To cite this article: Freund R, et al.

Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent

tuberculosis infection before TNF-blockers therapy. Presse Med. (2018), https://doi.org/10.1016/j.lpm.2017.09.029

Presse Med. 2018; //: ///

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Original article
Cost-effectiveness analysis of strategies
using new immunological diagnostic tests
of latent tuberculosis infection before
TNF-blockers therapy

Romain Freund 1,10, Benjamin Granger 1,2,10, Cécile Francois 2, Guislaine Carcelain 3,4, Philippe Ravaud 5,6,
Xavier Mariette 7,8, Bruno Fautrel 1,8,9

Received 6 September 2016 1. Pierre et Marie Curie university-Paris 6, Sorbonne universités, GRC-08 (EEMOIS),
Accepted 28 September 2017 75013 Paris, France
Available online: 2. AP–HP, Pitié-Salpêtrière hospital, department of biostatistics, public health and
medical information (BIOSPIM), 75013 Paris, France
3. Sorbonne universités, UPMC université Paris 06, Inserm, centre d'immunologie et
des maladies infectieuses (CIMI-Paris), UMR 1135, ERL CNRS 8255, 91, boulevard
de l'hôpital, 75013 Paris, France
4. Assistance Publique–Hôpitaux de Paris, departement d'immunologie, CHU Pitié-
Salpêtrière, 47–83, boulevard de l'hôpital, 75013 Paris, France
5. AP–HP, epidemiology center, Hotel-Dieu, 75004 Paris, France
6. René Descartes university, inserm, UMR 1153, Hotel-Dieu, 75181 Paris cedex,
France
7. AP–HP, Bicêtre hospital, université Paris-Sud, department of rheumatology,
94270 Le Kremlin Bicêtre, France
8. CRI-IMIDIATE clinical research network, 75013, Paris, France
9. AP–HP, Pitié-Salpêtrière hospital, rheumatology department, 75013 Paris, France

Correspondence:
Bruno Fautrel, Pitié-Salpêtrière hospital, department of rheumatology, 83,
boulevard de l'hôpital, 75013 Paris, France.
bruno.fautrel@aphp.fr

Summary
Several tests have been proposed to detect latent tuberculosis (LTB).
Objective > To evaluate the cost-effectiveness of different interferon-gamma release assays based
strategies used to screen LTB before tumour necrosis factor (TNF) blockers initiation.
Methods > Consecutive patients with rheumatoid arthritis, spondyloarthritis or Crohn's disease for
whom TNF-blockers were considered, were recruited in 15 tertiary care centres. All were screened
for LTB with tuberculin skin test (TST), QuantiFERON TB Gold® in tube (QFT) and T-SPOT.TB® (TSpot)
on the same day. Cost-minimization and cost-effectiveness analysis, testing 8 screening test
combinations, were conducted. Effectiveness was defined as the percentage of LTB treatment
avoided and compared with TST alone. Cost were elicited in the payer perspective, included all the
costs related to the screening procedure.

10
These 2 authors have performed a similar amount of work and have to be considered a co-first author.

tome xx > n8x > xx 2018

1

https://doi.org/10.1016/j.lpm.2017.09.029
© 2018 Elsevier Masson SAS. All rights reserved.

LPM-3513
 To cite this article: Freund R, et al. Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent
tuberculosis infection before TNF-blockers therapy. Presse Med. (2018), https://doi.org/10.1016/j.lpm.2017.09.029

R. Freund, B. Granger, C. Francois, G. Carcelain, P. Ravaud, X. Mariette, et al.

Original article

Results > No tuberculosis reactivation was observed after TNF-blocker initiation. TST followed by
QFT if TST was positive was found as the best screening strategy, i.e. the less costly ( 54 s
compared to reference) and most effective (effectiveness 0.93), resulting in an incremental cost-
effectiveness ratio of 192 s per treatment avoided. A probabilistic sensitivity analysis confirmed
this result in 72.3% of simulations.
Conclusion > TST followed by QFT if TST was positive is the most cost-effective strategy in screening
for LTB in patients before starting anti-TNF therapy.
TrialRegNo > NCT00811343.

Résumé
Analyse coût–efficacité des stratégies utilisant les nouveaux tests diagnostiques
immunologiques dans le dépistage de la tuberculose latente avant traitement par anti-
TNF

De nombreux tests existent dans le dépistage de la tuberculose latente (TBL).

Objectif > Évaluer l'efficience des stratégies basées sur les nouveaux tests à l'interféron (IGRAs)
dans le dépistage de la TBL avant initiation d'un traitement par anti-TNF.
Méthode > Des patients consécutifs ayant une polyarthrite rhumatoïde, une spondylarthrite ou
une maladie de Crohn chez qui un traitement par anti-TNF était considéré, ont été recrutés dans
15 centres. Tous les patients ont été dépistés pour la TBL par intradermoréaction à la tuberculine
(IDR), QuantiFERON TB Gold® in tube (QFT) and T-SPOT.TB® (TSpot) le même jour. Des analyses de
coût-efficacité et de minimisation de coût, testant 8 combinaisons de tests de dépistage pour TBL
ont été conduites. L'efficacité était définie comme le pourcentage de traitement pour TBL évité et
comparé à l'IDR seule. Les coûts utilisés, dans la perspective du payeur, incluaient l'ensemble des
coûts liés à la procédure de dépistage.
Résultats > Aucune tuberculose maladie par réactivation n'a été observée après initiation du
traitement par anti-TNF. L'IDR suivie de QFT si l'IDR était positive était la meilleure stratégie de
dépistage, c'est-à-dire, la moins chère ( 54 s comparée à la référence) et la plus efficace
(efficacité 0,93), se traduisant par un ratio différentiel coût-résultat de 192 s par traitement
évité. Une analyse de sensibilité a confirmé ce résultat dans 72,3 % des simulations.
Conclusion > L'IDR suivie de QFT si l'IDR est positive est la stratégie la plus efficiente dans le
diagnostic de la TBL avant initiation d'un traitement par anti-TNF.
TrialRegNo > NCT00811343.

Introduction Diagnosis of LTB relies on immunodiagnostic methods, which

The prognosis of patients with immune-mediated inflammatory
diseases (IMID) such as rheumatoid arthritis (RA), spondylar-
thropathies (SpA), Crohn's disease (CD), psoriasis and juvenile
idiopathic arthritis, has been transformed by the launch of TNF-
blockers 15 years ago [1]. These treatments have been associ-
ated with an increased risk of either de novo tuberculosis (TB) or
reactivation of latent tuberculosis (LTB) [2–4]. In RA, the excess
risk of TB due to TNF-blocker treatment has been estimated to
approximately 4 compared to RA controls not treated with such
agents [5]. Thus, LTB screening has been considered essential
prior to initiate any TNF-blocker and has been included in all
national or international clinical practice guidelines [6,7].
2
includes Tuberculin Skin Test (TST) and Interferon-gamma
release assays (IGRAs). Developed more recently [8], IGRAs play
a critical role in the field of LTB diagnosis. IGRAs test the capacity
of circulating lymphocytes to release interferon-gamma in
response to Mycobacterium Tuberculosis-specific antigens.
The advantage of these tests relies on their capacity to detect
an immune response specific to Mycobacterium Tuberculosis,
with no cross-reaction with Bacillus Calmette-Guerin (BCG) vac-
cine or the majority of other non-tuberculosis mycobacteria.
IGRAs seem to display a good sensitivity and a better specificity
than TST [9]. Indeterminate results occur in 2.8%–6.4% [10]
which constitutes an obvious limitation and their price, higher

tome xx > n8x > xx 2018

 To cite this article: Freund R, et al. Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent
tuberculosis infection before TNF-blockers therapy. Presse Med. (2018), https://doi.org/10.1016/j.lpm.2017.09.029
Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent tuberculosis
infection before TNF-blockers therapy
than TST, remains a substantial concern in developing countries.
In developed countries, the use of IGRAs is increasingly recom-
mended [11,12]. In France, guidelines from the Health Authority
[13,14] recommend IGRA in case of previous BCG, i.e. in the
majority of the population.
To progress in IGRAs evaluation, a study was conducted in France
from 2008–2012 to assess the performance of the 3 different
tests in the context of LTB screening before TNF-blocker initiation
as well as to identify the optimal test combination to minimize
the risks of LTB reactivation in the one hand and of unnecessary
TB prophylaxis in the other hand. In this study, replacing TST with
IGRA for determining LTB infection allowed the proportion of
patients with IMID needing prophylactic anti-TB antibiotics
before beginning anti-TNF agents to be reduced by half [10].
We prolonged the previous clinical work by a cost-effectiveness
assessment in order to identify the optimal LTB screening pro-
cedure from a payer perspective and thus, to improve the
strength of future guidelines.
Methods
Population sample
Patients with RA, SpA or CD with an indication for initial biologi-
cal treatment with TNF-blockers agents in 15 tertiary care hos-
pitals were included in the ETAT study (TrialRegNo.:
NCT00811343) [10]. Patients gave their informed consent to
participate in the study and were followed for 1 year.
Strategies
Before TNF-blocker therapy was started, patients underwent TST
and a blood sample was taken for QFT-Gold IT ® (QFT) (Cellestis
Limited, Chadstone, Vic., Australia) and T-SPOT.TB® (TSpot)
(Oxford Immunotec, Abingdon, UK) within 3 days. The TST
was carried out according to the intradermal Mantoux method
with 0.1 mL of tuberculin purified derivative (Tubertest, Sanofi
Pasteur, France). IGRAs were performed in 15 hospital labora-
tories (see acknowledgments) and interpreted according to the
manufacturers' instructions by local immunologists who were
blind to the TST results [10].
Medico economic assessment
The economic analysis was performed from a payer perspective,
i.e. the national health insurance perspective.
Costs
The study considered only the direct medical outpatient con-
sultations, costs of tests, LTB chemoprophylaxy (isoniazid plus
rifampicin for 3 months) and its biological monitoring according
to the national guidelines [7]. Consultation fees were obtained
from the national tariff list (nomenclature générale des actes
médicaux). Unit costs for biological workups were obtained from
the French nomenclature des actes de biologie médicale
(NABM) [15]. As QFT and TSpot were not registered in NABM,
their costs were obtained from the Nomenclature de Montpel-
lier, dedicated to work-ups for which non-reimbursement tariff
tome xx > n8x > xx 2018
Original article
is available [16]. Indirect costs were not considered since the
health payer perspective was chosen.
Effectiveness measure
De novo TB or LTB reactivation prevalence after TNF-blocker
initiation was considered as clinical outcome. As no tuberculosis
reactivation was observed after TNF-blocker initiation [10], we
conducted a cost-effectiveness analysis based on the number of
LTB treatment avoided, i.e. considered as the percentage of
patient adequately untreated.
Model structure
A decision tree was used to represent the clinical pathways
associated with diagnosis of LTB before TNF-blocker. Eight dif-
ferent screening scenarios from several national recommenda-
tions were investigated:
 base strategy: TST alone which was considered as the refe-
rence strategy [6,7,11,13,14,17];
 strategy 1: TSpot followed by TST if TSpot was indeterminate
[12,13];
 strategy 2: QFT followed by TST if QFT was indeterminate
[12,13];
 strategy 3: TST followed by QFT if TST was positive [13,14];
 strategy 4: TST followed by TSpot if TST was positive [13,14];
 strategy 5: 2 IGRAs concomitantly, followed by TST if both
IGRAs were indeterminate (Adapted from [12–14]);
 strategy 6: TSpot followed by QFT when TSpot was indetermi-
nate, and TST if QFT was indeterminate (Adapted from
[12–14]);
 strategy 7: QFT followed by TSpot when QFT was indetermi-
nate, and TST if TSpot was indeterminate (Adapted from
[12–14]).
Model parameters
Model was filled with probability values sourced from the ETAT
study [10] and direct medical costs. The incremental cost (IC)
was calculated by the difference between the strategy analysed
and the base strategy TST. The incremental cost-effectiveness
ratio (ICER) was defined by the difference in cost between two
possible interventions, divided by the difference in their effec-
tiveness. A probabilistic sensitivity analysis (PSA) based on
Monte Carlo simulation of 1,000 repetitions/iterations explored
the model uncertainty. Construction of the decision tree and all
analyses were performed using TreeAge Pro 2012 (TreeAge
Software Inc., Williamston, MA, USA).
Results
Patient characteristics
A total of 429 TNF-blocker naïve patients were included in ETAT
study, of whom 392 (91.4%) had complete data, i.e. results for
the TST and both IGRAs. Patient main characteristics were; males
162 (41.3%), median age 45 [IQR 34–56] and previous BCG
immunization 257 (65.6%), RA 123 (31.4%), SpA 178 (45.4%)
and CD 91 (23.2%). A total of 140 (35.7%) were treated
3
 To cite this article: Freund R, et al. Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent
tuberculosis infection before TNF-blockers therapy. Presse Med. (2018), https://doi.org/10.1016/j.lpm.2017.09.029
R. Freund, B. Granger, C. Francois, G. Carcelain, P. Ravaud, X. Mariette, et al.
Original article
by corticosteroids and 234 (59.7%) by immunomodulatory
agents [10].
Costs
Costs of medical resource used in the study are presented in
2013 euro (Supplementary file 1). The strategy 3 – TST followed
by QFT if positive TST – was the less costly with a total cost of
98 s and an incremental cost of 54 s (cost saving). Cost and
incremental cost of the other screening strategies are shown in
(Supplementary file 2).
Budget impact analysis
In 100 patients with rheumatoid arthritis, spondyloarthritis or
Crohn's disease for whom TNF-blockers are considered, the use
of strategy 3 – TST followed by QFT if positive TST – compared to
TST alone would save 5,400 s (= 100  54 s). In our cohort of
429 patients, the amount saved would have been 23,166 s
(= 429  54 s).
Effectiveness
The most effective strategy, i.e. considered as the lowest per-
centage of patient adequately untreated compared with TST
only (reference strategy), was also the strategy 3 (effectiveness:
0.93). Effectiveness of the other screening strategies are shown
in (Supplementary file 2).
Incremental cost-effectiveness ratio
The ICER of strategy 3 was 192 s per inadequate treatment
avoided and appeared to be the most cost-effective screening
strategy. Decision tree including cost-minimization and cost-
effectiveness analysis of the eight different screening scenarios,
is shown in (Supplementary file 2).
The PSA confirmed the results: the strategy 3 found to be the
most cost-effective strategy in 72.3% of the simulations, fol-
lowed by strategy 2 (26.2%), strategy 4 (1.4%) and strategy
1 (0.1%). A cost-effectiveness scatterplot is shown in
(Supplementary file 3).
Discussion
In this Markov model, we examined the incremental cost-effec-
tiveness ratio of seven different IGRA-based LTB screening strat-
egies comparatively to TST in patients before starting TNF-
blockers therapy. We have shown that replacing TST alone with
TST followed by QFT if TST was positive in screening for LTB was
the most cost-effective strategy. It allowed reducing the number
of patients requiring antibiotic prophylaxis. Decreasing the num-
ber of LTB treatment leads to a diminution of cost but also a
diminution of potential antibiotic resistance, a better quality of
life for patients not experimenting antibiotic side-effects and
their TNF-blockers alpha treatment is not delayed because of LTB
treatment.
To our knowledge, only one medico-economic study on diag-
nosis LTB prior to initiating treatment with TNF-blockers was lead
[18]. This Japanese study evaluated the cost-effectiveness of QFT
4
and TST in a hypothetical cohort of 1000 RA patients. Main
results were that QFT screening was more effective and less
costly than the TST for both BCG-vaccinated and non-BCG-vacci-
nated RA patients prior to TNF alpha antagonist therapy in Japan.
Unlike the Japanese study, our study was based on a real-life
prospective study involving 429 patients with IMID.
Determining the clinical efficacy as technical simplicity and less
time-consuming, the second strategy: QFT followed by TST if QFT
was indeterminate, can be considered as efficient. Moreover, a
previous clinical work found that replacing TST with IGRA for
determining LTB infection allowed the proportion of patients
with immune-mediated inflammatory diseases needing prophy-
lactic anti-TB antibiotics before beginning anti-TNF agents to be
reduced by half [10]. In the present study, we prolonged the
previous clinical work by a cost-effectiveness assessment in order
to identify the optimal LTB screening procedure from a payer
perspective thus, to improve the strength of future guidelines.
The main limitation of our study relates to the absence of
tuberculosis reactivation after TNF-blocker initiation [10]. This
lack of event can be related to the efficacy of the TB screening
but also to the small number of patients included. However, this
lack of event was expected regarding the low annual incidence
rate of TB for patients receiving anti-TNF therapy in the French
population: 116.7 per 100,000 patient-years (95% CI 10.6–222.9
per 100,000 patient-years) [4]. Moreover, patients were followed
during one year allowing a risk of late undiagnosed TB. Never-
theless, Tubach et al. demonstrated in the RATIO registry that the
risk of TB was higher during the first year of anti-TNF treatment,
thus limiting the risk of TB underestimation in our study [4].
Conclusion
From eight different IGRA-based LTB diagnostic strategies com-
paratively to TST in patients before starting TNF-blockers therapy,
we have shown that replacing TST alone by TST followed by QFT if
TST was positive is the most cost-effective strategy. These results
could lead to a modification of guidelines for LTB screening
procedure.
the study was authorised by the ethics committee of Paris Île de
France (CPP Île de France II, No. 2008-07-04).
Acknowledgments and affiliations: the authors want to thank S.
Makhlouf and N. Nicolas (Unité de recherche clinique, hôpital Bichat-
Claude Bernard) for their help in collecting cases. They also want to thank
all the investigators of the ETAT Study Group, i.e.: the 15 immunology
laboratories: Dr S. Benzaken (Nice), Dr F. Bienvenu (Lyon), Dr G. Carcelain
(Paris), Dr A. Chevailler (Angers), Dr J.M. Gomberg and Dr A. Barra
(Poitiers), Dr B. Heym (Paris), Pr M. Labalette (Lille), Dr C. Lambert (Saint-
Étienne), Pr S. Martin (Paris), Dr D. Monnier (Rennes), Dr C. Rabian (Paris),
Dr Y. Taoufik (Paris), Pr G. Thibault (Tours), Dr J.P. Vendrell (Montpellier);
the 14 rheumatology departments: Pr M. Audran (Angers), Pr T. Bardin
(Paris), Pr P. Orcel (Paris), Pr P. Bourgeois (Paris), Pr B. Combe
(Montpellier), Pr F. Debiais (Poitiers), Pr L. Euller Ziegler (Nice), Pr R.M.
Flipo (Lille), Pr J.M. Le Parc (Paris), Pr X. Mariette (Paris), Pr O. Meyer
(Paris), Pr A. Perdriger (Rennes), Pr T. Thomas (Saint-Étienne) and the
5 gastroenterology departments: Pr M. Allez (Paris), Pr J.F. Colombel
(Lille), Pr X. Hebuterne (Nice), Dr A.L. Pelletier (Paris), Dr L. Picon (Tours).
tome xx > n8x > xx 2018
 To cite this article: Freund R, et al. Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent
tuberculosis infection before TNF-blockers therapy. Presse Med. (2018), https://doi.org/10.1016/j.lpm.2017.09.029

Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent tuberculosis
infection before TNF-blockers therapy

Original article
Supplementary data
Supplementary data available online at La Presse Médicale (https://doi.org/10.1016/j.lpm.2017.09.029).
Distribution of the direct medical costs per patient
Latent tuberculosis infection diagnosis model
Sensitivity analysis: cost effectiveness scatterplot

Funding: this study was funded by the French Ministry of Health thanks to Disclosure of interest: the authors declare that they have no competing
a stratégies thérapeutiques innovantes couteuses (STIC) grant. The sponsor interest.
was the département de la recherche clinique et du développement of
the Assistance Publique–Hôpitaux de Paris (STIC0717, P070310).

Contributors: RF, BG, CF and BF had full access to all of the data in the
study and take responsibility for the integrity of the data and the accuracy
of the data analysis.

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