2Sir H. N. Reliance Foundation Hospital and Research Centre, Raja Ram Mohan Roy Road, Prarthana Samaj, Girgaum, Mumbai 400004, Maharashtra, India.
3Deptment of Chest Medicine, Topiwala National Medical College and B Y L Nair Hospital, Mumbai.
Objective: The objective of this study was to investigate the agreement between the interferon gamma release assays (IGRAs) and Tuberculin Skin Test (TST) in the Rheumatoid Arthritis (RA) patients compared with the Controls.
Methods: 42 consecutive RA patients diagnosed according to the 1987 ACR criteria were recruited for our study. 50 culture-positive Tuberculosis (TB) patients were enrolled and 50 Healthy Controls were taken for comparison. QFT-GIT assay, Elispot Plus assay and TST were performed on all the study participants. BCG vaccination status and current medication was noted.
Result: The QFT-GIT and TST demonstrated 60.71 % agreement; k= 0.313 in patients with RA and 70.83 % agreement; k= 0.408 in healthy controls. The Elispot assay and TST demonstrated 53.57 % agreement; k= 0.308 in patients with RA and 79.17 % agreement; k= 0.565 in healthy controls. There is a moderate agreement in between the two IGRAs (78.5%; k=0.593). The sensitivity of TST and IGRA was equally low, but the specificity of IGRA was higher than TST.
Conclusion: Our study showed low moderate agreement between the results of the interferon gamma release assays (IGRAs) and the TST in RA patients, but in controls, moderate agreement was observed between the tests.
Keywords: QFT-GIT, Elispot, TST, LTBI, RA.
According to the World Health Organisation (WHO) Global TB report, 2015 approximately one-third of the world population is infected with Mycobacterium tuberculosis (MTb).[6] India is the highest TB-burden country accounting for one-fifth (21%) of the global incidence.[7] Being TB endemic country, Bacillus Calmette-Guerin (BCG) is mandatory at birth in India. Infections like tuberculosis are a leading cause of morbidity and mortality in rheumatoid arthritis patients. Since many years, TST was the only available tool for the detection of LTBI despite its lack of specificity due to cross-reactivity with the BCG vaccine and other non-tuberculosis mycobacterium and its low sensitivity in immuno compromised patients.[8] This poor sensitivity can lead to false-negative results, with a subsequent risk of TB reactivation following anti-TNF α therapy. There is a need for a more accurate test for MTb infection in patients with RA. [9] TST requires a return visit to read the test and it may produce false-positive results owing to prior BCG vaccination or non tuberculosis mycobacterial infection, this poor specificity can lead to unnecessary LTBI treatment, with the risk of drug toxicity. [10]
There is no gold standard for LTBI. Currently, two vastly different methods of testing are available: the traditional Tuberculin Skin Test (TST) and the newly developed Interferon Gamma Release Assays (IGRAs). The TST measures type IV hypersensitivity in response to purified protein derivative (PPD), which contains a mixture of antigens of Mycobacterium tuberculosis that are also present in Mycobacterium bovis BCG, and other non tuberculous mycobacteria. [3] The development of interferon-gamma release assays (IGRAs) is an important advance in the diagnosis of latent tuberculosis infection (LTBI). IGRAs are in vitro blood tests of cell-mediated immune response; they measure T cell release of interferon (IFN)-gamma following stimulation by antigens unique to Mycobacterium tuberculosis. [11] IGRAs cannot distinguish between latent infection and active tuberculosis (TB) disease and should not be used for diagnosis of active TB, which is a microbiological diagnosis. IGRAs have been approved by the CDC as an alternative screening strategy to TST for the diagnosis of LTBI. Some current national guidelines for screening prior to anti-TNF treatment recommend the use of the IGRA instead of the TST. [10]
A particular concern in immune mediated inflammatory diseases is that the TST may also be modified by concomitant immunosuppressive drugs and produce false-negative results, exposing patients to the risk of TB reactivation when treated with anti-TNF therapy. [12] Because IGRAs are not affected by Bacille Calmette-Guérin (BCG) vaccination status, IGRAs are useful for evaluation of LTBI in BCG-vaccinated individuals, particularly in settings where BCG vaccination is administered after infancy or multiple (booster) BCG vaccinations are given. [12] Neither the TST nor IGRAs have been proven to be 100% accurate. TST’s main weakness appears to be its low sensitivity in immuno suppressed patients because of their deficient cell-mediated immunity and \or chronic use of immuno suppressents. [3] An important concern for patients with rheumatic disease is that the immuno suppression due to disease itself and TST will impact on the performance of both tests. It has been shown that TST is more likely to produce false negative result in rheumatic patients than the general population due to the weakened cellular immune response. [13]
Anti-tumor necrosis factor-alpha (TNF-α) agents are increasingly being used to treat RA. However, they have been reported to increase the risk of infection, and in particular, to reactivate latent infections. A temporal association between anti-TNF-α antibodies and reactivation of latent tuberculosis infection (LTBI) has been established. TNF-α is one of the key molecules involved in granuloma formation and maintenance of TB infection. [14] Guidelines have been developed in many countries for screening for latent tuberculosis before starting TNF-α antagonists. [15] Thus, the detection and treatment of LTBI by prophylactic therapy are essential before prescribing anti- TNF agents, because this screening has reduced the incidence of TB. [16] Identification of genes in the TB genome that are absent in BCG and most environmental mycobacterium offers an opportunity to develop more specific tests to investigate TB infection, particularly LTBI. [17] Advances in mycobacterial genomics have led to the development of 2 new blood interferon-γ release assays (IGRA) in response to 3 unique antigens, ESAT-6, CFP- 10 and TB 7.7 that are highly specific for M. tuberculosis, and which are absent from M. bovis, M. avium, and most other non tuberculosis mycobacteria. One assay, the enzyme-linked immunospot (Elispot Plus, Mabtech) enumerates IFN-γ-secreting T cells; the other measures IFN-γ concentration in supernatant by Enzyme Linked Immunosorbent Assay (ELISA) (QuantiFeron- TB Gold In-Tube; Cellestis, Carnegie, Australia); the QuantiFeron- TB Gold In-Tube (QFT-GIT) assay (Cellestis Limited) has replaced the second-generation QuantiFeron-TB Gold (QFT-G) assay. The usefulness of interferon r release assays (IGRAs) has been evaluated in populations with a moderate or high prevalence of TB disease, in contact tracing after fresh TB outbreaks and in patients receiving immunosuppressive therapy for systemic autoimmune disorders. These studies have consistently demonstrated that IGRAs are sensitive and have a higher specificity for TB infection than TSTs, irrespective of BCG vaccination status. A high level of concordance between different IGRAs was generally seen.[12] The aim of our study were to compare the prevalence of LTBI in RA patients and age matched controls as estimated by TST and positivity by two interferon gamma release assays (IGRAs), and to determine the level of agreement between these tests.
ELISPOT plates precoated with monoclonal antibody to interferon-gamma (Mabtech AB, Stockholm, Sweden) were used. Briefly, the whitish layer of cells obtained after overnight incubation from the tubes, were layered over a Ficoll gradient and then centrifuged for 12 mins at 1500 rpm to get the peripheral blood mononuclear cells (PBMC). The cells were then suspended in complete RPMI media which consists of RPMI 1640 medium (Sigma Aldrich) plus 10% fetal bovine serum (FBS, Himedia). Plates were seeded with 2•5 x 105 peripheral blood mononuclear cells per well. After overnight incubation at 37°C, 5% carbon dioxide, the wells were washed and developed with a conjugate against the antibody used and an enzyme substrate. Assays were scored by automated ELISPOT reader (Immunospot, Cellular Technology Limited, USA). The responses were considered positive if the test wells contained a higher mean number of spotforming cells (SFC) than the mean number plus two standard deviations (SD) in the negative control wells and when the number of SFC per million PBMC in the stimulated wells (minus the values of the negative control wells) was ≥ 20. (Figure 1) When the mean number of SFC per million PBMC in the positive control wells was < 100, the responses in the test wells were considered intermediate.
Characteristic |
RA patients (n=38) |
TB patients (n=50) |
Healthy Controls(n=50) |
Age, mean ± SD yrs |
45 ± 12.12 |
34 ± 15.64 |
38.75 ± 7.26 |
BCG Vaccination, % |
82% |
69% |
88% |
History of TB, % |
39.40% |
- |
- |
Disease Duration, moths |
53.6 moths |
- |
- |
RF Positivity, % |
71.40% |
- |
- |
DAS28 CRP, mean ± SD |
4.9 ± 0.97 |
- |
- |
Methotrexate, % |
42.10% |
- |
- |
Leflunomide, % |
15.80% |
- |
- |
Hydroxychloroquine, % |
65.80% |
- |
- |
Sulfasalazine, % |
13.20% |
- |
- |
TST +ve, % |
28.57% |
91% |
58.33% |
QFT-GIT +ve, % |
39.29% |
87.50% |
50% |
Elispot +ve, % |
42.85% |
84.30% |
52% |
Overall, the rate of TST positivity in RA patients was only 49% of that for the Controls, lower than for the IGRAs. The positivity rate of QFT-GIT for RA patients was 78% of that for the Controls. For Elispot assay, the positivity rate for RA patients was 82 % of that for the Controls.
Table 2 shows that around 63.64 % of the RA patients had normal x-ray findings and 36.36 % had abnormal X-ray findings suggesting of latent TB infection in RA patients. About 94.44 % of healthy controls showed normal x-ray findings. The x-rays of all TB patients suggest active pulmonary TB. (Table 2)
Chest X-ray |
RA patients (n=38) |
TB patients (n=50) |
Healthy Controls (n=50) |
Normal |
63.64% |
Nil |
94.44% |
Suggestive LTBI |
36.36% |
Active TB |
5.56% |
As seen in Table 4, the overall agreement between TST and Elispot assay was low moderate in RA patients and a moderate agreement in Healthy Controls (53.57% vs. 79.17%). TST +ve / Elispot –ve results were similar in RA patients and Controls (10.5% vs. 8%); the TST -ve /Elispot +ve result was higher in RA patients compared with that in Controls (21.1% vs. 12%). (Table 4)
From Table 5, it is observed that the sensitivity of QFT-GIT and Elispot assay is 55.56 % and 52.9 % respectively and the specificity of the QFT-GIT and Elispot assay is 92.3 % and 85.7% respectively according to the latent TB screening using abnormalities in the
|
QFT –GIT Positive (%) |
QFT-GIT Negative (%) |
Total |
Agreement (%) |
kappa |
RA: TST Positive |
7 (18.4) |
7 (18.4) |
14(36.8) |
60.71 |
0.313 |
TST Negative |
8 (21.1) |
16 (42.1) |
24 (63.2) |
||
HC: TST Positive |
21 (42) |
8 (16) |
29 (58) |
70.83 |
0.408 |
TST Negative |
6 (12) |
15 (30) |
21 (42) |
RA: Rheumatoid Arthritis; HC: Healthy Controls
|
Elispot Positive (%) |
Elispot Negative (%) |
Total |
Agreement (%) |
kappa |
RA: TST Positive |
10 (26.3) |
4 (10.5) |
14(36.8) |
53.57 |
0.308 |
TST Negative |
8 (21.1) |
16 (42.1) |
24(63.2) |
||
HC: TST Positive |
25 (50) |
4 (8) |
29(58) |
79.17 |
0.565 |
TST Negative |
6 (12) |
15 (30) |
21(42) |
Test |
Sensitivity |
Specificity |
TST |
37.50% |
75% |
QFT-GIT Elisa |
55.56% |
92.30% |
Elispot assay |
52.90% |
85.70% |
Figure 2 shows that the positivity of Elispot assay and QFTGIT is lower than TST in Healthy Controls. The TST positivity is 58.33% compared to 52% and 50% for Elispot assay and QFT-GIT assay respectively. (Figure 2)
India, being a TB burden country, our patients are at high risk of TB. The number of patients who tested positive was more comparable between RA patients and controls with QFTGIT (39.29% vs. 50%) and Elispot assay (42.85% vs. 52 % ), whereas the TST detected less LTBI among patients with RA than controls (28.57% vs. 58.33%). These findings suggest that the sensitivity of the QFT-GIT for the diagnosis of LTBI could be higher than that of the TST in patients with RA, even in cases of RA immunosuppression. To our knowledge, this is the first study in indian population to determine the agreement between TST and IGRAs in RA patients, TB patients and Healthy Controls.
The TST positivity rate in controls in this study commensurate with high prevalence of LTBI among the general population of our country. [11] Also, the TST result in RA patients is in concordance with the findings, in a TB-endemic population by Ponce de Leon et al [9] They reported that the TST is severely compromised in patients with RA. 26.7% of RA patients in their study were TST positive and 65.6% of the controls were TST positive.
It has been suggested that the IFN gamma assays may be less affected by immunosuppression than the TST in the RA population. Ewer et al has showed the interference of BCG vaccination with a positive TST.[20] The TST positivity in the control group in this study might explain the related interference. It was shown that BCG vaccination increase the likelihood of false-positive TST results for upto 15 years. A study by Cobanoglu et al showed that when comparing subjects under 25 years of age to subjects aged older than 25 years, repeated BCG vaccinations were related to high discordance between the TST and QFT-G in subjects older than 25 years. [21]
QFT-GIT test results are shown to be independent from BCG vaccination, it is not influenced by the disease activity, and it seems to be significantly more accurate than the skin test for the diagnosis of LTBI. [22] QGT-G In Tube (QFT-GIT) showed less indeterminate results as compared to QFT-Gold test. Takahashi et al reported in 14 patients only 5 % of QFT tests were indeterminate. [23] TST is dependent on a normal T-cell function, and a negative TST result may either rule out LTBI or reflect abnormal delayed-type hypersensitivity (DTH) due to deficient cell-mediated immunity. IFN gamma assays are based on the production of IFN gamma by mononuclear cells exposed to TB antigens. Peripheral T-cells from RA patients stimulated with phytohaemagglutinin or anti-CD3 are reported to have produced significantly less interferon response than T-cells from healthy controls. [8]
It has been shown that TST reaction is suppressed in patients with RA. [24, 25] Conflicting evidence has been reported concerning impaired cell mediated immunity in RA patients, which may be due to the disease itself or to immunosuppressive drugs.[8] In our study, four patients of RA showed no reaction to TST. A high number of patients showed no TST reaction compared to healthy controls in a study by Inanc et al, supporting the limitations of TST, especially in immuno compromised patients. [26] Immuno compromised patients are often anergic, and results of previous studies have suggested that the rate of TST false–negative results is ~ 40% in patients with RA.[27]
In our study, overall agreement between TST and IGRAs in healthy subjects was high as compared to the RA patients. The small sample size can be considered as a limitation in our study. There was a low moderate agreement observed between IGRAs and TST in RA patients while a moderate agreement was seen in healthy controls between the tests. In our study, the sensitivity of TST and IGRAs was equally low but the specificity of IGRAs was higher. The specificity of the QFT-GIT and Elispot assay is 92.3 % and 85.7% respectively according to the latent TB screening using abnormalities in the chest x-ray and having history of tuberculosis. Mariette et al [17] reported that the sensitivity of TST was low as compared to TST but the specificity of IGRA was higher with regard to the 57 patients considered to have LTBI on questioning or x-ray independently from the tests. A recent metaanalysis showed that QFT-G has high specificity (96%) whereas TST has low and highly variable specificity in BCG-vaccinated populations. [28, 29] Two main factors are known to affect TST specificity: environmental mycobacteria and BCG vaccination. [30] In our study, 87.5% TB patients were positive by QFT-GIT assay and 84.3% patients were positive by Elispot assay. In a study conducted by James et al in patients with TB patients in India, the QFT-IT was positive in all patients with active TB. [7] Lee et al also reported that T-SPOT and QFT-G assay demonstrated superior specificity to TST in a cohort of patients with active TB infection. [31] In our study, a moderate agreement was seen in healthy controls between the TST and IGRAs. Kabeer et al [32] conducted a study in indian population which included 186 healthy controls and 200 healthy household contacts. In this study, the agreement between TST and QFT-IT was moderate (k=0.490). A previous study conducted using ESAT-6 and CFP-10 based ELISPOT in the Mumbai city reported that 80% of healthy adults (age range 18- 70; mean 47 years) were positive for M. tuberculosis infection. [32]
The differences between IGRAs and TST results are reported in various studies. Chapman et al [33] compared invitro assay with TST in Zambian individuals. Sellam et al [34] found that the IGRA was significantly less affected by immunosuppression than the TST in patients with RA. Matulis et al [35] reported that QFTGIT results were significantly associated with the presence of LTBI risk factors in patients with auto-immune diseases receiving immunosuppressive drugs, including anti-TNF alpha inhibitors.
Studies show that positive results on the IGRA have a greater association with TB risk factors than positive results on the TST, suggesting that the IGRA has better sensitivity and specificity than the TST.[27] The limiting factor for the use of IGRAs in high burden, resource limited countries are the high material costs and the need for laboratory infrastructure and trained personnel. [12] Martin et al evaluated 150 patients with inflammatory arthritis with a minimum BCG vaccination rate of 82%. They reported a concordance between the two IFN-γ assays of 98.4%. Kleinert et al have studied 90 rheumatic patients. [36] The agreement between the three tests were of 83.1% (k=0.44). Bocchino et al. compared the performance of two commercial interferon IFN-γ assays: TSPOT.TB and QFT-GIT with TST for the detection of LTBI in patients with RA, psoriatic arthritis and inflammatory bowel disease, and concluded that INF-γ assays may confirm positive TST results and reveal additional cases of LTBI in selected patients, when TST false-negative results are suspected. [37]
In conclusion, TST response is suppressed in patients treated with immunosuppressive drugs, and there is low moderate agreement between the IGRAs and TST in patients with inflammatory diseases. Clinicians should pay particular attention to immunosuppressed patients with negative TST and indeterminate IGRA test results and always consider individual clinical factors more heavily than equivocal test results. Our study shows that the IGRAs are more accurate than the TST in diagnosing latent TB infection among a high risk population of RA patients. Several screening algorithms have already been proposed. One of them has suggested replacing TST with a dual IGRA strategy (Elispot assay and QFT-G). Another dual testing strategy based on both TST and IGRA results has also been proposed. [30] However further studies are needed to validate these strategies.
Dr. Arun Chogle: Principal Investigator and Conception of the project, recruitment of the patients and excellent clinical inputs during the conduct of the study.
Dr. Jyostna Joshi: Co-Investigator, recruitment of the patients and excellent clinical inputs during the conduct of the study.
Dr. Sudha S Deo: Co-Principal Investigator, Conception of the project and finalizing the manuscript.
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