Rheumatoid Arthritis and Tuberculosis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects joints, leading to progressive deterioration and potentially permanent joint damage [1]. Compared with the general population, the risk of disability and mortality is greater in the affected population [2]. Based on global epidemiological studies, the incidence of RA is expected to increase by approximately 80.2% between 2020 and 2050 [3]. Mycobacterial infections are strongly associated with the occurrence of RA, and complications of pulmonary infections are a major cause of death in patients with rheumatic disease [4]. Tuberculosis (TB) infections are the main cause of lung infections and the treatment process is complicated to cure them completely. TB is particularly dangerous for people with a weakened immune system, such as those receiving immunosuppressive therapy for RA [5, 6]. A cross-sectional study indicated that 29.5% of RA patients had latent tuberculosis infection (LTBI) and 3.4% developed active TB during treatment, underscoring the heightened risk of TB infection in RA patients due to their disease and its treatment [7]. The connection between RA and TB has been the subject of considerable research; however, the evidence base remains insufficient to demonstrate a causal relationship. The reliability of findings from observational studies is affected by a lack of consideration and control of potential confounding factors and biases, and there is a risk of reverse causality [8]. Therefore, the correlations found do not provide definitive evidence of a causal relationship between RA and TB.

This study utilized a two-sample bidirectional Mendelian Randomization analysis with Genome-Wide Association Study data to explore the potential causality between RA and TB. The primary method was the inverse variance weighted approach, supported by MR-Egger regression and the weighted median method for a thorough analysis. We also conducted reverse MR analysis to investigate any potential reverse causal effects. Our research involved 19 and 10 independent single nucleotide polymorphisms in studying the effect of RA on tuberculosis and the effect of tuberculosis on RA. There was a significant association between genetically predicted RA and TB risk in IVW (odds ratio (OR) = 1.132, 95% confidence interval (CI):1.080–1.188, p = 3.732e-07) and there was no significant correlation between genetic TB and RA (OR = 1.011, 95% CI: 0.966–1.058, p = 0.635) as shown in Table 1. No significant heterogeneity or horizontal pleiotropy was found for the instrumental variables, suggesting that these results were reliable and robust (see Table 1). The results indicate that RA is a risk factor for the development of TB, while TB does not appear to influence the onset of RA.

The World Health Organization's Global TB Report 2023 indicates that individuals with rheumatic diseases such as RA are at increased risk of TB reactivation. Compared with the general population, RA patients have been found to have a fourfold increased risk of TB infection [9]. Further confirmation was provided by a case–control study highlighting specific risk factors in RA patients that increase the risk of TB in patients who have not yet been treated with biologic. It is estimated that approximately 2 billion people worldwide have LTBI, with the majority being asymptomatic [10]. These individuals show no obvious signs or symptoms and lack clinical bacteriological or radiological evidence of active TB. Nevertheless, a significant proportion, approximately 5%–10% of LTBI patients, may progress to active TB infection. The prevalence of active TB infection is significantly higher in RA patients.

The increased risk of tuberculosis infection in RA patients is likely attributed to the perturbations in their immune system and the immunosuppressive medications used in their treatment regimen. While immunological drugs have demonstrated remarkable efficacy in managing RA, they significantly dampen the immune response, thereby substantially elevating the susceptibility to TB in individuals with RA. This underscores the importance of vigilant monitoring and preventive measures to mitigate the risk of TB in this patient population [11]. Furthermore, the risk of reactivation of LTBI to active TB infection is increased in RA patients treated with biologics, particularly TNF inhibitors [12]. Research data suggest that the incidence rate of active TB in RA patients receiving anti-TNF therapy is five to seven times higher than that of the general population. In addition to TNF inhibitors, the treatment of RA also includes a range of immunosuppressive therapies, including various disease-modifying anti-rheumatic drugs and biological agents [13]. These drugs work through specific mechanisms to modulate the immune system to slow the progression of RA and relieve its symptoms [14]. For instance, DMARDs, such as methotrexate, can inhibit cell proliferation and reduce inflammatory reactions. Additionally, biological agents, including IL-6 receptor antagonists or anti-CD20 monoclonal antibodies, can precisely target specific immune cells or cytokines, offering a more focused approach to managing RA [15].

Our findings suggest that RA is a risk factor for the development of TB, but TB does not appear to influence the onset of RA. This study highlights the importance of timely TB prevention and screening for RA patients, with significant implications for public health strategies aimed at reducing the TB burden.

Qianshi Zhang, Yifang Mei, and Dongyan Wang contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Qianshi Zhang, Xu Dong, and Pengqi Zhang. The first draft of the manuscript was written by Qianshi Zhang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

The authors declare no conflicts of interest.