ABSTRACT
There is limited evidence to support the association between tuberculosis (TB) and the occurrence of Takayasu arteritis (TAK). To investigate the incidence of active TB (ATB) in TAK and explore the impact of anti-rheumatic therapy on the occurrence of ATB or reactivation of Latent TB infection (LTBI) and their effect on interferon-γ release assay (IGRA) results, we conducted a prospective study based on the Chinese Registry for Systemic Vasculitis cohort. The standard incidence ratio (SIR) was calculated and stratified by age. Kaplan–Meier analysis was used to determine the effect of variables on ATB or LTBI reactivation in patients with TAK. Data from 825 patients with TAK in the registry were analysed. During a median follow-up of 5 years, 5 patients developed ATB with a crude incidence of 154 (95%CI:57–381) person-years/100,000. The SIR was 5.59 (95%CI:1.81–13.04). Glucocorticoids and conventional disease-modifying anti-rheumatic drugs (cDMARDs) did not increase the risk of ATB or LTBI reactivation (P > 0.05). However, the use of tumour necrosis factor inhibitor (TNFi) increased the risk of ATB in patients with LTBI (P < 0.001). Furthermore, the value of the IGRA assay decreased after treatment (P < 0.05). In conclusion, the incidence of TB infection is markedly increased in patients with TAK and patients with TAK are at high risk of developing ATB. Treatment with glucocorticoids and cDMARDs does not significantly increase the risk for ATB in patients with TAK. Moreover, IGRA may have limited effectiveness in monitoring ATB infection or LTBI reactivation in patients with TAK.
Introduction
Takayasu arteritis (TAK) is a chronic granulomatous vasculitis that occurs most commonly in Asian young females [Citation1] and primarily affects the aorta and its major branches [Citation2]. The association between tuberculosis (TB) and TAK has long been suspected but there lacks high-quality evidence to support this assumption [Citation3,Citation4]. Neither the incidence of TB in TAK patients nor the role of TB infection in the pathogenesis of TAK has been elucidated due to disease rarity [Citation5]. Furthermore, anti-rheumatic medications have long been recognized to increase the risk of TB infection or LTBI reactivation [Citation6–8].
Interferon-γ release assay (IGRA) has been widely used in TB pandemic areas such as Asian countries as it is least affected by Bacillus Calmette-Guerin vaccination. It has been recommended by some academic organizations as a screening and monitoring tool for LTBI [Citation9]. However, the effectiveness of using IGRA as a monitoring tool for the occurrence of active TB (ATB) in patients treated with immunosuppressive agents and GCs remains controversial [Citation9–12].
In this study, we aimed to determine the incidence of TB in a large TAK patient cohort and to investigate whether treatment with immunosuppressive medications and GCs can increase the risk of developing ATB in TAK patients. We also aimed to assess whether the IGRA assay could be used as a tool for monitoring the occurrence of ATB or LTBI reactivation in TAK patients.
Materials and methods
Study design
This is a prospective cohort study based on the Chinese Registry for Systemic Vasculitis cohort in Peking Union Medical College Hospital (PUMCH) [Citation13]. Patients were recruited consecutively from July 2013 to December 2022. All patients fulfilled the 1990 American College of Rheumatology classification criteria for TAK [Citation2].
In the first part of the study, we explored the incidence of ATB in patients with TAK. Patients with a history of ATB or missing date variables necessary for incidence analysis were excluded [Citation14] (Item Supplementary Figure S1).
In the second part, we analysed the impact of treatment with glucocorticoids and immunosuppressive agents on ATB occurrence or LTBI reactivation in patients with TAK. Patients without ATB at the time of TAK diagnosis were included. Patients included in this study were categorized into two groups according to the result of the IGRA assay: LTBI (IGRA-positive) and non-LTBI (IGRA-negative). Subsequently, the two groups were further divided into four groups according to the history of ATB infection: Group A (LTBI with a history of ATB), Group B (LTBI without a history of ATB), Group C (non-LTBI with a history of ATB), and Group D (non-LTBI without a history of ATB) (Item Supplementary Figure S2).
In the third part of the study, we compared the results of IGRA before and after treatment.
This study was approved by the Institutional Review Board/Ethics Committee of PUMCH (JS-2038). Written informed consents were obtained from all participants.
Definition
The diagnostic criteria of ATB [Citation15] are listed in Item Supplementary Table S1. We followed a strict diagnostic algorithm for ATB that integrated laboratory test results and imaging findings. Additionally, for patients without pathogenic evidence of Mycobacterium TB (MTB) infection, we followed the patients for 3 months to assess the effectiveness of anti-TB treatment to make sure the diagnosis was correct. Moreover, the diagnosis of ATB was independently made by two physicians, with consultation from a senior expert on TB infection in case of disagreement. LTBI was defined as a positive test result for MTB-complex infection without clinical manifestation of ATB [Citation16].
For patients with TAK, we monitored ATB infection in the following ways: for high-risk patients for TB infection (with a history of TB infection and positive IGRA test), constitutional symptoms for TB infection were checked during each follow-up visit, IGRA test and chest CT scan were repeated every 6 months. For patients without these risk factors, IGRA tests and chest CT scans were done every year. For patients who are diagnosed with LTBI, isoniazid, rifampin, and ethambutol, or a combination of isoniazid and rifampin were generally prescribed and patients during the follow-up, elaborate work-up was carried out to investigate whether the patient has transformed to ATB infection, which included chest CT scan, gene, and pathological tests for bronchoscopy lavage fluid. If there were new nodules on the chest CT scan and active TBI were suspected, CT-guided needle biopsy was performed to get pathological evidence. In addition, the diagnosis of ATB was independently made by two physicians and a senior doctor was consulted to make sure that the diagnosis of active MTB was correct.
Treatment medications were categorized as GCs (prednisone and methylprednisolone), conventional disease-modifying anti-rheumatic drugs (cDMARDs) [(methotrexate, cyclophosphamide, mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine, and azathioprine)], biological DMARDs (bDMARDs) [(TNF inhibitors (TNFi), interleukin-6 receptor (IL-6R) inhibitors, IL-17A inhibitor)], Janus kinase (JAK) inhibitors, and anti-tuberculosis treatment. The dosages and durations of drug regimens were also recorded.
Interferon-gamma release assay
The T-SPOT®.TB(Oxford Immunotec) was used following the manufacturer's guidelines [Citation17]. Peripheral blood (4 mL) was collected and specific T-cell responses to the region of difference 1 encoded antigens were detected by T-SPOT.TB within 6 h. AIM-V was used as the nil control and phytohemagglutinin was used as the positive control. A 6 kDa early secreted antigenic target (ESAT-6) and a 10 kDa culture filtrate protein (CFP-10) were used as specific antigens. Peripheral blood mononuclear cells (PBMCs) from each subject (2.5 × 105/well) were plated on a plate pre-coated with the antibody against Interferon γ (IFN-γ). After 16–18 h of incubation at 37°C in 5% carbon dioxide, wells were developed with a conjugate against the antibody and an enzyme substrate. Spot-forming cells (SFCs) were counted using an automated ELISPOT reader (AID-ispot, Strassberg, Germany), with each SFC representing an antigen-specific T-cell-secreting IFN-γ. All T-SPOT.TB assays were conducted by a single senior technician, and the results were interpreted by her and another technician.
Data collection
The demographic data, clinical profiles, laboratory test results, and treatment medications were recorded at baseline and every follow-up visit. All data collected were uploaded to the registry database. Patients were followed up every 1–3 or 6 months based on the disease status of each patient. All enrolled patients were followed up until the date of the last visit. In patients who developed ATB during the follow-up period, their follow-up duration was calculated from the baseline to the date of ATB diagnosis. The age-specific incidence rates of ATB in the general population were obtained from the National TB Management Information System (https://weekly.chinacdc.cn/) [Citation18].
Statistical analysis
Data were presented as medians (interquartile range) or percentages for continuous or qualitative variables. Chi-square or Fisher’s exact test was used to compare qualitative variables, paired data, and non-paired data were compared by Wilcoxon signed-rank test or Mann–Whitney U test, respectively.
The incidence of ATB in TAK was calculated as person-years/100,000 assuming a Poisson distribution and standardized to that of the general population of China. Due to concerns about potentially small sample sizes, standardization was performed using age but not additionally by sex because age is recognized as a stronger risk factor than sex for TB infection [Citation19,Citation20]. Standardized incident ratios (SIR) were reported with 95% confidence intervals (CI).
Kaplan–Meier analysis was used to determine the effect of variables on ATB or LTBI reactivation in patients with TAK. Statistical analyses were conducted using the R statistical software (R Foundation for Statistical Computing, Vienna, Austria), adopting the package Epitools. P < 0.05 was defined as statistical significance.
Results
Demographic data and clinical characteristics
The demographic data of patients with TAK at baseline are summarized in Supplementary Table S1. A total of 825 patients were enrolled, of which 109 (13%) were male, the median age at TAK diagnosis was 27 (22, 35) years. The number of patients who were treated with GCs, cDMARDs, and bDMARDs was 751 (91%), 724 (88%), and 179 (22%), respectively. The median duration of GC use was 3 (2, 5) years, with a median dosage of 14 (10, 19) mg/day.
Incidence of ATB
756 patients were included when exploring the incidence of ATB (62 patients with a history of ATB and 7 patients lacking necessary data for incidence analysis were excluded). During a median follow-up of 5 (3, 6) years, 5 patients developed ATB with a crude incidence of 154 (95% CI: 57–381) person-years/100,000. The overall incidence rate of ATB was 6 times as high as that for the age-matched general adult population of China. The SIR was 5.59 (95% CI: 1.81–13.04).
Risk factors for ATB occurrence or LTBI reactivation
A total of 635 patients were enrolled. The demographic and clinical characteristics of patients with LTBI and non-LTBI are shown in and Supplementary Table S2. The median duration of exposure to GCs was 3 (2, 5) and 4 (2, 6) years, with accumulative dosages of 12 (5, 22) and 20 (13, 30) g in LTBI and non-LTBI patients, respectively. The proportion of patients with LTBI who received GC treatment was lower compared to non-LTBI [176 (88%) vs. 409 (94%), P = 0.004]. Similarly, the proportion of patients with LTBI who received treatment with biologics, including IL-6R inhibitors, TNFi, and JAK inhibitors, was lower compared to non-LTBI [5 (2%) vs. 61 (14%), 5 (2%) vs. 79 (18%) and 5 (2%) vs. 35 (8%), respectively, all P < 0.05].
Table 1. Demographic and clinical characteristics of patients with Takayasu arteritis in LTBI and non-LTBI.
About 42, 159, 17, and 417 patients were allocated to group A, B, C. and D respectively, the median duration of follow-up time was 5 (3, 6), 4 (3, 6), 5 (4, 6), and 4 (3, 6) years in each group, respectively.
During the follow-up, 1 LTBI reactivation happened in group A, and 4 LTBI reactivation occurred in group B. No ATB infection in group C was observed. Only 1 ATB occurred in group D. For the 6 patients who developed ATB during follow-up, the time of ATB diagnosis of these patients was 26, 16 years, 33, 27, 22, and 29 months after the diagnosis of TAK was confirmed, respectively. The clinical characteristics and treatment of patients with ATB occurrence or LTBI reactivation are summarized in .
Table 2. The medications used and the locations of active tuberculosis infection in patients with ATB.
GCs treatment
Patients who received GCs treatment in groups A, B, C, and D were 36 (86%), 140 (88%), 16 (94%), and 393 (94%), respectively (). GCs did not increase the risk of LTBI reactivation or ATB occurrence in groups A, B, and D (P = 0.729, P = 0.501, P = 0.849, respectively) ((A,D,G)).
Figure 1. Kaplan–Meier curve with a cumulative probability of active tuberculosis infection in patients with Takayasu arteritis. A, B, and C: the probability of active tuberculosis infection in patients with or without glucocorticoids/cDMARDs/bDMARDs in group A. D, E, and F: the probability of active tuberculosis infection in patients with or without glucocorticoids/cDMARDs/bDMARDs in group B. G, H, I: the probability of active tuberculosis infection in patients with or without glucocorticoids/cDMARDs/bDMARDs in group D. Abbreviations: LTBI, latent tuberculosis infection; TAK, Takayasu arteritis; GCs, glucocorticoids; TB, tuberculosis, ATB, active tuberculosis; cDMARDs, conventional disease-modifying anti-rheumatic drugs; TNFi, tumour necrosis factor inhibitor; bDMARDs, biological disease-modifying anti-rheumatic drugs; NGCs, non-glucocorticoids; N-cDMARDs, non-conventional disease-modifying anti-rheumatic drugs; N-bDMARDs, non-biological disease-modifying anti-rheumatic drugs.
cDMARDs treatment
The number of patients with TAK who received cDMARDs treatment in groups A, B, C, and D were 38 (90%), 146 (92%), 17 (100%), and 398 (95%), respectively (). There was no difference in the number or proportion of patients with LTBI reactivation or ATB recurrence. (P = 0.729, P = 0.594, P = 0.878, respectively) ((B,E,H)).
bDMARDs treatment
The number of patients treated with biologics in groups A, B, C, and D was 4 (7%), 11 (7%), 5 (29%), and 133 (32%), respectively. The bDMARDs were categorized into TNFi and non-TNFi. Non-TNFi did not increase the risk of LTBI reactivation or ATB recurrence in groups A and D (P = 0.956 and P = 0.076, respectively). However, TNFi treatment increased the risk of LTBI reactivation in group B compared with patients who were treated with non-TNFi or are bDMARDs-naive (P < 0.001) ( (C,F,I)).
IGRA
IGRA tests were performed on a total of 207 patients before and after treatment at a median duration of 24 (11, 44) months. Among these patients, 47 were prescribed anti-TB medication (Supplementary Table S3). The median of IFN-γ producing SFCs declined after treatment compared with baseline in response to ESAT-6 + CFP-10 [0 (0, 276) vs. 0 (0, 224) SFC/106PBMC, P = 0.003] ().
Figure 2. The change of spot-forming cells before and after treatment. Abbreviations: SFC: Spot-forming cells; PBMC, peripheral blood mononuclear cells; ESAT-6, 6 kDa early secreted antigenic target; CFP-10, 10 kDa culture filtrate protein.
For the 3 patients diagnosed with ATB, the sensitivity, specificity, positive predictive values (PPV), and negative predictive values were 100%, 61%, 3.6%, and 100%, respectively (Supplementary Table S4).
IGRA results among different groups
The median of IFN-γ-producing SFCs before and after treatment within groups A, B and D is shown in Supplementary Table S5. The median-IFN-γ-producing SFCs declined after treatment in group B (P < 0.05).
IGRA test results between ATB and non-ATB
For the 207 patients, 4 ATB cases occurred (1 in group A, 2 in group B, and 1 in group D). To clarify whether the results of the IGRA assay could effectively monitor the occurrence of ATB, the 207 patients were divided into two groups based on the presence or absence of ATB; however, no significant difference in the results of IGRA could be found between the two groups (P > 0.05) (Supplementary Table S6).
Discussion
The etiology of TAK is generally unknown although the disease has been well-recognized for decades. There are very a few studies that investigate the incidence of ATB infection in TAK patients primarily due to the rarity of the disease. A report from Japan showed that the incidence of TB in TAK patients was much higher than that of the general population from 1967 to 1987[Citation3,Citation21]. In this study, we have shown that the SIR of ATB in patients with TAK is approximately 6 times higher than that of the general population in China during the same period [Citation22].
It is commonly assumed that anti-rheumatic treatment could increase the incidence of ATB or reactivation of LTBI [Citation6–8]. However, the risk of ATB in rheumatic disease patients treated with GCs is still controversial [Citation23]. A cohort study [Citation24] in patients with rheumatic arthritis (RA) found that GC treatment was not a risk factor for ATB. It is also reported that the risk of ATB might be influenced by factors such as the duration or cumulative dose of GCs [Citation25]. A population-based cohort study revealed that the use of cDMARDs was associated with an increased TB risk in RA patients [Citation26]. However, a similar study did not show a significant increase in the risk of TB in patients with psoriasis treated with cDMARDs [Citation27]. These conflicting results may be related to different cDMARD combinations or dosages used. In this study, we showed that GC and/or cDMARDs did not increase the risk of ATB occurrence or LTBI reactivation in patients with TAK during a median follow-up for 5 years.
Although the present study showed that the exposure to cDMARDs did not increase the risk of ATB in patients with TAK, regardless of their LTBI status or history of TB infection, the results showed that TNFi increased the risk of ATB in patients with LTBI, which has become a well-known phenomenon. As TNF plays a critical role in TB clearance and granuloma formation [Citation28], TNFi may loosen the granuloma and thus facilitate the reactivation of LTBI infection [Citation29]. There is increased ATB risk in patients treated with TNFi, but not in those treated with other bDMARDs [Citation30,Citation31].
IGRA has been recommended to be used as one of the diagnostic tools for LTBI by some authorities, academic organizations, and clinical studies [Citation9,Citation32,Citation33] although the test results of IGRA are not consistent. In our study, the IFN-γ-producing SFCs decreased after being treated with anti-rheumatic agents, including TNFi. One important reason might be that the effect of GC and immunosuppressive agents could decrease the specific cell population (T-cells, antigen-presenting cells) necessary to produce ex vivo antigen-specific IFN-γ responses [Citation34,Citation35]. Another reason is that TAK patients, who were treated with GCs and DMARDs, were in an immunosuppressed state with decreased mononuclear cell response [Citation36,Citation37]. Immunosuppressive therapy might lead to false-negative results in IGRA [Citation38]. The decrease in the IFN-γ-producing SFCs is not suggestive of TB infection containment or mycobacteria clearance but might be a reflection of the immune suppression. Therefore, we suggested that we need to monitor clinical presentations and imaging evidence of ATB rather than the IGRA test in patients with TAK who were treated with GC and/or immunosuppressive agents.
IGRA has reduced sensitivity and has low predictive value for progression to ATB in immunocompromised patients [Citation39,Citation40], so, the predictive value of IGRA tests for LTBI reactivation is very limited [Citation39,Citation41,Citation42]. Our study results are consistent with this as indicated by the low PPV. However, the high sensitivity of IGRA assay might suggest that IGRA might have the power to exclude ATB.
There are some limitations in this study. Firstly, some patients did not have follow-up IGRA tests, especially patients who were negative at baseline. Therefore, changes in IGRA test results could not be evaluated in this patient population. The second limitation is that the number of patients with ATB is very limited, so we are unable to account for potential confounding factors within each group while investigating the effects of different treatment approaches on ATB or LTBI reactivation.
In conclusion, TB infection is associated with TAK and patients with TAK are at high risk of developing ATB. In addition, GC and cDMARD treatments do not increase the risk of ATB occurrence or reactivation of LTBI in patients with TAK. However, TNFi treatment increases the risk of ATB in TAK patients with LTBI. Furthermore, our study results added the evidence that the IGRA test might have very limited value in monitoring ATB or LTBI reactivation in immunocompromised patients.
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Z.P., J.L., Z.R., and Y.Z.Z. are co-first authors, who collected the clinical data and drafted the manuscript. Y.H.W. and Y.W.provided statistical assistance. Z.R., G.Z.Z, and Y.J.Y provided language help. X.P.T. and X.F.Z contributed equally to this manuscript as corresponding authors and were responsible for evaluating and screening participants and supervising the entire research.
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The data underlying this article will be shared upon reasonable request to the corresponding author.
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References
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