Abstract
Objective To describe the incidence, risk factors, and outcomes associated with serious infections in patients with Takayasu arteritis (TA).
Methods Serious infections, defined as infections resulting in hospitalization or death or unusual infections like tuberculosis, were identified from a cohort of patients with TA. Corticosteroid and disease-modifying antirheumatic drug (DMARD) use at the time of serious infection was noted. Demographic characteristics, clinical presentation, angiography, and disease activity at presentation, and the use of DMARDs during follow-up were compared between patients with TA with or without serious infections. Mortality in patients with TA who developed serious infections was compared to those who did not using hazard ratios (HR; with 95% CI).
Results Of 238 patients with TA, 38 (16%) had developed serious infections (50 episodes, multiple episodes in 8; 3 episodes resulted in death). Among the 38 initial episodes, 11/38 occurred in those not on corticosteroids and 14/38 in those not on DMARDs. Pneumonia (n = 19) was the most common infection, followed by tuberculosis (n = 12). Patients with TA who developed serious infections vs those who did not had higher disease activity at presentation (active disease 97.4% vs 69.5%, mean Indian Takayasu Arteritis Activity Score 2010 12.7 (SD 7.3) vs 10.2 (SD 7.0), mean Disease Extent Index in Takayasu Arteritis 11.2 (SD 6.1) vs 8.8 (SD 6.1) and were more frequently initiated on corticosteroids or DMARDs. HRs calculated using exponential parametric regression survival-time model revealed increased mortality rate in patients with TA who developed serious infections (HR 5.52, 95% CI 1.75-17.39).
Conclusion Serious infections, which occurred in the absence of immunosuppressive treatment in approximately one-fifth of patients with TA, were associated with increased mortality in patients with TA.
Takayasu arteritis (TA) is a rare large-vessel vasculitis that is more prevalent in Asia and often affects young female individuals.1,2 Patients with TA deemed to have active arterial wall inflammation are treated with immunosuppressive agents such as corticosteroids (CS), usually combined with other disease-modifying antirheumatic drugs (DMARDs).3-5 Akin to other rheumatic diseases, the use of immunosuppressive agents is associated with infections in TA.4 A higher incidence of TA has been described in some areas with a high prevalence of tuberculosis (TB).6 However, a causal link between TB and TA remains unproven.6
Work from our group7 and from others have identified increased mortality risk in TA when compared with the general population.8,9 Infections are an important cause of death in TA.8,9 Three of the 12 deaths in patients with TA from our cohort7 were due to infections. Serious infections were associated with higher mortality risk.7 In our present study, we elaborate on serious infections in our cohort of patients with TA; analyze demographic, clinical, angiographic, and treatment-related correlates of patients with TA who developed serious infections; and reevaluate the association of serious infections with mortality in TA.
METHODS
Study cohort. From an ambispective, monocentric cohort of patients with TA,7,10,11 the hospital records of patients with angiographically proven disease were screened to identify episodes of serious infections (defined as infections requiring hospitalization or resulting in death, or opportunistic infections such as TB). The cohort comprised a prospective-retrospective registry of patients with TA who first visited the hospital between 1996 and 2023 and were following up at a dedicated vasculitis clinic since January 2017. The prospective registry was established in 2023. Data before 2017 (ie, from the time the patient was first seen at our hospital) was collected retrospectively from the patient records. Standardized case record forms were used to retrospectively retrieve the relevant data of patients following up in the vasculitis clinic from the time of their registration in the hospital. Written informed consent was obtained for those enrolled in the prospective registry, whereas the information for those patients seen between 2017 and 2022 without visits thereafter was retrieved from the clinic files and electronic medical records of in-patient admissions (waiver of written consent was obtained for this purpose from the ethics committee). Approval for the registry had been obtained from the Institute Ethics Committee of Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India (prospective registry: document submission no. 2022-152-IMP-129, approval obtained on January 12, 2023; retrospective registry: ethics submission no. 2023-34-IMP-EXP-51, date of approval April 3, 2023). Data for this analysis were censored in October 2023.
Patients with TA included in the study fulfilled classification criteria for TA (for adult TA: 1990 American College of Rheumatology [ACR], 2022 ACR/European Alliance of Associations for Rheumatology [EULAR] classification criteria, or the 2012 Chapel Hill Consensus Conference definition; for pediatric TA: 2008 EULAR/Paediatric Rheumatology International Trials Organization/Paediatric Rheumatology European Society classification criteria).12,13
Covariates. The information collected in the standardized proformas included age (at disease onset, at diagnosis [and diagnostic delay], at entry into the cohort), sex, follow-up duration, presenting features, angiographic extent of disease at the initial assessment, and angiographic subtype according to Hata classification.14 Disease activity at presentation was recorded using the Indian Takayasu Arteritis Clinical Activity Score 2010 (ITAS2010), Disease Extent Index in Takayasu Arteritis (DEI.Tak), or physician global assessment of disease activity (PGA) as active or inactive.15 Prevalent comorbidities (diabetes mellitus, chronic renal failure, smoking, cancer, heart failure, acute coronary syndrome, stroke or transient ischemic attack, chronic pulmonary disease) were noted. Treatment with immunosuppressive drugs was recorded. For each episode of infection, the type of infection, microbiological evidence to support the infection, and CS or DMARD use at the time of infection were noted. Outcome at the last visit (survival or mortality) and dates of the first and last visit (or mortality) were recorded for survival analyses. Patients without a recent visit (last visit earlier than 2022) were contacted by telephone and their outcomes or complications were recorded.
Statistical analyses. Comparisons were performed between patients with TA with or without serious infections during the period of observation. Continuous variables, reported as means (SD), were compared using the t test. Categorical variables were compared using chi-square test or Fisher exact test (the latter if any of the 4 cells had < 5 events recorded). The association between clinical features at presentation with serious infections was evaluated using univariable logistic regression to generate odds ratios (with 95% CI).
Survival among patients with TA with or without episodes of serious infections was depicted using Kaplan-Meier curves. Thereafter, hazard ratios (HRs; with 95% CI) for mortality for patients with TA with any episode of serious infection were computed. The proportionality of hazards was checked using Schoenfeld residuals for Cox regression models (using the estat phtest function in Stata; P < 0.05 indicated evidence against the proportional hazards assumption). If the condition of proportionality was not met, then exponential parametric regression survival-time models were used to compute HRs. Statistical analyses were undertaken using Stata 16.1 I/C (StataCorp) or Prism 10 for MacOS (GraphPad).
RESULTS
Patient characteristics. The registry comprised 245 patients with TA, of whom 238 with available angiography to support the diagnosis of TA were included in this analysis. Serious infections had been recorded in 38 (16%) patients in the cohort. Patients with TA with serious infections had similar age, sex distribution, delay to diagnosis, disease duration, follow-up duration, and prevalent comorbid conditions than those without any episode of serious infections. Patients with TA with serious infections more frequently had active disease by PGA, higher ITAS2010 and DEI.Tak scores at presentation, were more likely to have been initiated on CS or DMARDs, and had been treated with a greater number of DMARDs than those without serious infections. However, the dose of CS at initiation, duration of CS therapy, percentage reduction in CS dose from the dose at initiation, and the proportion of patients who had successfully stopped CS were similar between groups (Table 1). Most patients who had been initiated on DMARDs were on conventional DMARDs; biologic DMARD use was scarce (5/246 courses of DMARDs).
Characteristics of the cohort.
Serious infections in the cohort. Fifty episodes of serious infections were noted in 38 patients with TA (a single episode in 30, 2 episodes in 7, and 6 episodes in 1 patient). Eleven of the 38 initial episodes of serious infection (overall, 11/50 episodes) occurred in patients with TA not taking CS. The mean (SD) daily dose of CS during the remaining 39 episodes was 13.03 (10.41) mg equivalent of prednisolone. Fourteen of the 38 initial episodes of serious infections (overall, 17/50 episodes) occurred in patients who were not on any DMARDs. Overall, among the 33 episodes of serious infections where a DMARD had been prescribed at that time, methotrexate (MTX) was the most common DMARD (n = 12), followed by tacrolimus (n = 8), azathioprine (n = 6), mycophenolate (n = 5), tacrolimus with MTX (n = 1), and cyclophosphamide (n = 1).
Twelve episodes of serious infection were due to TB, which was microbiologically proven in 3 patients. The rest were based on a clinical diagnosis of granulomatous lymphadenitis or characteristic lesions in the lungs on imaging or tubercular meningitis, with therapeutic response to antitubercular therapy. Pneumonia (n = 19), gastrointestinal infections (n = 6), and urinary tract infections (n = 5) were the most frequent infections. One patient had a fungal pneumonia. Of 37 episodes of bacterial infections, 12 had culture evidence of bacterial infection (including 1 with nocardiosis; Table 2), the rest were possible or likely infections based on a clinical diagnosis and response to antimicrobial therapy. In the 1 patient with 6 episodes of lower respiratory tract infection, the patient was ambulatory, renal functions and serum Ig levels were normal, the patient was on DMARDs during 4 episodes (tacrolimus during 3 episodes and MTX during 1 episode), and the daily dose of prednisolone was between 1.25 mg and 6.25 mg for 4 of the episodes (the first episode was while not on CS, whereas during the other episode, the dose of CS was equivalent to 16 mg daily prednisolone). Apart from underlying heart failure, there was no evident cause for recurrent pneumonia.16
Details of serious infections (n = 50).
Clinical and angiographic features between patients with TA with or without serious infections. Patients with TA with or without serious infections had similar clinical features at presentation (Supplementary Table S1, available with the online version of this article). Those with serious infections were more likely to have abdominal aorta, renal artery, or iliac artery involvement without observed differences in Hata angiographic subtypes (Supplementary Table S2).
Mortality due to serious infections. Three of the 50 episodes of infections had resulted in death, whereas 7 of the patients who ever had an episode of serious infection had died (1 each due to intractable heart failure and recurrent stroke; the other 2 were out-of-hospital deaths due to suspected strokes). The hazard for mortality with serious infections failed to satisfy the assumptions for proportionality (P value for Schoenfeld residuals = 0.03), therefore, HRs were calculated using exponential parametric regression survival-time models. The mortality rate in patients with TA with any episode of serious infections was increased (HR 5.52, 95% CI 1.75 - 17.39; Figure).
Risk of mortality in patients with TA with or without serious infections, using an exponential parametric regression survival-time model. HR: hazard ratio; TA: Takayasu arteritis.
DISCUSSION
Fifty episodes of serious infections were observed in 38 patients with TA in our cohort. About one-fifth of the infections occurred in patients with TA not taking CS, whereas one-third occurred in patients not taking DMARDs. Bacterial infections were the most frequent, most commonly pneumonia, gastrointestinal infections, and urinary tract infections. TB accounted for one-fourth of the infections; other notable unusual infections included 1 patient with nocardiosis. Patients with TA who had developed serious infections had more active disease at presentation and were more often initiated on CS or DMARDs than those without serious infections. A higher mortality rate was observed in patients with TA who had serious infections than those without serious infections.
Infections accounted for 3 of the 12 deaths in our cohort. Analysis of nationwide data from the Netherlands identified 9 deaths in patients with TA (one due to infection).8 A multicentric French cohort of patients with TA reported infections as the cause of death in 3/16 patients with TA.9 Of greater concern was the fact that 7 of the 12 deaths in our cohort occurred in patients who had experienced at least 1 episode of serious infection. The rate of mortality was increased among patients with TA who had experienced serious infections. Infections have also been associated with an increased risk of dying in systemic lupus erythematosus and antineutrophil cytoplasmic antibody–associated vasculitis, particularly in South Asia.17,18 Given the lack of a validated damage index for use in patients with TA, any episode of serious infection may be considered as an item for inclusion in a future damage index devised for patients with TA.2,15
A considerable proportion of serious infections in our patients with TA were during periods when they were not taking CS or other DMARDs. Further, nearly a sixth of our cohort of patients with TA developed serious infections despite the scant use of biologic or targeted synthetic DMARDs. Although tumor necrosis factor inhibitors (TNFi) are standard of care for patients with TA, the infrequent use of these agents in our cohort relates largely to their inaccessibility to patients due to high costs, which have to be borne out-of-pocket. The high background rate of infections relate to the greater propensity to develop infections in tropical countries. Intriguingly, an association between immunodeficiency and TA has been recently described. A report described pediatric-onset TA beginning at age 14 in a child with lipopolysaccharide-sensitive beige-like anchor deficiency and another child with X-linked severe combined immunodeficiency with onset at 16 years.19 The same study identified 17 other published cases of immunodeficiency associated with TA (including 13 adults).19 We have not evaluated our patients with TA for concomitant immunodeficiency, except for the single patient with recurrent infections whose Ig levels were normal. Evaluation of incipient immunodeficiency disorders in TA might be an agenda for future research.
Twelve of the 50 episodes of serious infections in patients with TA in our cohort were due to TB. TB is endemic in India.20 The prevalence of TB in patients with TA worldwide ranges from 6% to 20%.6 Given that TA is more common in areas of the world where TB is endemic and the common pathological finding of granulomatous inflammation in both diseases,6 a causal link has been proposed between TB and TA but remains unproven.
The present study had its limitations. Given the retrospective retrieval of data from clinic files, there was a possibility of missing out on episodes of infections. However, our hospital has an electronic medical records system to track inpatients, which enabled us to identify with confidence any episodes of serious infections leading to hospitalization; however, some episodes of infections requiring hospitalization elsewhere might have been missed. None of the patients in the cohort had admissions due to coronavirus disease 2019 (COVID-19). Because our hospital was the main referral center for COVID-19 in the region and patients without visits after 2021 were telephonically contacted, we are unlikely to have missed out on any hospitalizations due to COVID-19 in the cohort. However, there remains a possibility that some individuals with TA might have been hospitalized with severe COVID-19 at hospitals nearer to their place of residence. One limitation of our study is that we were unable to calculate the cumulative dose of CS in our cohort. Despite the retrospective retrieval of data and the associated limitations of retrospective observational studies,21 few patients were ineligible for inclusion due to missing data, as the data had been recorded systematically in vasculitis clinic files since 2017. Since TA is a rare large-vessel vasculitis, most large cohort studies of TA have analyzed retrospective data.22 Microbiological evidence of infection was identifiable in approximately one-third of patients with TA with serious infections. However, in real-world settings, microbiological cultures are frequently negative.23-25 Despite the lack of a validated damage index for TA, we analyzed the association of features suggestive of vascular damage, such as pulse inequality or loss, vascular bruits, hypertension, limb claudication, stroke, or renal failure with serious infections (none of which were associated with serious infections). The large number of patients with TA, a rare form of vasculitis, and the reasonably large number of episodes of serious infections enabled us to undertake analyses to identify associations of characteristics of patients with TA with serious infections. However, the small number of events of mortality did not permit us to perform multivariable adjusted analyses for mortality rate after accounting for factors such as differences in disease activity at presentation or immunosuppressive use, which was also a limitation of the study.
In conclusion, serious infections were prevalent in one-sixth of the patients with TA in our cohort and were associated with a greater risk of mortality. The high prevalence of TB makes it reasonable to consider screening for latent TB infection through modalities such as the Mantoux test or the interferon-γ release assay in all patients with TA before the initiation of immunosuppressive therapy. The effectiveness of such a screening strategy should form an agenda for future research that might benefit patients with TA and other forms of vasculitis.
Footnotes
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication March 10, 2024.
- Copyright © 2024 by the Journal of Rheumatology
REFERENCES
DATA AVAILABILITY
All the analyses performed for this article have been reported in the main text. Data pertaining to the article shall be shared upon reasonable request to the corresponding author.
