1. Lo screening della
tubercolosi latente
Daniela Rossi
Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare
(CMID)
Ospedale Emergenza Torino Nord, G. Bosco, Torino
Coordinamento Interregionale Malattie Rare del Piemonte e della Valle d’Aosta

2. The risk of incident tuberculosis during anti-TNF therapy
Therapeutic blockade of tumour necrosis factor alpha (TNF)
has emerged as an effective treatment in immune-mediated
inflammatory diseases such as rheumatoid arthritis, ankylosing
spondylitis, Crohn's disease and psoriatic arthritis. However,
TNFα is a key cytokine in protective host defence against
Mycobacterium tuberculosis and, together with TNF-dependent
chemokines play an important role in the development and
maintenance of the granuloma which compartmentalises
tubercle bacilli during infection.
Lavani and KA Millington Autoimmun Rev. 2008 December ; 8(2): 147–152.

3. The Mycobacterium tubercolosis life cycle
Hanekorn 2008 W 2007

4. TNF Action in Granuloma Dynamics and
Immunity to Pathogenic Mycobacteria
Elizabeth A. Miller and Joel D. Ernst Immunity 29, August 15, 2008: 175

5. Susceptibility to tuberculosis in RA patients
In USA an increased incidence of TB in patients
with RA was not observed (1).
In contrast, a substantial increase in the risk of
acquiring TB in RA has been reported in Europe [a
3.68-fold increased risk] (2) and in Asia [a 8.9-
fold increased risk] (3) 1. Wolfe F et al 2004
2. Carmona L et al 2003
3. Seong SS et al 2007
Incidence rate of TB ingeneral population 4.2 cases/100.000 persons/yr
Incidence rate of TB in RA (Years 1980-2003) 50 cases/24.282 i.e.,45.8 /100.000/yr

7. Relationship between number of TB cases and patient exposure
*
Total EU/N US EIP
140 300000
Patients Exposed in period-(Line)
245.030
Number of Cases (Bars)
120 212.945 250000
period
100 171.681
200000
149.839
80
68.179 150000
60
44.623 100000
40 36.132
23.754
20 20.466 50000
0 0
02/99 08/99 02/00 08/00 02/01 08/01 02/02 08/02 02/03
Period
* EIP = Patient Exposed Period
PSUR 7: Pg. 53-54.

8. Cumulative incidence of tuberculosis as a function of the duration of anti–tumor
necrosis factor (anti-TNF) treatment, in total and for individual anti-TNF agents.
70 – total
Cumulative frequency of tuberculosis
60 –
50 –
40 –
30 – Infliximab
Adalimumab
20 –
10 –
Etanercept
0–
‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬ ‫׀‬
0 6 12 18 24 30 36 42 48 54 60
Time from onset of last anti TNF treatment (months)
F. Tubach et al. Arthritis & Rheumatism. Vol. 60, No. 7, July 2009, pp 1884–1894

9. Tubercolosis in randomized controlled trails
Patients Cases of tubercolosis
Etanercept
TEMPO (1) (ETA v MTX+ETA 454 0 (2-year study)
COMET (2) (MTX v MTX+ETA) 542 0
Infliximab
START (3) (MTX v INF) 721 7 (52-week study)
IMPACT (4) 69 0 (2-year study)
ASSERT (5) (Placebo v INF) 227 0 (2-year study)
Adalimumab
PREMIER (6) (ADA v MTX) 542 3 (2-year study)*
36 clinical trials (7) 19000 53
*although one patient subsequently developed TB during the third year of follow up.
1) Van der Heijde D. et al, Arthritis Rheum. 2006; 54, 4: 1063-1074; 2) Emery P, et al Lancet 2008; 372:375–382;
3) Winthrop KL et al. Arthritis Rheum 2005; 52:2968–2974; 4) Antoni CE, et al. J Rheumatol 2008; 35:869–876.
5) Braun J et lal Arthritis Rheum 2008; 59:1270–1278;6) Breedveld CF et al. Arthrotis Rheum. 2006, 54, 1: 26-37
7) Burmester GR, et al. Ann Rheum Dis 2009, 68: 1863-1869

10. Annual incidence rate of TB in patients with
anti TNF therapy
Incidence rate / 100.000 United Kingdom France Spain
General population 8-44.8 8.7 25
Patients receiving etanercept 39 9.3 114
Patients receiving infliximab 136 187 383
Patients receiving adalimumab 144 215 176
Dixon WG et al. Ann Rheum Dis, 2009
Tubach F et al. Arthritis Rheum. 2009, 60 (7): 1184-1194
Gomes-Reino et al.Arthritis Rheum 2007, 57 (5):756-761

12. Risk of tuberculosis in patients treated with TNF antagonists
due to incomplete prevention of reactivation of latent infection
J. J. Gomez-Reino, L. Carmona, and MN Descalzo, For The BIOBADASER Group.
Arthritis & Rheumatism Vol. 57, No. 5, June 15, 2007, pp 756–761

13. screening test
The TST is a measure of the delayed-type
hypersensitivity reaction to intradermal
inoculation of purified protein derivative (PPD),
a crude mixture of more than 200 M.
tuberculosis proteins.
Because antigens within PPD are also found in
other mycobacteria, the TST suffers from poor
specificity in bacille Calmette–Guérin (BCG)-
vaccinated persons.
Moreover, the sensitivity of the tuberculin skin
test used to diagnose LTBI is compromised in
patients on immunosuppressive therapy with a
high rate of false-negative TST test results.

14. The tuberculin skin test disadvantages
1. low specificity with false-positive results in bacillus
Calmette–Guérin (BCG)-vaccinated subjects
2. lower sensitivity in immunosuppressed patients
compared with healthy subjects
3. limit above which the TST is considered positive
(i.e. indicative of latent infection) differs according
to countries and guidelines (5–10 mm)

15. Tuberculin skin test and T-cell interferon-
gamma release assays

16. An ELISPOT assay testing for Tuberculosis infection.
T cells are stimulated in plastic wells with molecules
derived from TB and their response measured by
identifying inflammatory molecules that are released
on activation with special dyes. In this plate Patient A
is positive for TB infection whilst patient B is
negative.

17. There is no gold-standard test for latent tuberculosis.
In the absence of a gold-standard reference test, it is not possible to
measure directly the sensitivity and specificity of a new test for
latent tuberculosis.
2006

18. Clinical performance of IGRAs in patients on anti-TNF
therapy
Three studies to date report on the performance of IGRAs in patients already on anti-TNF agents.
Neither corticosteroids nor DMARDs significantly affected the QFT-Gold in-tube response in
patients with inflammatory rheumatic conditions, but the odds for a positive IFN-γ result were
decreased in patients treated with TNFα inhibitors [Ann Rheum Dis 2008;67(1):84–90 ].
In a second study, the magnitude of the IFN-γ response measured by ELISpot significantly
decreased 14 weeks after the start of anti-TNF treatment [Arthritis Res Ther 2006;8:R114 ].
In a third study using QFT-G, 2 patients with positive IGRA results at 12 months of adalimumab
therapy developed active TB [Arthritis Rheum 2008;59(6):800–806 ].
The performance of IGRAs during anti-TNF treatment therefore needs to be
systematically assessed to determine whether these tests can be used, if
required,for regular screening of patients on anti-TNF agents in high
prevalence countries or after an exposure event.

19. NTM other
species*
n = 11
NTM
unspecif
n = 13
Mycobacterium avium
n = 52
M marinum
n=6
M chelonae
n= 4
M fortuitum
n=4
Mycobacterium avium
M abscessus
n = 52
N = 12
Reported causes of 105 confirmed and probable non-tuberculous mycobacteria
(NTM) infections associated with antitumor necrosis factor-α agents, US Food and
Drug Administration MedWatch database, 1999–2006. *Other species include
Mycobacterium kansasii (n = 3), M. xenopi (n = 3),
M. haemophilum (n = 2), and M. mucogenicum (n = 1).

20. Screening for tuberculosis infection prior to
initiation of anti-TNF therapy
Current clinical practice
In the absence of a gold standard test for diagnosis of LTBI,
current clinical management of patients with IMID requiring
anti-TNF therapy involves
1) checking for a history of untreated or partially treated TB,
2) risk-stratification for exposure to cases of active TB,
3) evidence of residual changes indicative of prior TB
infection on a chest radiograph and
4) tuberculin skin test (TST).

21. Screening for tuberculosis infection prior to initiation
of anti-TNF therapy
Ajit Lalvani and Kerry A. Millington
Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute,
Imperial College London, Norfolk Place, London W2 1PG, UK.
T-cell interferon-gamma release assays (IGRA) are more specific and
probably more sensitive than the tuberculin skin test for the diagnosis of
latent tuberculosis infection. Patients with immune-mediated
inflammatory diseases and suspected latent tuberculosis infection who
are candidates for anti-TNF therapy are at a significant risk of TB
reactivation yet are prone to false-negative TST results because they are
already on immunosuppressive medications.
The role of these new blood tests in this patient population is therefore of
considerable interest but is currently unclear.

22. Screening for tuberculosis infection prior to initiation of
anti-TNF therapy
National guidelines
LTBI screening
and TNF blocker Rusk assessment
use national examination and First-time LTBI
Guidelines chest radiograph TST TST detail Positive TST treatment Reference
UK All patients Patients on One step 5 mm in unvaccinated 6 months INH BTS (1)
immunosuppressive 15 mm in vaccinated
therapy excluded
USA All patients All patients One step 5 mm, ignore BCG 9 months INH MMWR (2)
(chest radiograph
in TST positive)
Spain All patients All patients Two steps 5 mm 9 months INH
Gomez-Reino
et al (3)
France All patients All patients One step 10 mm 2 month RIF/PZA Mariette and
Salmon (4)
Ireland All patients All patients One step 5 mm, ignore BCG 9 months INH avanagh
et al (5)
Switzerland All patients IGRA recommended IGRA TST not recommended 9 months INH Berglinger
preferred et al (6)
Italy All patients All patients One step 5 mm 9 months INH ANTARES (7)
BCG: Bacillus Calmette-Guerin; IGRA:Interferon Gamma Release Assay; INH: isoniazid; LTBI: latent tuberculosis infection ;
PZA: pyrazinamide; RIF: rifampicin; TNF: tumor necrosis factor; TST:tubercolin skin test.
1) British Thoracic Society, Standards of Care Committee.Thorax 2005;60:800–805.; 2) Centers for Disease Control and Prevention. 2003. MMWR Morb Mortal
Wkly Rep 2004;53:683–686.; 3) Gomez-Reino JJ et al . Arthritis Rheum 2007; 57,756-61. 4) Mariette X et al . Ann Rheum Dis 2003; 62:791; 5) Kavanagh
P et al. Irish Med J 2008;101:6–7; .6) Beglinger C et al. Swiss Med Wkly 2007; 137:620–622, ; 7) ANTARES, Ministero della Salute, 24 may 2001

23. Most importantly, active TB must first be excluded by history and chest
radiograph.
Screening for LTBI should include checking for a history of untreated or partially
treated TB, risk-stratification for exposure to cases of active TB and searching for
evidence ofresidual changes indicative of untreated prior TB infection on a chest
radiograph-
Given the apparent diagnostic superiority of IGRAs over TST, one or the other of the
new blood tests should be performed.
However, given the very limited size of the evidence-base in support of IGRAs to date
and the vulnerability of these patients to develop severe and disseminated forms
of TB on TNF blockade, it may be prudent to perform TST in parallel with IGRA to
maximise the diagnosticsensitivity of screening, at least until the IGRA evidence-
base in this population has expanded sufficiently.

24. Screening for tuberculosis infection prior to initiation of
anti-TNF therapy
National guidelines
LTBI screening
and TNF blocker Rusk assessment
use national examination and First-time LTBI
Guidelines chest radiograph TST TST detail Positive TST treatment Reference
UK All patients Patients on One step 5 mm in unvaccinated 6 months INH BTS (1)
immunosuppressive 15 mm in vaccinated
therapy excluded
USA All patients All patients One step 5 mm, ignore BCG 9 months INH MMWR (2)
(chest radiograph
in TST positive)
Spain All patients All patients Two steps 5 mm 9 months INH
Gomez-Reino
et al (3)
France All patients All patients One step 10 mm 2 month RIF/PZA Mariette and
Salmon (4)
Ireland All patients All patients One step 5 mm, ignore BCG 9 months INH Kavanagh
et al (5)
Switzerland All patients IGRA recommended IGRA TST not recommended 9 months INH Berglinger
preferred et al (6)
Italy All patients All patients One step 5 mm 9 months INH ANTARES (7)
BCG: Bacillus Calmette-Guerin; IGRA:Interferon Gamma Release Assay; INH: isoniazid; LTBI: latent tuberculosis infection ;
PZA: pyrazinamide; RIF: rifampicin; TNF: tumor necrosis factor; TST:tubercolin skin test.
1) British Thoracic Society, Standards of Care Committee.Thorax 2005;60:800–805.; 2) Centers for Disease Control and Prevention. 2003. MMWR Morb Mortal
Wkly Rep 2004;53:683–686.; 3) Gomez-Reino JJ et al . Arthritis Rheum 2007; 57,756-61. 4) Mariette X et al . Ann Rheum Dis 2003; 62:791; 5) Kavanagh
P et al. Irish Med J 2008;101:6–7; .6) Beglinger C et al. Swiss Med Wkly 2007; 137:620–622, ; 7) ANTARES, Ministero della Salute, 24 may 2001

25. CONTINUING MEDICAL EDUCATION
Tuberculosis in the age of biologic therapy2008
Claudia Hernandez, Chicago and Joliet, Illinois,
J Am Acad Dermatol 2008;59:363-80.