1. Pre-anti TNF treatment screening - where are we now?
Onn Min Kon
TB Clinics
St Mary’s Hospital + Hammersmith Hospital

2. Latent TB Infection in Rheumatological Conditions An ongoing debate…….
Epidemiology
How do we evaluate LTBI?
TST
IGRA
CXR

3. Anti-TNF- therapies k Infliximab (Remicade) - chimaeric MoAB
Mouse
binding site for TNF-a
Infliximab (Remicade) -
chimaeric MoAB
Adalimumab (Humira) -
fully human MoAB
Golimumab (Simponi) -
human IgG1 k MoAB
Certolizumab pegol (Cimzia) -
PEGylated Fab' fragment of a humanized TNF inhibitor MoAB
Human (IgG1)
Enbrel (Etanercept) :
soluble TNF-receptor
dimeric p75 TNFR
bound to Fc of IgG1

4. Post 4 months anti-TNF

6. Infliximab and TB Keane et al, NEJM 2001
70 reported cases from 147,000 given infliximab worldwide between
40 (56%) extra-pulmonary TB (US rate 18%)
17 (24%) disseminated TB (US rate < 2%))
Most within 3 treatment cycles (median 12 wks)
No granuloma in lung biopsy in one patient
Probable reactivation
64/70 patients from areas of low incidence (< 20 per 100,000)

8. Different risks associated with specific agents
Tubach et al Arthritis Rheum 2009 French registry data 3y on TB
Case control analysis to investigate risk of TB associated with specific anti-TNF agents
69 patients (40 RA, 18 spondyloarthritides, 9 inflammatory colitis, 1 psoriasis) treated with various anti-TNF agents
Standardised incidence ratios of TB:
Infliximab ( )
Adalimumab (20.3 – 42.4)
Etanercept ( )

9. Risk of tuberculosis in patients with rheumatoid arthritis in Hong Kong - the role of TNF blockers in an area of high tuberculosis burden
RA compared to the general population Hong Kong 2004 and 2008
2441 RA patients followed at the 5 centres
Standardised Incidence Ratio Active TB -
- TNF naïve RA: 2.35, 95% CI , p=0.013
- TNF treated RA: 34.92, 95% CI , p<0.001
Independent variables associated with increased risk of active TB
- older age at study entry (RR 1.05, p=0.013)
- a past history of pulmonary TB (RR 5.48, p=0.001)
- extra-pulmonary TB (RR 16.45, p<0.001)
- Felty's syndrome (RR 43.84, p=0.005)
- prednisolone>10mg daily (RR 4.44, p=0.009)
- TNF blockers (RR 12.48, p<0.001)
Tam LS et al. Clin Exp Rheumatol Sep-Oct;28(5):679-85

10. Different risks associated with specific agents
British Society for Rheumatology Biologics Registry (BSRBR)
adalimumab (144 events/ pyrs)
infliximab (136 events/ pyrs)
etanercept (39 events/ pyrs)
IRR compared with etanercept-treated patients
- infliximab was 3.1 (95% CI 1.0, 9.5)
- adalimumab 4.2 (95% CI 1.4, 12.4)

11. Risks associated with different countries
Infliximab
Spanish registry per
Korea per
Japan per
Portugal per
USA per
Sweden per

12. Rheumatoid Arthritis RR 3.2 Ankylosing spondylitis RR 4.2
Analysis database of linked statistical records :
Hospital admissions and death certificates for the whole of England (1999 to 2011)
+ Oxford Record Linkage Study - southern England
Rate ratios for TB comparing immune-mediated disease cohorts with comparison cohorts
Particularly high levels of risk :
Addison's disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7))
Goodpasture's syndrome (RR = 10.8 (95% CI 4.0 to 23.5))
SLE (RR = 9.4 (95% CI 7.9 to 11.1))
polymyositis (RR = 8.0 (95% CI 4.9 to 12.2))
polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4))
dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5))
scleroderma (RR = 6.1 (95% CI 4.4 to 8.2))
autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4))
Rheumatoid Arthritis RR 3.2
Ankylosing spondylitis RR 4.2
Crohn’s RR 3.7
Psoriasis RR 2.6

13. Corticosteroids and risk of TB
Arthritis Rheum Feb 15;55(1): Glucocorticoid use, other associated factors and the risk of tuberculosis. Jick SS, Lieberman ES, Rahman MU, Choi HK.
Case-control TB cases UK GP Research Database
4 controls were matched to each case
497 new cases of tuberculosis and 1,966 controls derived from 16,629,041 person-years at risk (n = 2,757,084 persons)
Adjusted odds ratio TB for current use glucocorticoid compared with no use was 4.9 (95% confidence interval [95% CI] )
<15 mg 2.8 (95% CI )
>15 mg of prednisone or its equivalent daily dose were and 7.7 (95% CI )
AOR of TB 2.8 for patients with BMI <20 compared with normal
AOR
1.6 for current smokers compared with nonsmokers
3.8 history of diabetes
3.2 emphysema
2.0 bronchitis
1.4 asthma
(all P values <0.05)

14. Agent
Adjusted RR
Any DMARDs
3.0
MTX
3.4
Leflunomide
11.7
Cyclosporine
3.8
Other
1.6
Corticosteroids
2.5
Arthritis Rheum Mar 15;61(3):300-4.
Rheumatoid arthritis, its treatments, and the risk of tuberculosis in Quebec, Canada.
Brassard P et al.

15. The missing ‘gold standard’
So how do we diagnose LTBI in pre-TNF cases?
The missing ‘gold standard’

16. So how do we diagnose LTBI in pre-TNF cases?

17. BTS 2005 – pre IGRA Thorax 2005;60:800-805
Recommendations for assessing risk and for managing Mycobacterium Tuberculosis infection and disease in patients due to start anti-TNF-a treatment.
Thorax 2005;60:

18. If immunosuppressed
no TST – risk stratify only
If not immunosuppressed
even if TST positive – risk stratify
If negative TST – no action

19. TB risk adjusted x5 for anti TNF
Example Risk Tables
Case type
Annual risk of TB
/100,000
TB risk adjusted x5 for anti TNF
Risks of prophylaxis
Risk/
Benefit conclusion
White
age 55-74
UK born 7 35
278
Observe
Indian Sub continent age>35
In UK 3 years
593
2965
Chemo
Prophylaxis
Black African
Age 35-54
168
840
Other ethnic
Age 35+
In UK>5 years 39
195

20. Epidemiology versus risk of treatment
‘Individual’ risk
Prior LTBI/ TB - never treated
Close contact
‘Population’ risk
Ethnicity
Country of birth
Where one lives

21. Plain CXR
Evidence of LTBI?

22. Tuberculin Test

23. US statistics on latent TB activation and Mantoux

24. TST is attenuated in RA

25. Treatment of TST positive RA cases post implementation of screening
reduced TB incidence
INH 9 months given if:
1) history of untreated or partially treated TB, or exposure to an active TB case 2) CXR showing residual changes indicative of prior TB infection
3) reaction of 5 mm in diameter TST or 2-step TST ( 359 patients - 28%)
risk ratio for the incidence of active TB, compared with the background population, before March 2002 was (95% CI 14.05–45.17) and dropped 74% to 6.72 (95% CI 0.16–41.07) following the official recommendations date

26. Interferon-gamma release assays - new biomarkers of TB infection
2004
ELISpot
quantification IFN-g-releasing cells
ELISA
quantification released IFN-g
Interferon-gamma release assays - new biomarkers of TB infection 26

27. ELISA versus TST
associated better with risk factors for LTBI
ELISA poorly correlated to TST
ELISA less affected by BCG
Used 5mm cutoff (?higher TST +ve rate)
TST remote to IGRA
Swiss Hospital
High (83%) BCG vaccinated
TST still had a positive association

28. 101 RA patients and 93 controls 5mm cutoff on RA/ 10mm in controls
Comparison of an interferon-gamma assay with tuberculin skin testing
for detection of tuberculosis (TB) infection
in patients with rheumatoid arthritis in a TB-endemic population.
Lima Peru
101 RA patients and 93 controls
5mm cutoff on RA/ 10mm in controls
QFT comparable between RA and controls (44.6% vs 59.1% NS)
TST significantly less in RA (26.7%) than controls (65.6%)
Ponce de Leon et al
J Rheumatol May;35(5):

29. Overall IGRA in place of TST halved those receiving chemoprophylaxis
In ‘LTBI’ (CXR and/or history of contact) -
Mariette X et al.
Multi-centre
French Study

30. Patients in 62 German rheumatology centres - screened TST and IGRA (TSPOT or QFT)
TST, TSPOT and QFT
‘LTBI’
8.0% - positive TST and no previous BCG
7.9% - positive IGRA
11.1% Combination
Clinical risk factors (CRF) for LTBI in 122 patients
TST influenced by CRF (OR 6.2; CI 4.08 to 9.44, p<0.001) and BCG vaccination status (OR 2.9; CI 2.00 to 4.35, p<0.001)
QFT and TSPOT only influenced by CRF (QFT: OR 2.6; CI 1.15 to 5.98, p=0.021; TSPOT: OR 8.7; CI 4.83 to 15.82, p<0.001)
‘In patient populations with low rates of TB incidence and BCG vaccination, the use of both TST and IGRA may maximise sensitivity in detecting LTBI but may also reduce specificity’

31. Combined TST and IGRA highest sensitivity
Prignano F
Florence, Italy
Combined TST and IGRA highest sensitivity

32. Overlapping positives and context
All
BCG naive
BCG
Hsia et al.

33. Even small doses of steroids affect QFT

34. A UK study Singanayagam A et al. Thorax 2013;68:955-961
Flow chart of patient entry into study. Abbreviations: BTS, British Thoracic Society; CXR, chest radiograph; TB, tuberculosis; TNF, tumour necrosis factor; TST, tuberculin skin test.
Singanayagam A et al. Thorax 2013;68:

35. Overlapping yield for tests when mutually positive.
Singanayagam A et al. Thorax 2013;68:
Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.

36. 3/7 triple positive
2/7 TST only
2/7 double IGRA only
(total 5/7 double IGRA)

37. Case 1 48 year old woman (?ethnicity) with IBD TST negative / Tspot indeterminate No prophylaxis – stopped Infliximab Three months later - Travelled in country incidence 101 per Returned - TB meningitis 5 weeks later and died 2 weeks later Case 2 41 year old Moroccan man with Ankylosing Spondylitis TST/Tspot negative - Infliximab Travelled to Morocco (approximately 82 per 100,000) 6 weeks Returned 3 months later EPTB - M.bovis
Thorax :

38. What we think we know in inflammatory disease……
Differential effect of anti-TNF treatment - type and setting
Steroids and Immunosuppression affects IGRA and TST sensitivities
IGRA more specific than TST
IGRA and TST in inflammatory disease - only minor overlap
QFT versus T Spot in inflammatory disease - some overlap
Epidemiology and TST or IGRA - only minor overlap
?Double and triple tests increase ‘sensitivity’
In moderate to high prevalence or risk factors > 1 mode
In low incidence or no risk factors + immunocompetent –
- 1 mode reasonable as likely low false negative (?IGRA)
Patients develop TB - post negative screening

39. BSR 2010
Recommendation 4: prior to commencing treatment with anti-TNF therapy, all patients should be screened for mycobacterial infection in accordance with the latest National guidelines. Active mycobacterial infection needs to be adequately treated before anti-TNF therapy can be started. (Level IIb evidence, Grade of recommendation B.) Recommendation 5: prior to commencing anti-TNF therapy, consideration of prophylactic anti-TB therapy (as directed by the latest National guidelines) should be given to patients with evidence of potential latent disease (past history of TB or abnormal chest X-ray). (Level IIb evidence, Grade of recommendation B.) Recommendation 6: all patients commenced on anti-TNF therapies should be closely monitored for mycobacterial infections. This should continue for at least 6 months after stopping treatment due to the prolonged elimination phase of the drug. (Level IV evidence, Grade of recommendation C.)

40. Anti-TNF and TB screening - suggested approach
Use IGRA/ TST/ CXR – chemoprophylaxis if any positive
If negative and immunosuppressed -
use epidemiological risk factors and history of recent exposure/ new entrant + balance treatment risk
Newly acquired infection and repeat screening: no guidance
Need to have high index of suspicion for TB

41. ‘Imperial’ Model Yes No Either test positive or high risk
Symptoms suggest
active TB/contact history or previous history
of untreated TB/abnormal
chest radiograph?
Yes No
Fully investigate to rule out TB OR
Offer chemoprophylaxis if no active TB and prior untreated or evidence granulomas
Perform TST and IGRA and risk assess using BTS risk stratification tables
Either test positive or high risk
All tests negative and low risk
Treat with chemoprophylaxis
New entrant to UK < 5 years AND on immunosuprressants?
Yes No
‘Imperial’ Model
Risk assess by using originating country rates
High risk
low risk
Treat with chemoprophylaxis
No treatment required

43. Sester 2014 – a TBNet study AJRCCM In RA:
Indeterminates QFT>Elispot
More +ve TST>IGRAs

44. All 3 tests
Best correlation IGRA to IGRA
Lesser correlation TST to either IGRA

45. Sester et al 2014 in press AJRCCM
Mixed conditions – retrospective
Some given chemoprophylaxis
Test modality – none ideal
TST most predictive in HIV
All who were given chemoprophylaxis - none progressed

46. IGRA in all - Is it cost effective? BSR 2013
At the age of 50 years UK White Caucasian population
- incidence of active TB disease 5/
- incidence of latent TB is approximately 10 times this level (50/ )
- Number of tests to detect 1 case LTBI 2000
- (£ Quantiferon and £ T-spot)
Cost effectiveness better in older patients
Cost effectiveness worse (more than double the cost) < 35 years
Cost-effectiveness better for ethnic minorities
- South Asia 120/ numbers needed to test 82
- black Africans 240/ numbers needed to test 41
‘The true-negative predictive value of a negative test or the true-positive predictive value of a positive test is still not known,’

47. 29 year old woman RA sulphasalazine and hydroxychloroquine (MTX prior)
UK born caucasian
No TB contacts/ HIV negative
Holidays - Sri Lanka 2009/ Egypt 2010
Oct 2013 – CXR NAD/ TST and IGRA non reactive
Nov 2013 – Infliximab

50. Progress…. BAL negative but commenced Rx for TB
EBUS – non caseating granuloma/ PCR and smear negative
Culture positive
Visited Sri Lanka pre screening – 66 per 100,000
Visited Egypt pre screening – 17 per 100,000
Lives in Brent per 100,000

51. Summary points Immune mediated disease - higher risk for TB
Some other therapies increase risk of progression
Screen for LTBI/TB before initiating steroids/immunosuppressive treatment/anti-TNF
Effect of steroids and DMARDs on tests
Most ‘sensitive’ approach is tri-modality (TST/IGRA/CXR)
IGRA more specific (+ more practical?) but prognosis unclear
Epidemiology useful once on immunosuppressants
Rifampicin/Isoniazid 3 months OR Isoniazid 6 months if drug interactions important
Consider rescreen if new exposure or travel
Vigilance even in ‘screen negatives’

53. Unanswered questions in pre-TNF screening
Prognostic value of a TST+ve/ IGRA –ve test?
Prognostic value of a TST-ve/ IGRA +ve test?
What is the utility of just using a TST or IGRA?
Hepatotoxicity in this cohort
Cost effectiveness of mode of approach in low versus high incidence settings or individuals
How do we quantitate high risk travel?
How do we rescreen?
We think we know what we don’t know…
NICE due 2015…..

54. https://www1. imperial. ac