Investigation Finds Tuberculosis May Be Risk Factor for Behçet Disease

An analysis of human genetic and biomarker data found that tuberculosis was a risk factor for Behçet disease, a noninfectious uveitis condition.

An analysis of human genetic and biomarker data published in JAMA Ophthalmology found tuberculosis, an infectious agent, was a risk factor for Behçet disease, a noninfectious uveitis condition.

Uveitis, one of the leading causes of visual acuity loss, can be clinically categorized as infectious or noninfectious; “epidemiological data show that noninfectious uveitis can account for most cases of uveitis in some populations,” the researchers wrote. It is also estimated that approximately 25% of the global population may have a latent tuberculosis infection and 5% to 10% could progress to active disease throughout their lifetime.

Previous experimental studies have found that infectious agent exposure may trigger an aberrant immune response and lead to noninfectious uveitis. However, the causal association of a definite pathogen has not been well established.

Using data from genome-wide association studies (GWAS) that identified common genetic variants associated with tuberculosis, investigators performed a mendelian randomization to assess if the condition is a risk for Behçet disease, Vogt-Koyanagi-Harada disease, uveitis associated with ankylosing spondylitis, and Fuchs uveitis syndrome.

All genetic variants were amassed from Chinese and Japanese GWAS data sets between July 2019 and January 2020. A total of 2584 patients with uveitis and 4417 healthy control participants were included in the Chinese cohort, along with 611 individuals with Behçet disease and 737 healthy control participants in the Japanese cohort. In the current study, the Chinese cohort constituted the primary analysis while the Japanese data set was used as a replication.

“Five genetic variants (rs4240897, rs2269497, rs41553512, rs12437118, and rs6114027) associated with tuberculosis at genome-wide significance (P < 5.0 × 10−8) in the Chinese population were used as the instrumental variable for tuberculosis exposure,” authors wrote.

Of the 2584 Chinese patients, 999 had Behçet disease, 608 had Vogt-Koyanagi-Harada disease, 477 had uveitis associated with ankylosing spondylitis, and 500 had Fuchs uveitis syndrome. Of the 611 patients in the Japanese cohort, 509 (83.3%) had uveitis.

Researchers also performed a prospective observational study in which they examined the T-SPOT.TB positivity rate in individuals with Behçet disease (n = 116) compared with control participants (n =121).

Analyses revealed:

  • The odds ratio (OR) for Behçet disease per 2-fold increase in tuberculosis incidence was 1.26 (95% CI, 1.12-1.43; P = 1.47 × 10−4).
  • No associations were detected for Vogt-Koyanagi-Harada disease, uveitis associated with ankylosing spondylitis, and Fuchs uveitis syndrome.
  • Replication using the Japanese cohort yielded similar results (OR, 1.16; 95% CI, 1.08-1.26).
  • In T-SPOT.TB assays, having a positive result, indicating a history of tuberculosis infection, was found to be an independent risk factor for Behçet disease (OR, 2.26; 95% CI, 1.11-4.60).
  • The T-SPOT.TB positivity rate was 32.8% in individuals with Behçet disease.

Overall, results showed that an increased risk of tuberculosis infection was associated with a higher risk of Behçet disease among individuals with a history of uveitis, and clinical biomarker data suggested that tuberculosis was an independent risk factor for developing Behçet disease, authors said.

“The present study provides evidence in people linking infectious agents to the risk of noninfectious uveitis and may also add to our knowledge concerning the pathologic consequences of tuberculosis,” they added.

Findings provide several implications for clinical practice, including:

  • a potential need to carry out Behçet disease screening for tuberculosis;
  • in terms of the frequent use of glucocorticoids and immunosuppressive or biologic agents, special attention should be paid to the risk of reactivation or progression of tuberculosis, especially in patients with positive T-SPOT.TB assays; and
  • to prevent and treat Behçet disease, understanding the role of infectious agents in its development may be helpful.

Due to a lack of data, the researchers could not confirm tuberculosis infection status in the cohorts, marking a limitation to the study. “Although much effort was made to address potential bias in the T-SPOT.TB analysis, because of the observational design, some unmeasured confounders may not have been completely excluded,” the authors concluded.


Zhong Z, Su G, Zhou Q, et al. Tuberculosis exposure with risk of Behçet disease among patients with uveitis. JAMA Ophthalmol. Published online February 18, 2021. doi:10.1001/jamaophthalmol.2020.6985