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Multicenter Study
. 2024 Apr 15:15:1354969.
doi: 10.3389/fimmu.2024.1354969. eCollection 2024.

Association of high disease activity and serum IL-6 levels with the incidence of inflammatory major organ events in Behçet disease: a prospective registry study

Lisa Hirahara  1 , Yohei Kirino  1 , Yutaro Soejima  1 , Yuki Iizuka  1 , Ryusuke Yoshimi  1 , Yuichiro Fujieda  2 , Tatsuya Atsumi  2 , Toshihiro Tono  3 , Daisuke Kobayashi  4 , Akira Meguro  5 , Masaki Takeuchi  5 , Kentaro Sakamaki  6 , Mitsuhiro Takeno  7 , Nobuhisa Mizuki  5 , Hideaki Nakajima  1
Affiliations
Multicenter Study

Association of high disease activity and serum IL-6 levels with the incidence of inflammatory major organ events in Behçet disease: a prospective registry study

Lisa Hirahara et al. Front Immunol. .

Abstract

Background: Little is known about the relationship between the disease activity of Behçet disease (BD) and the incidence of inflammatory major organ events.

Objectives: In this prospective registry study, we investigated the association between the Behçet Disease Current Activity Form (BDCAF) and incidence of inflammatory major organ events, defined as the inflammation of the ocular, central nervous, intestinal, and vascular systems in BD.

Methods: We enrolled participants from Japanese multicenter prospective cohorts. The BDCAF was evaluated annually. BD-related symptoms, including inflammatory major organ events, were monitored. The association between BDCAF and inflammatory major organ events was analyzed by time-to-event analysis. An unsupervised clustering of the participants' BDCAF, therapeutic agents, and multiple serum cytokines was also performed to examine their association with inflammatory major organ events.

Results: A total of 260 patients were included. The patients had a median BDCAF score of 2 [Interquartile range, 1-3] at the enrolment and remained disease active at 1- and 2-year follow-ups, indicating residual disease activity in BD. Patients with a BDCAF score of 0 had a longer inflammatory major organ event-free survival at 52 weeks than those with a score of 1 or higher (p=2.2 x 10-4). Clustering analysis revealed that patients who did not achieve remission despite treatment with tumor necrosis factor inhibitors had high serum inflammatory cytokine levels and incidences of inflammatory major organ events. Among the elevated cytokines, IL-6 was associated with inflammatory major organ events.

Conclusion: This study suggests that treatment strategies targeting overall disease activity and monitoring residual serum IL-6 may help prevent inflammatory major organ events in BD.

Keywords: Behçet disease; cluster analysis; disease activity; disease registry; systemic vasculitis.

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Conflict of interest statement

YK has received support from Amgen speaking fees, support for attending meetings and travel, and advisory board, Novartis speaking fees and advisory board, and Nippon Shinyaku grants. Mitsuhiro Takeno has received consulting and speaking fees from Amgen; research grants and speaking fees from AbbVie, Asahi Kasei, Chugai, Eisai, Tanabe-Mitsubishi, and Taisyo; and speaking fees from Astellas, Asympti, Boehringer-Ingelheim, Eli Lily, Jansen Pharma, Nippon Shinyaku, Novartis, Ono Pharmaceuticals, Takeda, UBC Japan, and Viatris. Tatsuya Atsumi has received grants from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Nippon Boehringer Ingelheim Co., Ltd., TEIJIN PHARMA LIMITED., Eisai Co., Ltd., and Eli Lilly Japan K.K. Tetsuya Atsumi has also received consulting fees from Sanofi K.K, GlaxoSmithKline plc, AbbVie Inc., AstraZeneca plc, Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Janssen Pharmaceutical K.K., Gilead Sciences, Inc., Eli Lilly Japan K.K., and ONO PHARMACEUTICAL CO., LTD. TA has also received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Pfizer Inc., Alexion Inc., Novartis Pharma K.K., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., AbbVie Inc., Nippon Boehringer Ingelheim Co., Ltd., Amgen Inc. UCB Japan Co. Ltd., AstraZeneca plc, and Eisai Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Flow chart of this study. BDCAF, Behçet Disease Current Activity Form.
Figure 2
Figure 2
Distribution of BDCAF scores and trends over time in Behçet disaese patients in this study. (A) Histogram of BDCAF scores at the 1st survey for YCU of 189 patients and the other institutions of 71 patients. The red dotted line represents the median BDCAF score for each cohort. (B) Plot of absolute change in BDCAF scores from the first BDCAF survey, color-coded according to the first BDCAF score. The blue dotted line represents the asymptote; the P-Value shows the p-Value of survey time estimated by a linear mixed model with survey time as the fixed effect and individuals as the random effect. (C) Alluvial plot showing the BDCAF scores of the 133 patients who completed up to the third survey. One line represents one patient, color-coded according to BDCAF score, and the percentages represent the percentage of each BDCAF score category at the time of each survey. (D) Swimmer plot showing dense BDCAF tracking survey (n=102). One line represents a single patient, color-coded by BDCAF score, and the horizontal axis represents days. BDCAF, Behçet Disease Current Activity Form; SD, Standard deviation.
Figure 3
Figure 3
Kaplan–Meier curve and survival decision tree analysis for inflammatory major organ events in Behçet disease patients in this study. (A) Kaplan–Meier curves for the first BDCAF survey data (n=258) stratified by BDCAF score 0, 1, ≥2. (B) Kaplan–Meier curves for the first BDCAF survey data (n=258) stratified by BDCAF score 0 or ≥1. (C) Kaplan–Meier curves for the second BDCAF survey data (n=152) in the same patients as (B) stratified by BDCAF score 0 or ≥1. (D) Survival decision trees were constructed using Classification and regression tree (CART) algorithm with each symptom as a variable for the first BDCAF survey data (n=258) and the second BDCAF survey data (n=152). The number in each node represents the relative hazard ratio (HR), with darker orange of node indicating higher HR and the darker green of node indicating lower HR. (E) Kaplan–Meier curve of the first BDCAF survey data (n=258), which divides patients into two groups; “low disease activity” or not. Low disease activity is defined as patients with BDCAF score 0 or only OU. (F) The Kaplan-Meier curve constructed for the definition of ‘low disease activity’ applied to the second BDCAF survey data (n=152). BDCAF, Behçet disease current activity form; CI, confidence intervals; RMST, Restricted mean survival time, EFS, Event-free survival, HR, Hazard ratio.
Figure 4
Figure 4
Summarized heatmap depicting serum cytokine concentration using combined data from Behçet disease patients and healthy subjects. The pie charts below the heatmap depict the percentage of BD patients and healthy controls within each cluster (top), as well as the distribution of disease activity and TNF inhibitor usage among BD patients in each cluster (middle and bottom). BD, Behçet disease; HC, Healthy controls; TNF, Tumor necrosis factor.
Figure 5
Figure 5
Cluster analysis of cytokines combined with BDCAF and therapeutic agents, and exploration of expression variation cytokines. (A) Heatmap of consensus matrices of k=5 (left). The same patients are symmetrically placed in rows and columns. The right is a Cumulative Distribution Function (CDF) plot, where the x-axis is the consensus index, and the y-axis is the cumulative percentage of patients. (B) Summarized heatmap depicting serum cytokine concentrations and percentage of non-remission (BDCAF ≥ 1) and percentage of TNF inhibitor use for each cluster. Cytokines are expressed as a Z-score. (C) Kaplan–Meier curves for each cluster. (D) A Volcano plot illustrating the difference in cytokine expression between Cluster A and E. The vertical axis represents log10FDR, with the green line indicating an FDR of 0.05. (E) Kaplan–Meier curves for the first BDCAF survey data (n=251) stratified by serum IL-6 concentration. (F) pruned survival decision trees with the minimum cross-validation error constructed for the first survey data (n=251, left), and the second survey data (n=135, right). Disease activity, TNF inhibitors use, and serum IL-6 concentration was used as variable. In each node, color indicates relative hazard ratio (HR), with darker orange signifying higher and darker green suggesting lower. BDCAF, Behçet disease current activity form; TNF, Tumor necrosis factor; IL, Interleukin; IFN, Interferon; MCP, Macrophage chemotactic protein.
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