Currently, the most clinically used biological agents for the treatment of rheumatic diseases are mainly tumor necrosis factor (TNF) antagonists, including infliximab, adalimumab, etanercept, etc.
While the efficacy of TNF inhibitors is well known, the safety of their long-term application is of greater concern. For this reason, researchers around the world have conducted several studies to evaluate the long-term safety of TNF inhibitors, especially the occurrence of serious infections, malignancies and cardiovascular diseases.
Biological agents belong to the category of biological products, and with the development of the social market, they can be divided into two types from the current concept: health care preparations that prevent diseases and enhance the immunity of the body to achieve health effects and medical preparations that aim to achieve the effect of treating diseases. Recent medical research has revealed that the inflammatory factor called “tumor necrosis factor” is the cause of some rheumatic diseases.
In the history of rheumatic disease treatment, the invention and application of biological agents is undoubtedly a revolutionary breakthrough. In the past decade, there are more than ten kinds of biologics approved for the treatment of rheumatic diseases in North America and Europe, and there are new varieties emerging all the time. Biological agents are developing rapidly and becoming an important part of rheumatic disease treatment. With the popularization of various biologic agents, their safety and adverse effects are gradually attracting more and more attention.
Therapeutic risks indicate disease complexity
Some tumor necrosis factor inhibitors have been used over the past decade or so, and serious treatment-related adverse effects have gradually emerged. This also suggests that the etiology and pathology of rheumatic diseases is a complex system, and no single factor is independent of its pathogenesis and pathogenesis, nor is the tumor necrosis factor system.
Since the first TNF inhibitors were introduced to the market, these drugs have shown promising recent results in the treatment of rheumatic diseases and have therefore become rapidly popular worldwide, with an increasing number of rheumatologists using them as a killer treatment for refractory rheumatic diseases, as well as being recognized and accepted by patients.
Some TNF inhibitors have been used over the past decade or so, and serious treatment-related adverse effects have gradually emerged. This also suggests that the etiology and pathology of rheumatic diseases is a complex system and no single factor is independent of its pathogenesis and pathogenesis, and the same applies to the TNF system.
Therefore, rheumatologists should take advantage of its beneficial aspects for disease treatment, but also be constantly alert to its interference with and destruction of the body’s immune system. In clinical application, attention needs to be paid to patient screening, selection of the appropriate type of TNF inhibitor, and not blindly increasing the therapeutic dose. TNF inhibitors are a double-edged sword that can only benefit more patients with rheumatic diseases if applied correctly and rationally.
Consensus 1: Prefer receptor-based agents for cautious tuberculosis infection
The structure and immunogenicity of various TNF inhibitors are different, resulting in different adverse effects and safety.
Currently, most of the data on serious infections associated with TNF inhibitors are from the ATTRA, BSRBR, ARTIS and BIOBADASER studies. The types of infections include Mycobacterium tuberculosis, Herpes zoster virus, Legionella, Listeria spp. and other common or rare pathogens.
China is a country with a high rate of tuberculosis infection, and the potential for pulmonary or extrapulmonary tuberculosis in rheumatology patients treated with TNF inhibitors is a major concern for rheumatologists in China.
In an analysis of adverse reaction records by the U.S. Food and Drug Administration, the incidence of latent tuberculosis infection due to the application of receptor-based TNF inhibitors was lower compared to antibody-based TNF inhibitors. In addition, there is evidence that screening patients reduces the risk of tuberculosis (Table 2). Therefore, it is important to conduct a comprehensive TB screening when applying TNF inhibitor therapy. In addition to a detailed history, chest X-ray, and tuberculin test, the T-cell enzyme-linked immunospot assay developed in recent years is useful in improving the diagnosis of patients with latent TB infection.
Various TNF inhibitors have different structures and immunogenicity, and have different adverse effects and safety profiles. Several studies are also currently addressing the differences in the safety of different TNF inhibitors. Available data suggest that the probability of serious infection with etanercept is lower than with infliximab and adalimumab, but there is no significant difference in malignancy and other adverse effects. Therefore, receptor-based TNF inhibitors may be a safer choice for patients with potential infection, especially latent TB infection.
Consensus 2: Be aware of the high risk of tumor development in special populations
For rheumatic diseases treated with TNF inhibitors, especially in children and adolescents, regular screening for tumors is necessary.
The relationship between TNF inhibitor therapy and malignant tumors has been questioned since the beginning of its application due to the killing or inhibiting effect of TNF on tumor cells. As TNF inhibitors are used for a longer period of time and the relevant research continues to focus on them, their relationship with tumors will be gradually revealed.
Some studies have shown that TNF inhibitors do not increase the incidence of solid tumors and primary cancers, i.e., there is no data to show that TNF inhibitors are associated with an increased risk of any primary cancer. However, other studies are inconsistent with the conclusion that “whether TNF inhibitors increase the risk of lymphoma in patients with rheumatoid arthritis”.
In addition, the U.S. Food and Drug Administration has reported that investigations of TNF inhibitors and the development of lymphoma and other neoplasms in pediatric and adolescent users have shown an increased risk of disease associated with the use of TNF inhibitors in the United States, mostly after 30 months of use. Therefore, regular tumor screening is necessary for patients with rheumatic diseases treated with TNF inhibitors, especially for pediatric and adolescent patients.
Consensus 3: Be alert to the high risk of tumors in special populations with an overall cardiovascular safety profile
Currently, the clinical progress of patients with rheumatic diseases and the occurrence of cardiovascular diseases during the treatment process are among the hot topics of current research, and therefore studies related to TNF inhibitor therapy and cardiovascular risk are gradually increasing.
Some studies have shown that TNF inhibitor therapy may reduce the risk of cardiovascular adverse effects in patients with rheumatoid arthritis. Patients with rheumatoid arthritis who are treated with TNF inhibitors and have a good response to TNF inhibitors have a lower incidence of myocardial infarction than those treated with palliative antirheumatic drugs. In addition, because TNF inhibitors reduce inflammatory responses, the benefits outweigh the risks for patients with heart failure, and TNF inhibitors do not increase the risk of worsening heart failure. Overall, TNF inhibitor therapy is considered safe for patients with cardiovascular disease.