Dr. Julie Li-Yu presented updated recommendations on how to screen and treat tuberculosis in patients with rheumatic diseases. Dr. Li-Yu and Dr Juan Javier Lichauco were representatives of the Philippine Rheumatology Association to the Task Force developing guidelines for TB management in the country. The slides posted were presented during the Joint Rheumatoid Arthritis - Osteoarthritis Special Interest Symposium held at the F1 Hotel in Taguig City last 28 November 2014.

1. Active and Latent TB in the
Vulnerable Group:
Persons with Rheumatologic
Diseases
Julie T. Li-Yu, MD, MSPH
Juan Javier Lichauco, MD
Philippine Rheumatology Association

4. Philippine Guidelines
Recommendations 2006
• Patients for biologic therapy should be screened for latent and
active TB prior to initiating treatment.
• All patients who are candidates for biologic agents should be
screened by tuberculin skin test for latent TB, and a chest
radiograph for active tuberculosis.
• Household and close contacts of candidate patients should be
screened for active tuberculosis.
• All household and close contacts of candidate patients should be
screened for active TB using chest radiograph.
• Treat latent and active tuberculosis according to local guidelines.
• Delay treatment with biologic agents in patients with latent or
active tuberculosis.
• Administer tuberculosis prophylaxis to the patient for biologic
therapy exposed to household contacts with active tuberculosis.

5. Update on the Phil CPG for the Diagnosis
and Treatment of Adult TB 2014
Task Force includes professional and medical societies and
government agencies:
• Philippine Coalition Against Tuberculosis (PHILCAT) – to
represent non-government organizations not considered
professional medical groups
• Philippine Society for Microbiology and Infectious Diseases
(PSMID)
• Philippine College of Chest Physicians (PCCP)
• Philippine College of Physicians (PCP)
• Philippine College of Radiology (PCR)
• Philippine Academy of Family Physicians (PAFP)
• Philippine College of Occupational Medicine (PCOM)
• Department of Health (DOH)

6. Five (5) major TWCs:
• Committee on Diagnosis
• Committee on Treatment
• Committee on MDR-TB
• Committee on TB-HIV and other Vulnerable
Populations
• Committee on Prevention and Control
Committee on TB-HIV and other Vulnerable Groups -
Team Leader: Mario Panaligan, MD (PSMID)
Members:
• PCCP, PSCO, PHS, PSEM, PRA, POGS, PSMID

7. Objectives/Key Issues
Main Issue:
Diagnosis and Management of LTBI and active TB among patients with
rheumatic diseases commencing and on biologic agents
Specific issues:
– What is the epidemiology of TB disease in patients with rheumatic
diseases?
– How useful is screening for LTBI?
• What is the most appropriate screening tool?
• What is the risk of conversion to active TB?
– Among LTBI patients, what is the most suitable chemoprophylactic
drug/s? Dose? Duration? Monitor treatment response?
– What is the most appropriate test to diagnose active TB?
– Among patients with active TB, what is the most suitable treatment
regimen? Dose? Duration? Monitor treatment response?
– Should we be screening household contacts/co-workers?
– What is the interval time for TB screening while patient is on biologics?

8. Methodology
• International organizations – ACR 2012, EULAR 2013, APLAR (ongoing)
• Country specific guidelines – Hongkong 2011, Portugal 2012, Japan 2007,
Canada 2010, Australian 2010
• Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument
• Issues not addressed in international CPGs
– Search engine: Pubmed
– Search terms:
 Latent tuberculosis etanercept
• Guidelines infliximab
• Rheumatic diseases adalimumab
• Rheumatoid arthritis tocilizumab
• Psoriasis rituximab
• Spondylarthritis anakinra
• Ankylosing spondylitis certolizumab
• Biologic therapy
• Limitations: publications in English language
• Period: January 2006 to December 2013

9. Epidemiology
• Incidence of TB among patients with
rheumatic diseases
• Review of records of RA patients ± IFX/ETN
– Korea (2001-2004): 67.2/100,000PY (gen pop)
• Naïve TNF blocker RA pts: 257/100,000PY
• IFX treated RA pts: 2558/100,000PY
• ETN treated RA pts: 0/73.67PY
– Risk of TB greater in RA patients RR 8.9 (4.6-
17.2) vs IFX users RR 30.1 (7.4-122.3) vs gen pop
Sang-Seokg Seong et al. J Rheumatol 2007;34:706-11

10. Epidemiology
• National Network of Epidemiological
Surveillance Report (Spain 1990-2000)
• Mean incidence of TB 23 cases/100,000
– 7 cases in RA cohort
– Mean annual incidence 134/100,000 patients
– Incidence RR of PTB in RA is 3.68 (2.36-5.92)
Carmona L, et al. Increased risk of tuberculosis among RA patients. J Rheumatol 2003

11. Epidemiology
• Systematic study tertiary referral center (1997-2004)
• Incidence rate of serious infections before anti-TNF
therapy (3.4/100PY) vs after 1st dose of anti-TNF
(10.5/100PY) = NNH 14
• Multivar analysis: risk factors were prev joint surgery and
use of corticosteroids
• US: incidence of TB in general pop 5.8/100,000
• 10,000 RA patients: incidence of TB 6.2/100,000 (biologic
naïve)
Salliot C, et a. Infections during anti-TNF blocker therapy for rheumatic diseases in daily practice.
Rheumatology 2007
US Department of Health and Human Services CDC Atlanta 2001
Wolfe et al. Tuberculosis infections in patient with RA and the effect of IFX therapy. Arthritis Rheum 2004

12. Biologics in Rheumatic Diseases
• 40 cases of TB reported in anti-TNF cohort
• Rate of TB in ADA (144/100,000PY), INF (136/100,000PY), ETA
(39/100,000PY)
• Median time to event
– INF 5.5 mos, ETA 13.4 mos, ADA 18.5 mos
• Risk of SI in RA patients treated with anti-TNF
– Prospective observational study (BSRBR)
– 11798 anti-TNF treated patients vs 3598 nbDMARDs
– 1808 patients with SI (anti TNF 1512; nbDMARD 296)
– Incidence rates: anti-TNF 42/1000PY nbDMARD 32/1000PY
– Risk is not different with 3 anti-TNFs – ETN, INF, ADA
– aHR for anti-TNF 1.2 (95% CI 1.1, 1.5), risk highest in 1st 6 mos therapy
aHR 1.8 (95% CI1.3, 2.6)
Dixon et al. Drug-specific risk of TB in patients with RA treated with anti-TNF therapy, the BSRBR. ARD 2010
Updated results from BSRBR with special emphasis on risks in the elderly. Rheumatology 2011

13. Epidemiology
Navarra S, et al. Risk of TB with anti-TNF therapy: substantially higher number of patients at risk in Asia. IJRD 2014

14. Projected incremental TB risks in Asian countries
Navarra S, et al. Risk of TB with anti-TNF therapy: substantially higher number of patients at risk in Asia. IJRD 2014

15. Navarra S, et al. Risk of TB with anti-TNF therapy: substantially higher number of patients at risk in Asia. IJRD 2014

16. AGREE II
Guidance for rating each item:
Domain 1: Scope and Purpose (3)
Domain 2: Stakeholder Involvement (3)
Domain 3: Rigor of Development (8)
Domain 4: Clarity of Presentation (3)
Domain 5: Applicability (4)
Domain 6: Editorial Independence (2)
Overall Guideline Assessment
Each item rated on a 7-point rating scale (1-strongly disagree, 7- strongly agree)
A quality score calculated for each domain.
High quality – ≥75% vs low quality - ≤ 25%
2 appraisers
Guideline generally recommended if both reviewers scored it 7, recommended with
provision if either 5 or 6, not recommended if ≤ 4.

17. Recommendation
All patients with rheumatic disease who are
candidates for use of biologic therapy should be
screened for active and latent tuberculosis infection.
1. How useful is screening for LTBI?
• Summary of Evidence: (AGREE: Recommend = 7)
– All 7 guidelines addressed the concern on LTBI
screening (medical history, RF)
• Comments:
– There is high quality of evidence to recommend
screening for LTBI in patients starting biologic
therapies as part of their RA therapy.

18. 2. What is the best screening tool for
LTBI?
Summary of Evidence: (AGREE: Recommend = 7)
• TST – Acr/Aus (2-step)/Can/HK /Japan/ Portuguese/
EULAR
• IGRA – Acr/Aus/Can (false+TST)/Portuguese/EULAR
• Discordance between TST and IGRAs
Recommendation
In the absence of gold standard in diagnosing LTBI, it is
recommended to use skin test (TST) on all patients
commencing biologic drugs. IGRA maybe an option for
those with previous BCG vaccination.

19. IGRA vs TST in patients with RA
• Objective: analyze results of IGRA and TST to detect LTBI in
patients with RA
• Methodology:
– Systematic review: 7 studies ( 5 CCS, 2 CSS) – 405 RA, 339 controls
– IGRA and/or TST
• Results:
– IGRA positivity rate 31.6% (89/282), range 11.4%-44.6%
– TST positivity rate 23% (78/339), range 14.6% - 45%
– Concordance rate 40%-76%, discordance rate 24%-29.7%
– Poor agreement between IGRA and TST in RA (69.6%, k=0.33)
• Recommendations:
– Both IGRA and TST are needed to detect LTBI in RA
Song GG, Bae SC, Lee YH. IJRD 2013;16:279-283

20. Agreement bet IGRA and TST
IGRA + IGRA - Total Agreement Kappa
TST + 32 17 49 69.6 0.33
TST – 34 85 119
Total 66 102
Subjects IGRA + /total tested TST +/total tested
RA 72/236 78/316
Control 74/185 200/339
RR (RA vs control) 0.802 (0.629-1.023),
p = 0.075
0.680 (0.331-0.339),
p = 0.295
IGRA and TST positivity rates among RA vs controls
Song GG, Bae SC, Lee YH. IJRD 2013;16:279-283

21. 3. What is the cut-off for a positive
LTBI?
Summary of Evidence:
(AGREE: Recommend w provision = 4, no recommendation = 3)
ACR/EULAR/AusRA)
CanRA ≥5 mm immunosuppressed (10mm cut-off: w/o RF)
HK ≥10mm
Portuguese ≥10mm immunocompetent, ≥5mm
immunocompromised
Japan ≥20mm
Recommendation
An induration ≥10 mm is considered positive.

22. T-cell based assays for the diagnosis of
latent tuberculosis infection: an update
Objective: diagnostic accuracy of QFT-G, QFT-GIT, T.SpotTB
Methodology: meta-analysis of 30/38 studies (3/2008)
Results:
• Pooled sensitivity of 22 QFT-G/QFT-GIT 76% (72%-80%) and
13 T.SpotTB 90% (86%-93%)
• Pooled specificity 98% (96%-99%) for all QFT-G and QFT-GIT,
93% (86%-100%) for T.SpotTB
• Heterogenous sensitivity for TST, pooled estimate 77% (71%-
82%)
• Pooled specificity (non-BCG vaccinated) 97% (955-99%) vs
BCG vaccinated 59% (46%-72%)
Pai M, Zwerling A, Menzies D. Ann Intern Med 2008;149:177-184

23. TNF antagonists and TB in patients
with RA: An Asian perspective
• Low TB burden countries: specificity for T.SpotTB 98%-100%
and QFT-GIT 99.4%
• Pooled positive predictive value for IGRA 2.3% to 3.2% and
TST 1.2% to 1.7%, increased to 6.8% and 2.4% respectively
in high risk groups
• Pooled negative predictive value 99.7% (IGRA) and 99.4%
(TST)
• Diel R, et al. Meta-analysis. Of predictive value of IGRA and TST.
Chest 2012
• IGRA more superior in predicting TB than TST
• T.SpotTB performs better than QFT-GIT in predicting
progression to LTBI esp in immunocompromised patients
To KW, Reino JJG, Yoo DH, Tam LS. Respirology 2013

24. 4. What is the most cost-effective
chemoprophylactic drug for LTBI?
Recommendation
Patients screened positive for LTBI should receive 300
mg/day isoniazid for 9 months.
Summary of Evidence:
(AGREE: Recommend = 4, Recommend w provision = 3)
ACR/EULAR – local guidelines
CanRA/HK/Japan/Portuguese – INH x 9 mos (except Japan)
AusRA – INH 5mg/kg/day x 6-9 mos or Rif 10mg/kg/day x 4 mos

25. Summary of Evidence
Drug Duration
Hongkong 2011 INH
*if biologics not urgent, tx x 4 mos
9 mos
ACR 2012 Refer to specialist for treatment
EULAR 2013 According to local guidelines
(INH started for a month before bologics)
Australian 2010 INH 5 mkd (max < 300mg/day) + pyridoxine (25 mg/d) 6-9 mos
INH 10 mkd (max 600 mg/day) 4 mos
Canadian 2012 INH 9 mos
Japan 2007 INH 300 mg/day
Portuguese 2012 INH 9 mos

26. 5. What is the interval screening
period for patients on biologics?
Summary of Evidence:
(AGREE: Recommend = 1, no recommendations = 6)
Patients may remain TST or IGRA positive after successful
treatment of TB. Monitor patients for clinical signs and
symptoms of recurrent TB.
Recommendation
Annual testing in RA patients who live, travel, or
work in areas where TB exposure is likely while
they continue receiving biologic therapies.

27. Frequent conversions of TB screening
tests during anti-TNF therapy in patients
with rheumatic diseases
• Objective: rate of TB screening test conversion during
anti-TNF therapy among baseline negative patients
• Methodology:
– Greece (2009-2013)
– Prospective study
– Assays: TST, T-spot TB, QuantiFERON TB Gold in tube (QFT-
GIT)
– 70 patients (RA, spondylo, etc)
– Anti-TNFs (ADA, ETN, IFX, Goli, certo) x 1 year
Hatzara C, Hadziyannis E, Kandili A, Koutsianas C, et al. ARD 2014

28. Results:
• 20 (29%): conversion of at least 1 assay after 12 mos
[TST 9 (13%), T-spot TB 7 (10%), QFT-GIT 5 (7%)]
• 1 conversion of more than 1 screening test
• IFX dec rate of screening test conversion (OR 0.048,
0.004-0.606, p=0.017)
• No patient (40% received INH therapy) developed
active TB during follow up (27±12 mos)
Conclusion:
• 1/3 conversion of screening tests during biologic
therapy
Hatzara C, Hadziyannis E, Kandili A, Koutsianas C, et al. ARD 2014
Frequent conversions of TB screening
tests during anti-TNF therapy in patients
with rheumatic diseases

29. Questions?