Lo screening dellatubercolosi latente                             Daniela Rossi Centro di Ricerche di Immunopatologia e Do...
The risk of incident tuberculosis during anti-TNF therapyTherapeutic blockade of tumour necrosis factor alpha (TNF)has eme...
The Mycobacterium tubercolosis life cycle            Hanekorn 2008 W 2007
TNF Action in Granuloma Dynamics and          Immunity to Pathogenic MycobacteriaElizabeth A. Miller and Joel D. Ernst Imm...
Susceptibility to tuberculosis in RA patients     In USA an increased incidence of TB in patients    with RA was not obser...
Relationship between number of TB cases and patient exposure                                                              ...
Cumulative incidence of tuberculosis as a function of the duration of anti–tumor                                       nec...
Tubercolosis in randomized controlled trails                                                              Patients        ...
Annual incidence rate of TB in patients with                    anti TNF therapyIncidence rate / 100.000            United...
Risk of tuberculosis in patients treated with TNF antagonistsdue to incomplete prevention of reactivation of latent infect...
screening testThe TST is a measure of the delayed-typehypersensitivity reaction to intradermalinoculation of purified prot...
The tuberculin skin test disadvantages1. low specificity with false-positive results in bacillus   Calmette–Guérin (BCG)-v...
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 ...
There is no gold-standard test for latent tuberculosis. In the absence of a gold-standard reference test, it is not possib...
Clinical performance of IGRAs in patients on anti-TNF                                 therapyThree studies to date report ...
NTM other                           species*                           n = 11                NTM                unspecif  ...
Screening for tuberculosis infection prior to         initiation of anti-TNF therapyCurrent clinical practiceIn the absenc...
Screening for tuberculosis infection prior to initiationof anti-TNF therapyAjit Lalvani and Kerry A. MillingtonTuberculosi...
Screening for tuberculosis infection prior to initiation of                               anti-TNF therapy                ...
Most importantly, active TB must first be excluded by history and chestradiograph.Screening for LTBI should include checki...
Screening for tuberculosis infection prior to initiation of                               anti-TNF therapy                ...
CONTINUING MEDICAL EDUCATIONTuberculosis in the age of biologic therapy2008Claudia Hernandez, Chicago and Joliet, Illinois...
Rossi daniela lo screening della tubercolisi latente torino gennaio 2011_14° convegno patologia immune e
Rossi daniela lo screening della tubercolisi latente torino gennaio 2011_14° convegno patologia immune e
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Rossi daniela lo screening della tubercolisi latente torino gennaio 2011_14° convegno patologia immune e

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Rossi daniela lo screening della tubercolisi latente torino gennaio 2011_14° convegno patologia immune e

  1. 1. Lo screening dellatubercolosi latente Daniela Rossi Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare (CMID) Ospedale Emergenza Torino Nord, G. Bosco, TorinoCoordinamento Interregionale Malattie Rare del Piemonte e della Valle d’Aosta
  2. 2. The risk of incident tuberculosis during anti-TNF therapyTherapeutic blockade of tumour necrosis factor alpha (TNF)has emerged as an effective treatment in immune-mediatedinflammatory diseases such as rheumatoid arthritis, ankylosingspondylitis, Crohns disease and psoriatic arthritis. However,TNFα is a key cytokine in protective host defence againstMycobacterium tuberculosis and, together with TNF-dependentchemokines play an important role in the development andmaintenance of the granuloma which compartmentalisestubercle bacilli during infection. Lavani and KA Millington Autoimmun Rev. 2008 December ; 8(2): 147–152.
  3. 3. The Mycobacterium tubercolosis life cycle Hanekorn 2008 W 2007
  4. 4. TNF Action in Granuloma Dynamics and Immunity to Pathogenic MycobacteriaElizabeth A. Miller and Joel D. Ernst Immunity 29, August 15, 2008: 175
  5. 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 2007Incidence rate of TB ingeneral population 4.2 cases/100.000 persons/yrIncidence rate of TB in RA (Years 1980-2003) 50 cases/24.282 i.e.,45.8 /100.000/yr
  6. 6. 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.
  7. 7. 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 – totalCumulative 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
  8. 8. Tubercolosis in randomized controlled trails Patients Cases of tubercolosisEtanerceptTEMPO (1) (ETA v MTX+ETA 454 0 (2-year study)COMET (2) (MTX v MTX+ETA) 542 0InfliximabSTART (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)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: 26-37 7) Burmester GR, et al. Ann Rheum Dis 2009, 68: 1863-1869
  9. 9. Annual incidence rate of TB in patients with anti TNF therapyIncidence rate / 100.000 United Kingdom France SpainGeneral population 8-44.8 8.7 25Patients receiving etanercept 39 9.3 114Patients receiving infliximab 136 187 383Patients 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
  10. 10. Risk of tuberculosis in patients treated with TNF antagonistsdue 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
  11. 11. screening testThe TST is a measure of the delayed-typehypersensitivity reaction to intradermalinoculation of purified protein derivative (PPD),a crude mixture of more than 200 M.tuberculosis proteins.Because antigens within PPD are also found inother mycobacteria, the TST suffers from poorspecificity in bacille Calmette–Guérin (BCG)-vaccinated persons.Moreover, the sensitivity of the tuberculin skintest used to diagnose LTBI is compromised inpatients on immunosuppressive therapy with ahigh rate of false-negative TST test results.
  12. 12. The tuberculin skin test disadvantages1. low specificity with false-positive results in bacillus Calmette–Guérin (BCG)-vaccinated subjects2. lower sensitivity in immunosuppressed patients compared with healthy subjects3. limit above which the TST is considered positive (i.e. indicative of latent infection) differs according to countries and guidelines (5–10 mm)
  13. 13. Tuberculin skin test and T-cell interferon- gamma release assays
  14. 14. 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.
  15. 15. There is no gold-standard test for latent tuberculosis. In the absence of a gold-standard reference test, it is not possible tomeasure directly the sensitivity and specificity of a new test forlatent tuberculosis. 2006
  16. 16. Clinical performance of IGRAs in patients on anti-TNF therapyThree 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 study using QFT-G, 2 patients with positive IGRA results at 12 months of 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.
  17. 17. 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 = 12Reported causes of 105 confirmed and probable non-tuberculous mycobacteria(NTM) infections associated with antitumor necrosis factor-α agents, US Food andDrug Administration MedWatch database, 1999–2006. *Other species includeMycobacterium kansasii (n = 3), M. xenopi (n = 3), M. haemophilum (n = 2), and M. mucogenicum (n = 1).
  18. 18. Screening for tuberculosis infection prior to initiation of anti-TNF therapyCurrent clinical practiceIn the absence of a gold standard test for diagnosis of LTBI,current clinical management of patients with IMID requiringanti-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).
  19. 19. Screening for tuberculosis infection prior to initiationof anti-TNF therapyAjit 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. 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.
  20. 20. 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 MortalWkly 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) KavanaghP 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
  21. 21. Most importantly, active TB must first be excluded by history and chestradiograph.Screening for LTBI should include checking for a history of untreated or partiallytreated 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.
  22. 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 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 MortalWkly 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) KavanaghP 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. 23. CONTINUING MEDICAL EDUCATIONTuberculosis in the age of biologic therapy2008Claudia Hernandez, Chicago and Joliet, Illinois, J Am Acad Dermatol 2008;59:363-80.

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