Supplementary Table 1. Cohort studies of infections associated with biologic DMARD use in patients with rheumatoid arthritis.
Article
Country
Main
Comparator
Outcome
Finding
Newuser
design
Chiang
2014S1
Bountha
vong
2014S2
Alawneh
2014S3
Yun
2014S4
Yoo
2014S5
Curtis
2014S6
Cho
2014S7
Taiwan
Etanercept
Adalimumab
Serious infection
Adjusted HR was 2.04 for etanercept.
Yes
Activecompar
ator
design
Yes
USA
Etanercept
Adalimumab,
Infliximab
Infection event
(secondary)
No significant difference in rates of infections
Yes
Yes
Jordan
Infliximab
No
Yes
TNF inhibitors
Yes
Infliximab
Adalimumab
Adjusted HR 0.80 for abatacept and 0.83 for
etanercept.
No significant difference in rates of infections
No
Korea
Yes
Yes
USA
TNF inhibitors
Rituximab, Abatacept
HR 2.3 for infliximab compared to etanercept
Yes
Yes
Korea,
Japan
Korean TNF inhibitor
users
Japanese TNF inhibitor
users
Higher unadjusted incidence rate of infection in
Japan
Yes
Yes
Ke
2013S8
Koike
2014S9
Lee
2013S10
Johnston
2013S11
Taiwan
TNF inhibitors
Traditional DMARDs
Severe infection and
tuberculosis
Hospitalized
infection
Serious infection and
tuberculosis
Hospitalized
bacterial infections
Serious adverse
events including
infection
Active tuberculosis
No significant difference among groups
USA
Adalimumab,
Etanercept
Abatacept, Rituximab
Adjusted HR was 4.87 for TNF inhibitor users.
Yes
Yes
Japan
Tocilizumab
-
Serious infection
Yes
No
Korea
TNF inhibitors
General population
No
No
USA
Rituximab as second
agent
Compared to rituximab, adjusted HR were elevated
for adalimumab, etanercept, infliximab.
Yes
Yes
Bello
2012S12
van
Dartel
2013S13
Curtis
2012S14
Atzeni
2012S15
Thyagara
jan
2012S16
Dewedar
2012S17
VenturaRíos
2012S18
Italy
Abatacept,
Adalimumab,
Etanercept, Infliximab
as second agents
Biological DMARDs
Mycobacterial
infections
Infections
Higher age, longer RA duration, comorbidity, and
glucocorticoids were risk factors.
Standardize incidence ratio of 6.4.
General population
Influenza-like illness
Increased incidence of influenza-like illness
No
No
Netherla
nds
Etanercept
Adalimumab,
Infliximab
Serious infections
Adjusted HR was significantly lower for etanercept.
Yes
Yes
USA
Infliximab
Serious infections
Infliximab had a significantly higher adjusted rates.
Yes
Yes
Italy
Infliximab
Serious infections
Yes
Adalimumab
Adjusted HR was increased for infliximab and
adalimumab compared to etanercept.
Rates of fatal infections were similar among three
agents.
Yes
USA
Etanercept,
Adalimumab
Adalimumab,
Etanercept
Etanercept, Infliximab
Yes
Yes
Saudi
Arabia
Mexico
TNF inhibitors
Traditional DMARDs
Unadjusted rates were not significantly different.
No
Yes
Biological DMARDs
Traditional DMARDs
Adverse drug effects
including infections
Safety including
infections
Higher infection risk than traditional bDMARDs.
No
Yes
Fatal infections
(secondary)
-1-
NguyenKhoa
2012S19
Gallowa
y 2013S20
Sakai
2012S21
Grijalva
2011S22
Lang
2012S23
USA
TNF inhibitor switcher
TNF inhibitor
non-switcher
First significant
infection
Adjusted HR was 0.93
No
Yes
UK
Biological DMARDs
Traditional DMARDs
Soft tissue infections
Adjusted HR for zoster was high for bDMARDs.
No
Yes
Japan
TNF inhibitors
Traditional DMARDs
Serious infections
Yes
Yes
USA
TNF inhibitors
Traditional DMARDs
Yes
Yes
Germany
Tocilizumab
-
Hospitalized
infections
Infections
Yes
No
Koike
2011S24
Strangfel
d 2011S25
Gallowa
y 2011S26
Curtis
2011S27
Komano
2011S28
Lane
2011S29
Momoha
ra
2011S30
Gallowa
y 2011S31
Gottenb
erg
2010S32
Suwanna
lai
2009S33
Peña-Sag
redo
2009S34
Dixon
2010S35
Greenbe
rg
2010S36
Aggarwa
l 2009S37
Strangfel
d 2009S38
Peña-Sag
redo
2008S39
Japan
Tocilizumab
-
Yes
No
Germany
TNF inhibitors
Traditional DMARDs
Safety including
infections
Serious infections
Yes
Yes
UK
TNF inhibitors
Traditional DMARDs
Septic arthritis
Adjusted incidence rate ratio was elevated during
the first year for biological bDMARDs.
TNF inhibitor initiation was not associated with an
increased risk of hospitalized serious infections.
Among tocilizumab users, risk factors included
longer disease duration and exposure to multiple
previous treatments.
Most frequent serious adverse events were
infections.
Adjusted incidence rate ratio was 1.8 for TNF
inhibitors.
Adjusted HR was 2.3 for TNF inhibitors.
No
Yes
USA
Biological DMARDs
Serious infections
Patient risk factors contributed more to infections.
Yes
Yes
Japan
TNF inhibitors
Biological DMARD
switchers
Traditional DMARDs
Serious infections
Adjusted RR was 2.37 for TNF inhibitors.
No
Yes
USA
TNF inhibitors
Traditional DMARDs
Adjusted HR was 1.24 for TNF inhibitors.
Yes
Yes
Japan
Biological DMARDs
Traditional DMARDs
Hospitalized
infections
Acute surgical-site
infections
Adjusted RR was elevated for biological bDMARDs
No
Yes
UK
TNF inhibitors
Traditional DMARDs
Serious infections
No
Yes
France
Rituximab
-
Severe infections
Adjusted HR was 1.8 for TNF inhibitors during the
first 6 months.
Baseline comorbidities were associated with
infections.
Yes
No
Thailand
Etanercept
Infliximab
Serious infections
Overall infection rate was higher among infliximab
users.
Yes
Yes
Spain
TNF inhibitors
Traditional DMARDs
Non-typhi
Salmonella infections
Infection incidence was not elevated, but was more
severe.
No
Yes
UK
Etanercept
Tuberculosis
Yes
Other Traditional
DMARDs
Infections including
opportunistic
No
Yes
-
Tuberculosis
Tuberculosis incidence were elevated in infliximab
and adalimumab compared to etanercept.
TNF inhibitors and methotrexate users had
increased risk of infection compared to other
Traditional bDMARDs
No active tuberculosis was found.
Yes
USA
Infliximab,
adalimumab
TNF inhibitors with or
without methotrexate,
methotrexate
Etanercept
Yes
No
Germany
TNF inhibitors
Traditional DMARDs
Herpes zoster
Yes
Yes
Spain
TNF inhibitors
-
Listeria infections
No increased risk for TNF inhibitor class, HR 1.82 for
infliximab and adalimumab.
Incidence was higher than general population.
Yes
No
USA
-2-
Favalli
2009S40
Garcia-Vi
dal
2009S41
Curtis
2007S42
Dixon
2007S43
Curtis
2007S44
Seong
2007S45
den
Broeder
2007S46
Salliot
2007S47
Dixon
2006S48
Giles
2006S49
Italy
Infliximab
Serious infections
Incidence did not differ among TNF inhibitors.
Yes
No
Infliximab
Adalimumab,
Etanercept
-
Spain
Opportunistic
infection
Incidence was elevated during first year of
treatment.
Yes
No
USA
TNF inhibitors
Methotrexate
Bacterial infections
Yes
Yes
UK
TNF inhibitors
Traditional DMARDs
Serious infection
No
Yes
USA
TNF inhibitors
Methotrexate
No
Yes
Korea
TNF inhibitors
General population
Serious bacterial
infection
Tuberculosis
Incidence of infection was elevated during first 6
months of TNF inhibitor treatment.
Incidence rate ratio 4.6 for TNF inhibitors in first 90
days.
Adjusted HR was 1.9 for TNF inhibitors.
No
No
Netherla
nds
TNF inhibitors
Traditional DMARDs
Surgical site
infections
Adjusted RR was 8.9 for TNF inhibitor users
compared to general population.
No elevated risk of surgical site infection was
associated with TNF inhibitors.
No
Yes
France
TNF inhibitors
Traditional DMARDs
Serious infections
No
Yes
UK
TNF inhibitors
Traditional DMARDs
Serious infections
No
Yes
USA
TNF inhibitors
Traditional DMARDs
No
Yes
Listing
2005S50
Germany
Etanercept, Infliximab
Traditional DMARDs
Adjusted RR was non-significant.
Yes
Yes
Maillard
2005S51
Neven
2005S52
France
Infliximab
-
No
Infliximab
-
Older age and high-dose glucocorticoid therapy
were associated with an increased risk.
Infection was the most common adverse event.
No
Netherla
nds
Serious
postoperative
orthopedic infections
Serious and
nonserious
infections
Severe pyogenic
infections
Adverse drug effects
including infections
Relative risk was 3.1 compared to period before TNF
inhibitor initiation.
Serious skin and soft tissue infection was increased
in TNF inhibitors.
Significant association between TNF inhibitors and
postoperative infection.
Yes
No
References:
S1. Chiang, Y.-C., Kuo, L.-N., Yen, Y.-H., Tang, C.-H. & Chen, H.-Y. Infection risk in patients with rheumatoid arthritis treated with etanercept or
adalimumab. Comput Methods Programs Biomed 116, 319–327 (2014).
S2. Bounthavong, M., Madkour, N. & Kazerooni, R. Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population. PeerJ 2, (2014).
S3. Alawneh, K. M. et al. Anti-TNF therapy in Jordan: a focus on severe infections and tuberculosis. Biologics 8, 193–198 (2014).
S4. Yun, H. et al. Risk of hospitalised infection in rheumatoid arthritis patients receiving biologics following a previous infection while on treatment with
anti-TNF therapy. Ann Rheum Dis (2014). doi:10.1136/annrheumdis-2013-204011
S5. Yoo, I. K. et al. Incidences of serious infections and tuberculosis among patients receiving anti-tumor necrosis factor-alpha therapy. Yonsei Med J 55, 442–
448 (2014).
S6. Curtis, J. R. et al. Risk of hospitalized bacterial infections associated with biologic treatment among US veterans with rheumatoid arthritis. Arthritis Care
Res (Hoboken) 66, 990–997 (2014).
S7. Cho, S.-K. et al. A comparison of incidence and risk factors for serious adverse events in rheumatoid arthritis patients with etanercept or adalimumab in
Korea and Japan. Mod Rheumatol 24, 572–579 (2014).
S8. Ke, W.-M., Chen, L.-S., Parng, I.-M., Chen, W.-W. & On, A. W. F. Risk of tuberculosis in rheumatoid arthritis patients on tumour necrosis factor-alpha
-3-
inhibitor treatment in Taiwan. Int J Tuberc Lung Dis 17, 1590–1595 (2013).
S9. Koike, T. et al. Effectiveness and safety of tocilizumab: postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan. J Rheumatol 41,
(2014).
S10.Lee, S. K. et al. Mycobacterial infections in patients treated with tumor necrosis factor antagonists in South Korea. Lung 191, 565–571 (2013).
S11.Johnston, S. S. et al. Risk of infections in rheumatoid arthritis patients switching from anti-TNF agents to rituximab, abatacept, or another anti-TNF agent, a
retrospective administrative claims analysis. Seminars in Arthritis and Rheumatism 43, 39–47 (2013).
S12.Bello, S. L. et al. Incidence of influenza-like illness into a cohort of patients affected by chronic inflammatory rheumatism and treated with biological
agents. Reumatismo 64, (2012).
S13.Van Dartel, S. A. A. et al. Difference in the risk of serious infections in patients with rheumatoid arthritis treated with adalimumab, infliximab and
etanercept: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Ann Rheum Dis 72, (2013).
S14.Curtis, J. R. et al. Use of a disease risk score to compare serious infections associated with anti-tumor necrosis factor therapy among high- versus lower-risk
rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 64, 1480–1489 (2012).
S15.Atzeni, F. et al. Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: comparison of adalimumab,
etanercept and infliximab in the GISEA registry. Autoimmun Rev 12, 225–229 (2012).
S16.Thyagarajan, V., Norman, H., Alexander, K. A., Napalkov, P. & Enger, C. Risk of mortality, fatal infection, and fatal malignancy related to use of
anti-tumor necrosis factor-alpha biologics by rheumatoid arthritis patients. Semin Arthritis Rheum 42, 223–233 (2012).
S17.Dewedar, A. M. et al. Lack of adverse effect of anti-tumor necrosis factor-alpha biologics in treatment of rheumatoid arthritis: 5 years follow-up. Int J
Rheum Dis 15, 330–335 (2012).
S18.Ventura-Rios, L. et al. Patient survival and safety with biologic therapy. Results of the Mexican National Registry Biobadamex 1.0. Reumatol Clin 8, 189–
194 (2012).
S19.Nguyen-Khoa, B.-A. et al. Risk of significant infection in rheumatoid arthritis patients switching anti-tumor necrosis factor-alpha drugs. Semin Arthritis
Rheum 42, 119–126 (2012).
S20.Galloway, J. B. et al. Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the
British Society for Rheumatology Biologics Register. Ann Rheum Dis 72, 229–234 (2013).
S21.Sakai, R. et al. Time-dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients
with rheumatoid arthritis. Arthritis Care Res (Hoboken) 64, 1125–1134 (2012).
S22.Grijalva, C. G. et al. Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases.
JAMA 306, 2331–2339 (2011).
S23.Lang, V. R. et al. Risk of infections in rheumatoid arthritis patients treated with tocilizumab. Rheumatology (Oxford) 51, 852–857 (2012).
S24.Koike, T. et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis 70, 2148–
2151 (2011).
S25.Strangfeld, A. et al. Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and
what does this imply for the individual patient? Ann. Rheum. Dis. 70, 1914–1920 (2011).
S26.Galloway, J. B. et al. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for
Rheumatology Biologics Register. Ann Rheum Dis 70, 1810–1814 (2011).
S27.Curtis, J. R. et al. The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis 70,
1401–1406 (2011).
S28.Komano, Y. et al. Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a report
from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety. J Rheumatol 38, 1258–1264 (2011).
S29.Lane, M. A. et al. TNF-alpha antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis. Medicine
(Baltimore) 90, 139–145 (2011).
-4-
S30.Momohara, S. et al. Prosthetic joint infection after total hip or knee arthroplasty in rheumatoid arthritis patients treated with nonbiologic and biologic
disease-modifying antirheumatic drugs. Mod Rheumatol 21, 469–475 (2011).
S31.Galloway, J. B. et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6
months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly.
Rheumatology (Oxford) 50, 124–131 (2011).
S32.Gottenberg, J.-E. et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab
registry. Arthritis Rheum 62, 2625–2632 (2010).
S33.Suwannalai, P., Auethavekiat, P., Udomsubpayakul, U. & Janvitayanujit, S. The infectious profiles of anti-tumor necrosis factor agents in a Thai population:
a retrospective study a the university-based hospital. Int J Rheum Dis 12, 118–124 (2009).
S34.Pena-Sagredo, J. L. et al. Non-typhi Salmonella infection in patients with rheumatic diseases on TNF-alpha antagonist therapy. Clin Exp Rheumatol 27,
920–925 (2009).
S35.Dixon, W. G. et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society
for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 69, 522–528 (2010).
S36.Greenberg, J. D. et al. Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic
infections in the CORRONA registry. Ann Rheum Dis 69, 380–386 (2010).
S37.Aggarwal, R., Manadan, A. M., Poliyedath, A., Sequeira, W. & Block, J. A. Safety of etanercept in patients at high risk for mycobacterial tuberculosis
infections. J Rheumatol 36, 914–917 (2009).
S38.Strangfeld, A. et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA 301, 737–744 (2009).
S39.Pena-Sagredo, J. L. et al. Listeria monocytogenes infection in patients with rheumatic diseases on TNF-alpha antagonist therapy: the Spanish Study Group
experience. Clin Exp Rheumatol 26, 854–859 (2008).
S40.Favalli, E. G. et al. Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 8, 266–273 (2009).
S41.Garcia-Vidal, C. et al. Risk factors for opportunistic infections in infliximab-treated patients: the importance of screening in prevention. Eur J Clin
Microbiol Infect Dis 28, 331–337 (2009).
S42.Curtis, J. R. et al. Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis
Rheum 56, 1125–1133 (2007).
S43.Dixon, W. G. et al. Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting
data from observational studies. Arthritis Rheum 56, 2896–2904 (2007).
S44.Curtis, J. R. et al. Drug-specific and time-dependent risks of bacterial infection among patients with rheumatoid arthritis who were exposed to tumor
necrosis factor alpha antagonists. Arthritis Rheum 56, 4226–4227 (2007).
S45.Seong, S.-S. et al. Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers. J
Rheumatol 34, 706–711 (2007).
S46.Den Broeder, A. A. et al. Risk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with
special attention for anti-tumor necrosis factor: a large retrospective study. J Rheumatol 34, 689–695 (2007).
S47.Salliot, C. et al. Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of
709 patients. Rheumatology (Oxford) 46, 327–334 (2007).
S48.Dixon, W. G. et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving
anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 54, 2368–2376 (2006).
S49.Giles, J. T. et al. Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum 55,
333–337 (2006).
S50.Listing, J. et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 52, 3403–3412 (2005).
S51.Maillard, H. et al. Severe pyogenic infections in patients taking infliximab: a regional cohort study. Joint Bone Spine 72, 330–334 (2005).
-5-
S52.Neven, N. et al. Adverse events in patients with rheumatoid arthritis treated with infliximab in daily clinical practice. Ann Rheum Dis 64, 645–646 (2005).
-6-