Abstract

Importance

Tumor necrosis factor (TNF) inhibitors have been used extensively to treat various autoimmune diseases. However, there are ongoing debates about the risk of inflammatory central nervous system (CNS) disease events following TNF inhibitor therapy, as well as uncertainty about how this risk varies across different autoimmune diseases or TNF-blocking agents.

Objective

To evaluate the risk of inflammatory CNS diseases after anti-TNF initiation and assess the difference in risk among different types of underlying autoimmune diseases or TNF inhibitors.

Data sources

Separate searches were conducted across PubMed, Embase, and the Cochrane Library from inception until March 1, 2024.

Study selection

Observational studies assessing the association between anti-TNF therapy and inflammatory CNS diseases relative to a comparator group.

Data extraction and synthesis

Study eligibility assessment and data extraction were independently conducted by 2 investigators following PRISMA guidelines. The risk ratio (RR) was used as the effect measure of the pooled analysis.

Main Outcomes and Measures

The primary outcome was the risk of incident inflammatory CNS events after anti-TNF therapy for autoimmune diseases. Secondary analyses were performed based on different types of underlying autoimmune diseases and TNF inhibitors.

Results

Eighteen studies involving 1 118 428 patients with autoimmune diseases contributing more than 5 698 532 person-years of follow-up were analyzed. The incidence rates of new-onset inflammatory CNS events after initiating TNF inhibitors ranged from 2.0 to 13.4 per 10 000 person-years. Overall, exposure to TNF inhibitors was associated with a 36% increased risk of any inflammatory CNS disease compared to conventional therapies (RR, 1.36; 95% CI, 1.01-1.84; I 2 , 49%), mainly attributed to demyelinating diseases (RR, 1.38; 95% CI, 1.04-1.81; I 2 , 31%). Secondary analyses revealed a similar risk of inflammatory CNS diseases across different types of underlying autoimmune diseases (rheumatic diseases: RR, 1.36; 95% CI, 0.84-2.21; inflammatory bowel disease 1.49; 95% CI, 0.93-2.40; P for subgroup = .74) and TNF inhibitors (anti-TNF monoclonal antibodies vs etanercept: RR, 1.04; 95% CI, 0.93-1.15; I 2 , 0%).

Conclusions and Relevance

Compared to conventional therapies, exposure to TNF inhibitors was associated with a 36% increased risk of inflammatory CNS diseases, irrespective of background autoimmune disease or TNF inhibitor type.

Key Points

Question  Is using tumor necrosis factor (TNF) inhibitors for autoimmune diseases associated with an increased risk of inflammatory central nervous system (CNS) diseases and does this risk differ between different underlying autoimmune diseases or TNF inhibitors?

Findings  This systematic review and meta-analysis of 18 studies including more than 1 million patients with autoimmune diseases revealed that exposure to TNF inhibitors was associated with 36% increased risk of inflammatory CNS diseases, especially demyelinating diseases. The risk of inflammatory CNS events following anti-TNF therapy did not differ by types of autoimmune diseases or prescribed TNF inhibitors.

Meaning  These results suggested an increased risk of inflammatory CNS events after anti-TNF therapy across all indications compared to conventional therapies; physicians should be aware of the risk and provide appropriate management.

요약

소개

종양 괴사 인자(TNF) 억제제는 다양한 자가면역 질환을 치료하기 위해 널리 사용되고 있다. 그러나 TNF 억제제 치료 후 염증성 중추신경계 질환 발생의 위험에 대한 논란이 계속되고 있으며, 이러한 위험이 다양한 자가면역 질환이나 TNF 차단제에 따라 어떻게 달라지는지에 대해 불확실하다. 따라서 본 연구에서는 항-TNF 치료 시작 후 염증성 중추신경계 질환의 위험을 평가하고, 다양한 자가면역 질환 유형이나 TNF 억제제에 따라 위험도의 차이가 있는가를 평가하고자 한다.

방법

본 연구는 대조군과 비교하여 항-TNF 치료와 염증성 중추신경계 질환 간의 연관성을 평가하는 관찰 연구로 진행되었다. 주요임상결과(primary outcome)은 자가면역 질환에 대한 항-TNF 치료 후 발생하는 염증성 중추신경계 발생의 위험도였고, 자가면역질환의 종류와 항-TNF 약제 종류에 따른 위험도 차이에 대해 이차분석을 진행하였다.

결과

1. 전반적으로 TNF 억제제에 노출된 환자들은 기존 치료를 받은 그룹에 비해 모든 염증성 중추신경계 질환의 발생 위험이 36% 증가하는 것으로 나타났고, 많은 경우 탈수초 질환이 발생했다(31%).

2. 자가면역 질환의 종류와 TNF 억제제의 종류에 따른 위험도를 확인한 이차분석 결과 질병의 종류나 치료제 종류 사이에는 염증성 중추신경계 발생 위험도 차이가 유사했다.

결론 및 의의

TNF 억제제를 사용한 환자에서 염증성 중추신경계(CNS) 질환의 위험이 36% 증가하는 것으로 나타났고, 특히 탈수초 질환에서의 위험의 증가가 두드러진다. 따라서 TNF 억제제를 사용한 환자에서 염증성 CNS 사건의 위험이 기존 치료에 비해 증가하므로, 이러한 위험을 인지하고 적절한 관리 방안을 마련해야 한다.