Active and Latent TB in Patients with Rheumatic Diseases

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

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.

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)

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

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?

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

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

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

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

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

Epidemiology

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

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

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

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.

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.

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.

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

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

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.

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

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

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

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

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.

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

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

Questions?