Clinical Rheumatology

https://doi.org/10.1007/s10067-020-05225-x

ORIGINAL ARTICLE

Factors associated with active tuberculosis in Colombian patients

with systemic lupus erythematosus: a case-control study
Luis Alonso González-Naranjo 1 & Jaime Alberto Coral-Enríquez 1 & Mauricio Restrepo-Escobar 1 &
Carlos Horacio Muñoz-Vahos 1 & Daniel Jaramillo-Arroyave 1 & Adriana Lucía Vanegas-García 1 & Ruth Eraso 1,2 &
Gloria Vásquez 1 & Fabián Jaimes 3,4,5

Received: 8 March 2020 / Revised: 22 May 2020 / Accepted: 8 June 2020

# International League of Associations for Rheumatology (ILAR) 2020

Abstract
Objective To identify factors associated with active tuberculosis (TB) in patients with systemic lupus erythematosus (SLE).
Methods We performed a retrospective case-control study in two tertiary care teaching hospitals in Medellín, Colombia. From January
2007 to December 2017, a total of 268 patients with SLE were included. SLE patients with TB (cases) were matched 1:3 with SLE
patients without TB (controls) by disease duration and the date of the hospitalization in which the diagnosis of TB was made (index
date of cases) to the nearest available rheumatology hospitalization in the matched controls (± 2 years). Conditional univariable and
multivariable logistic regression analyses were performed.
Results Sixty-seven cases and 201 controls were assessed. Only pulmonary TB occurred in 46.3%, only extrapulmonary TB in 16.4% and
disseminated TB in 37.3% of cases. Multivariable logistic regression analysis showed that lymphopenia (OR, 2.91; 95% CI 1.41–6.03; P =
0.004), 12-month cumulative glucocorticoid dose ≥ 1830 mg (OR, 2.74; 95% CI 1.26–5.98; P = 0.011), and having been treated with ≥ 2
immunosuppressants during the last 12 months (OR, 2.81; 95% CI 1.16–6.82; P = 0.022) were associated with TB after adjusting for age,
sex, ethnicity, disease duration, disease activity, and comorbidity index. A trend towards an association of kidney transplantation with TB was
also found (OR, 3.77; 95% CI 0.99–14.30; P = 0.051).
Conclusion Among SLE patients, cumulative glucocorticoid dose, lymphopenia, and the use of ≥ 2 immunosuppressants during the last
12 months were associated with active TB infection.

Key Points
• Among SLE patients, a cumulative dose of glucocorticoids equivalent to 5 mg/day of prednisone during the last 12 months is independently associated
with the development of TB.
• The use of two or more immunosuppressants during the last 12 months is also a risk factor for TB infection development is SLE patients.
• Lymphopenia is predominant in SLE patients with TB, being especially profound in those with disseminated TB.
• Renal transplant recipients with SLE also have an elevated risk of TB.

Keywords Systemic lupus eryhematosus . Tuberculosis . Opportunistic infections . Glucocorticoids . Immunosuppressants

* Luis Alonso González-Naranjo 3

Department of Internal Medicine, Universidad de Antioquia,
[email protected]; [email protected] Medellín, Colombia
4
GRAEPIC - Clinical Epidemiology Academic Research Group
1
Division of Rheumatology, Department of Internal Medicine, School (Grupo Académico de Epidemiología Clínica), Universidad de
of Medicine, Universidad de Antioquia, Hospital Universitario de Antioquia, Medellín, Colombia
San Vicente Fundación, Bloque 7. Calle 64 N°51 D – 154, 5
Research Direction, Hospital Universitario San Vicente Fundación,
Medellín, Colombia Medellín, Colombia
2
Department of Pediatrics, Division of Rheumatology, Hospital Pablo
Tobón Uribe, Medellín, Colombia
 Clin Rheumatol

Introduction Fundación and Hospital Pablo Tobón Uribe, in Medellín,

Colombia. This study was conducted according to the decla-
It is well-known that various relationships exist between in- ration of Helsinki and was approved by the institutional re-
fections and rheumatic diseases [1]. For example, there is a view boards of the participating institutions. We searched the
complex interaction between systemic lupus erythematosus hospital’s registry for all SLE patients from January 1, 2007 to
(SLE) and tuberculosis (TB) in which one may trigger the December 31, 2017, using the WHO’s International
development of the other [1, 2]. SLE patients are at increased Classification of Diseases, Tenth Revision (ICD-10), coding
risk of developing infections as a consequence of either the system. Then, a second search was performed using TB ICD-
intrinsic immune dysfunction in SLE or the immunosuppres- 10 codes to identify those patients who were diagnosed with
sant drugs used to treat the disease [3]. The majority of infec- SLE and TB. All patients met the 1997 American College of
tions results from gram-positive and gram-negative bacteria, Rheumatology (ACR) revised classification criteria for SLE
but infections by Mycobacterium tuberculosis may also occur [20]. The diagnosis of TB was made on the basis of TB-
and are potentially fatal in most cases [3, 4]. On the other associated symptoms and/or signs and one or more of the
hand, infections, including TB, may induce autoimmune dis- following: che st radiographic findings, positive
eases in genetically predisposed patients [1, 2]. Mycobacterium tuberculosis culture, a positive sputum smear
TB, a global health issue, remains an important cause of microscopy, a positive polymerase chain reaction (PCR) assay
morbidity and mortality, particularly in developing countries. for M. tuberculosis complex, or histopathological findings
In 2017, as reported by the World Health Organization compatible with TB. Tuberculosis infection was categorized
(WHO), 10.0 million people developed TB disease worldwide as pulmonary, extrapulmonary, and disseminated TB.
and more than 1.3 million people died from TB [5]. In 2017, Extrapulmonary TB refers to TB involving an organ other
according to the Colombian Ministry of Health and Social than the lungs (e.g., pleura, lymph nodes, genitourinary tract,
Protection, 14,480 cases of TB in all its forms were reported, skin, joints, or meninges) while disseminated TB is defined as
and 1439 deaths were due to TB [6]. TB involving the blood stream, two or more noncontiguous
Compared to the general population, patients with SLE are organs or miliary TB [21].
more susceptible to TB, particularly in endemic regions, but Cases were defined as those patients with a diagnosis of
the actual incidence varies depending on the specific region SLE and TB as previously described. The diagnosis of TB
[2, 3, 7–9]. The incidence of TB among SLE patients from the prior to the diagnosis of SLE was considered as an exclusion
Basque Country, Spain, was seven-fold higher compared to criterion. SLE patients without TB infection from the same
the general population [8], whereas in Hong Kong, where TB registry were selected as controls and matched in a 3:1 ratio
is endemic, the incidence of TB in SLE patients was 15-fold to cases by SLE duration and the date of the hospitalization in
higher than that expected in the general population [9]. In SLE which the diagnosis of TB was made (index date of cases) to
patients, TB is characterized by a higher frequency of the nearest available rheumatology hospitalization in the con-
extrapulmonary involvement, a more extensive pulmonary trols (± 2 years, or inclusion or index date in the controls), in
affectation and a higher relapse rate [9–19]. order to avoid biases due to the use of different immunosup-
The diagnosis of TB infection can be delayed in patients pressive therapies in the previous years.
with SLE, especially in those with extrapulmonary and atyp- Sociodemographic, clinical, laboratory, and therapeutic da-
ical manifestations; thus, it is important to recognize the risk ta were obtained from medical records. Sociodemographic
factors for the development of TB in these patients. Some variables included: age, gender, ethnicity (African-Latin
previous studies have reported the cumulative dose of gluco- American and non-African-Latin American (Mestizo,
corticoids [9, 18, 19], maximum dose of glucocorticoids [14, Caucasian and Amerindian)). Clinical variables included the
16], duration of glucocorticoids treatment [16], the presence following cumulative SLE-related clinical manifestations:
of lupus nephritis [9, 10], and lymphopenia [16, 18, 19] as a mucocutaneous (acute lupus, subacute cutaneous lupus, dis-
risk factors for TB among patients diagnosed with SLE. Thus, coid lupus, alopecia, oral ulcers, and/or photosensitivity),
we performed a case-control study to determine the character- musculoskeletal (arthritis or myositis), renal involvement (ne-
istics and the risk factors associated with the development of phritis by histopathology [WHO class II-VI], proteinuria ≥
TB infection in a population of Colombian patients with SLE. 0.5 g/24-h and/or active urinary sediment (≥ 5 red blood
cells(RBC)/high-power field [hpf]), ≥ 5 white blood cells
[WBC]/hpf, or cellular cast [RBC or WBC casts]), pulmonary
Study population and methods involvement (pleuritis, acute pneumonitis, pulmonary hemor-
rhage, and/or interstitial lung disease), neurologic involve-
We carried out a retrospective matched case-control study in a ment (seizures, psychosis, headaches, cerebrovascular acci-
population of SLE patients who attended two tertiary care dent, neuropathies, transverse myelitis, and/or myelopathy),
teaching hospitals, Hospital Universitario de San Vicente and hematological involvement (thrombocytopenia [<
Clin Rheumatol

100,000/mm3], leucopenia [< 4000/mm3], lymphopenia [< cumulative dose of glucocorticoids, we chose the value of
1000/mm3], autoimmune hemolytic anemia, and/or microan- the lower quartile as the variable to include in these analyses.
giopathic hemolytic anemia). Individual hematological mani- Variables with a p ≤ 0.05 in the univariable analyses and those
festations such as leukopenia and lymphopenia were deter- considered clinically important were included in multivariable
mined at the time of TB diagnosis for the cases or the index logistic regression analysis to identify the factors associated
date for the controls. Chronic comorbid conditions were also with active TB in patients with SLE. Results are presented as
studied using the Charlson comorbidity index, which was cat- odds ratio (OR) with their 95% CIs. Statistical analysis was
egorized into four grades: 0 points (none), 1–2 points (low), performed using Stata version 12.0.
3–4 points (moderate) and ≥ 5 points (high) [22]. In addition,
the history of organ transplantation and specific comorbidities
that may predispose these patients to TB including diabetes Results
mellitus, liver cirrhosis, human immunodeficiency virus in-
fection (HIV), and chronic alcoholism were also recorded A total of 4738 patients met the 1997 ACR revised classifica-
separately. Disease duration, defined as the time period from tion criteria for SLE. Among them, we found 124 potential
the diagnosis of SLE to either the date of TB diagnosis for cases of TB. Of these, 34 patients were excluded because of
cases or the index date of the controls was also recorded. TB diagnosis prior to SLE diagnosis (n = 2), absence of a
Disease activity at the time of TB diagnosis or at the index confirmed diagnosis of tuberculosis (n = 9), another non-
date of the controls was assessed using the SLE disease activ- tuberculous infection was the definitive diagnosis (n = 10),
ity index (SLEDAI) [23]. Scores > 4 points were considered and incomplete data and lost medical records (n = 13). Thus,
as active SLE. Immunological and laboratory variables were a total of 67 (1.4%) SLE patients with active TB infection
recorded at the time of TB diagnosis for the cases or the index were matched to 201 controls by year of hospital admission.
date for the controls. These variables included: anti-dsDNA No recurrent TB infection was diagnosed in these patients.
positivity, C3 and/or C4 hypocomplementemia, hypoalbu- Data for SLE patients with and without active TB are de-
minemia (< 3 g/dl), and lymphocyte count. Therapeutic vari- scribed in Table 1.
ables included cumulative dose of glucocorticoids (predni- Among SLE patients who developed active TB infection,
sone or its equivalent) within the last 12 months before TB 83.6% (56/67) were female, Mestizo was the predominant
(cases) or the index date for the controls; the median daily ethnic group (89.6%) while the remaining were African-
steroid dose during the month prior to tuberculosis infection, Latin Americans (10.4%). The median age at SLE diagnosis
for the cases, or to the index date, for the controls; antimalar- was 28 years (interquartile range (IQR), 19–34) and the me-
ials used and the number and types of immunosuppressant dian age at TB diagnosis was 34 years (IQR, 24–45).
drugs (azathioprine, cyclophosphamide, mycophenolate mo- Regarding clinical manifestations, there were no significant
fetil, methotrexate, cyclosporine, tacrolimus, sirolimus, ritux- differences between cases and controls. However, lymphope-
imab, and leflunomide) received during the last 12 months. nia (< 1000/mm3) was more frequent in cases (56.7%) than in
controls (34.8%, p = 0.001) and the median of the lymphocyte
Statistical analysis count in the cases was significantly lower than in the control
group (804/mm3 (IQR, 597–1200) vs. 1200 (750–1900), p =
The minimum sample size needed to detect an odds ratio (OR) 0.001). Similarly, a history of renal transplantation was more
of at least 1.5 was based on the estimated frequency of gluco- frequent in cases than in controls (11.9% vs. 4.5%, p = 0.044).
corticoid exposure in cases in the year prior to diagnosis of There were 7 deaths in cases attributable to TB infection.
TB, establishing an exposure frequency of 60% in cases ver- However, there was no statistical difference with respect to
sus 40% among controls [24], with an estimated power of the control group in which 13 deaths were reported (p =
80%. The calculated sample was 51 cases and 152 controls. 0.298). Among the cases who died, 6 had disseminated tuber-
Continuous variables were presented as mean ± standard culosis and one had pulmonary tuberculosis.
deviation (SD) or median (interquartile range, IQR), accord- Within the last 12 months, the cumulative glucocorticoid
ing to its probability distribution, while categorical variables dose was higher in cases than in controls (3.65 g (IQR 1.83–
were presented as absolute (number) and relative frequencies 5.50) vs. 2.10 (2.10–4.50), p = 0.01) while the cases received
(percentage). Comparisons between cases and controls were ≥ 2 different immunosuppressants more frequently than the
assessed by using the Chi-square test or the Fisher exact test controls (26.9% vs. 10.9%, p = 0.023). Among cases, myco-
for categorical variables, the Student’s t test for continuous phenolate mofetil was the most prescribed immunosuppres-
variables with normal distribution and the Mann-Whitney U sant (24/67; 35.8%) followed by azathioprine (17/67; 25.4%),
test for continuous variables with non-normal distribution. intravenous cyclophosphamide (9/67; 13.4%), rituximab
Conditional logistic regression analyses were performed to (6/67; 9%), methotrexate (3/67; 4.5%), cyclosporine (2/67;
identify the factors associated with TB. With regard to the 3%), and tacrolimus (2/67; 3%). Regarding the use of
 Clin Rheumatol

Table 1 Comparison of demographic, clinical, laboratory, and therapeutic characteristics between SLE patients with TB and without TB

Characteristics Cases (n = 67) Controls (n = 201) P value

Demographic
Female sex, n (%) 56 (83.6) 173 (86.1) 0.605
Age at SLE diagnosis, years, median (IQR) 28.0 (19.0–34.0) 28.8 (19.0–41.0) 0.318
Age at TB diagnosis or age at index date, years, median (IQR) 34.0 (24.0–45.0) 36.0 (23–48) 0.340
Ethnic group
Mestizo, n (%) 60 (89.6) 187 (93.0%) 0.349
African-Latin American, n (%) 7 (10.4) 14 (7.0)
Clinical
Mucocutaneous involvement, n (%) 36 (53.7) 129 (64.2) 0.397
Malar rash, n (%) 19 (28.4) 57 (28.4) 1.000
Discoid rash, n (%) 4 (6.0) 21 (10.4) 0.284
Photosensitivity, n (%) 16 (23.9) 67 (33.3) 0.150
Oral ulcers, n (%) 16 (23.9) 51 (25.4) 0.806
Musculoskeletal, n (%) 45 (67.2) 143 (71.1) 0.203
Arthritis, n (%) 45 (67.2) 134 (66.7) 0.940
Serositis, n (%) 19 (28.4) 49 (24.4) 0.516
Pulmonary involvement, n (%) 16 (23.9) 46 (22.9) 0.758
Hematologic disorder, n (%) 35 (52.2) 117 (58.2) 0.647
Neurological disorder, n (%) 8 (11.9) 43 (21.4) 0.089
Nephritis, n (%) 46 (68.7) 124 (61.7) 0.342
SLEDAI, median (IQR)a 4 (0–8) 4 (0–10) 0.741
Disease duration, months, median (IQR)b 60 (19–117) 39 (3–120) 0.542
Laboratory findingsc
Lymphopenia (< 1000/mm3), n (%) 38 (56.7) 70 (34.8) 0.001
Lymphocyte count/mm3, median (IQR) 804 (597–1200) 1200 (750–1900) 0.001
Low complement (low C3 and/or low C4), n (%) 34 (50.7) 107 (53.2) 0.626
Anti-dsDNA positive, n (%) 28 (41.8) 105 (52.2) 0.141
Hypoalbuminemia, n (%) 37 (55.2) 88 (43.8) 0.150
Comorbid conditions
Charlson comorbidity index 1 (1–3) 1 (1–3) 0.477
Diabetes mellitus, n (%) 2 (3.0) 6 (3.0) 1.000
Liver cirrhosis, n (%) 2 (3.0) 4 (2.0) 0.640
Chronic alcoholism, n (%) 1 (1.5) 2 (1.0) 0.741
Smoking 6 (9.0) 10 (5.0) 0.225
HIV virus infection, n (%) 0 (0) 0 (0) 1.000
Organ transplantation, n (%) 8 (11.9) 9 (4.5) 0.044
Deaths, n (%) 7 (10.4) 13 (6.5) 0.298
Medications within the last 12 months prior to TB onset (cases) or index date (controls)
Cumulative dose of glucocorticoids (g), median (IQR)d 3.65 (1.83–5.50) 2.10 (2.10–4.50) 0.010
Prednisone dose (mg/day), median (IQR)e 12 (5–20) 7.5 (0–15) 0.108
Azathioprine, n (%) 17 (25.4) 45 (22.4) 0.615
Cyclophosphamide, n (%) 9 (13.4) 27 (13.4) 1.000
Mycophenolate mofetil, n (%) 24 (35.8) 46 (22.9) 0.038
Methotrexate, n (%) 3 (4.5) 13 (6.5) 0.551
Cyclosporine, n (%) 2 (3.0) 0 (0.0) 0.014
Rituximab, n (%) 6 (9.0) 6 (3.0) 0.041
Tacrolimus, n (%) 2 (3.0) 1 (0.5) 0.094
Antimalarials, n (%) 37 (55.2) 104 (51.7) 0.611
Clin Rheumatol

Table 1 (continued)

Characteristics Cases (n = 67) Controls (n = 201) P value

Number of immunosuppressants
0 22 (32.8) 87 (43.3) 0.023
1 27 (40.3) 92 (45.8)
2 15 (22.4) 18 (8.9)
3 3 (4.5) 3 (1.5)
4 0 (0.0) 1 (0.5)
a
SLEDAI, systemic lupus erythematosus disease activity index: disease activity at the time of TB diagnosis or at the index date of controls
b
Disease duration: the time period from the diagnosis of SLE to either, the date of TB diagnosis for cases or the index date of the controls
c
Laboratory variables: determined at the time of TB diagnosis for cases or the index date for the controls
d
Mean daily dose of prednisone
e
Median daily prednisone dose (mg/day) during the month prior to TB diagnosis (cases) or prior to index date (controls)

antimalarials, there was no difference between cases and con- Characteristics of TB infection in SLE patients
trols (55.2% vs. 51.7%, p = 0.611).
Regarding TB presentation, pulmonary only was the most
common presentation (31/67, 46.3%), followed by dissemi-
Factors associated with active TB in SLE patients nated TB (25/67, 37.3%) and extrapulmonary only (11/67,
16.4%). Pulmonary involvement of TB was found in 54
Results of the conditional logistic regression analyses are (80.6%) cases. The most frequent extrapulmonary site was
shown in Table 2. Univariable analysis showed that 12- extrathoracic lymph node (12/67; 17.9%), followed by
month cumulative dose of glucocorticoids ≥ 1830 mg, renal intraabdominal (11/67; 16.4%), central nervous system
transplantation, lymphopenia, and having been treated with (4/67; 6%), musculoskeletal system (4/67; 6%), renal (2/67;
≥ 2 immunosuppressants during the last 12 months were as- 3%), larynx (4/67; 6%), eye (1/67; 1.5%), and skin and soft
sociated with development of TB infection. Multivariable tissues (1/67; 1.5%) (Table 3 and Fig. 1).
analyses showed that 12-month cumulative dose of glucocor- As to pulmonary radiological findings, alveolar consolida-
ticoids ≥ 1830 mg (OR, 2.74; 95% CI, 1.26–5.98), lympho- tion (13/54; 24.1%) and miliary pattern (9/54; 16.7%) were
penia (OR, 2.91; 95% CI 1.41–6.03), and having been treated the most frequent radiological patterns. On the other hand, the
with ≥ 2 immunosuppressants during the last 12 months (OR, most frequent positive diagnostic tests were polymerase chain
2.81; 95% CI 1.16–6.82) were independently associated with reaction for M. tuberculosis complex (25/67; 37.3%) and di-
TB infection, after adjusting for age, sex, ethnicity, disease rect sputum smear microscopy (23/67; 34.3%). Other charac-
duration, disease activity, and comorbidity index. teristics of TB infection in SLE patients are shown in Table 3.

Table 2 Factors associated with

active tuberculosis in patients Univariable conditional Adjusted Multivariable conditional
with SLE by conditional logistic logistic regression logistic regression a
regression analyses
Variable OR (95% CI) P value Adjusted OR (95% CI) P value

Cumulative dose of glucocorticoidsb 3.25 (1.69–6.25) < 0.001 2.74 (1.26–5.98) 0.011
Number of immunosuppressants (≥ 2) 2.94 (1.46–5.94) 0.003 2.81 (1.16–6.82) 0.022
Lymphopenia (< 1000/mm3)c 2.67 (1.46–4.89) 0.001 2.91 (1.41–6.03) 0.004
Organ transplantation 2.66 (1.03–6.91) 0.044 3.77 (0.99–14.30) 0.051
a
Multivariable logistic regression analyses adjusted for age, sex, ethnicity, disease duration, disease activity, and
comorbidity index
b
12-month cumulative dose of prednisone ≥ 1830 mg
c
At the time of TB diagnosis for cases or the index date for the controls
 Clin Rheumatol

Table 3 Characteristics of tuberculosis infection in patients with SLE from Medellín, Colombia (n = 67)

Characteristics N (%)

Tuberculosis disease site

Pulmonary only 31 (46.3)
Extrapulmonary only 11 (16.4)
Disseminated 25 (37.3)
Distribution of tuberculosis
Lung 31 (46.3)
Renal 1 (1.5)
Peritoneum 2 (3.0)
Skin and soft tissue 1 (1.5)
Extrathoracic lymph nodes 5 (7.5)
Bone and joints 1 (1.5)
Larynx 1 (1.5)
Miliary lung disease 5 (7.5)
Lung + gastrointestinal 3 (4.5)
Lung + gastrointestinal + skeletal muscle 1 (1.5)
Lung + extrathoracic lymph nodes 2 (3.0)
Lung + bone marrow 1 (1.5)
Lung + central nervous system 1 (1.5)
Lung (miliary disease) + central nervous system 2 (3.0)
Lung (miliary disease) + central nervous system + extrathoracic lymph nodes 1 (1.5)
Lung + spine 2 (3.0)
Lung + liver 2 (3.0)
Lung + larynx 1 (1.5)
Lung + extrathoracic lymph nodes + spleen 1 (1.5)
Lung (miliary disease) + extrathoracic lymph nodes + eye 1 (1.5)
Gastrointestinal + extrathoracic lymph nodes 1 (1.5)
Renal + extrathoracic lymph nodes +gastrointestinal 1 (1.5)
Radiological patterns of pulmonary tuberculosis a
Miliary pattern 9/54 (16.7)
Nodule 6/54 (11.1)
Alveolar consolidation 13/54 (24.1)
Cavitary lesion 2/54 (3.7)
Tree-in-bud pattern b 3/54 (5.5)
Pleural effusion 2/54 (3.7)
Normal 2/54 (3.7)
Extent of pulmonary involvement c
One lobe 18/31 (58.1)
Two or more lobes 11/31 (35.5)
No reported lobar involvement 2/31 (6.4)
Positive diagnostic test d
Microbiologic culture 12 (17.9)
Direct sputum smear microscopy 23 (34.3)
Chest radiographic findings e 12 (17.9)
Polymerase chain reaction for Mycobacterium tuberculosis complex 25 (37.3)
Histopathology 5 (7.5)
Clin Rheumatol

a
All patients with lung disease are included
b
On HRCT
c
Pulmonary only cases and categories are not mutually exclusive
d
Categories are not mutually exclusive
e
Micronodular or cavitary

When comparing patients with pulmonary only, that reported in studies conducted in the Philippines [11], China
extrapulmonary only and disseminated TB, the lymphocyte [19], South Africa [16], India [27], and Indonesia [28], countries
count was significantly lower in those patients with dissemi- known to have a higher prevalence of TB than any country in
nated TB, while no significant differences were found be- Latin America [30]. In fact, China and India have the highest
tween the groups regarding the cumulative dose of glucocor- reported prevalence of TB [30].
ticoids and number of immunosuppressants received during In our study, cumulative dose of glucocorticoids, the use of
the last 12 months. These data are presented in Table 4. ≥ 2 immunosuppressants during the last 12 months and lym-
phopenia were found to be risk factors of TB infection in SLE
patients. Previous studies have reported that glucocorticoid
Discussion therapy is a major risk factor for TB in SLE patients [14, 16,
18, 19]. As reported by Torres-Gonzalez et al. [18] and Lao
In this observational study, we investigated the frequency, et al., [19], we also showed that a cumulative dose of gluco-
associated factors, and characteristics of TB infection in SLE corticoids in the previous 12 months was independently asso-
patients. ciated with the development of TB.
The prevalence of TB in SLE varies between different pub- In the current study, we examined the value of the lower
lished series and regions, ranging from 0.7 to 17% [8–13, 15, 16, quartile of the cumulative glucocorticoid dose and its effect on
18, 19, 25–28]. We found 67 episodes of active TB in 4738 SLE TB development and found that a 12-month cumulative dose
patients with a prevalence of 1.4%, which is similar to that re- of prednisone ≥ 1.83 g was a risk factor for TB. This cumula-
ported in another case-control study in Mexico City (1.3%) [18]. tive dose is lower than that reported by Torres-González, ≥ 3 g
Both studies are case-control design and included about 5000 during the 12 months prior to TB onset [18], and Lao, ≥ 2.3 g
SLE patients from two Latin American countries where SLE during the 3 months before the onset of TB [19]. Our results
patients are mostly Mestizos, an ethnic group with more severe are noteworthy because they suggest that a daily dose of pred-
forms of lupus and, thus, experiencing more intense immunosup- nisone of 5 mg during 12 months is a risk factor for the de-
pressive regimens [29]. However, our prevalence was lower than velopment of TB in SLE patients. Tam et al., also showed that

Fig. 1 Tuberculous cellulitis. a

Erythematous, tender, ill-defined
plaque on the posterior aspect of
the right tight which did not re-
spond to intravenous antibiotic
therapy in a woman with systemic
lupus erythematosus. B
Perivascular and perineural gran-
ulomas in the deep dermis. White
arrow: nerve; black arrow: granu-
loma; yellow arrow: blood vessels
[hematoxylin-eosin (HE), ×10].
C. Granuloma with central necro-
sis surrounded by a lymphocyte
collar in the deep dermis (HE, ×
40). D Ziehl–Neelsen staining
showing acid-fast bacilli (black
arrows, × 100)
 Clin Rheumatol

Table 4 Lymphopenia, number

of immunosuppressants, and Variable Pulmonary Extrapulmonary Disseminated P
cumulative steroid dose according only (n = 31) only (n = 11) (n = 25) value
to tuberculosis disease site
12-month cumulative dose of 25 (80.6) 7 (63.6) 22 (88.0) 0.235
prednisone ≥ 1850 mg (n, %)
Number of immunosuppressants (≥ 2), 10 (32.3) 1 (9.1) 7 (28) 0.326
(n, %)
Lymphocyte count/uL, median (IQR)a 1000 (661–1230) 1100 (798–1300) 618 (419–790) 0.008
a
At the time of TB diagnosis for cases

cumulative dose of prednisone is an independent risk factor SLE patients. In this study, about a quarter of the infected
for the development of TB in lupus patients and that an in- cases (27%) and 11% of controls were treated with ≥ 2 differ-
crease in the dose of prednisone by 1 g was associated with a ent immunosuppressants in the previous year.
23% increased risk of developing TB [9]. Consistent with Immunosuppressants have not been found to be linked to TB
these findings, in a nested case-control study in the Lupus- infection in SLE, probably due to the small number of patients
Cruces cohort, those patients with major infections, including exposed to these agents in different studies that assessed the risk
TB, had a median dose of prednisone of 7.5 mg/day. They factors for TB in SLE [9, 10, 14, 18, 19]. However, it is well-
also demonstrated that the probability of major infection in- known that the risk of serious infections in SLE patients is in-
creases by 12% per each daily milligram of prednisone [31]. creased by the inclusion of cytotoxic drugs, mainly cyclophos-
On the other hand, in a case-control study based on a large phamide, in therapeutic regimens [3, 36, 37].
general practice population in the UK, a daily dose of < As reported in other studies [16, 18, 19], we found that
7.5 mg/day of prednisone or its equivalent was associated with lymphopenia was independently associated with TB in SLE
an approximately 3-fold increased risk of TB compared with patients. In our study, lymphopenia was predominant in SLE
non-prednisone users while no clear effect of duration or cu- patients with TB, being especially profound in those with
mulative dose on the risk of TB was found. In this study, disseminated TB as recently reported by Lao et al. [19].
however, only 9% of TB cases had a rheumatic disease, and Likewise, other studies in patients with non-HIV TB patients
among them, only one patient had lupus [32]. also demonstrated significantly lower CD4 lymphocyte count
Long-term administration of glucocorticoids increases the in disseminated than localized forms of TB [38, 39]. In SLE
susceptibility to mycobacterial infection and lead to reactivation patients, lymphopenia is a risk factor for the development of
of latent bacilli through different mechanisms. These drugs reg- severe infection independent of immunosuppressive therapy
ulate adaptive immunity by inhibiting lymphocyte activation and and disease activity [40]. In clinical practice, lymphopenia in
causing lymphocyte apoptosis. They preferentially suppress the SLE patients is associated with the use of glucocorticoids and
responses of TH1 cells and TH17 cells [33]. Protective immune cytotoxic drugs and with disease activity [41]. CD4 T cells are
responses against M. tuberculosis are mainly mediated by CD4+ decreased in peripheral blood of SLE patients as a result of T
Th1 cells, which secrete IFN-γ. This IFN-γ Th1 responses are cell apoptosis and high serum concentrations of anti-CD4 an-
essential to maintain control of M. tuberculosis chronic infection tibodies [42, 43]. Therefore, as lymphocytes, particularly CD4
[34]. Glucocorticoids also have effects on innate anti- T cells, are an essential defense mechanism against
mycobacterial host defense. They inhibit antimicrobial nitric ox- M. tuberculosis, these pathogenic mechanisms of lymphope-
ide production, autophagy, and maturation of mycobacterial nia in lupus may explain the high susceptibility to TB infec-
phagosomes in macrophages, thus facilitating the survival of tion in these patients.
mycobacteria in macrophages [35]. We also found a trend towards an association of organ
We could not find differences between cases and controls transplantation with active TB. All lupus transplanted patients
regarding the use of each immunosuppressant except for my- underwent a kidney transplant. Patients with chronic kidney
cophenolate mofetil, cyclosporine, and rituximab. However, disease, on dialysis, and after kidney transplantation are at
the number of patients treated with these immunosuppressants significantly increased risk of TB, because they have an im-
was too small to make a valuable interpretation of these data. paired cellular-mediated immunity. In addition, comorbid
Thus, we decided to examine whether exposure to several conditions such as autoimmune diseases and long-term immu-
immunosuppressants was a risk factor for the development nosuppressive therapy are used to prevent graft rejection, fur-
of TB and found that being exposed to ≥ 2 immunosuppres- ther impairing immunity making these patients susceptible to
sants in the previous year was independently associated with TB infection [44].
the occurrence of TB. This likely reflects the fact that more TB in the setting of SLE is characterized by higher frequen-
intense immunosuppression leads to an increased risk of TB in cy of extrapulmonary involvement and a more extensive
Clin Rheumatol

pulmonary involvement [9]. In different studies, outcome, it is possible that some relevant risk factors may
extrapulmonary involvement has been reported between 25 not reach statistical significance.
and 67% of lupus patients with TB [9–19]. Consistent with Despite these limitations, our data provide important infor-
these data, we found that extrapulmonary and disseminated mation. SLE patients with more intense immunosuppression
TB are frequent among our SLE patients (53.7%). The high due to a cumulative dose of glucocorticoids that is equivalent
frequency of extrapulmonary disease suggests reactivation of to 5 mg/day of prednisone and the exposure to two or more
a past infection rather than a primary infection. In fact, in immunosuppressants during the last 12 months, lymphopenia
patients with extrapulmonary TB without lung involvement, and having undergone renal transplantation are a higher risk of
M. tuberculosis persists in several extrapulmonary sites and developing active TB. Furthermore, extrapulmonary and dis-
cell types with limited antigen-presentation abilities (e.g., ep- seminated TB are frequent among our SLE patients and those
ithelial cells) which may constitute reservoirs that can reacti- patients with disseminated disease have significantly lower
vate infection, producing extrapulmonary disease [45]. lymphocyte counts than those with localized disease. As pa-
Interestingly, in a recent study that investigated the relation- tients with SLE are a high-risk group for developing active TB
ship between infections and antinuclear antibodies (ANA) test and they frequently develop atypical pulmonary involvement
status found that among those patients with infectious diseases or extrapulmonary disease, a high index of suspicion should
with a positive ANA test, TB was the most common infection be maintained especially if these risk factors are present.
and most of them had extrapulmonary TB which may reflect
the frequent use of ANA testing in the differential diagnosis of Compliance with ethical standards
extrapulmonary forms of TB [1]. This is a very important
issue to consider as infections like TB may induce a lupus- Disclosures None.
like disease, a lupus flare, or transient autoimmune features [1,
2]. The similarity between mycobacterial cell wall glycopep-
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