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

Pre-anti TNF treatment screening - where are we now?

Onn Min KonTB Clinics

St Mary’s Hospital + Hammersmith Hospital

Latent TB Infection in Rheumatological Conditions

An ongoing debate…….

• Epidemiology• How do we evaluate LTBI?

TST IGRA CXR

Anti-TNF- therapies

Infliximab (Remicade) - chimaeric MoAB

Adalimumab (Humira) - fully human MoAB

Golimumab (Simponi) - human IgG1 MoAB

Certolizumab pegol (Cimzia) - PEGylated Fab' fragment of a humanized TNF inhibitor MoAB

Human (IgG1)

Mousebinding sitefor TNF-

Enbrel (Etanercept) : soluble TNF-receptordimeric p75 TNFR bound to Fc of IgG1

Post 4 months anti-TNF

Infliximab and TBKeane et al, NEJM 2001

– 70 reported cases from 147,000 given infliximab worldwide between 1998-2001

– 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)

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 18.6 (13.4-25.8)Adalimumab 29.3 (20.3 – 42.4)Etanercept 1.8 (0.7 -4.3)

Risk of tuberculosis in patients with rheumatoid arthritis in Hong Kong - the role of TNF blockers in an area of high

tuberculosis burden

Tam LS et al. Clin Exp Rheumatol. 2010 Sep-Oct;28(5):679-85

RA compared to the general population Hong Kong 2004 and 20082441 RA patients followed at the 5 centres

Standardised Incidence Ratio Active TB - - TNF naïve RA: 2.35, 95% CI 1.17-4.67, p=0.013 - TNF treated RA: 34.92, 95% CI 8.89-137.20, 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)

British Society for Rheumatology Biologics Registry (BSRBR)

•adalimumab (144 events/100 000 pyrs)•infliximab (136 events/100 000 pyrs) •etanercept (39 events/100 000 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)

Different risks associated with specific agents

• Spanish registry 1113 per 100 000

• Korea 2558 per 100 000

• Japan 325 per 100 000

• Portugal 1500 per 100 000

• USA 62 per 100 000

• Sweden 145 per 100 000

Risks associated with different countriesInfliximab

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

Arthritis Rheum. 2006 Feb 15;55(1):19-26.Glucocorticoid use, other associated factors

and the risk of tuberculosis.Jick SS, Lieberman ES, Rahman MU, Choi HK.

• Case-control TB cases 1990-2001 - 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] 2.9-8.3) <15 mg 2.8 (95% CI 1.0-7.9)

>15 mg of prednisone or its equivalent daily dose were and 7.7 (95% CI 2.8-21.4)

• 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)

Corticosteroids and risk of TB

Agent Adjusted RR

Any DMARDs 3.0

MTX 3.4

Leflunomide 11.7

Cyclosporine 3.8

Other 1.6

Corticosteroids 2.5

Arthritis Rheum. 2009 Mar 15;61(3):300-4. Rheumatoid arthritis, its treatments, and the risk of tuberculosis in Quebec, Canada.Brassard P et al.

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

The missing ‘gold standard’

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

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.

• If immunosuppressed no TST – risk stratify only

• If not immunosuppressed even if TST positive – risk

stratify

If negative TST – no action

Example Risk TablesCase type Annual

risk of TB/100,000

TB risk adjusted x5 for

anti TNF

Risks of prophylaxi

s/100,000

Risk/Benefit

conclusion

White age 55-74UK born

7 35 278 Observe

Indian Sub continent age>35

In UK 3 years

593 2965 278 ChemoProphylaxi

s

Black African Age 35-54

168 840 278 ChemoProphylaxi

s

Other ethnicAge 35+

In UK>5 years

39 195 278 Observe

Epidemiology versus risk of treatment

• ‘Individual’ risk― Prior LTBI/ TB - never treated― Close contact

• ‘Population’ risk― Ethnicity― Country of birth― Where one lives

Plain CXR

Evidence of LTBI?

Tuberculin Test

US statistics on latent TB activation and Mantoux

TST is attenuated in RA

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 infection3) 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 25.15 (95% CI 14.05–45.17) and dropped 74% to 6.72 (95% CI 0.16–41.07) following the official recommendations date

2004

ELISpotquantification IFN--releasing cells

ELISAquantification released IFN-

Interferon-gamma release assays - new biomarkers of TB infection

• 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

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%)

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.

Ponce de Leon et alJ Rheumatol. 2008 May;35(5):776-81.

Mariette X et al.

Multi-centre French Study

Overall IGRA in place of TST halved those receiving chemoprophylaxis

In ‘LTBI’ (CXR and/or history of contact) -

• Patients in 62 German rheumatology centres - screened TST and IGRA (TSPOT or QFT)

• 1529 - TST, 844 - TSPOT and 685 - 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’

Prignano FFlorence, Italy

Combined TST and IGRA highest sensitivity

All

BCG

BCG naive

Hsia et al.

Overlapping positives and context

Even small doses of steroids affect QFT

A UK study

Singanayagam A et al. Thorax 2013;68:955-961

Overlapping yield for tests when mutually positive.

Singanayagam A et al. Thorax 2013;68:955-961

Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.

3/7 triple positive2/7 TST only2/7 double IGRA only(total 5/7 double IGRA)

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 100 000

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 2013 68: 1079-1080

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

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.)

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

Symptoms suggestactive TB/contact history or

previous historyof untreated TB/abnormal

chest radiograph?

Yes

All tests negative and low risk

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

No treatment required

Risk assess by using originating country rates

Treat with chemoprophylaxis

Treat with chemoprophylaxisNew entrant to UK < 5 years

AND on immunosuprressants?

High risk low risk

Yes No

‘Imperial’ Model

In RA:•Indeterminates QFT>Elispot•More +ve TST>IGRAs

Sester 2014 – a TBNet studyAJRCCM

• All 3 tests• Best correlation IGRA to IGRA• Lesser correlation TST to either IGRA

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

IGRA in all - Is it cost effective? BSR 2013

• At the age of 50 years UK White Caucasian population - incidence of active TB disease 5/100 000 - incidence of latent TB is approximately 10 times this level (50/100 000) - Number of tests to detect 1 case LTBI 2000

- (£70 000 Quantiferon and £200 000 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 120/100 000 numbers needed to test 82- black Africans 240/100 000 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,’

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

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 - 100.6 per 100,000

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’

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…..

https://www1.imperial.ac.uk/nhli/training/educationcentre/shortcourses/london_tb/