effectiveness and patient satisfaction, making secukinumab a strong treatment option for EORA patients.

Guselkumab is a fully humanized monoclonal antibody that targets interleukin-23 (IL-23) by binding to its p19 subunit thereby inhibiting its signaling. This action prevents the differentiation of Th17 cells and the associated pro-inflammatory responses. IL-23 activates Th17 cells through the JAK-STAT pathway, which contributes to the inflammatory processes and bone loss observed in rheumatoid arthritis (RA). Studies have shown that IL-23 levels are significantly elevated in the serum and synovial fluid of RA patients, with the levels correlating closely with disease activity and bone erosion, supporting the potential of IL-23 as a therapeutic target for RA. In terms of efficacy, guselkumab has demonstrated strong anti-inflammatory effects in other immune-mediated diseases, such as psoriasis and psoriatic arthritis. However, its clinical efficacy for the treatment of EORA remains inconclusive. A Phase II clinical trial showed guselkumab failed to significantly improve DAS28 scores or meet primary efficacy endpoints, suggesting that its effectiveness in RA treatment requires further investigation. This suggests that, while guselkumab has shown promise in managing other immune-mediated diseases, its potential application in EORA still requires more robust clinical data to support its use (Yuan et al., 2019; Pastor-Fernández et al., 2020). From a safety perspective, guselkumab has generally shown good tolerability. The most common adverse events include mild infections (e.g., upper respiratory tract infections) and injection site reactions, while the incidence of severe infections is low, comparable to other biologic agents (see Table 1). However, since IL-23 plays a crucial role in maintaining immune tolerance, long-term inhibition of IL-23 may increase the risk of autoimmune diseases or infections. Therefore, regular monitoring of patients—especially those in the EORA population, who have a higher risk of infection—is critical during treatment. Although current clinical evidence does not fully support the widespread use of guselkumab in the treatment of EORA, its mechanism of inhibiting the IL-23/IL-17 axis offers a promising new therapeutic approach. As more clinical research and data accumulate, guselkumab may become an important therapeutic option for patients with EORA.

Abatacept is a T-cell co-stimulation inhibitor that works by selectively blocking T-cell activation, thereby reducing the transmission of inflammatory signals. It is particularly well-suited for EORA, who often have compromised immune systems and a higher risk of infections. As such, abatacept has become a key treatment option in the management of EORA (Nawrot et al., 2018). Clinical studies have shown that there is no significant difference in treatment outcomes between RA patients aged ≥65 years and those aged <65 years, with abatacept demonstrating comparable efficacy in both groups (Serhal et al., 2020). This suggests that abatacept offers stable and reliable efficacy in elderly patients, especially in those with impaired immune function. Additionally, abatacept has a notably higher drug retention rate compared to other biologics, with a median retention period of 254.1 weeks—significantly longer than that of TNF-α inhibitors (184 weeks) and JAK inhibitors (139.1 weeks). Its 2-year retention rate is 66.3%, further emphasizing its sustained effectiveness in long-term treatment (Rasch et al., 2003). These findings suggest that abatacept not only effectively controls disease activity in the short term but also provides long-lasting therapeutic benefits, which is particularly important for elderly patients who require ongoing treatment. Despite its strong efficacy and safety profile, inadequate response remains the primary reason for treatment discontinuation in elderly patients, with approximately 66.1% of patients stopping treatment due to insufficient effectiveness (Manfredi et al., 2024). Other factors such as smoking, joint erosion, and diabetes have also been identified as major risk factors for discontinuation (Sugihara, 2022). These considerations highlight the need for personalized treatment plans that take into account individual patient characteristics, in order to better manage disease progression and reduce the likelihood of premature discontinuation. Additionally, the economic burden of treatment can significantly affect adherence, particularly when the costs are high. Therefore, it is essential to factor in the patient’s immune status, comorbidities, and financial situation when developing a treatment strategy. Regular monitoring of disease activity and health status is also crucial to ensure timely adjustments to the treatment plan, maximizing efficacy while minimizing adverse effects (Ebina et al., 2019). With its low infection risk and long drug retention period, abatacept provides a safe and effective treatment option for elderly EORA patients, particularly those with compromised immune systems and a higher risk of infections. This positions it as one of the most clinically valuable therapeutic options for this patient population.

Rituximab is a monoclonal antibody that targets CD20 on B cells, leading to their depletion and a subsequent reduction in antibody-mediated immune responses. This mechanism makes rituximab a particularly effective treatment option for EORA patients, especially those who have failed to respond to other biologic therapies. By inhibiting B cell-driven immune responses, rituximab not only controls disease activity but also helps modulate the overall immune system, offering a valuable alternative for EORA patients who are refractory to other treatments. While rituximab may not be as effective as certain other biologics, such as tocilizumab, in improving specific biomarkers like PON1 activity, it has demonstrated significant benefits in controlling disease activity and alleviating immune-mediated inflammation. Clinical studies have shown that rituximab can effectively improve Disease Activity Score (DAS28-CRP) and Clinical Disease Activity Index (CDAI) scores, with some patients achieving long-term remission. These improvements are reflected in reduced joint inflammation, lower disease activity, and improved quality of life for patients (Razmjou et al., 2024). However, rituximab use carries significant safety risks, particularly regarding infections. It is crucial to closely monitor for early signs of bacterial and viral infections during treatment, with timely prophylactic measures being essential. Additionally, rituximab’s immunosuppressive effects may result in infusion-related reactions and other long-term adverse events related to immune suppression, including an increased risk of malignancies (see Table 1). Severe infections or poor drug tolerance are the primary reasons for discontinuation, underscoring the need for individualized patient management, particularly during the initiation and maintenance phases of treatment. In EORA patients, who often have naturally declining immune function, special attention should be given to monitoring immune status and infection risks to ensure the safety of the treatment. Despite the safety concerns, rituximab’s ability to control disease activity and reduce immune-mediated inflammation makes it an effective treatment option for many EORA patients, especially those who have not responded to other biologics (Pappas et al., 2014). To optimize its therapeutic benefits and minimize risks, clinical management should emphasize close monitoring, timely interventions, and careful patient selection. This approach will help ensure the most effective and safe use of rituximab in the treatment of EORA.