Lo screening della

tubercolosi latente

Daniela Rossi

Centro di Ricerche di Immunopatologia e Documentazi one su Malattie Rare (CMID)

Ospedale Emergenza Torino Nord, G. Bosco, TorinoCoordinamento Interregionale Malattie Rare del Piem onte e della Valle d’Aosta

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,

The risk of incident tuberculosis during anti-TNF therapy

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.

The Mycobacterium tubercolosis life cycle

Hanekorn 2008 W 2007

TNF Action in Granuloma Dynamics and

Immunity to Pathogenic Mycobacteria

Elizabeth A. Miller and Joel D. Ernst Immunity 29, August 15, 2008: 175

� 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)

Susceptibility to tuberculosis in RA patients

1. Wolfe F et al 2004fold 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

Relationship between number of TB cases and patient exposure

171.681

212.945

245.030

100

120

140

Num

ber

of C

ase

s (B

ars

)

250000

300000

Pat

ien

ts E

xpo

sed

in p

erio

d-(

Lin

e)

Total EU/N US EIP*

PSUR 7: Pg. 53-54.

44.623

20.466

36.132

68.179

149.839

171.681

23.754

0

20

40

60

80

100

02/99 08/99 02/00 08/00 02/01 08/01 02/02 08/02 02/03Period

Num

ber

of C

ase

s (B

ars

)

0

50000

100000

150000

200000

Pat

ien

ts E

xpo

sed

in p

erio

d

* EIP = Patient Exposed Period

70 –

60 –

50 –

40 –

total

Cumulative incidence of tuberculosis as a function of the duration of anti–tumornecrosis factor (anti-TNF) treatment, in total and for individual anti-TNF agents.

Cum

ulat

ive

freq

uenc

y of

tube

rcul

osis

40 –

30 –

20 –

10 –

0 –׀ ׀ ׀ ׀ ׀ ׀ ׀ ׀ ׀ ׀ ׀

0 6 12 18 24 30 36 42 48 54 60

InfliximabAdalimumab

Etanercept

Time from onset of last anti TNF treatment (months)

Cum

ulat

ive

freq

uenc

y of

tube

rcul

osis

F. Tubach et al. Arthritis & Rheumatism. Vol. 60, No. 7, July 2009, pp 1884–1894

Patients Cases of tubercolosis

EtanerceptTEMPO (1) (ETA v MTX+ETA 454 0 (2-year study)COMET (2) (MTX v MTX+ETA) 542 0

InfliximabSTART (3) (MTX v INF) 721 7 (52-week study)IMPACT (4) 69 0 (2-year study)

Tubercolosis in randomized controlled trails

IMPACT (4) 69 0 (2-year study)ASSERT (5) (Placebo v INF) 227 0 (2-year study)

AdalimumabPREMIER (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: 26-377) Burmester GR, et al. Ann Rheum Dis 2009, 68: 1863-1869

Annual incidence rate of TB in patients withanti 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, 2009Tubach F et al. Arthritis Rheum. 2009, 60 (7): 1184-1194Gomes-Reino et al.Arthritis Rheum 2007, 57 (5):756-761

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

The TSTis 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 poorspecificity in bacille Calmette–Guérin (BCG)-vaccinated persons. Moreover, the sensitivity ofthe tuberculin skin

screening test

Moreover, the sensitivity ofthe tuberculin skin test used to diagnose LTBI is compromised in patients on immunosuppressive therapy with a high rate of false-negative TST test results.

1. low specificity with false-positive results in bacillus

Calmette–Guérin (BCG)-vaccinated subjects

2. lower sensitivity in immunosuppressed patients

compared with healthy subjects

The tuberculin skin test disadvantages

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)

Tuberculin skin test and T-cell interferon-

gamma release assays

An ELISPOT assay testing for Tuberculosis infection.T cells are stimulated in plastic wells with moleculesderived from TB and their response measured byidentifying inflammatory molecules that are releasedon activation with special dyes. In this plate Patient Ais positive for TB infection whilst patient B isnegative.

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 measure directly the sensitivity and specificity of a new test for latent tuberculosis.

2006

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 inpatients with inflammatory rheumatic conditions, but the odds for a positive IFN-γ result weredecreased 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 significantlydecreased 14 weeks after the start of anti-TNF treatment [Arthritis Res Ther 2006;8:R114].

In a third studyusingQFT-G, 2 patientswith positiveIGRA resultsat 12 monthsof adalimumabIn a third studyusingQFT-G, 2 patientswith positiveIGRA resultsat 12 monthsof adalimumabtherapy developed active TB [Arthritis Rheum 2008;59(6):800–806 ].

The performance of IGRAs during anti-TNF treatment therefore needs to besystematically assessed to determine whether these tests can be used, ifrequired,for regular screening of patients on anti-TNF agents in highprevalence countries or after an exposure event.

NTM unspecif

n = 13

NTM other

species*

n = 11

M marinum

n = 6

Mycobacterium avium

n = 52

M chelonae

n= 4

M fortuitum

n = 4

M abscessus

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).

Mycobacterium avium

n = 52

Current clinical practice

In the absence of a gold standard test for diagnosis of LTBI,

current clinical management of patients with IMID requiring

Screening for tuberculosis infection prior to initiation of anti-TNF therapy

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).

T-cell interferon-gamma release assays (IGRA) are more specific andprobably more sensitive than the tuberculin skin test for the diagnosis oflatent tuberculosis infection. Patients with immune-mediatedinflammatory diseases and suspected latent tuberculosis infection whoare candidates for anti-TNF therapy are at a significant risk of TB

Screening for tuberculosis infection prior to initi ation of anti-TNF therapy

Ajit Lalvani and Kerry A. MillingtonTuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute,Imperial College London, Norfolk Place, London W2 1PG, UK.

are candidates for anti-TNF therapy are at a significant risk of TBreactivation yet are prone to false-negative TST results because they arealready on immunosuppressive medications.

The role of these new blood tests in this patient population is therefore ofconsiderable interest but is currently unclear.

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)

Screening for tuberculosis infection prior to initiation of

anti-TNF therapy

National guidelines

(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

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.

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)

Screening for tuberculosis infection prior to initiation of

anti-TNF therapy

National guidelines

(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

CONTINUING MEDICAL EDUCATIONTuberculosis in the age of biologic therapy2008Claudia Hernandez, Chicago and Joliet, Illinois, J Am Acad Dermatol 2008;59:363-80.