Supplementry Box 1
| Screening and prophylaxis of latent TB
TNF is important in the control of TB granuloma integrity and function. TNF antagonists increase the risk of reactivation of TB
in patients with latent infection, especially in patients with diabetes mellitus or chronic renal disease.S1 Strict screening for
latent TB before initiating anti-TNF therapy (with subsequent prophylactic therapy) is supported by studies showing a decrease
in the number of active TB cases.S2
IGRA specific for M. tuberculosis (T-Spot.TB® [Oxford Immunotec, UK] and QuantiFERON®[Qiagen, Netherlands]) are now
replacing less specific TSTs. TSTs do not distinguish between previous exposure to TB and BCG vaccination.S3–S5 The different
pretest probabilities according to different geographic regions should be considered with IGRA.S5 In areas with low rates of TB,
false-positive TSTs are a concern, supporting the use of IGRA, whereas in areas of high TB transmission, the risk of false
negativity might justify using TSTs.S6 The following conditions need to be fulfilled before initiating prophylactic TB therapy:
IGRA should be performed before beginning any immunosuppressive treatment. Any therapy decreasing the activity or
number of antigen-presenting cells or T cells can increase the risk of false-negative resultsS7–S10
Patient medical history, including previous active TB, therapies, risk of exposure, origin and residence in TB endemic areas,
needs to be carefully reviewed
Radiography might be needed
If evidence of latent TB, start prophylactic treatment with isoniazid for 9 months (5 mg/kg up to a maximum 300 mg per dose,
once daily) or rifampicin for 4 months (10 mg/kg per day: maximum dose of 600 mg per day).S11 Treatment with TNF
antagonists can be initiated 1 month after beginning TB prophylaxisS1
In patients previously treated for active TB, prophylaxis is not needed if compliance with prior TB therapy is established
Abbreviations: IGRA, IFN-γ release assay; TB, tuberculosis; TST, tuberculin skin test.
References
s1. Winthrop, K.L., Siegel, J.N., Jereb, J., Taylor, Z. & Iademarco, M.F. Tuberculosis associated
with therapy against tumor necrosis factor α. Arthritis Rheum. 52, 2968-2974 (2005).
s2. Carmona, L. et al. Effectiveness of recommendations to prevent reactivation of latent
tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum. 52,
1766-1772 (2005).
s3. Hsia, E.C. et al. Comprehensive tuberculosis screening program in patients with
inflammatory arthritides treated with golimumab, a human anti-tumor necrosis factor antibody, in
Phase III clinical trials. Arthritis Care Res. (Hoboken) 65, 309-313 (2013).
s4. Mariette, X. et al. Influence of replacing tuberculin skin test with ex vivo interferon γ release
assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy.
Ann. Rheum. Dis. 71, 1783-1790 (2012).
s5. Kleinert, S. et al. Screening for latent tuberculosis infection: performance of tuberculin skin
test and interferon-γ release assays under real-life conditions. Ann. Rheum. Dis. 71, 1791-1795 (2012).
s6. Kardos, M. & Kimball, A.B. Time for a change? Updated guidelines using interferon γ
release assays for detection of latent tuberculosis infection in the office setting. J. Am. Acad.
Dermatol. 66, 148-152 (2012).
s7. Jung, J.Y. et al. Questionable role of interferon-γ assays for smear-negative pulmonary TB in
immunocompromised patients. J. Infect 64, 188-196 (2012).
s8. Martyn-Simmons, C.L., Mee, J.B., Kirkham, B.W., Groves, R.W. & Milburn, H.J. Evaluating
the use of the interferon-γ response to Mycobacterium tuberculosis-specific antigens in patients with
psoriasis prior to antitumour necrosis factor-α therapy: a prospective head-to-head cross-sectional
study. Br. J. Dermatol. 168, 1012-1018 (2013).
s9. Mori, T. Usefulness of interferon-γ release assays for diagnosing TB infection and problems
with these assays. J. Infect. Chemother. 15, 143-155 (2009).
s10. Sanduzzi, A. et al. Screening and monitoring of latent tubercular infection in patients taking
tumor necrosis factor-alpha blockers for psoriatic arthritis. J. Rheumatol. 89, 82-85 (2012).
s11. No authors listed. Targeted Tuberculin Testing and Treatment of Latent Tuberculosis
Infection. American Thoracic Society and CDC Statement Committee. MMWR Recomm. Rep. 49,
1-51 (2000).
Supplementary Table 1 | Biologic agents used to treat rheumatic and immunological disorders
Target
Biologic agent
(commercial
name)
Structure
Dose*
T1/2
Indications
mAb (IgG4κ)
Route
of
adminis
tration
IV
α4-integrin
(CD49d)
Natalizumab§
(Tysabri®)
300 mg
every
4 weeks
11 days
Belimumab
(Benlysta®)
mAb (IgG1)
IV
19 days
CD20
Rituximab
(MabThera®)
mAb (IgG1)
IV
22 days
RA, AAV
CD80
Abatacept
(Orencia®)
CTLA-4–IgG1-Fc
IV
15 days
RA, JIA
IL-1Rα and
IL-1β
IL-1β
Anakinra
(Kineret®)
Canakinumab
(Ilaris®)
recombinant
IL-1Ra
mAb (IgG1κ)
SC
5 hours
RA, CAPS
26 days
CAPS
IL-1β
Gevokizumab
(XOMA-052)
mAb (IgG2)
SC
22 days
IL-1α, IL-1β
and IL-1Ra
IL-6Rα
Rilonacept
(Arcalyst®)
Tocilizumab
(RoActemra®)
sIL-1R–IgG1-Fc
SC
9 days
Noninfectious
posterior uveitis,
Behçet uveitis
CAPS
mAb (IgG1)
IV
12 days
RA, JIA
IL-17RA
Brodalumab
(AMG 827)
mAb (IgG2)
SC
NA
Psoriasis╪
IL-17A
Ixekizumab
(LY2439821)
mAb (IgG4)
SC
NA
Psoriasis╪
IL-17A
Secukinumab
(AIN457)
mAb (IgG1κ)
IV
28 days
Psoriasis╪
p40 subunit of
IL-12 and
IL-23
TNF
Ustekinumab
(Stelara®)
mAb (IgG1κ)
SC
21 days
Psoriasis
Adalimumab
(Humira®)
mAb (IgG1)
SC
15 days
TNF
Certolizumab
pegol
(Cimzia®)
PEG-Fab’ (IgG1)
SC
RA, JIA, AS,
Crohn disease,
psoriasis
Crohn disease,
RA
TNF and
lymphotoxin-β
Etanercept
(Enbrel®)
TNFR2–IgG1-Fc
SC
TNF
Golimumab
(Simponi®)
mAb (IgG1)
SC
TNF
Infliximab
mAb (IgG1)
IV
10 mg/kg
every
4 weeks
4×375 mg/
m2 or
2×500–
1000 mg
500–
1000 mg
every
4 weeks
100 mg
every day
150 mg
every
8 weeks
60 mg
every
4 weeks
160 mg
every week
4–8 mg/kg
every
4 weeks
140 mg
every
2 weeks
80 mg
every
4 weeks
10 mg/kg
every
3 weeks
45 mg
every
12 weeks
40 mg
every
2 weeks
200–
400 mg
every 2–
4 weeks
2×25 mg
every week
or
1×50 mg
every week
50–100)
mg every
4 weeks
3–
Relapsing
remitting
multiple
sclerosis, Crohn
disease
SLE
BAFF
SC
14 days
4 days
RA, JIA, AS,
Crohn disease,
psoriasis
14 days
RA, AS, psoriatic
arthritis
9 days
RA, JIA, AS,
(Remicade®)
10 mg/kg
Crohn disease,
every 4–
ulcerative colitis,
8 weeks
psoriasis
*Dose is only exemplary and does not replace consultation of the pharmaceutical package insert. Indications are approved
for rheumatic and immunological disorders, except those marked ╪. §Natalizumab was temporarily withdrawn from the
market in 2004 and reintroduced in 2006. Abbreviations: AAV, anti-neutrophil cytoplasmic antibody-associated vasculitis;
AS, ankylosing spondylitis; BAFF, B-cell-activating factor; CAPS, cryopyrin-associated periodic syndrome; CTLA-4, cytotoxic
T lymphocyte antigen 4; IL-1Ra, IL-1 receptor antagonist; IL-6Rα, IL-6 receptor α; IV, intravenous; JIA, juvenile idiopathic
arthritis; mAb, monoclonal antibody; NA, not available; PEG-Fab’, pegylated Fab’ fragment; RA, rheumatoid arthritis; SLE,
systemic lupus erythematosus; SC, subcutaneous; sIL-1R, soluble IL-1 receptor; TNFR2, TNF receptor 2;