What is the different risk of infection in patients with RA using different biological agents?

*It is only for medical professionals to read for reference.
Choosing the right biological agent can reduce the risk of infection.

The advent of biologics is a milestone in the treatment of rheumatoid arthritis (RA).
It can not only improve patients' joint symptoms and reduce disease activity, but also delay the progress of imaging and improve the quality of life of patients.

But everything has two sides.
Biological agents may affect the normal immune response to a certain extent by inhibiting certain key targets of the immune system and increase the risk of infection in patients.

Different biological agents have different chances of causing related infections.

In the past, many researchers focused on this and conducted statistics and reports on the risk of infection caused by different biological agents.

Many clinical research data show that the use of tumor necrosis factor (TNF) inhibitor treatment can increase the risk of infection [1-2], and among the non-TNF inhibitor biologics, the selective T cell co-stimulation immunomodulator Abbas The risk of general infection is relatively low [3-7].

So, is this still the case in large population cohort studies? In the era of big data today, clinical data provided by large population cohort research is very important for the realization of precision medicine.
They are important research methods of evidence-based medicine, which can provide more convincing information and reflect clinical reality.

Many cohort studies have observed and explored the infection risk of using biological agents in RA patients, which can provide references for clinical safe and rational drug use.

1 Data from a cohort study spanning ten years and enrolling 10,000 people: Which is the higher the risk of infection and hospitalization? In January 2020, a prospective real-world study published in Arthritis Care & Research (IF:4.
056) collected data from the Truven MarketScan database (2006-2015) that included most of the commercial insurance, health care, and medical data in 50 states in the United States.
11248 pairs of propensity score matching (PSM) RA patients were identified, and their relative risk of hospitalization due to infection after treatment with TNF inhibitors and abatacept was compared [3].

Figure 1: The results of the trial design study showed that compared with TNF inhibitors, RA patients in the abatacept group had a lower risk of hospitalization for infection, with a hazard ratio (HR) of 0.
78 (95% CI 0.
64-0.
95) (Table 1).

In the specific assessment of the type of infection, the risk of respiratory tract infection in RA patients treated with abatacept was significantly lower than that of the TNF inhibitor group, and there was no significant difference in the risk of other types of infection.

Table 1: Risk analysis of hospitalization for infection caused by abatacept and TNF-α inhibitors 2 What is the risk of infection compared with other non-TNF inhibitor biologics? TNF plays an important role in the host's defense against bacterial and viral invasion, and participates in many important immune responses, such as the formation of granulomas and phagosomes, the activation and differentiation of macrophages, and the immune response to viruses and pathogens.

Inhibition of TNF may disrupt these body defense processes, which is associated with an increased risk of serious infections [1].

In fact, in addition to TNF inhibitors, the biological agents currently used in the treatment of RA include a class of non-TNF inhibitors, including abatacept and rituximab (anti-CD20 monoclonal antibody, targeting B cells).
) And tocilizumab (a monoclonal antibody targeting IL-6 receptor).

So, what is the difference in infection risk among these non-TNF inhibitor biologics? A Danish observational cohort study evaluated and compared the use of rituximab, tocilizumab and abatacept in the treatment of RA patients in 0-12 patients by collecting relevant medical data in the DANBIO database (2010-2017).
Months and 0-24 months of drug-related infection risk [4].It was found that among the three biological agents, rituximab had a relatively high risk of infection, while abatacept had a relatively low risk of infection (Table 2).

Table 2: Relative infection risk (95% CI) of RA patients treated with three different biological agents.
Model A: Adjusted according to the patient’s age and gender; Model B: According to the patient’s age, gender, course of disease, smoking, disease activity, Functional status and glucocorticoid use will be adjusted; Model C: Based on Model B, it will be adjusted based on the patient's previous hospitalized infections, cancer, chronic obstructive pulmonary disease, and antibiotic use.

3 Is the timing of the use of biological agents related to the risk of infection? When the same biological agent is used at different times, the risk of infection may be different: if the patient has used other types of biological agents before the target biological agent is given, it may affect the risk of infection during the follow-up period.

In the above cohort studies, although the safety of abatacept infection has been initially verified, the difference in the infection risk of abatacept as a first-line biological treatment or a post-conversion treatment is not clear.

A number of cohort studies have explored the impact of biological agents on the risk of infection at different timings, and a large number of results have further confirmed the good safety of abatacept in infection: an observational cohort study conducted across the United States (2005- 2015) The results showed that whether as a first-line biological treatment plan or a subsequent conversion treatment plan, the risk of hospitalization for infection caused by abatacept in the treatment of RA patients is lower than other biological agents (Table 3) [8].

Table 3: The first-line biological treatment plan for the infection and hospitalization risk of abatacept and other biological agents in the treatment of RA under different time of use: A population-based cohort study collected data on RA patients in Truven MarketScan and Medicare database from 2007 to 2014, among which Including 5727 patients who were initially treated with abatacept and 78,556 patients who were initially treated with other biological agents.

The results showed that compared with other biological agents, abatacept was not related to the incidence of serious infections, and its risk of infection did not change with the prolonged treatment time [9].

Table 4: Compared with other biological agents, the risk ratio of severe infection caused by the initial use of abatacept a: the incidence rate (incidence rate) is per 100 patient-years; b: the adjusted risk ratio (Adjusted HR) is Adjusted according to propensity score and age; bDMARD: biological agent; HR: risk ratio.

Post-conversion treatment plan: A retrospective cohort study collected new biologics in the Medicare database from 2006 to 2011 [including etanercept, adalimumab, certuzumab, golimumab, and Inflix Clinical data of RA patients with Cimumab (TNF inhibitor, Abatacept, Rituximab, and Tocilizumab).
The enrolled patients must have received at least one other biological agent treatment before.
Analysis of the post-conversion Infection risk of biological therapy.

The results showed that the risk of hospitalization for infection (aHR) in patients with RA who had previously received biologics treatment after etanercept, infliximab or rituximab treatment was significantly higher than that of abatacept.

Among the biological agents studied, the abatacept group had the lowest incidence of infection at 13.
1/100 patient-years (Table 5) [10].

Table 5: In the 12 months before the follow-up, the incidence and risk ratio of hospitalizations for infections caused by various biological agents Figure 2: The cumulative incidence of hospitalizations for infections caused by various biological agents during the 1-year follow-up period 4 Summary Although abatacept was in 2020 Approved for listing in China in 2009, with limited application experience.

But as early as 2005, it has been listed in the United States and Canada, and has accumulated a lot of clinical practice data.

Numerous large-scale cohort studies have shown that compared with other biological agents, whether as a first-line biological agent or a post-conversion biological agent treatment plan, abatacept has a relatively low risk of infection in the treatment of RA, which can ensure the safety of patients with long-term medication.
, Is conducive to the chronic disease management of RA patients. References: [1] Lortholary O, Fernandez-Ruiz M, Baddley JW, et al.
Infectious complications of rheumatoid arthritis and psoriatic arthritis during targeted and biological therapies: a viewpoint in 2020[J].
Ann Rheum Dis, 2020,79( 12):1532-1543.
[2] Galloway JB, Hyrich KL, Mercer LK, et al.
British Society for Rheumatology Biologics Register.
Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly[J].
Rheumatology (Oxford), 2011, 50(1):124-31.
[3] Chen SK, Liao KP, Liu J, et al.
Risk of Hospitalized Infection and Initiation of Abatacept Versus Tumor Necrosis Factor Inhibitors Among Patients With Rheumatoid Arthritis:A Propensity Score-Matched Cohort Study[J].
Arthritis Care Res (Hoboken).
2020, 72(1):9-17.
[4] Grøn KL, Glintborg B, Nørgaard M, et al.
Overall infection risk in rheumatoid arthritis during treatment with abatacept, rituximab and tocilizumab;an observational cohort study[J].
Rheumatology (Oxford), 2020, 59(8): 1949-1956.
[5] Kremer JM, Dougados M, Emery P, et al.
Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial[J].
Arthritis Rheum, 2005, 52(8):2263-2271.
[6] Westhovens R, Kremer JM, Emery P, et al.
Long-term safety and efficacy of abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: a 7-year extended study[J].
Clin Exp Rheumatol, 2014, 32(4 ):553-562.
[7] Padovan M, Filippini M,Tincani A, et al.
Safety of Abatacept in Rheumatoid Arthritis With Serologic Evidence of Past or Present Hepatitis B Virus Infection[J].
Arthritis Care Res (Hoboken), 2016, 68(6):738-743.
[8] Ozen G , Pedro S, Schumacher R, et al.
Safety of abatacept compared with other biologic and conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: data from an observational study[J].
Arthritis Res Ther.
2019, 21(1) :141.
[9] Montastruc F, Renoux C, Hudson M, et al.
Abatacept initiation in rheumatoid arthritis and the risk of serious infection: A population-based cohort study[J].
Semin Arthritis Rheum.
2019, 48(6) :1053-1058.
[10] Yun H, Xie F, Delzell E, Levitan EB, et al.
Comparative Risk of Hospitalized Infection Associated With Biologic Agents in Rheumatoid Arthritis Patients Enrolled in Medicare[J].
Arthritis Rheumatol.
2016, 68(1):56-66.