|Ahead of print publication
Characteristics and diseases associations of tuberculosis in lupus: A retrospective single-center analysis
Dunga Sai Kumar1, Sanket Ishwarbhai Shah2, Chengappa Kavadichanda1, Aishwarya Gopal1, Prakash Babu Narasimhan1, Vir Singh Negi1
1 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry; Department of Medicine, C. U. Shah Hospital and Medical College, Surendranagar, Gujarat, India
|Date of Submission||16-Jul-2021|
|Date of Acceptance||21-Nov-2021|
|Date of Web Publication||06-Jul-2022|
Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
Source of Support: None, Conflict of Interest: None
Objective: The objective of this study is to identify factors associated with active tuberculosis (TB) in patients with systemic lupus erythematosus (SLE) and to study the impact of TB on SLE disease activity.
Methodology: We screened case records of 643 individuals with SLE for the diagnosis of TB. SLE patients with TB (cases) (n = 29) were matched for age, sex, and disease duration in the ratio of 1:3 with controls (n = 94) (SLE without TB).
Results: Pulmonary TB was seen in 41% (n = 12) and extrapulmonary TB in 59% (n = 17). Musculoskeletal TB (n = 6; 34.2%) was the most common extrapulmonary manifestation. TB was seen among those with lupus nephritis (55% vs. 38.4%) (P < 0.005) and those with autoimmune hemolytic anemia (48% vs. 38%). A higher median dose of daily glucocorticoids 11.5 (7.5–30) in 1 month preceding TB diagnosis was associated with a higher incidence of TB. Upon multivariable analysis, 1 month mean daily dose of glucocorticoids ≥ 7.5 mg (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.07–2) was independently associated with TB. On a follow-up duration of 16 months, SLE flare was more among those with TB as compared to the controls (OR-2.49 95%; CI-1.39–4.48; P = 0.002).
Conclusion: Extrapulmonary TB is the most common form in individuals with SLE. A higher steroid dose seems to predispose to TB infection. TB infection may increase the risk of SLE disease flare.
Keywords: Immunosuppressives, infection, latent tuberculosis, lupus nephritis, mycobacterium, systemic lupus erythematosus
|How to cite this URL:|
Kumar DS, Shah SI, Kavadichanda C, Gopal A, Narasimhan PB, Negi VS. Characteristics and diseases associations of tuberculosis in lupus: A retrospective single-center analysis. Indian J Rheumatol [Epub ahead of print] [cited 2022 Aug 20]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=350016
| Introduction|| |
Infections are a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE), with nearly 50% of patients experiencing primary infection during their disease course. Individuals with SLE have impaired cellular immunity, which increases the risk of infections with intracellular organisms, including tuberculosis (TB). Several clinical features of TB such as fever, malaise, lymphadenopathy, serositis, skin ulcers, and neurological involvement are at times indistinguishable from those due to lupus. Even the laboratory features of SLE including lymphopenia, leukopenia, and occasionally pancytopenia can be seen with TB. This makes early diagnosis of TB in SLE based solely on clinical presentation difficult, especially in high TB prevalence. It is hence important to describe the presentations of TB and the associated lupus manifestations from countries with high burden of infection. In this study, we described the clinical profile of TB from a large cohort of patients with lupus. We then examined the disease associations of SLE among those with and without TB. We also analyzed the impact of TB infection on the treatment of SLE and on lupus disease activity.
| Methodology|| |
This is a hospital-based retrospective case–control study from a tertiary care center in India. Case records of 643 patients classified as SLE according to the Systemic Lupus Collaborating Clinics criteria were screened for documentation of TB. TB was defined as either microbiologically proven or clinically diagnosed. Microbiologically confirmed TB case refers to patients with any of their biological specimen positive for Acid-fast bacilli (AFB) staining or positive on culture or positive through a quality-assured rapid diagnostic molecular test such as polymerase chain reaction or cartridge-based nucleic acid amplification test (CBNAAT). Clinically diagnosed TB case refers to a presumptive TB who does not satisfy the above microbiological criteria but has been diagnosed by the treating clinician based on imaging abnormalities, histopathology, or clinical signs with an intention to treat the patient with the entire course of anti-TB treatment (ATT). Those patients with lupus satisfying either of the case definitions for TB were included in the study. Individuals with SLE without TB infection were selected as controls from the same cohort and matched for age, gender, and duration of SLE in a 1:3 ratio. We identified the type and manifestation of TB and then compared various lupus-related parameters between cases and controls. We then assessed for the changes in the treatment strategy of lupus and changes in diseases activity following diagnosis of TB during follow-up. SLE disease flare was defined according to SELENA-SLEDAI. The study was approved by the institutional ethics committee (JIP/IEC/2021/036).
| Results|| |
A total of 643 case records were screened, and 29 satisfied the case definition for TB. Controls (n = 94) satisfying the matching criteria were identified and included for analysis. The demographic and clinical details of cases and controls are presented in [Table 1].
|Table 1: Comparison of demographic, clinical, laboratory, and therapeutic characteristics between systemic lupus erythematosus patients with tuberculosis and without tuberculosis|
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Characteristics and outcome of tuberculosis
The median age at TB diagnosis was 26.5 (interquartile range [IQR], 23–36) years. The median duration for TB after SLE diagnosis was 24 months (IQR, 20–168). Seventeen (59%) patients had a proven microbiological evidence of TB by either CBNAAT from exudates or positive sputum for AFB. In patients without microbiological evidence, TB was diagnosed based on radiological evidence (n = 7) or histopathological evidence (n = 5). Of 29 patients, isolated pulmonary TB was seen in 12 (41%), while 17 (59%) had extrapulmonary TB. Musculoskeletal TB (n = 6/17; 34.2%) was the most common site for extrapulmonary TB. Of which, 4 had monoarthritis, 1 had polyarticular TB, and 1 had Pott's Spine. All patients received ATT according to the national guidelines. The mean duration of ATT intake in pulmonary TB was 6 (±2) months, and extrapulmonary TB was 9 (±3) months. Of 29 patients, cure was documented in 26 patients, and one of them developed residual lung fibrosis with bronchiectasis. None of the patients had drug-resistant TB. Two patients were lost to follow-up while one succumbed to the infection. Disease characteristics among TB cases are described in [Table 2].
|Table 2: Tuberculosis sites, clinical features, diagnosis, and outcome among cases|
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Factors associated with active tuberculosis in systemic lupus erythematosus patients
TB infection was significantly associated (P < 0.005) with lupus nephritis (55% vs. 38.4%), having received ≥2 immunosuppressants (38% vs. 26.5%), and a higher median dose of glucocorticoids 11.5 (7.5–30), in 1 month preceding TB diagnosis. Multivariate analyses showed that past 1 month mean daily dose of glucocorticoids ≥ 7.5 mg (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.07–2), alone was independently associated with TB infection, after adjusting for age, sex, disease duration, and disease activity [Table 3].
|Table 3: Univariable and multivariable regression of potential predictive factors for tuberculosis in systemic lupus erythematosus|
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Effect of tuberculosis on systemic lupus erythematosus
Seven patients (24%) had TB at a median duration of 14 months (range, 12–58) before lupus diagnosis, and 5 (17%) were diagnosed with TB and lupus concomitantly. The rest of the 17 (59%) patients developed TB after lupus diagnosis during the follow-up. Of 29 patients, there was a median delay of 2 months (IQR 1–4) in initiating immunosuppressant in 11 (37.9%) patients. Immunosuppressants were stopped in five patients upon diagnosis of TB. During the median follow-up duration of 16 months (range 8–121) after diagnosing TB, 40 SLE flares were observed in 21 (72.4%) patients while 52 flares in 46 (49%) controls (OR-2.49; 95% CI-1.39–4.48; P = 0.002). Similar trend was observed in major and minor flares [Table 1].
| Discussion|| |
The prevalence of TB in SLE from our study was 4.5% which was lesser than previously reported studies from India 11.6% to 6.4%. Previously reported prevalence of TB in SLE across the world is between 0.7% and 17%., Reason for the low prevalence in our study may be due to the cross-sectional design of the study or due to referral bias given the fact that the study center is a tertiary care hospital with multiple specialties. We found an increased incidence of extrapulmonary TB (58.6%) in lupus. The prevalence of extrapulmonary TB in SLE across the world ranged from 18%–74%. In a study by Zhang et al., and Hou et al., the most common extrapulmonary TB was disseminated TB followed by combined skin and joint TB, respectively., These are in contrast to our study as musculoskeletal TB is the most common form of extrapulmonary TB. Less mortality and the presence of only two cases with disseminated TB are two dissimilar features to the reported literature of TB in SLE.
In our study, the mean glucocorticoid dose ≥7.5 mg in the past 30 days was found to be associated with TB infection in SLE patients. Several studies have reported that both cumulative steroid dose and mean daily steroid dose are major risk factors for TB in SLE., A study in the lupus-cruces cohort showed that patients with TB had a median daily prednisone dose of 7.5 mg/day and also demonstrated that the probability of major infection increases by 12% per each daily milligram of prednisone. Similarly, another study from the UK showed that a nearly 3-fold increased risk of TB was seen in prednisolone users with daily dose of >7.5 mg/day or it is equivalent compared with nonprednisone users while no clear effect of duration or cumulative dose on the risk of TB was found. This can be explained due to the deleterious effects of long-term administration of glucocorticoids on innate antimycobacterial host defense and preferential suppression of Th1 and Th17 cells of adaptive immunity. Apart from these, other risk factors demonstrated in several studies were lymphopenia and concomitant immunosuppressive usage., We were not able to show this difference between cases and controls, probably owing to the small sample size and the study design.
Antibody-mediated manifestations such as lupus nephritis and autoimmune hemolytic anemia (AIHA) were also higher among individuals with TB suggesting the role of chronic infections in diseases pathogenesis. Besides, the delay in initiating or optimizing immunosuppressive agents could also have resulted in significant numbers of lupus flares among patients with TB. ATT drugs such as rifampicin are potent enzyme inducers and can decrease the effective levels of immunosuppressive agents and have to be kept in mind when a patient on ATT has a lupus flare.
TB infection in SLE is quite challenging for the clinician to diagnose, especially if there is a coexistent disease flare. For example, weight loss, arthralgia, arthritis, pleural effusion, and pericardial effusion which can occur in both situations may cause a significant delay in diagnosis of TB and may increase the risk of dissemination with inadvertent treatment with immunosuppressives. Our report may be a primer for treating clinicians about the masquerading behavior of TB.
There are several limitations for our study. The retrospective study design and the possible introduction of selection bias as data were collected from available medical records cannot be ruled out. It is possible that some relevant risk factors may not have reached statistical significance given the small sample size. However, the retrospective nature of the data has allowed us to see the effect of TB on lupus flare and is an important outcome. Having a high index of suspicion for TB among individuals with SLE combined with early and aggressive treatment of both TB and lupus will potentially improve outcomes among these patients. Every attempt to taper and withdraw glucocorticoids in lupus must be made in this context once SLE activity is optimally controlled. There is also an urgent need to identify the prevalence and effect of latent TB among patients with SLE. This strategy may help in identifying a group of people who are at risk for developing TB who can be treated for the same before or during the initiation of immunosuppressive agents.
| Conclusion|| |
Our study shows the higher propensity of extrapulmonary TB, predominantly musculoskeletal TB in SLE. TB infection in SLE patients seemed to increase the risk of disease flare. Mean daily prednisolone dose of more than 7.5 mg, exposure to two or more immunosuppressants, and AIHA are associated with developing TB in SLE patients.
Patient consent and ethical approval
The study was conducted in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments after obtaining clearance from the Jawaharlal institute of postgraduate medical education and research institute ethics committee (JIP/IEC/2021/036). Written informed consent was obtained from the study participants.
Availability of data and material
The data that support the findings of this study are available from the corresponding author, KC, upon reasonable request.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]